Preoperative Methylprednisolone Preoperative Methylprednisolone Administration Maintains Coagulation Administration Maintains Coagulation

Homeostasis in Patients Undergoing Liver Homeostasis in Patients Undergoing Liver Resection: Importance of Inflammatory Resection: Importance of Inflammatory

Cytokine ModulationCytokine ModulationPulitanò C., Aldrighetti L., Arru M., Finazzi R., Catena M.,

Guzzetti E., Soldini L., Comotti L., Ferla G.

Liver Unit – Department of SurgerySan Raffaele Scientific Institute

Vita-Salute San Raffaele UniversityMilan, Italy

Introduction

The liver plays a major role in The liver plays a major role in maintaining coagulation homeostasis. maintaining coagulation homeostasis.

Despite the improvement in surgical Despite the improvement in surgical and anesthetic techniques, the risk for and anesthetic techniques, the risk for perioperative complications associated perioperative complications associated with with alterations in haemostatic balance alterations in haemostatic balance remains.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.

Studies on coagulation after liver resection Studies on coagulation after liver resection have revealed significant alterations in have revealed significant alterations in prothrombin time, AT-III, and platelet values prothrombin time, AT-III, and platelet values and an increase in fibrinolysisand an increase in fibrinolysis

These haemostatic findings resemble those These haemostatic findings resemble those seen in DICseen in DIC an event mainly mediated by the an event mainly mediated by the production and the release of inflammatory production and the release of inflammatory cytokines.cytokines.

Coagulation alteration following liver resection

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.

Previous studies have shown that Previous studies have shown that administration of IL-6 and TNF-administration of IL-6 and TNF- may induce may induce disseminated intravascular coagulation (DIC). disseminated intravascular coagulation (DIC).

High concentrations of inflammatory cytokines High concentrations of inflammatory cytokines are related to increased risk of are related to increased risk of thromboembolic complications and increased thromboembolic complications and increased postoperative mortality and morbidity ratespostoperative mortality and morbidity rates..

The role of inflammatory cytokines

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.

Aims of the study

To determine whether preoperative To determine whether preoperative methylprednisolone administration has a methylprednisolone administration has a protective effect against the development of protective effect against the development of coagulation disorders in patients undergoing coagulation disorders in patients undergoing liver surgery.liver surgery.

Shock, vol.28, No.4, pp 401-405, 2007

Inclusion CriteriaInclusion Criteria Patients undergoing Patients undergoing

elective hepatic elective hepatic resection under resection under intermittent portal intermittent portal clampingclamping

Patients older than 18 Patients older than 18 yearsyears

Informed consent Informed consent before the enrollment before the enrollment in the trialin the trial

Exclusion CriteriaExclusion Criteria Total ischemia time of less Total ischemia time of less

than 20 minutesthan 20 minutes Child-Pugh class B or C diseaseChild-Pugh class B or C disease Concomitant additional Concomitant additional

ablation therapiesablation therapies Concomitant thoracic or Concomitant thoracic or

colorectal surgerycolorectal surgery Clinical evidence of infective Clinical evidence of infective

diseasesdiseases Chronic corticosteroid Chronic corticosteroid

therapiestherapies

Trial design

Intraoperative red blood cells or Intraoperative red blood cells or fresh frozen plasma are fresh frozen plasma are associated with a bad prognosis associated with a bad prognosis impact. impact. 1, 21, 2

Intermittent portal pedicle clamping Intermittent portal pedicle clamping (Pringle maneuver): (Pringle maneuver): encircling encircling the hepatoduodenal ligament the hepatoduodenal ligament with a tape and then applying a with a tape and then applying a tourniquet or a vascular clamptourniquet or a vascular clamp..

1: Koobi DA, et al. Influence of transfusion on 1: Koobi DA, et al. Influence of transfusion on perioperative and long term outcone in patients perioperative and long term outcone in patients following hepatic resection for colorectal following hepatic resection for colorectal metastases. metastases. Ann Surg Ann Surg 2003;237:860-8702003;237:860-8702: Wu CC, et al. Prediction and limitation of 2: Wu CC, et al. Prediction and limitation of hepatic tumor resection without blood transfusion hepatic tumor resection without blood transfusion in cirrhotic patients. in cirrhotic patients. Arch Surg Arch Surg 1998;133:1007-1998;133:1007-10101010

Intermittent portal clamping

Patients were randomly assigned by sealed envelope to Patients were randomly assigned by sealed envelope to a steroid or control groupa steroid or control group

Patients in the Steroid Group intravenously received 500 Patients in the Steroid Group intravenously received 500 mg of Methylprednisolone at the induction of anesthesiamg of Methylprednisolone at the induction of anesthesia

Intermittent portal clamping was applied at the time of Intermittent portal clamping was applied at the time of liver transection and consisted of inflow occlusion of 20 liver transection and consisted of inflow occlusion of 20 minutes followed by 10 minutes of reperfusion. The minutes followed by 10 minutes of reperfusion. The procedure was repeated as necessaryprocedure was repeated as necessary

Each patient was operated under the supervision of the Each patient was operated under the supervision of the same Hepatobiliary Surgeon (unaware of the patient’s same Hepatobiliary Surgeon (unaware of the patient’s group allocation)group allocation)

First-generation cephalosporin (Cefazoline) was First-generation cephalosporin (Cefazoline) was routinely applied just before the surgery.routinely applied just before the surgery.

Trial design

Serum ParametersSerum Parameters PT-INRPT-INR FibrinogenFibrinogen D-DimerD-Dimer PlateletsPlatelets Anti-Thrombin III (AT-III)Anti-Thrombin III (AT-III) Interleukin-6 (IL-6) Interleukin-6 (IL-6) Tumor Necrosis Factor-Tumor Necrosis Factor-

(TNF-(TNF-))

Clinical ParametersClinical Parameters Diagnoses and type of Diagnoses and type of

proceduresprocedures Ischemia timeIschemia time Length of surgeryLength of surgery Blood losses and Blood losses and

transfusions transfusions Postoperative Postoperative

complicationscomplications Hospital stayHospital stay

Serum and clinical parameters

38 patients received preoperative 38 patients received preoperative Methylprednisolone treatmentMethylprednisolone treatment

38 patients received preoperative 38 patients received preoperative Methylprednisolone treatmentMethylprednisolone treatment

37 Patients were included37 Patients were includedIn the Analysis (In the Analysis (Control GroupControl Group))

37 Patients were included37 Patients were includedIn the Analysis (In the Analysis (Control GroupControl Group))

36 Patients were included In 36 Patients were included In the Analysis (the Analysis (Steroid groupSteroid group))

36 Patients were included In 36 Patients were included In the Analysis (the Analysis (Steroid groupSteroid group))

2 patients were excluded2 patients were excludedbecause the portal because the portal clamping was not appliedclamping was not applied

2 patients were excluded2 patients were excludedbecause the portal because the portal clamping was not appliedclamping was not applied

38 patients were not 38 patients were not treatedtreated

38 patients were not 38 patients were not treatedtreated

1 patient was excluded1 patient was excludedbecause of concomitant because of concomitant termoablationtermoablation

1 patient was excluded1 patient was excludedbecause of concomitant because of concomitant termoablationtermoablation

76 Consecutive Patients Were 76 Consecutive Patients Were Randomly AssignedRandomly Assigned

76 Consecutive Patients Were 76 Consecutive Patients Were Randomly AssignedRandomly Assigned

Results: patients allocation

Results: preoperative variables

Results: operative variables

PT-INRPT-INR PlateletsPlatelets

Results

AT-IIIAT-III FibrinogenFibrinogen

Results

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

Results: complications

The results of this study suggest that a The results of this study suggest that a surge in circulating inflammatory surge in circulating inflammatory cytokines may play a significant role in cytokines may play a significant role in inducing coagulation alteration in patients inducing coagulation alteration in patients undergoing liver resection. undergoing liver resection.

It is of clinical interest that It is of clinical interest that methylprednisolone administration before methylprednisolone administration before liver surgery maintains coagulation liver surgery maintains coagulation homeostasis by attenuating inflammatory homeostasis by attenuating inflammatory cytokine response.cytokine response.

Conclusion