Pulitanò C., Aldrighetti L., Arru M., Finazzi R., Catena M., Guzzetti E. , Soldini L., Comotti L., Ferla G. Liver Unit

1. Preoperative Methylprednisolone Administration Maintains Coagulation Homeostasis in Patients Undergoing Liver Resection: Importance of Inflammatory Cytokine Modulation Pulitanò C., Aldrighetti L., Arru M., Finazzi R., Catena M., Guzzetti E., Soldini L., Comotti L., Ferla G. Liver Unit – Department of Surgery San Raffaele Scientific Institute Vita-Salute San Raffaele University Milan, Italy

2. Introduction • The liver plays a major role in maintaining coagulation homeostasis. • Despite the improvement in surgical and anesthetic techniques, the risk for perioperative complications associated with alterations in haemostatic balance remains. Siniscalchi A, et al. Increased Prothrombin Time and Platelet Counts in Living Donor Right Hepatectomy: Implications for Epidural Anesthesia. Liver Transpl 2004;10:1144–1149. Mammem EF. Coagulopathies of liver disease. Clin Lab Med 1994; 14(4):769-780.

3. Coagulation alteration following liver resection • Studies on coagulation after liver resection have revealed significant alterations in prothrombin time, AT-III, and platelet values and an increase in fibrinolysis • These haemostatic findings resemble those seen in DICan event mainly mediated by the production and the release of inflammatory cytokines. Nagino M, et al. Disseminated intravascular coagulation after liver resection: retrospective study in patients with biliary tract carcinoma Surgery. 1995 May;117(5):581-5. Siniscalchi A, et al. Increased Prothrombin Time and Platelet Counts in Living Donor Right Hepatectomy: Implications for Epidural Anesthesia. Liver Transpl 2004;10:1144–1149.

4. The role of inflammatory cytokines • Previous studies have shown that administration of IL-6 and TNF-a may induce disseminated intravascular coagulation (DIC). • High concentrations of inflammatory cytokines are related to increased risk of thromboembolic complications and increased postoperative mortality and morbidity rates. Van der Poll T, et al. Activation of coagulation after administration of tumor necrosis factor to normal subjects. N Engl J Med 1990; 322: 1622-1627. Stouthard JM, Levi M, Hack CE, et al. Interleukin-6 stimulates coagulation, not fibrinolysis, in humans. Thromb Haemost. 1996; 76(5):738-742.

5. Aims of the study • To determine whether preoperative methylprednisolone administration has a protective effect against the development of coagulation disorders in patients undergoing liver surgery. Shock, vol.28, No.4, pp 401-405, 2007

6. Trialdesign Inclusion Criteria • Patients undergoing elective hepatic resection under intermittent portal clamping • Patients older than 18 years • Informed consent before the enrollment in the trial Exclusion Criteria • Total ischemia time of less than 20 minutes • Child-Pugh class B or C disease • Concomitant additional ablation therapies • Concomitant thoracic or colorectal surgery • Clinical evidence of infective diseases • Chronic corticosteroid therapies

7. Intermittent portal clamping Intraoperative red blood cells or fresh frozen plasma are associated with a bad prognosis impact. 1, 2 Intermittent portal pedicle clamping (Pringle maneuver): encircling the hepatoduodenal ligament with a tape and then applying a tourniquet or a vascular clamp. 1: Koobi DA, et al. Influence of transfusion on perioperative and long term outcone in patients following hepatic resection for colorectal metastases. Ann Surg 2003;237:860-870 2: Wu CC, et al. Prediction and limitation of hepatic tumor resection without blood transfusion in cirrhotic patients. Arch Surg 1998;133:1007-1010

8. Trialdesign • Patients were randomly assigned by sealed envelope to a steroid or control group • Patients in the Steroid Group intravenously received 500 mg of Methylprednisolone at the induction of anesthesia • Intermittent portal clamping was applied at the time of liver transection and consisted of inflow occlusion of 20 minutes followed by 10 minutes of reperfusion. The procedure was repeated as necessary • Each patient was operated under the supervision of the same Hepatobiliary Surgeon (unaware of the patient’s group allocation) • First-generation cephalosporin (Cefazoline) was routinely applied just before the surgery.

9. Serum and clinical parameters Serum Parameters • PT-INR • Fibrinogen • D-Dimer • Platelets • Anti-Thrombin III (AT-III) • Interleukin-6 (IL-6) • Tumor Necrosis Factor-a (TNF-a) Clinical Parameters • Diagnoses and type of procedures • Ischemia time • Length of surgery • Blood losses and transfusions • Postoperative complications • Hospital stay

10. Results: patients allocation 76 Consecutive Patients Were Randomly Assigned 38 patients were not treated 38 patients received preoperative Methylprednisolone treatment 2 patients were excluded because the portal clamping was not applied 1 patient was excluded because of concomitant termoablation 37 Patients were included In the Analysis (Control Group) 36 Patients were included In the Analysis (Steroid group)

11. Results: preoperative variables

12. Results: operative variables

13. Results PT-INR Platelets

14. Results AT-III Fibrinogen C. Pulitanò et.al. Inihibition of cytokine response by methylprednisolone attenuates Antithrombin III reduction following hepatic resection. Thromb Haemost 2005.

15. Results: complications

16. Conclusion The results of this study suggest that a surge in circulating inflammatory cytokines may play a significant role in inducing coagulation alteration in patients undergoing liver resection. It is of clinical interest that methylprednisolone administration before liver surgery maintains coagulation homeostasis by attenuating inflammatory cytokine response.