Goran B. G. Klintmalm MD, PhD, FACS Baylor Simmons Transplant Institute Dallas

1. Liver Transplantation, from an experiment to practice; Thoughts from a “Second Generation” surgeon. Goran B. G. Klintmalm MD, PhD, FACS Baylor Simmons Transplant Institute Dallas

2. Francis Moore1913-2001 Harvard Medical School Peter Bent Brigham Hospital Medical Pioneer Innovator -Fluid and electrolyte therapy after surgery -Burn treatment -Kidney Transplant -Liver Transplant (dogs, ASA 1960)

3. ASA 1960 – hall way discussion David Hume (Richmond) told TES about study in his lab (in dogs) of Charles Zukoski and H.M. Lee to substitute X-ray therapy with pharmacologic immunosuppression. 6-mercaptopurine The stage had been set.

4. Corticosteroids René Küss and Jean Hamburger (Paris) Kidney transplants, use of X-ray, 6-mercaptopurine and unspecified amounts of steroids – “The Cocktail” 1960-61, three of six patients survived ---- five, seventeen and eighteen months.

5. GBK’13

6. GBK’13 Surg Gynecol Obstet 1963;117:385

8. Paul Taylor and the first long term survivor after liver transplantation. GBK’13

9. March 1, 1963 First human liver transplant. Four more in 1963; May, June, July, Oct. (Three died from pulmonary emboli.) Three auxiliary in 1965. Two more orthotopic, 1966 and 1967 GBK’14

10. Denver 1967 Carl Groth with the First Three Survivors

11. Immunosuppression 1970 Induction ALG Maintenance Azathioprine Corticosteroids Rejection Therapy Corticosteroids ALG GBK’14

12. Alternatives 1970 Cyclophosphamide (1963) As effective as Azathioprine More bone marrow toxicity Thoracic Duct Drainage (1964) Requires pretreatment Cumbersome Irradiation (1960) Difficult to control side effects TLI Graft Irradiation GBK’14

13. Where Were We in 1970? Kidney Transplantation Graft Survival: 45% Patient Survival: 80% Liver Transplantation Patient Survival (Denver): 27% Patient Survival (Cambridge): 22% Heart, Pancreas, Lung, Intestine Patient and Graft Survival Marginal- GBK’14

14. GBK’14

15. The Operation • Pre op order for blood – 15 u for the opening of the abdomen. Gave the Blood Bank time to get lined up for the case. • Traumatic needles – scrub nurse loaded each suture on the needle. (catgut, cotton, silk) • No electrocautery. The Ruby coagulator appeared in 1982 – (and later blinded TES permanently on the right fovea)

16. The Operation • No self retaining retractors – Residents called up to hang on. When they dropped, replacements were called in from the ER. • Routinely cracked the chest for access to suprahepatic cava. • Anesthesia’s control of coagulation was rudimentary – more blood, platelets, FFP. No Amicar, etc. No TEG. Treatment for hemolysis – pack the wound, pour it all in, go take a brake.

17. The Operation • Skin-to-Skin time 1979-1981 • Best case 15 hours. • Bad case 25 hours. • Average case 20 hours • Patients kept in CRC unit – including two rooms with ventilators. • Length of stay – what are you talking about? (4-6 weeks.)

18. TES – time to go to bed during donor run 1980 GBK’14

19. Donor Runs…. • United flight Denver to Seattle; Sleeping on a gurney outside OR until time to do donor – timed to catch return United flight to Denver. Attendants were “uncomfortable” about the content of the cooler in the cabin. • Somewhere in Mississippi – patrol car broke speed record down main street. • Outside Corpus Christi – patrol car got air born when crossing railroad, dropping hub caps on landing.

20. Donor Runs…. • January, Pittsburgh to Chicago in Lear. Helicopter into NW. On return, door is frozen, can not be closed. Tied it shut with a rope. Returned to Pittsburgh at 1000 feet. • February, Pitt to NYC. Air control shut down the airspace over NYC to have us fly in and out.

22. GBK’14 Tolypocladium inflatum GAMS

23. GBK’14 Agents and Actions 1976;6:468

25. Steroid Use Prior to CyA 1 g Methylprednisolone Intra-op 200 mg/d Prednisolone Post-op Day #1 200 mg/d Prednisolone Post-op Day #2 190 mg /d Prednisolone Post-op Day #3 190 mg/d Prednisolone Post-op Day #4 180 mg/d Prednisolone Post-op Day #5 180 mg/d Prednisolone Post-op Day #6 170 mg/d Prednisolone Post-op Day #7 30-40 mg/d Prednisolone Post-op Day #30 20 mg/d Prednisolone Post-op Day #365 GBK’14

26. “The Elevator Conference”or “The Scientific Design of The Steroid Taper” on December 30, 1979 Participants: Thomas E. Starzl and Goran B. Klintmalm Location: VA Elevator – Floors 5th to 1st Background: All CyA treated patients experienced rejection within 6 days post-op Scientific Rationale: Steroids are good for you, especially if you have rejection. GBK’14

27. “The Elevator Conference (cont.)” Scientific deliberations: “Let’s give some steroids so we avoid rejection.” “Ok. How much?” “Let’s start at 200.” “But CyA patients probably don’t need much. We should get down to 20 within a week.” “Ok. If we start at 200, we could reduce by 30…” “If we do it by 40, we could give 200, 160, 120, 80, 40, and 20.” “Let’s do 200, 160, 120, 80, 40, 30 and 20 so they are covered for the first week.” Scientific Conclusion: “Ok. Sounds good.” “Let’s start with the next case.” GBK’14

28. GBK’14

29. New Engl J Med 305:266-269, 1981

30. Galileo Before the Inquisition, June 22, 1633, for “Dialogue” and the theory of Heliocentrism. Pope Urban VIII, Inquisitor VincinzoMaculani

31. TES throwing the first ball at Three River Stadium 1983 GBK’14

32. Transplantation Today Characterized by Regulatory Oversight

35. Second Generation Surgeon: • Privileged to have experienced the Golden Age of liver transplantation. • Future breakthrough will be done by Ph.D.’s.

36. Second Generation Surgeon: • Privileged to have experienced the Golden Age of liver transplantation. • Future breakthrough will be done by Ph.D.’s. • Great surgeons don’t die, they just fade away.

37. "I worked like a horse and I ate like a hog and I slept like a dead man.“ - Kipling

42. Starzl in his office, Denver 1979 GBK’13

44. New Engl J Med 305:266-269, 1981

45. The Final Rule CMS March 30, 2007

46. The Joint Commission

47. Blank player slide UNOS Living Donor July 2007

48. Proposed addition to our CMS regulations.  It was posted in the Federal Register on 12/27 and open for public comment until 2/25."§ 482.78 Condition of participation: Emergency preparedness for transplant centers. • A transplant center must have policies and procedures that address emergency preparedness. • Standard: Agreement with at least one Medicare approved transplant center. A transplant center or the hospital in which it operates must have an agreement with at least one other Medicare-approved transplant center to provide transplantation services and related care for its patients during an emergency. The agreement must address the following, at a minimum: • (1) Circumstances under which the agreement will be activated. • (2) Types of services that will be provided during an emergency. • (b) Standard: Agreement with the Organ Procurement Organization (OPO) designated by the Secretary. The transplant center must ensure that the written agreement required under § 482.100 addresses the duties and responsibilities of the hospital and the OPO during an emergency. • I was able to find the complete regulation at this link starting on page 102.  (I think there may be other ways to access it as well.) • http://www.ofr.gov/OFRUpload/OFRData/2013-30724_PI.pdf

49. Coagulation problem…. Addenbrook, Sir Roy Calne, late 60-ies – calling the blood bank, telling the physician in charge that there was a problem with coagulation. RC told non-believing blood banker to come and see for himself. Blood banker: “how do I find which room you are in?” RC: “just find the room where there is blood running out under the door”.