1. Jacques Belghiti Silvio Balzan, Fabien Stenard, Satoshi Ogata Department of Hepato-Pancreatico-Biliary and United Federation of Hepato-Gastroenterology and Digestive Surgery of Beaujon Hospital, Clichy, University Paris 7. France Mortality after Liver Resection

2. 427 Resection of HCC: 1990 - 2003 Normal Chronic Liver Liver Disease Mortality1.2%7.7% Bleeding2%8% Ascites15%45% Jaundice 4%12% Infection 15%25% Renal failure0%8% Liver Failure0.5%6% Absence or insufficient liver regeneration

3. Post Operative Days Early post operative deaths within 3 days Myocardiac infarction (n = 1) Peritonitis due to bowel necrosis (n = 2) In-Hospital Mortality (n = 26) 3.3% Median post operative deaths POD 16 (range 5-39) Elective Liver Resection n = 775 (1998 – 2002)

4. Liver Parenchymal Status Post Operative Days Normal (n = 5) Disead (n = 18) 78%

5. Severe Infection or Renal Failure Post Operative Days Incidence: 74% Median POD: 10 (range 2-18) Occurrence before or at POD 5: 30 ％

6. In Hospital Deaths (n = 26) Post Operative Days Early post operative deaths within 3 days Myocardiac infarction (n = 1) Peritonitis due to bowel necrosis (n = 2) Median post operative deaths Link to liver Failure POD 16 (range 5-39)

7. Postoperative Liver Failure remains the most dangerous complication after Liver Resection Risk of Death –Insufficient absolute or functional liver parenchyma. –Impaired tolerance to infectious complications. Definition ? Prevalence ? Impact on postoperative mortality ?

8. What is Post operative Liver Failure ? Clinical Biological - Encephalopathy- Bilirubinemia > 150 µmol/L - Jaundice- PT < 50% - - Ascites - Factor V < 50% - ICG 15 min > 20 or 15% Encephalopathy, ascites or coagulopathy requering specific treatment. Hemming AW et al. Ann Surg 2003,5:686-93. Prolonged hyperbilirubinemia, ascites,coagulopathy requering fresh- frozen plasma, and/or encephalopathy. Jarnagin WR et al. Ann Surg 2003,4:397-407. Bilirubinemia > 5 mg/dL (85 µmol/L), PT < 50% for 3 or more consecutive days. Imamura H. Arch Surg 2003,138:1198-1206. Two of Bilirubinemia >60 µmol/L, asterixis, and prothrombin time<30%. Azoulay D. Ann Surg 2000,232:665-72

9. Objective Criteria of Post operative Liver Failure predicting high mortality rate. –Simple: quick, cheap and non invasive. –Efficient: allowing early diagnosis and early management. –Standardized: compare results.

10. FIFTY-FIFTY AT DAY FIVE CRITERIA Child-Pugh Score Encephalopathyabsentcontrolled medically poorly controlled Ascitesabsentcontrolled medically poorly controlled Albumin (g/l)> 3528 – 35< 28 Serum Bilirubin (µmol/l) 50 Prothrombin Time (%) > 50 40 – 50< 40 Peri-operative risk assessment in cirrhosis:

11. Child-Pugh Score: Criteria of POLF Encephalopathypoorly controlled Ascitespoorly controlled Albumin (g/l)< 28 Serum Bilirubin (µmol/l)> 50 Prothrombin Time (%)< 50 Post operative period ⇨ Not applicable (anesthesia) ⇨ Frequent after liver resection ⇨ Useless (post. hemodiluition) ⇨ When ?

12. Liver Tests after Major Hepatectomy 50 55 60 65 70 75 80 85 90 95 100 105 TPj-1TPj1TPj3TPj5TPj7TPj9TPj11 5 10 15 20 25 30 35 40 Bbj-1Bbj1Bbj3Bbj5Bbj7Bbj9Bbj11 40 60 80 100 120 140 160 180 200 GGTJ-1 GGTJ1GGTJ3GGTJ5GGTJ7GGTJ9 GGTJ11 0 50 100 150 200 250 300 350 ASTj-1ASTj1ASTj3ASTj5ASTj7ASTj9ASTj11 0 50 100 150 200 250 300 350 ALTj-1ALTj1ALTj3ALTj5ALTj7ALTj9ALTj11 100 110 120 130 140 150 160 170 180 190 200 210 PAj-1PAj1PAj3PAj5PAj7PAj9PAj11 Prothrombin TimeBilirubinemia GGT ASAT ALATALP

13. Prospective Database from 1998 – 2002 775 elective liver resection* Aged:54 ± 10 years Malignant tumors:531 (69%) Major resection: 464 (60%) Diseased Liver present:307 (40%) –Fibrosis237 (31%) –Cirrhosis 94 (12%) –Steatosis >30%: 107 (14%) In hospital mortality: (n=26) 3.3%

14. Postoperative Liver Tests 1998 – 2002: 775 elective liver resection

15. In Hospital Deaths (n = 26) Post Operative Days Median post operative deaths Link to liver Failure POD 16 (range 5-39)

16. Postoperative Morbidity vs No Complications ALP PT Bilirubinemia ASAT

17. 50 55 60 65 70 75 80 85 90 95 100 105 TPj-1TPj1TPj3TPj5TPj7TPj9TPj11 Prothrombin Time (%) PT < 50% 1357 Incidence21%16%6%4% Mortality if present 10%16%33%40% absent1.5 %1.3 %1.3 %1%

18. 5 10 15 20 25 30 35 40 Bbj-1Bbj1Bbj3Bbj5Bbj7Bbj9Bbj11 Bilirubinemia > 50 µml/L 1357 Incidence17%19%16%11% Mortality if present 7%11%15%17% absent2 %2 %1 %1%

19. Mortality day 5 PT < 50% 33% SB > 50 µml/L 15% PT 50 µml/L 59%

20. Fifty – Fifty at day Five Criteria after Hepatectomy 59 % 4 % Bil > 50 µmol/L 7 %1 % Bil < 50 µmol/L PT <50%PT >50%DAY 5 Mortality according to PT 50 µmol/L

21. 25 Patients with 50-50 criteria 14 deaths 11 Severe Morbidity ICU : 22 days (4 – 57) Hospital stay: 43 days (17 – 69) -Dead without 50-50 criteria at day 5 (n=7) 3digestive bleeding with portal thrombosis 2biliar peritonites and septicemia by candida 4severe sepsis

22. Conclusions The presence at day 5 of the criteria 50 – 50 (PT 50 µmol/L) is an early and strong predictor (60%) of mortality

23. “50-50 criteria” At day 5 the criteria 50 – 50 (PT 50 µmol/L) which is an early and strong predictor (60%) of mortality can be used as a criteria of Postoperative Liver Failure. Most importantly, this criteria which precede any clinical evidence of complication and death by a median of 5 and 10 days can be used for: –early assessment of infection or portal thrombosis and –to implement specific therapeutic interventions such as prophylactic antimicrobial therapy, artificial liver support or even liver transplantation.

24. Case 75 yrs male 30/03/2004 Right hemicolectomy Dukes C, 2 metastases in right liver - 12/2004 Systemic chemotherapy (Oxaliplatin+5FU+LV) 10/02/2005 Right hepatectomy Labo data AST: 43 IU/L ALT: 66 IU/L GGT: 248 IU/L T-Bil: 5 µmol/L PT: 76%

25. Death MARS PT Bil

26. FIFTY-FIFTY AT DAY FIVE CRITERIA -Dead with 50-50 criteria at day 5 present 1 no context of liver failure 12infected ascites – portal thrombosis pneumopathy -Dead without 50-50 criteria at day 5 3digestive bleeding – biliar peritonites septicemia by candida 7portal thrombosis – infected ascites (3) -No dead despite 50-50 criteria present 3transient criteria (only at day 5) – uncomplicated outcome 9100% of morbidity USI 22 days (4 - 57) Hospitalization 43 days (17 - 69)

27. FIFTY-FIFTY AT DAY FIVE CRITERIA -Deaths without 50-50 criteria at day 5 3digestive bleeding biliar peritonites septicemia with candida 7portal thrombosis infected ascites (3)

28. Prothrombin Time (%) 50 55 60 65 70 75 80 85 90 95 100 105 TPj-1TPj1TPj3TPj5TPj7TPj9TPj11

29. Bilirubinemia 5 10 15 20 25 30 35 40 Bbj-1Bbj1Bbj3Bbj5Bbj7Bbj9Bbj11