Renal Perfusion During Thoracoabdominal Aortic Operations: Cold Crystalloid is Superior to Normothermic Blood

Renal Perfusion During Thoracoabdominal Aortic Operations: Cold Crystalloid is Superior to Normothermic Blood Cüneyt Köksoy, MD, Scott A. LeMaire, MD, Patrick E. Curling, MD, Steven A. Raskin, CCP, Zachary C. Schmittling, MD, Lori D. Conklin, MD, and Joseph S. Coselli, MD The Michael E. DeBakey Department of Surgery, Division of Cardiothoracic Surgery, Baylor College of Medicine, and The Methodist Hospital, Houston, Texas Background. Renal failure remains a common complication of thoracoabdominal aortic aneurysm repair. The purpose of this randomized clinical trial was to compare two methods of selective renal perfusion cold crystalloid perfusion versus normothermic blood perfusion and determine which technique provides the best kidney protection during thoracoabdominal aortic aneurysm repair. Methods. Thirty randomized patients undergoing Crawford extent II thoracoabdominal aortic aneurysm repair with left heart bypass had renal artery perfusion with either 4 C Ringer s lactate solution (14 patients) or normothermic blood from the bypass circuit (16 patients). Acute renal dysfunction was defined as an elevation in serum creatinine level exceeding 50% of baseline within 10 postoperative days. Results. One death occurred in each group. One patient in the blood perfusion group experienced renal failure requiring hemodialysis. Ten patients (63%) in the blood perfusion group and 3 patients (21%) in the cold crystalloid perfusion group experienced acute renal dysfunction (p 0.03). Multivariable analysis confirmed that the use of cold crystalloid perfusion was independently protective against acute renal dysfunction (p 0.02; odds ratio, 0.133). Conclusions. When using left heart bypass during repair of extensive thoracoabdominal aortic aneurysms, selective cold crystalloid perfusion offers superior renal protection when compared with conventional normothermic blood perfusion. (Ann Thorac Surg 2002;73:730 8) 2002 by The Society of Thoracic Surgeons Presented at the Forty-seventh Annual Meeting of the Southern Thoracic Surgical Association, Marco Island, FL, Nov 9 11, 2000. Address reprint requests to Dr Coselli, The Michael E. DeBakey Department of Surgery, Division of Cardiothoracic Surgery, Baylor College of Medicine, The Methodist Hospital, 6560 Fannin, Suite 1100, Houston, TX 77030; e-mail: jcoselli@bcm.tmc.edu. Despite improvements in anesthesia, surgical techniques, and postoperative care, renal dysfunction remains a significant and potentially lethal complication after thoracoabdominal aortic aneurysm (TAAA) repair. With varying definitions, reports reveal an incidence of acute renal failure ranging from 7% to 40% in patients who undergo TAAA repair [1 7]. The importance of renal failure after aortic operation relates to the associated increase in postoperative mortality [1]. In an attempt to prevent this complication and its attendant mortality, several techniques and intraoperative strategies have been suggested, including intraoperative administration of diuretics, minimization of ischemic times, renal hypothermia, and renal artery perfusion with oxygenated blood [1, 8, 9]. Selective blood perfusion of the renal arteries aims to reduce the time of renal ischemia during aortic cross-clamping. Because the viscera and kidneys are perfused with oxygenated blood throughout the period of aortic cross-clamping, the expected reperfusion injury and subsequent organ dysfunction are minimized. Despite the use of this technique, the incidence of kidney failure after TAAA repair ranges from 8% to 29% [1, 3, 10, 11]. In contrast, cold crystalloid renal artery perfusion aims to produce local hypothermia and reduce the metabolic needs of the kidneys [12, 13]. After TAAA repair using cold crystalloid renal artery perfusion, the incidence of renal failure ranges from 3% to 11% [1, 6, 14]. Although many centers treating TAAAs routinely use one of these two methods, the superiority of either method has not been determined by a prospective clinical study. The purpose of this randomized clinical trial was to compare two methods of selective renal perfusion cold crystalloid perfusion versus normothermic blood perfusion and determine which technique provides the best renal protection during TAAA operation. Patients and Methods Study Design The study was approved by the Baylor College of Medicine Institutional Review Board, and informed, written consent was obtained from all enrolled patients. The study group was strictly limited to Crawford extent II 2002 by The Society of Thoracic Surgeons 0003-4975/02/$22.00 Published by Elsevier Science Inc PII S0003-4975(01)03575-526

Ann Thorac Surg KÖKSOY ET AL 2002;73:730 8 RENAL PERFUSION DURING TAAA REPAIR 731 Fig 1. Crawford classification of thoracoabdominal aortic aneurysms. TAAA repairs performed with left heart bypass and selective visceral perfusion (Fig 1). From October 12, 1999, to April 14, 2000, all patients in whom extent II TAAA repairs were planned were evaluated for entry into the study. Preoperative exclusion criteria included: planned extent I, III, or IV repairs; false aneurysms; previous TAAA operations; age younger than 18 years; preoperative renal failure requiring dialysis; shock; and inability to obtain patient consent. Patients who met preoperative inclusion criteria were randomly arranged to two groups by card allocation: selective renal artery perfusion with normothermic blood versus cold crystalloid. The surgical team was not blinded to the treatment assignment. All randomized patients were included in an intent-to-treat analysis. Intraoperative exclusion criteria were determined a priori and included aortic repair less than the planned extent II, inability to use left heart bypass, need for hypothermic circulatory arrest, and inability to selectively perfuse the kidneys. Randomized patients who completed the study were included in the efficacy analysis. Patients The flow of patients enrolled in the study is illustrated in Figure 2. During the study period, extent II TAAA repairs were performed in 41 patients but planned preoperatively in only 38 patients. In the other 3 patients, a less extensive repair was planned initially, precluding their enrollment in the study. Of the 38 consecutive planned extent II repairs, 4 patients were excluded from enrollment because of preoperative renal failure (1 patient), enrollment in another clinical trial (1), or refusal to participate (2). Thirty-four patients met preoperative inclusion criteria, agreed to enroll, and provided informed consent: 17 patients were randomized to the cold crystalloid perfusion group and 17 patients were randomized to the blood perfusion group. The randomization sequence was strictly adhered to, and no patients were allowed to crossover. Four patients were secondarily excluded in the operating room because left heart bypass could not be used. Thirty patients completed the study, 14 in the cold crystalloid group and 16 in the blood group. Anesthetic Technique Intraoperative monitoring consisted of electrocardiography (modified leads V 5 and II), pulse oximetry, and nasopharyngeal temperature. Blood pressure was monitored with a right radial artery cannula and a left arm blood pressure cuff. An oximetric pulmonary artery catheter provided pulmonary artery pressures and mixed venous saturations. Anesthesia was induced with fentanyl, etomidate, and pancuronium. Methylprednisolone (2 g) and mannitol (12.5 g) were administered after induction. Anesthesia was maintained with isoflurane 0.5 to 1.5 minimal alveolar concentration. A left endobronchial tube was placed to allow single-lung ventilation; its proper position was confirmed by fiberoptic bronchoscopy. An 80-cm cerebral spinal fluid 5F catheter (NMT Neurosciences, Inc, Duluth, GA) was placed through the L3-4 or L4-5 interspace through a number 14 Tuohy needle, and pressure maintained at less than 10 mm Hg Fig 2. Flow of patients (pts.) in the renal perfusion study. (LHB left heart bypass; OR operating room.)

732 KÖKSOY ET AL Ann Thorac Surg RENAL PERFUSION DURING TAAA REPAIR 2002;73:730 8 Fig 3. Circuit used for left heart bypass with normothermic blood renal perfusion. with appropriate drainage. During cross-clamping, mean arterial blood pressure was maintained at 60 to 65 mm Hg using nitroglycerin and nitroprusside infusions. Volume was infused through a 12F cannula. Shed blood was salvaged and returned using a cell-saving device (Cobe Cardiovascular, Inc, Arvada, CO) and a rapid infusion system (Haemonetics Corp, Braintree, MA). Surgical Technique The surgical technique for repair of extent II TAAA has been reported previously in detail [15]. After a thoracoabdominal incision was performed, a myocardial temperature probe (Mon-a-therm, Mallinckrodt Medical, Inc, St. Louis, MO) was inserted in the parenchyma of the left kidney to monitor renal temperature. After systemic heparin administration (1 mg/kg), the left inferior pulmonary vein was cannulated with a 26F USCI aortic right-angled cannula (C.R. Bard, Inc, Tewksberry, MA), and the supraceliac aorta was cannulated with a 20F USCI aortic right-angled cannula (C. R. Bard, Inc). Left heart bypass was achieved with a Nikkiso centrifugal pump (Sorin Biomedical, Irvine, CA) circuit without a reservoir or heat exchanger. The proximal aortic clamp was applied either above or below the left subclavian artery, and the distal clamp was placed near the sixth intercostal space. Distal aortic perfusion was provided at a rate of 1.5 to 2.5 L/min. The aneurysm was opened between the two clamps, and an appropriately sized gelatin-impregnated polyethylene terephthalate fiber (Dacron) graft was selected. After completing the proximal anastomosis, left heart bypass was discontinued and the distal clamp was removed. The remaining portion of the aneurysmal aorta was opened longitudinally. The distal clamp was not replaced. For patients randomized to the blood perfusion group, four 9F Pruitt balloon irrigation catheters (Ideas for Medicine, St. Petersburg, FL), connected by means of a multifinger apparatus (Medtronic DLP, Minneapolis, MN), were inserted into the celiac axis, the superior mesenteric artery, and both renal arteries. Continuous perfusion from the bypass circuit at an aggregate rate of 400 ml/min was provided during intercostal, visceral, and renal artery reattachment (Fig 3). The individual perfusion rate to each vessel was not monitored. For patients in the cold crystalloid perfusion group, normothermic blood perfusion was administered only into the celiac axis and superior mesenteric artery through two balloon perfusion catheters from the bypass circuit (Fig 4). Two separate balloon perfusion catheters were inserted into the renal arteries. The perfusate was Ringer s lactate solution with mannitol (12.5 g/l) and methylprednisolone (125 mg/l) cooled to 4 C. The circuit consisted of a cardiotomy reservoir with 1 4 tubing going through a roller head pump. A bolus infusion (400 to 600 ml) of the solution was instilled into the renal arteries, followed by additional intermittent infusions (200 ml) until arterial flow was reestablished. A total of approximately 1.0 to 1.5 L of crystalloid solution was infused in an attempt to achieve a left renal temperature of 15 C. Larger volumes were avoided to limit the potential hazards of fluid overload (indicated by mean pulmonary artery pressure 30 mm Hg) and severe systemic hypothermia (indicated by nasopharangeal temperature 31 C). Once the visceral and distal anastomoses were completed, the aortic clamp was removed and blood flow was reestablished to the viscera, kidneys, and the lower extremities. In patients with an extensive infrarenal component, the proximal clamp was moved to the infrarenal portion of the graft to reduce the renal and visceral ischemic times. After completing the distal anastomosis, heparin was reversed with protamine sulfate. Postoperatively, all patients received low-dose dopamine infusion (2 to 3 g kg 1 min 1 ). Serum creatinine levels were measured daily while in the intensive care unit and thereafter until the value reached baseline. Definitions The extent of aortic graft replacement was defined using the classification of Crawford and associates [14]. Extent Fig 4. Circuit used for left heart bypass with normothermic blood visceral perfusion and cold crystalloid renal perfusion.

Ann Thorac Surg KÖKSOY ET AL 2002;73:730 8 RENAL PERFUSION DURING TAAA REPAIR 733 Table 1. Comparison of Preoperative Variables a Variable Normothermic Blood Perfusion (n 16) Cold Crystalloid Perfusion (n 14) p Value Age (y) 59.5 18.1 69 8.5 0.08 Sex Men 9 (56%) 7 (50%) 0.7 Women 7 (44%) 7 (50%) Diabetes 0 1 (7%) 0.6 Coronary artery disease 6 (38%) 6 (43%) 0.7 Marfan syndrome 2 (13%) 0 0.5 Forced expired volume in 1s(%ofpredicted) 80.8 22.9 71.7 12 0.3 Left ventricular ejection fraction (%) 61.1 9.2 57 7.9 0.3 Preoperative creatinine level (mg/dl) 1.21 0.5 1.04 0.3 0.3 Preoperative creatinine level 1.4 mg/dl 5 (31%) 3 (21%) 0.7 Preoperative blood urea nitrogen (mg/dl) 19.7 11.9 19 4.8 0.8 Previous nephrectomy or atrophic kidney 1 (6%) 1 (7%) 1 Previous coronary artery bypass graft 4 (25%) 3 (21%) 1 Previous ascending aortic operation 6 (38%) 3 (21%) 0.4 Previous transverse aortic arch operation 2 (13%) 1 (7%) 1 Previous abdominal aortic operation 1 (6%) 1 (7%) 1 Maximum diameter of the aneurysm (cm) 6.7 1.2 6.1 1.1 0.2 Symptoms from aneurysm Asymptomatic 7 (44%) 7 (50%) 0.7 Mild symptoms 6 (38%) 4 (29%) 0.7 Severe pain 3 (19%) 3 (21%) b 1 Presentation Elective 13 (81%) 12 (86%) 1 Emergent 3 (19%) 2 (14%) 1 Aneurysm cause Chronic fusiform medial degenerative disease 10 (63%) 9 (64%) 0.9 Chronic dissection 6 (38%) 4 (29%) 0.7 Chronic degenerative disease with acute dissection 0 1 (7%) 0.5 a Number of patients unless otherwise indicated. b One patient presented with severe pain caused by an acute distal aortic dissection; despite medical management, the aneurysm continued to expand and required elective repair 4 weeks after admission. II repairs extended from the upper descending thoracic aorta (above the sixth intercostal space) to the infrarenal abdominal aorta. Operations performed within 4 hours of admission because of immediate threat to life were classified as emergent. Perfusion and ischemic times were determined for each of the following regions: right kidney, left kidney, celiac axis, superior mesenteric artery, right leg, and left leg. Left heart bypass times were defined as the time during which a region received normothermic blood from the circuit through the distal aortic cannula. Selective perfusion times were defined as the time during which a region received normothermic blood from the circuit through a balloon perfusion catheter. Total ischemic times were defined as the time between initial aortic clamping and restoration of normal physiologic blood flow to a region. Unprotected ischemic times were defined as a region s total ischemic time minus the time that it received blood during left heart bypass and selective perfusion. The most recent preoperative serum creatinine value was considered the baseline value. Postoperative renal dysfunction was scored as proposed by Kashyap and colleagues [6]: 1. creatinine elevation less than 50% above baseline creatinine level 2. creatinine elevation 50% to 100% above baseline creatinine level 3. doubling of creatinine level but peak less than 3.0 mg/dl 4. acute renal failure: doubling of creatinine level and creatinine level greater than 3.0 mg/dl 5. acute renal failure requiring dialysis. Acute renal dysfunction was defined as an elevation in serum creatinine level exceeding 50% of baseline within 10 postoperative days (ie, scores 2). Statistical Analyses Data are presented as mean standard deviation. Analyses were performed using the SPSS 6.1 software package (SPSS Inc, Chicago, IL). Comparisons between groups were made using Fisher s exact test for categorical variables and Student s t test for continuous variables. Univariate analysis was used to evaluate preoperative and intraoperative variables for their association with renal dysfunction. All variables with p less than 0.25 on

734 KÖKSOY ET AL Ann Thorac Surg RENAL PERFUSION DURING TAAA REPAIR 2002;73:730 8 Table 2. Intraoperative Variables a Variable Normothermic Blood Perfusion (n 16) Cold Crystalloid Perfusion (n 14) p Value Total aortic cross-clamp time (min) 65 14.5 59.2 17 0.3 Left heart bypass time 25.6 9.2 23.2 6.6 0.4 Right kidney Selective perfusion time 24.0 5.8...... Perfusion time during left heart bypass 21.8 8.1 19.7 5.9 0.5 Unprotected ischemic time 19.0 9.8 39.4 14.6 0.001 Total ischemic time 64.8 14.9 59.2 17.0 0.3 Left kidney Selective perfusion time 25.9 10.4...... Perfusion time during left heart bypass 21.8 7.7 19.7 5.9 0.4 Unprotected ischemic time 21.0 10.7 40.7 18 0.001 Total kidney ischemic time 68.7 17.5 61.1 20 0.3 Celiac axis Selective perfusion time 22.0 7.2 20.2 6.2 0.5 Perfusion time during left heart bypass 21.8 8.0 19.7 5.9 0.4 Unprotected ischemic time 21.0 9.7 17.0 6.7 0.2 Total ischemic time 64.8 15 57.1 11 0.1 Superior mesenteric artery Selective perfusion time 21.5 7.2 20.2 6.2 0.5 Perfusion time during left heart bypass 21.8 7.7 19.7 5.9 0.4 Unprotected ischemic time 20.8 9.4 18.2 8.4 0.4 Total ischemic time 64.1 14 57.1 11 0.2 Right leg Unprotected ischemic time 45.2 8.3 39.0 11.0 0.1 Total ischemic time 66.9 14.0 59.3 13.0 0.1 Left leg Unprotected ischemic time 41.8 11.2 38.2 10.9 0.3 Total ischemic time 66.0 13.7 57.9 11.7 0.09 Urine output during operation (ml) 1,297 676 1,639 2,345 0.6 Urine clearance time (min) 17.7 8.3 14.9 5.7 0.3 Packed red blood cells (U) 3.37 1.6 3.4 1.7 0.9 Platelets (U) 10.6 8.1 10.1 7.2 0.5 Fresh frozen plasma (U) 6.2 4.6 4.8 4.8 0.8 Cell-saving device (U) 22.9 15.2 16.5 14 0.2 Lowest body temperature ( C) 31.8 1.2 31.9 0.7 0.7 Lowest left kidney temperature ( C) 29.8 1.4 19.7 7.3 0.001 Left kidney temperature below 15 C (no. patients) 0 4 (29%) 0.04 Right renal artery endarterectomy (no. patients) 1 (6%) 2 (14%) 0.6 Left renal artery endarterectomy (no. patients) 2 (13%) 1 (7%) 1 a All perfusion and ischemia times are presented in minutes. univariate analysis were entered into a multivariate analysis (stepwise logistic regression) to determine which variables were independently predictive of postoperative renal dysfunction. Results Efficacy Analysis To isolate renal perfusion strategy as a single variable, the efficacy analysis focused on only those patients who underwent extent II TAAA repairs with left heart bypass and the assigned renal perfusion technique. The preoperative clinical and surgical data for the 30 patients who completed the study are shown in Tables 1 and 2, respectively. The groups were similar with respect to age, sex, comorbidities, presentation, and cause of TAAA. The unprotected renal ischemic times were more than two times higher in the cold crystalloid perfusion group than in the normothermic blood perfusion group because blood was delivered to the kidneys after stopping left heart bypass in the latter group. The selective cold crystalloid perfusion led to a significant decline in renal parenchymal temperature. Although we attempted to reduce the kidney temperature to 15 C, we accomplished this goal in less than one third of the patients in this group. Two patients had only one functioning kidney at

Ann Thorac Surg KÖKSOY ET AL 2002;73:730 8 RENAL PERFUSION DURING TAAA REPAIR 735 Table 3. Incidence and Degree of Renal Dysfunction Renal Dysfunction Score (RDS) Normothermic Blood Perfusion (n 16) Cold Perfusion (n 14) p Value Overall incidence of renal dysfunction (RDS 2) 10 (63%) 3 (21%) 0.03 Score during first 10 days [1] 50% elevation in baseline creatinine level 6 (38%) 11 (79%) 0.02 [2] 50% to 100% elevation in baseline creatinine level 9 (56%) 2 (14%) a 0.01 [3] 100% elevation in baseline creatinine level 0 1 (7%) 0.5 [4] Doubling and creatinine level greater than 3.0 mg/dl 1 (6%) a 0 0.5 [5] Dialysis 0 0... Score at discharge [1] 50% elevation in baseline creatinine level 15 (94%) 12 (86%) 0.6 [2] 50% to 100% elevation in baseline creatinine level 0 0 [3] 100% elevation in baseline creatinine level 0 2 (14%) a 0.2 [4] Doubling and creatinine level greater than 3.0 mg/dl 0 0... [5] Dialysis 1 (6%) a 0 0.5 a One patient in normothermic blood perfusion died of multiple-organ dysfunction syndrome, and 1 patient in cold crystalloid perfusion group died of pulmonary embolism. the time of operation; therefore, only one kidney was perfused (one patient in each group). The mean volume of cold Ringer s lactate solution infused was 1,046 126 ml. Cold crystalloid perfusion significantly reduced the kidney temperature. However, there was no difference between groups regarding body temperature. No patient had intraoperative hypotension, defined as a systolic blood pressure being less than 70 mm Hg for longer than 5 minutes despite pharmaceutical maneuvers. One death occurred in each group. After a postoperative stroke, 1 patient in the blood perfusion group died of multiple-organ dysfunction syndrome on postoperative day 26. One patient in the cold crystalloid perfusion group died of pulmonary embolism on postoperative day 13 after multiple reoperations for bleeding and peripheral arterial embolism. Three patients in the entire study group experienced complications requiring reoperations. The patient who died in the crystalloid perfusion group had reoperations for peripheral arterial thromboembolism and bleeding from anastomoses. Two patients in the blood perfusion group underwent reoperations: one craniotomy for intracerebral bleeding and one repeat laparotomy for perforated colonic diverticulitis. Five patients in the blood perfusion group had respiratory failure requiring prolonged mechanical ventilation. One patient in the blood perfusion group had paraplegia. Ten patients (63%) in the blood perfusion group and 3 patients (21%) in the cold crystalloid perfusion group experienced acute renal dysfunction (p 0.03), ie, a renal dysfunction score (RDS) of 2 or more (Table 3). No patients required hemodialysis during the initial 10 postoperative days. Most patients with early renal dysfunction improved by the time they were discharged. Of the 10 patients with acute renal dysfunction in the blood perfusion group, 9 improved (initial RDS, 2 3 discharge RDS, 1) and 1 worsened (RDS 4 3 5); the latter patient experienced late kidney failure requiring hemodialysis and died of multiple-organ failure. Of the 3 patients with acute renal dysfunction in the cold crystalloid group, 1 patient improved (RDS 2 3 1), 1 remained stable (RDS 3 3 3), and 1 worsened (RDS 2 3 3) and died. Univariate analyses of variables examined for their association with postoperative renal dysfunction are displayed in Table 4. Factors associated with renal dysfunction included blood perfusion, higher kidney temperature, and increasing ischemic times. Cold crystalloid perfusion and lower kidney temperatures were associated with the absence of kidney dysfunction. Multivariable analysis confirmed that the use of cold crystalloid perfusion was independently protective against acute kidney dysfunction (p 0.02; odds ratio, 0.133). No other variables entered into the logistic regression analysis were predictive of postoperative renal status. Intent-to-Treat Analysis An intent-to-treat analysis was performed to validate the results of the efficacy analysis. Of the 17 patients randomized to the cold crystalloid group, only 3 experienced postoperative renal dysfunction (18%). In contrast, among the 17 patients in the normothermic blood group, 10 had renal dysfunction after TAAA repair (59%, p 0.032). Comment Selective renal perfusion with normothermic blood is a commonly used adjunct during TAAA repair [1, 3, 10, 11]. Because ischemia is a major cause of renal failure and the severity of renal injury increases with longer periods of ischemia, blood perfusion should reduce renal injury by delivering oxygen to the tissues and decreasing the ischemic time [4]. Theoretically, this buffers ph imbalance, reduces intracellular swelling, and prevents cell membrane damage. However, as demonstrated above, the maintenance of renal perfusion with normothermic blood during thoracic aortic occlusion does not alleviate postoperative renal dysfunction. In fact, some reports have suggested that normothermic blood perfusion may exacerbate renal injury. In their multivariate analysis of

736 KÖKSOY ET AL Ann Thorac Surg RENAL PERFUSION DURING TAAA REPAIR 2002;73:730 8 Table 4. Univariate Analysis of Variables Examined for Association With Acute Postoperative Kidney Dysfunction ( 50% Elevation in Baseline Creatinine Level in First 10 Days) a Variable Without Renal Dysfunction (n 17) With Renal Dysfunction (n 13) p Value Age (y) 67.3 11.3 59.5 18.3 0.16 Sex (male:female) 10:7 6:7 0.5 Diabetes (no. patients) 1 0 1 Left ventricular ejection fraction (%) 60 6.6 57.5 10 0.5 Forced expired volume at 1s(%ofpredicted) 73.4 14 79.2 23 0.48 Coronary artery disease (no. patients) 6 (35%) 6 (46%) 0.5 Previous nephrectomy or atrophic kidney (no. patients) 2 (12%) 0 (0%) 0.49 Baseline creatinine level (mg/dl) 1.08 0.4 1.2 0.46 0.5 Baseline creatinine level 1.4 mg/dl (no. patients) 4 (24%) 4 (31%) 0.7 Emergent or urgent operation (no. patients) 3 (18%) 2 (15%) 1 Aortic dissection (no. patients) 5 (29%) 6 (46%) 0.45 Maximum diameter of the aneurysm (cm) 6.3 1.1 6.5 1.4 0.7 Renal artery endarterectomy (no. patients) 4 (24%) 1 (8%) 0.35 Baseline blood urea nitrogen (mg/dl) 18.8 9.3 20.1 8.9 0.7 Total aortic cross-clamp time (min) 58 16.7 67.9 13.5 0.08 Left heart bypass time (min) 22.7 6.9 26.9 9 0.16 Perfusion technique (no. patients) Normothermic blood perfusion 6 (35%) 10 (77%) 0.03 Cold crystalloid perfusion 11 (65%) 3 (23%) 0.03 Right kidney Selective perfusion time 20.0 11 24.0 6.2 0.35 Perfusion time during left heart bypass 18.8 6.7 23.2 7.0 0.1 Unprotected ischemic time 32.0 18.7 25.0 11.3 0.24 Total ischemic time 58.3 17 66.7 14 0.16 Left kidney Selective perfusion time 24.1 16 25.2 6.5 0.8 Perfusion time during left heart bypass 19.0 6.5 23.2 7 0.1 Unprotected ischemic time 32.0 19 27.8 15 0.5 Total ischemic time 61.1 20 70.4 17 0.2 Celiac axis Selective perfusion time 18.8 6.8 24 5.5 0.8 Perfusion time during left heart bypass 18.8 6.7 23.2 7 0.1 Unprotected ischemic time 18.8 8.3 19.5 9.1 0.03 Total ischemic time 56.5 12.2 66.7 14 0.05 Superior mesenteric artery Selective perfusion time 18.5 6.7 24 5.5 0.02 Perfusion time during left heart bypass 19 6.5 23.2 7 0.1 Unprotected ischemic time 19.7 9 19.5 9.1 0.9 Total ischemic time 56.3 11.9 66.7 1.4 0.03 Right leg Unprotected ischemic time 40.6 11.3 44.6 8 0.3 Total ischemic time 59.9 13 67.9 13.5 0.12 Left leg Unprotected ischemic time 36.8 12 44.6 8 0.05 Total ischemic time 57.9 11.7 67.9 13.5 0.04 Urine output during operation (ml) 1,472 2,138 1,447 716 0.9 Urine clearance time (min) 15.7 5.4 17.3 9.3 0.6 Packed red blood cells (U) 3.23 1.5 3.6 1.7 0.5 Platelets (U) 9.9 6.3 10.9 9.3 0.7 Fresh-frozen plasma (U) 5.6 5.1 5.5 4.3 0.9 Cell-saving device (U) 16 13 24 16 0.1 Lowest left kidney temperature ( C) 22.7 8.2 27.8 4.5 0.05 a All perfusion and ischemia times are presented in minutes.

Ann Thorac Surg KÖKSOY ET AL 2002;73:730 8 RENAL PERFUSION DURING TAAA REPAIR 737 234 patients, Safi and coworkers [3] reported that selective renal artery perfusion was among the factors that predicted acute renal failure. Although the mechanisms behind the suboptimal renal protection provided by normothermic blood perfusion are not completely understood, several possible explanations exist. First, nonpulsatile flow has been demonstrated to activate the renin-angiotensin system and possibly increase renal vasoconstriction, which may have a deleterious effect [16]. Second, the perfusion pressure in the renal arteries may not be enough to compensate the metabolic requirements of the stressed kidney. Jacobs and associates [17] demonstrated that, in addition to sufficient flow, adequate arterial pressure appears to be essential in maintaining renal function during TAAA repair. They implied that the kidneys are more pressure dependent than flow dependent. Finally, in the setting of an ischemic insult, the benefits of nonphysiologic blood flow may be outweighed by the detrimental effect of maintaining renal normothermia. The other widely used intraoperative adjunct is selective renal hypothermia. Experimental data suggest that renal oxygen consumption is reduced to 40% with cooling of the renal parenchyma to 30 C, to 15% at 20 C, and to less than 5% at 10 C [8, 12, 13]. Crawford and coworkers [14] used this technique for the left kidney in many patients undergoing TAAA repair. They attempted to reduce the kidney temperature to 15 C in 70 patients, but accomplished this goal in only half of the cases because the volume of fluid administered had to be limited to prevent fluid overload or severe hypothermia. Svensson and colleagues [18] reported that perfusing both renal arteries with cold crystalloid solution resulted in a significantly lower incidence of renal complications in patients undergoing TAAA repair. Allen and associates [19] reported that there was a significant improvement in discharge creatinine levels in patients treated with renal hypothermia during repair of juxtarenal or suprarenal aortic aneurysms. In our study, reduced kidney temperature provided significant renal protection based on both univariate and multivariable analyses. Although we did not reduce the kidney temperature to less than 15 C in most patients, cold crystalloid perfusion offered superior renal protection when compared with normothermic blood perfusion. The use of the RDS, based on daily creatinine measurements, as the primary outcome measure is a limitation in our study. Using outcomes that have more substantial clinical relevance, eg, the need for dialysis, requires much larger study populations. The use of more subtle surrogate outcome measures is an expanding trend in clinical trials. By using the RDS as a subtler indicator of renal injury, for example, differences in outcome can be demonstrated with smaller study populations [6]. We agree, however, that it is difficult to know the true clinical significance of the RDS difference in our study. Although not available at the time of this study, we believe that molecular markers of renal injury will improve our ability to demonstrate differences in studies with relatively small numbers of patients. In future trials, we will use several molecular markers, including urinary microalbumin-to-creatinine ratio as an index of glomerular damage, urinary N-acetyl- -glucosamine as an index of renal tubular damage, and urinary retinol binding protein-to-creatinine ratio for evaluation of tubular function [20, 21]. The factors that contribute to renal dysfunction after TAAA repair include ischemia reperfusion injury, nonpulsatile flow in perfusion systems, transfusion of blood products, atheroembolism, and dissection of the renal artery. The multifactorial nature of renal injury mandates a multimodality approach to renal protection. In light of the differing benefits of blood perfusion and cold crystalloid perfusion, the next logical step is a combined approach, ie, cold blood perfusion [11]. A trial comparing cold blood and cold crystalloid perfusion is underway. References 1. Svensson LG, Coselli JS, Safi HJ, Hess KR, Crawford ES. Appraisal of adjuncts to prevent acute renal failure after surgery on the thoracic or thoracoabdominal aorta. J Vasc Surg 1989;10:230 9. 2. Coselli JS. Thoracoabdominal aortic aneurysms: experience with 372 patients. J Card Surg 1994;9:638 47. 3. Safi HJ, Harlin SA, Miller CC, et al. Predictive factors for acute renal failure in thoracic and thoracoabdominal aortic aneurysm surgery. J Vasc Surg 1996;24:338 45. 4. Svensson LG, Crawford ES, Hess KR, Coselli JS, Safi HJ. Experience with 1509 patients undergoing thoracoabdominal aortic operations. J Vasc Surg 1993;17:357 70. 5. Schmidt CA, Wood MN, Gan KA, Razzouk AJ. Surgery for thoracoabdominal aortic aneurysms. Am Surg 1990;56: 745 8. 6. Kashyap VS, Cambria RP, Davison K, L Italien GJ. Renal failure after thoracoabdominal aortic surgery. J Vasc Surg 1997;26:949 57. 7. Golden MA, Donaldson MC, Whittemore AD, Mannick JA. Evolving experience with thoracoabdominal aortic aneurysm repair at a single institution. J Vasc Surg 1991;13:792 7. 8. Levy M. Oxygen consumption and blood flow in the hypothermic perfused kidney. Am J Physiol 1959;197:1111 4. 9. Hanley MJ, Davidson K. Prior mannitol and furosemide infusion in a model of ischemic acute renal failure. Am J Physiol 1981;241:F556 64. 10. Morishita K, Yokoyama H, Inoue S, Koshino T, Tamiya Y, Abe T. Selective visceral and renal perfusion in thoracoabdominal aneurysm repair. Eur J Cardiothorac Surg 1999;15: 502 7. 11. Cina CS, Irvine KPA, Jones DK. A modified technique of atriofemoral bypass for visceral and distal aortic perfusion in thoracoabdominal aortic surgery. Ann Vasc Surg 1999;13: 560 5. 12. Harvey RB. Effects of temperature on function of isolated dog kidney. Am J Physiol 1959;197:181 6. 13. Semb G, Krog J, Johansen K. Renal metabolism and blood flow during local hypothermia, studied by means of renal perfusion in situ. Acta Chir Scand Suppl 1960;253:196 202. 14. Crawford ES, Crawford JL, Safi HJ, et al. Thoracoabdominal aortic aneurysms: preoperative and intraoperative factors determining immediate and long-term results of operations in 605 patients. J Vasc Surg 1986;3:389 404. 15. Coselli JS, Köksoy C, Schmittling ZC, LeMaire SA. Surgical treatment of acute and chronic dissections distal to the subclavian artery. In: Ballard JL, ed. Handbook of aortic surgery. Loma Linda: Landes Bioscience, 1999;319 339. 16. Joob AW, Dunn C, Miller E, Freedlender A, Kron IL. Effect of

738 KÖKSOY ET AL Ann Thorac Surg RENAL PERFUSION DURING TAAA REPAIR 2002;73:730 8 left atrial to left femoral artery bypass and renin-angiotensin system blockage on renal blood flow and function during and after thoracic aortic occlusion. J Vasc Surg 1987;5: 329 35. 17. Jacobs MJHM, Eijsman L, Meylaerts SA, et al. Reduced renal failure following thoracoabdominal aortic aneurysm repair by selective perfusion. Eur J Cardiothorac Surg 1998;14: 201 5. 18. Svensson LG, Crawford ES, Hess KR, Coselli JS, Safi HJ. Thoracoabdominal aortic aneurysms associated with celiac, superior mesenteric, and renal artery occlusive disease: methods and analysis of results in 271 patients. J Vasc Surg 1992;16:378 90. 19. Allen BT, Anderson CB, Rubin BG, Flye MW, Baumann DS, Sicard GA. Preservation of renal function in juxtarenal and suprarenal abdominal aortic aneurysm repair. J Vasc Surg 1993;17:948 59. 20. Ascione R, Lloyd CT, Underwood MJ, Gomes WJ, Angelini GD. On-pump versus off-pump coronary artery revascularization: evaluation of renal function. Ann Thorac Surg 1999; 68:493 8. 21. Tang AT, El-Gamel A, Keevil B, Yonan N, Deiraniya AK. The effect of renal dose dopamine on renal tubular function following cardiac surgery: assessed by measuring retinol binding protein. Eur J Cardiothorac Surg 1999;15: 717 21. DISCUSSION DR DARRYL S. WEIMAN (Memphis, TN): Joe, when you are doing your bypass, you put a left atrial cannula in? DR COSELLI: Yes. DR WEIMAN: Do you perfuse the legs at the same time or do you just come off of that into your branch vessels? DR COSELLI: In this particular group of patients, what we would do is come off left heart bypass as we took off the distal clamp and remove the distal cannula. All of the distal perfusion cannulas were placed in the lower descending thoracic aorta just above the celiac access. So then we would shut down all the flow distally. We would restart left heart bypass into the celiac and super mesenteric arteries in all cases, and what we were doing was randomizing the cold perfusion of the kidneys versus continued blood perfusion from the left heart blood. So there was no perfusion of the legs in any case after the left heart bypass was initially discontinued. DR JAKOB VINTEN-JOHANSEN (Atlanta, GA): That was a very nice presentation. Have you used any adjunctive antiinflammatory therapy, specifically for the kidneys, such as leukocyte depletion or adenosine, nitric oxide, something like that, that would attenuate the effect of inflammatory cells triggered at reperfusion? DR. COSELLI: No, we have not done so clinically. We are looking at some of those techniques in the lab, and this is obviously a very preliminary, embryonic study. There are multiple permutations on renal protection that can be derived, again, hopefully through some randomized prospective studies, to answer some of these questions, but, no, we have not used them clinically. The problem we have run into is that in some patients we were using cold, some patients we were using warm, and retrospectively evaluating it, it was a bit difficult to determine exactly which of the two techniques was better. So we set on this study to try to sort out the difference and found that the cold was better.