1. Strategies for Maximizing Outcomes in Liver Transplantation James D. Eason, M.D. Chief of Transplantation / Professor of Surgery University of Tennessee / Methodist Transplant Institute

2. Recent Publications (HTK) is associated with reduced graft survival in deceased donor livers, especially those donated after cardiac death. Stewart ZA, Cameron AM, Singer AL, Montgomery RA, Segev DL. Am J Transplant. 2009 Feb;9(2):286-93.

3. Results All deceased donor transplants (n = 4755 HTK and 12 673 UW) HR 1.14 (1.05–1.23) p = 0.002 Donor after cardiac death (n = 254 HTK and 575 UW) HR1.44 (1.05–1.97) p = 0.025

4. Problems Extended Criteria donors Age Steatosis DCD Ischemia Reperfusion Injury Cold and warm ischemia Cell Death over time Immunosupression Minimizing adverse events

5. UT Experience 120 Liver Transplants in 2008 9 th Largest in US 401 Cadaveric OLT over 40 months 24 DCD HTK perfusion in 90% of donors RATG induction Steroid-free immunosuppression

6. National Results PatientGraft United States88.3484.31 University of TN/Methodist 91.086.51 Cleveland Clinic90.0983.94 Indiana- Clarian88.3386.62 Johns Hopkins79.8172.41

7. Ischemia-Reperfusion HTK - Low viscosity Buffered- minimize drop in pH Biliary protective Endothelial protective

8. Timing is Everything! Cold Ischemic Time Usually under 6 hours Anastomotic time Reperfusion Arterialization Warm Ischemic time in DCD Rapid Cannulation

9. Immunosuppression RATG Induction May decrease immune contribution to ischemia- reperfusion

10. Results 9 th largest program in 2008 401 adult OLT over 40 months 20 combined liver/kidney Age at Transplant52.8 ± 9.42 years Male Recipient73.3% Caucasian Recipient72.4% MELD Score22 ± 4.89

11. A Matter of Time Warm Ischemic Time (anastomotic) 36.8 ± 11.9 minutes Cold Ischemic Time5.7 ± 2.2 hours Arterialization - 60 minutes Mean operative time 4 hours (2.1 – 6)

12. DCD results 24 DCD OLT over 3 years Mean F/U – 450 days 20 patients > 1 year 91% one -year patient survival 2 deaths within one year 1sepsis, 1 PNF 1 death at 13 months - heart failure 2 patients with intrahepatic strictures two years post-transplant

13. DCD MELD -median 18 (15-22) Donor age mean- 35years (15-52) Cannulation time – 2minutes Warm Ischemic time - (7-42 minutes)pressure / O2 sat < 80 Cold ischemic time - 5.47 hours (2.3 - 8.3) Anastomotic time - mean 32 minutes

14. DCD deaths

15. DCD protocol Staff surgeon – experience matters HTK Minimize times WIT Cannulation CIT arterialization Donor selection Proper recipient selection

16. Immunosuppression Protocol RATG 1.5 mg/kg in anhepatic phase and POD 2 – total 3mg/kg Premedication -500 mg methylprednisolone, 500 mg acetominophen and 25mg diphenhydramine MMF 1gram BID on Day 1 Tacrolimus begun on day 2 or when serum creatinine fell below 2mg/dl Primary sirolimus if serum creatinine > 2.5 or oliguric by Day 7

17. Immunosuppression (continued) Tacrolimus target level Day 7-12 weeks6-8 12-24 weeks3-5 6-12 months3 After 12 months1-3

18. Tacrolimus Initiation Mean 3.5+ 1.8 days Range 2 – 12 days 27 patients started day 4 – 12 7 subsequently converted to sirolimus Mean tacrolimus levels Day 7- 4.5 Day 30 - 6

19. Serum Creatinine Liver Transplant Recipients only (n= 101) Time Post-Transplantp<.001 for all time points from pretransplant P < 0.001 (for all time points)

20. Tacrolimus levels Day 71 month3 months6 monthsOne year 6.47.27.47.15.8

21. Sirolimus 40 patients started on primary sirolimus therapy within 15 days 25 additional patients converted after 30 days

22. Minimal Immunosuppression Single agent Tacrolimus Sirolimus Continue weaning to lowest levels

23. Maximizing Outcomes Control controllable factors Ischemic time Preservation solution- HTK Proper selection/ matching ofdonor – recipient Minimize immunosuppression to avoid complications

24. Conclusion Excellent outcomes that exceed expected survival can be achieved with HTK preservation when performed by experienced surgeons under controlled circumstances