Strategies for Maximizing Outcomes in Liver Transplantation

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 9th 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

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 9th largest program in 2008 401 adult OLT over 40 months 20 combined liver/kidney Age at Transplant 52.8 ± 9.42 years Male Recipient 73.3% Caucasian Recipient 72.4% MELD Score 22 ± 4.89

11. A Matter of Time • Warm Ischemic Time (anastomotic) 36.8 ± 11.9 minutes • Cold Ischemic Time 5.7 ± 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 weeks 6-8 12-24 weeks 3-5 6-12 months 3 After 12 months 1-3

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) P < 0.001 (for all time points) Time Post-Transplant p< .001 for all time points from pretransplant

20. Tacrolimus levels

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