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Ex Vivo Normothermic Machine Perfusion

  • Daniele Pezzati
  • Qiang Liu
  • Cristiano QuintiniEmail author
Chapter
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Abstract

Normothermic machine perfusion (NMP) involves perfusing organs ex vivo with normothermic oxygenated blood–based solutions that recreate the physiological environment, thereby tending to decrease the detrimental effects seen with standard cold storage (SCS). Several different NMP platforms exist that are in various stages of development. NMP has the potential to restore normal metabolic physiology, recondition marginal livers, and allow for the assessment of graft viability. The use of NMP for donation after circulatory death (DCD) liver grafts has been of particular interest, given the additional period of damaging warm ischemia these grafts are exposed to compared to donation after brain death (DBD) liver grafts. The present chapter describes the rationale for NMP, as well as providing a summary of pre-clinical and clinical studies that have investigated its application. The various platforms for NMP that have been utilized are also described.

Keywords

NMP normothermic machine preservation Machine perfusion DCD organ preservation Ex-vivo machine perfusion 

References

  1. 1.
    Todo S, Nery J, Yanaga K, Podesta L, Gordon RD, Starzl TE. Extended preservation of human liver grafts with UW solution. JAMA. 1989;261(5):711–4.CrossRefGoogle Scholar
  2. 2.
    Jaeschke H. Mechanism of reperfusion injury after warm ischemia of the liver. J Hepatobiliary Pancreas Surg. 1998;5:402–8.CrossRefGoogle Scholar
  3. 3.
    Fondevila C, Busuttil RW, Kupiec-Weglinski JW. Hepatic ischemia/reperfusion injury: a fresh look. Exp Mol Pathol. 2003;74:86–93.CrossRefGoogle Scholar
  4. 4.
    Ceresa CDL, Nasralla D, Jassem J. Normothermic machine preservation of the liver: state of the art. Curr Transplant Rep. 2018;5:104–10.  https://doi.org/10.1007/s40472-018-0186-9.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Ceresa C, Nasralla D, Coussios CC, Friend PJ. The case for normothermic machine perfusion in liver transplantation. Liver Transpl. 2018;24(2):269–75.  https://doi.org/10.1002/lt.25000.CrossRefPubMedGoogle Scholar
  6. 6.
    Penn I, Halgrimson CG, Starzl TE. Liver transplantation in man. Ann N Y Acad Sci. 1970;170:251–8.  https://doi.org/10.1111/j.1749-6632.1970.tb37018.x.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Clavien PA, Harvey PR, Strasberg SM. Preservation and reperfusion injuries in liver allografts. An overview and synthesis of current studies. Transplantation. 1992;53(5):957–78.CrossRefGoogle Scholar
  8. 8.
    Carini R, Autelli R, Bellomo G, Albano E. Alterations of cell volume regulation in the development of hepatocyte necrosis. Exp Cell Res. 1999;248(1):280–93.CrossRefGoogle Scholar
  9. 9.
    Gilbo N, Catalano G, Salizzoni M, Romagnoli R. Liver graft preconditioning, preservation and reconditioning. Dig Liver Dis. 2016;48:1265–74.  https://doi.org/10.1016/j.dld.2016.06.031.CrossRefPubMedGoogle Scholar
  10. 10.
    Ghinolfi D, Rreka E, Pezzati D, Filipponi F, De Simone P. Perfusion machines and hepatocellular carcinoma: a good match between a marginal organ and an advanced disease? Transl Gastroenterol Hepatol. 2017;2:87.  https://doi.org/10.21037/tgh.2017.10.01.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Xu H, Berendsen T, Kim K, Soto-Gutiérrez A, Bertheium F, Yarmush ML, et al. Excorporeal normothermic machine perfusion resuscitates pig DCD livers with extended warm ischemia. J Surg Res. 2012;173(2):e83–8.  https://doi.org/10.1016/j.jss.2011.09.057.CrossRefPubMedGoogle Scholar
  12. 12.
    Xystrakis E, Lozano J, Danger R, Martinez-Llordella M, Srinivasan P, Heaton N, et al. Normothemic machine perfusion of liver grafts promotes liver regeneration and inhibits tissue inflammation [abstract]. Am J Transplant. 2015;15 (suppl 3). https://atcmeetingabstracts.com/abstract/normothemic-machine-perfusion-of-liver-grafts-promotes-liver-regeneration-and-inhibits-tissue-inflammation/. Accessed April 27, 2020.
  13. 13.
    Liu Q, Nassar A, Farias K, Buccini L, Baldwin W, Mangino M, et al. Sanguineous normothermic machine perfusion improves hemodynamics and biliary epithelial regeneration in donation after cardiac death porcine livers. Liver Transpl. 2014;20(8):987–99.  https://doi.org/10.1002/lt.23906.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Schön MR, Kollmar O, Wolf S, Schrem H, Matthes M, Akkoc N, Schnoy NC, Neuhaus P. Liver transplantation after organ preservation with normothermic extracorporeal perfusion. Ann Surg. 2001;233(1):114–23. PMID: 11141233.CrossRefGoogle Scholar
  15. 15.
    Foley DP, Ricciardi R, Traylor AN, McLaughlin TJ, Donohue SE, Wheeler SM, Meyers WC, Quarfordt SH. Effect of hepatic artery flow on bile secretory function after cold ischemia. Am J Transplant. 2003;3(2):148–55. PMID:12603210.CrossRefGoogle Scholar
  16. 16.
    Brockmann J, Reddy S, Coussios C, Pigott D, Guirriero D, Hughes D, Morovat A, Roy D, Winter L, Friend PJ. Normothermic perfusion: a new paradigm for organ preservation. Ann Surg. 2009;250(1):1–6.  https://doi.org/10.1097/SLA.0b013e3181a63c10. PMID: 19561463.CrossRefGoogle Scholar
  17. 17.
    Fondevila C, Hessheimer AJ, Maathuis MH, Muñoz J, Taurá P, Calatayud D, Leuvenink H, Rimola A, Ploeg RJ, García-Valdecasas JC. Superior preservation of DCD livers with continuous normothermic perfusion. Ann Surg. 2011;254(6):1000–7.  https://doi.org/10.1097/SLA.0b013e31822b8b2f. PMID: 21862925.CrossRefPubMedGoogle Scholar
  18. 18.
    Boehnert MU, Yeung JC, Bazerbachi F, Knaak JM, Selzner N, McGilvray ID, Rotstein OD, Adeyi OA, Kandel SM, Rogalla P, Yip PM, Levy GA, Keshavjee S, Grant DR, Selzner M. Normothermic acellular ex vivo liver perfusion reduces liver and bile duct injury of pig livers retrieved after cardiac death. Am J Transplant. 2013;13(6):1441–9.  https://doi.org/10.1111/ajt.12224. PMID:23668775.CrossRefPubMedGoogle Scholar
  19. 19.
    St Peter SD, Imber CJ, Lopez I, Hughes D, Friend PJ. Extended preservation of non-heart-beating donor livers with normothermic machine perfusion. Br J Surg. 2002;89(5):609–16. PMID:11972552.CrossRefGoogle Scholar
  20. 20.
    Reddy SP, Bhattacharjya S, Maniakin N, Greenwood J, Guerreiro D, Hughes D, Imber CJ, Pigott DW, Fuggle S, Taylor R, Friend PJ. Preservation of porcine non-heart-beating donor livers by sequential cold storage and warm perfusion. Transplantation. 2004;77(9):1328–32. PMID:15167586.CrossRefGoogle Scholar
  21. 21.
    Liu Q, Nassar A, Farias K, Buccini L, Mangino MJ, Baldwin W, Bennett A, O'Rourke C, Iuppa G, Soliman BG, Urcuyo-Llanes D, Okamoto T, Uso TD, Fung J, Abu-Elmagd K, Miller C, Quintini C. Comparing normothermic machine perfusion preservation with different perfusates on porcine livers from donors after circulatory death. Am J Transplant. 2016;16(3):794–807.  https://doi.org/10.1111/ajt.13546. Epub 2015 Dec 10. PMID:26663737.CrossRefPubMedGoogle Scholar
  22. 22.
    Ravikumar R, Jassem W, Mergental H, Heaton N, Mirza D, Perera MT, Quaglia A, Holroyd D, Vogel T, Coussios CC, Friend PJ. Liver transplantation after ex vivo normothermic machine preservation: a phase 1 (first-in-man) clinical trial. Am J Transplant. 2016;16(6):1779–87.  https://doi.org/10.1111/ajt.13708. Epub 2016 Mar 7. PMID:26752191.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Angelico R, Perera MT, Ravikumar R, Holroyd D, Coussios C, Mergental H, Isaac JR, Iqbal A, Cilliers H, Muiesan P, Friend PJ, Mirza DF. Normothermic machine perfusion of deceased donor liver grafts is associated with improved postreperfusion hemodynamics. Transplant Direct. 2016;2(9):e97. eCollection 2016 Sep. PMID:27795989.CrossRefGoogle Scholar
  24. 24.
    Mergental H, Perera MT, Laing RW, Muiesan P, Isaac JR, Smith A, Stephenson BT, Cilliers H, Neil DA, Hübscher SG, Afford SC, Mirza DF. Transplantation of declined liver allografts following normothermic ex-situ evaluation. Am J Transplant. 2016;16(11):3235–45.  https://doi.org/10.1111/ajt.13875. Epub 2016 Jul 13. PMID:27192971.
  25. 25.
    Watson CJE, Kosmoliaptsis V, Randle LV, Gimson AE, Brais R, Klinck JR, Hamed M, Tsyben A, Butler AJ. Normothermic perfusion in the assessment and preservation of declined livers before transplantation: hyperoxia and vasoplegia-important lessons from the first 12 cases. Transplantation. 2017;101(5):1084–98.  https://doi.org/10.1097/TP.0000000000001661. PMID:28437389.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Watson CJE, Kosmoliaptsis V, Pley C, Randle L, Fear C, Crick K, Gimson AE, Allison M, Upponi S, Brais R, Jochmans I, Butler AJ. Observations on the ex situ perfusion of livers for transplantation. Am J Transplant. 2018;18(8):2005–20.  https://doi.org/10.1111/ajt.14687. Epub 2018 Mar 14. PMID:29419931.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Selzner M, Goldaracena N, Echeverri J, Kaths JM, Linares I, Selzner N, Serrick C, Marquez M, Sapisochin G, Renner EL, Bhat M, ID MG, Lilly L, Greig PD, Tsien C, Cattral MS, Ghanekar A, Grant DR. Normothermic ex vivo liver perfusion using steen solution as perfusate for human liver transplantation: first North American results. Liver Transpl. 2016;22(11):1501–8.  https://doi.org/10.1002/lt.24499. PMID:27339754.CrossRefPubMedGoogle Scholar
  28. 28.
    Bral M, Gala-Lopez B, Bigam D, Kneteman N, Malcolm A, Livingstone S, Andres A, Emamaullee J, Russell L, Coussios C, West LJ, Friend PJ, Shapiro AM. Preliminary single-center Canadian experience of human normothermic ex vivo liver perfusion: results of a clinical trial. Am J Transplant. 2017;17(4):1071–80.  https://doi.org/10.1111/ajt.14049. Epub 2016 Dec 9. PMID:27639262.CrossRefPubMedGoogle Scholar
  29. 29.
    Bral M, Dajani K, Leon Izquierdo D, Bigam D, Kneteman N, Ceresa CDL, Friend PJ, Shapiro AMJ. A back-to-base experience of human normothermic ex situ liver perfusion: does the chill kill? Liver Transpl. 2019;25(6):848–58.  https://doi.org/10.1002/lt.25464. PMID:30938039.CrossRefPubMedGoogle Scholar
  30. 30.
    Ceresa CDL, Nasralla D, Watson CJE, Butler AJ, Coussios CC, Crick K, Hodson L, Imber C, Jassem W, Knight SR, Mergental H, Ploeg RJ, Pollok JM, Quaglia A, Shapiro AMJ, Weissenbacher A, Friend PJ. Transient cold storage prior to normothermic liver perfusion may facilitate adoption of a novel technology. Liver Transpl. 2019;  https://doi.org/10.1002/lt.25584. PMID:31206217.
  31. 31.
    Nasralla D, Coussios CC, Mergental H, Akhtar MZ, Butler AJ, Ceresa CDL, Chiocchia V, Dutton SJ, García-Valdecasas JC, Heaton N, Imber C, Jassem W, Jochmans I, Karani J, Knight SR, Kocabayoglu P, Malagò M, Mirza D, Morris PJ, Pallan A, Paul A, Pavel M, Perera MTPR, Pirenne J, Ravikumar R, Russell L, Upponi S, Watson CJE, Weissenbacher A, Ploeg RJ, Friend PJ, Consortium for Organ Preservation in Europe. A randomized trial of normothermic preservation in liver transplantation. Nature. 2018;557(7703):50–6.  https://doi.org/10.1038/s41586-018-0047-9. Epub 2018 Apr 18. PMID:29670285.CrossRefGoogle Scholar
  32. 32.
    Ghinolfi D, Rreka E, De Tata V, Franzini M, Pezzati D, Fierabracci V, Masini M, Cacciatoinsilla A, Bindi ML, Marselli L, Mazzotti V, Morganti R, Marchetti P, Biancofiore G, Campani D, Paolicchi A, De Simone P. Pilot, open, randomized, prospective trial for normothermic machine perfusion evaluation in liver transplantation from older donors. Liver Transpl. 2019;25(3):436–49.  https://doi.org/10.1002/lt.25362. PMID:30362649.CrossRefPubMedGoogle Scholar
  33. 33.
    van Leeuwen OB, de Vries Y, Fujiyoshi M, Nijsten MWN, Ubbink R, Pelgrim GJ, Werner MJM, Reyntjens KMEM, van den Berg AP, de Boer MT, de Kleine RHJ, Lisman T, de Meijer VE, Porte RJ. Transplantation of high-risk donor livers after ex situ resuscitation and assessment using combined hypo- and normothermic machine perfusion: a prospective clinical trial. Ann Surg. 2019;  https://doi.org/10.1097/SLA.0000000000003540. PMID:31415002.
  34. 34.
    Feng S, Goodrich NP, Bragg-Gresham JL, Dykstra DM, Punch JD, DebRoy MA, Greenstein SM, Merion RM. Characteristics associated with liver graft failure: the concept of a donor risk index. Am J Transplant. 2006;6(4):783–90.CrossRefGoogle Scholar
  35. 35.
    Braat AE, Blok JJ, Putter H, Adam R, Burroughs AK, Rahmel AO, Porte RJ, Rogiers X, Ringers J. The eurotransplant donor risk index in liver transplantation: ET-DRI. European Liver and Intestine Transplant Association (ELITA) and eurotransplant liver intestine advisory committee (ELIAC). Am J Transplant. 2012;12(10):2789–96.  https://doi.org/10.1111/j.1600-6143.2012.04195.x.CrossRefPubMedGoogle Scholar
  36. 36.
    Collett D, Friend PJ, Watson CJ. Factors associated with short- and long-term liver graft survival in the United Kingdom: development of a UK donor liver index. Transplantation. 2017;101(4):786–92.  https://doi.org/10.1097/TP.0000000000001576.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Watson CJE, Jochmans I. From "gut feeling" to objectivity: machine preservation of the liver as a tool to assess organ viability. Curr Transplant Rep. 2018;5(1):72–81.  https://doi.org/10.1007/s40472-018-0178-9.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Dodero F, Benkoel L, Allasia C, Hardwigsen J, Campan P, Botta-Fridlund D, LE Treut YP, Chamlian A. Quantitative analysis of glycogen content in hepatocytes of human liver allograft after ischemia and reperfusion. Cell Mol Biol (Noisy-le-Grand). 2000;46(7):1157–61. PMID:11075945.Google Scholar
  39. 39.
    Cherid A, Cherid N, Chamlian V, Hardwigsen J, Nouhou H, Dodero F, Benkoel L, Le Treut YP, Chamlian A. Evaluation of glycogen loss in human liver transplants. Histochemical zonation of glycogen loss in cold ischemia and reperfusion. Cell Mol Biol (Noisy-le-Grand). 2003;49(4):509–14. PMID:12899441.Google Scholar
  40. 40.
    Sutton ME, op den Dries S, Karimian N, Weeder PD, de Boer MT, Wiersema-Buist J, Gouw AS, Leuvenink HG, Lisman T, Porte RJ. Criteria for viability assessment of discarded human donor livers during ex vivo normothermic machine perfusion. PLoS One. 2014;9(11):e110642.  https://doi.org/10.1371/journal.pone.0110642. eCollection 2014. PMID:25369327.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    WHO – The top 10 causes of death – Fact sheet. Updated January 2017. http://www.who.int/mediacentre/factsheets/fs310/en/.
  42. 42.
    Saidi RF. Utilization of expanded criteria donors in liver transplantation. Int J Organ Transplant Med. 2013;4:46–59.PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2020

Authors and Affiliations

  • Daniele Pezzati
    • 1
  • Qiang Liu
    • 2
  • Cristiano Quintini
    • 1
    Email author
  1. 1.Department of General SurgeryCleveland ClinicClevelandUSA
  2. 2.Cleveland Clinic Liver Transplant Center, Department of General SurgeryClevelandUSA

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