On-Pump Cardiopulmonary Bypass Versus Off-Pump Coronary Artery Bypass Grafting Surgery : Renal And Liver Function Tests

Objective: Cardiopulmonary bypass (CPB) triggers systemic inflammation. Inflammatory system activation may cause deteoriation in liver and renal functions. In our study we aimed to search the effect of on-pump CPB and beating heart off-pump coronary artery bypass grafting (CABG) surgery techniques on renal and liver functions. Methods: Sixty four patients who underwent coronary artery surgery were included in the study and were divided into two groups: on-pump CPB group (40) and beating heart off-pump CABG group (24), prospectively. The blood samples were collected for preoperative and postoperative levels of blood urea nitrogen (BUN), creatinine, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and AST to ALT ratio at 24 th and 48 th hours. Results: Clinical and demographic features were similar in both groups. There were no statistically significant difference in levels of preoperative BUN, creatinine, AST, ALT, AST to ALT ratio. The postoperative 24 th hour plasma levels of creatinine, AST and AST/ALT were lower in beating heart off-pump CABG group but BUN and ALT levels were similar among the two groups. The postoperative 48 th hour plasma levels of BUN, creatinine, AST and AST/ALT were lower in beating heart off-pump CABG group but levels of ALT were similar in both groups. Conclusion: Based on our findings we conclude that beating heart off-pump CABG has lower negative effect on liver and renal function than on-pump CPB. Abstract of this manuscript was presented in 7th Congress of Update in Cardiology and Cardiovascular Surgery in association with TCT Mediterranean as a poster.


INTRODUCTION
Cardiac surgery has progressed much in the last forty years.Inflammatory system activation triggered by cardiopulmonary bypass (CPB) may lead to a variety of complications including respiratory insufficiency, lung damage, cognitive dysfunction and brain damage (1)(2)(3).In the recent years, off-pump CABG procedure has been being performed more frequently without the need of CPB.The principal goal is to avoid the negative effects of cardiopulmonary bypass on physiological systems (4)(5)(6).CPB induced systemic inflammation activation may cause deteoriation in liver and renal functions contrubuting to increased morbidity and mortality (3)(4)(5).In the present study, we aim to investigate the effects of off-pump and on-pump CABG procedures on renal and liver functions.

METHODS
The study was approved by local ethical commitee, and informed consent forms were signed by all patients.All reported research involving "Human beings" conducted in accordance with the principles set forth in the Helsinki Declaration 2008.The patients were prospectively divided into two groups according to the use of extracorporeal circulation or not as follows: off-pump CABG group (n=24) and on-pump CPB group (n=40).Patients were assigned to an off-pump or on-pump strategy based upon surgeons' preference.
Exclusion criteria were as follows: occurrence of an acute myocardial infarction within one month, need for emergency coronary revascularization, creatinine level >2 mg/dL and/or the presence of acute renal failure, presence of an active infectious disease, presence of a systemic inflammatory disease, presence of a collagen tissue disorder, presence of a metastatic disease, being a patient receiving immunosuppressive medication and reoperation for bleeding.

Premedication and Anesthesia
All patients were premedicated by 10 mg oral diazepam 12 hours before the operation, 0.1 mg/kg subcutaneous morphine sulfate and 20-50 mg/kg intravenous cefazoline sodium 30 minutes before the operation.Patients were monitorized for DII standard derivation in the operative room.Anesthesia was induced by 5-7 mg/kg sodium thiopental.For the maintenance of anesthesia, 0.1 mg/kg pancuronium was administered as a muscle relaxant, 0.1-0.5 mcg/kg remifentanyl continuous infusion was administered as an analgesic.Isofloran was used as inhaled anesthetic as necessary.

Off-pump CABG technique
After median sternotomy, all patients were anticoagulated with 100-200 U/kg of heparin.An Octopus IV tissue stabilizer (Medtronic, Minneapolis, USA) was used for partial immobilization of the myocardial surface during the construction of distal anastomoses.An intracoronary shunt was placed for the vessel to be anastomosed.The heart was positioned using deep pericardial traction, Starfish heart positioner (Medtronic, Minneapolis, USA) and an apical suction device.Heart rate control was achieved preferably by esmolol infusion.Revascularization of the right coronary artery (RCA) was performed first, followed by the construction of distal anastomoses of the circumflex (Cx) artery territory, and the left anterior descending artery (LAD) territory.The left internal mammary artery (LIMA) was anastomosed to the LAD in all patients.Following the construction of distal anastomoses, the saphenous vein grafts were anastomosed to the aorta.

CPB technique
The patients were anticoagulated with 300-400 U/kg of heparin.CPB was initiated following cannulation of the aorta and the right atrium in a standart fashion.A Stockert SIII roller pump (Stockert Instrumente GmbH, Munich, Germany), a membrane type oxygenator and an uncoated CPB circuit (Dideco Compact Flo Evo, Sorin Group, Italy) were used.The pump prime solution contained 1000-1500 mL of lactated Ringer's solution to maintain a hematocrit level of %26±2.Pump flow was set at 2.2-2.4L/m 2 /minutes to maintain mean arterial pressure between 50-70 mmHg.Moderate hypotermia and cold blood cardioplegia administered in every 20 minutes in antegrade and retrograde fashion was used.Additional cold (4 °C) Isolyte S solution was topically applied onto the surface of the heart at the same intervals.

Sample collection
The blood samples were collected at preoperative and postoperative 24 th and 48 th hour .Blood samples were analyzed for BUN, AST, ALT and AST to ALT ratio.
Statistical Analysis SPSS 13.0 packet program (SPSS Inc., Chicago, IL) was used for the statistical analysis of the parameters obtained from the blood analysis results.. Descriptive statistics were shown as mean ± standard deviation.The statistical significances between two groups were assessed by Mann-Whitney U test.Chisquare test was used to assess differences of categorical variables between groups.Pearson's analysis was used to calculate the correlation coefficients.Values of P<0.05 were accepted as statistically significant.

RESULTS
Demographic and laboratory data with comparative results are listed in Table 1.No statistically significant difference was detected between the groups for age, body mass index, hypertension, diabetes mellitus, hyperlipidemia, smoking, myocardial infarction, ejection fraction or the number of grafts (P>0.05).There were no statistically significant difference in preoperative BUN, creatinine, AST, ALT, AST/ALT ratio measurements (Table 2).The postoperative 24 th hour plasma levels of creatinine, AST and AST/ALT ratio were lower in offpump group but BUN and ALT levels were similar between the two groups.The postoperative 48 th hour plasma levels of BUN, creatinine, AST and AST/ALT ratio were lower in off-pump group, but levels of ALT were similar between the two groups (Table 2).
Cardiopulmonary bypass and systemic inflammation cause important morbidity and mortality following open heart surgery.Combination treatment of steroids and antioxidants in order to prevent and treat these conditions may decrease postoperative morbidity.Off-pump CABG procedure has the advantage to exclude the negative effects of CPB.Performing coronary artery bypass graft (CABG) operation without CPB seems to be superior for decreasing inflammatory response.Off-pump surgery procedure has dramatically expanded coronary surgery indications in the recent years.Various studies have reported the relative advantages of this procedure compared to conventional CPB particularly for elder patients, cases with low ejection fraction, cerebrovascular diseases, liver disease, malign diseases , patient groups with bleeding anomalies or when utilization of blood and blood products is not allowed (4)(5)(6).
Many studies investigated the effects of off-pump and on-pump techniques on inflammation.Okubo et.al.analyzed the effects of off-pump/on-pump coronary surgery on IL-1, IL-8, IL-10 and TNF-α levels, and showed a significant increase in inflammatory markers in on-pump group while no difference in offpump CABG group was detected (10).Another study evaluating the effects of off-pump / on-pump surgery on endothelial activation and inflammatory response, concluded that off-pump CABG group has lower increase in vascular endothelial growth factor (VGEF) and monocyte chemo-attractant protein (MCP)-1), inflammatory markers and cytokine response (11).
Ascione et.al. (12) evaluated the effects of off-pump and on-pump CABG on the liver functions, and showed higher AST -ALT levels in the first postoperative day for on-pump group, but no difference in the monoethylglycinexylidide/ lidocaine ratio was seen.Yamada et.al. (13) analyzed the effects of off-pump/on-pump surgery on liver function analyzing alcohol dehydrogenase and alpha-glutathione S-transferase,.They showed an increase in serum alcohol dehydrogenase and alpha-glutathione S-transferase levels for off-pump group compared with on-pump CPB group.Both groups showed no clinical liver dysfunction.In the present study, 24 th hour postoperative AST and AST/ALT ratio were lower in off-pump group and ALT levels were found to be similar in both groups.The Forty-eight hour postoperative AST and AST/ALT ratio were lower in off-pump group, and ALT levels were similar in both groups.In patients undergoing on-pump coronary surgery, possible factors causing liver dysfunction may be the decrease in systemic vascular resistance, low CPB pressure, inflammatory activation and microemboluses (14,15).Fifty percent of patients undergoing CABG was shown to have temporary intestinal mucosal ischemia indicated by intramucosal acidosis.Temporary intestinal mucosal ischemia increases the permeability of intestinal mucosa to bacteria and endotoxins.Liver helps cleaning cytokines and bacteria originating from intestines (16).This mechanism is disturbed in patients with liver dysfunction.Expansion of endotoxins and bacteria is an important factor contributing to systemic inflammatory response and to multiple organ failure (17).
Renal dysfunction is an important complication of CPB and is associated with increased mortality, morbidity and hospital stay (18,19).It's pathogenesis is multifactorial and preexisting renal disease, elderly age and postoperative low cardiac output are general risk factors.Pump duration in CPB, low CPB pressure, systemic inflammatory response,and postoperative hypoperfusion are presumed mechanisms causing renal dysfunction (20,21).
Renal dysfunction due to CPB can be prevented with off-pump CABG.Loef BG et. al. (18) investigated the effects of off-pump /on-pump surgery on renal functions concluding that lower microalbuminuria and higher creatinine clearance was associated with off-pump CABG.Another study by Pramodh K et.al. (19) showed that postoperative 24 th and 48 th hour creatinine clearance was significantly lower in on-pump group compared with off-pump group.In our study, postoperative 24 th hour creatinine value was lower in off-pump CABG group and BUN was similar in both groups.Postoperative 48 th hour BUN and creatinine values were found to be lower in off-pump patients compared with on-pump group.
Hypothermia is a beneficial strategy for visceral organ protection during CPB.The protective effects of hypothermia on organ function in the setting of ischemic injury have been previously demonstrated in animal models.It is also found to have attenuating effects in acute renal failure and liver dysfunctions.However, Boodhwani et al reported that, re-warming while on CPB has been associated with increased renal injury and should be avoided (22).Hypothermia has little effect on hepatic arterial blood flow and may actually increase portal flow.There is no significant difference in hepatic blood flow between pulsatile and non-pulsatile perfusion at high flow rates (2.4 L/min/m 2 ) during hypothermia.The increase in total body oxygen consumption in the immediate hours after CPB may have an important role for development of inadequate gastrointestinal perfusion (23.24).

CONCLUSION
Our study has some limitations.The small number of patients enrolled in this study may have effected the precision of the outcomes.As moderate hypothermia was used for on-pump CABG and normotermia is naturally a part of off-pump surgery, temperature differences between two procedures may have altered the results of the laboratory findings as well.In conclusion, the results of this study suggest that off-pump CABG offers better than on-pump procedure in terms of negative consequences on renal and liver functions.