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SCIENTIFIC AND CLINICAL EVIDENCE
Evidence-based improvements in liver transplantation outcomes
A robust, clinical-trial and publication evidence base supports use of the ³Ô¹ÏºÚÁÏÍø metra®
To date, hundreds of donor livers have been studied in normothermic machine perfusion trials around the world, including 220 livers that formed the Consortium for Organ Preservation in Europe (COPE) randomised controlled trial published in Nature in April 2018.1 With clinical trials taking place across Europe and North America, the metra has an extensive evidence base.
Key trials and publications are summarised below.
Completed trials
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COPE European Trial
The COPE (Consortium for Organ Preservation in Europe) trial is now complete and results were published in Nature (Nasralla D, et al. Nature. 2018;558(7703):50–56).
This was the first randomised trial to assess machine perfusion versus static cold storage in liver transplantation and included 220 transplantations. Compared with static cold storage, the ³Ô¹ÏºÚÁÏÍø metra achieved a 50% lower level of graft injury despite a 50% lower rate of organ discard and a 54% longer mean preservation time.
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Birmingham VITTAL Study
The Viability Testing and Transplantation of Marginal Livers (VITTAL) study started in 2016 at the Queen Elizabeth Hospital, Birmingham, UK. It is led by Professor Darius Mirza and Mr Hynek Mergental and was designed to determine if a declined liver is viable using normothermic machine liver perfusion (NMLP). It aims to establish the suitability of livers which have been declined by all UK liver transplant centres by monitoring their function on the ³Ô¹ÏºÚÁÏÍø metra device; and transplant the liver if its function on the machine is satisfactory allowing it to be transplanted.
The clinical trial.gov identifier is
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Edmonton
Dr James Shapiro and colleagues from the University of Alberta, Edmonton, Canada, have recently completed a study of the use of ex vivo normothermic machine preservation prior to liver transplantation following static cold storage using the ³Ô¹ÏºÚÁÏÍø metra device. They were the first centre in North America to transplant a liver following normothermic preservation on the metra device (Bral M et al. Liver Transpl 2019; 25(6):848–858).
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Toronto
Dr Markus Selzner and colleagues from the University Hospital Toronto, Canada, have undertaken a study of ex vivo normothermic machine preservation using the ³Ô¹ÏºÚÁÏÍø metra device. The results of the pilot phase of this study have been published.
The clinical trial.gov identifier is
Ongoing trials
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A back-to-base experience of human normothermic ex situ liver perfusion: does the chill kill?
Bral M, Dajani K, Leon Izquierdo D et al. Liver Transpl. 2019;25:848–58.
A nonrandomised pilot study assessing whether the ³Ô¹ÏºÚÁÏÍø metra can be used with a back-to-base model without impacting patient outcomes.
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Liver transplantation with a normothermic machine preserved fatty nonagenarian liver: A case report
Manzia TM, Toti L, Quaranta C, et al. Int J Surg Rep. 2019;57:163–6.
This case report details how functional assessment of a nonagenarian liver with the ³Ô¹ÏºÚÁÏÍø metra resulted in successful transplantation.
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Liver transplantation from non-heart beating donors: Current status and future prospects.
Reddy S, Zivetti M, Brockmann J, McClaren A and Friend PJ – Liver Transplantation (2019) 10 1223-1232.
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Are We on Track to Increase Organ Utilization? An analysis of machine perfusion preservation for liver transplantation in the United States
Robinson, T., Vargas, P. A., Yemini, R., Goldaracena, N., & Pelletier, S. (2024). Are we on track to increase organ utilization? An analysis of machine perfusion preservation for liver transplantation in the United States. Artificial Organs.
UNOS database analysis showing that NMP was associated with less liver non-utilization, particularly ECD livers which had comparable outcomes to standard criteria livers if they underwent NMP.
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Impact of Back-to-Base Normothermic Machine Perfusion on Complications and Costs A Multi-Center, Real-World Risk-Matched Analysis
Wehrle, C. J., Zhang, M., Khalil, M., Pita, A., Modaresi Esfeh, J., Diago-Uso, T., Kim, J., Aucejo, F., Kwon, D. C. H., Ali, K., Cazzaniga, B., Miyazaki, Y., Liu, Q., Fares, S., Hong, H., Tuul, M., Jiao, C., Sun, K., Fairchild, R. L., Quintini, C., Fujiki, M., Pinna, A. D., Miller, C., Hashimoto, K., & Schlegel, A. (2024). Impact of back-to-base normothermic machine perfusion on complications and costs: A multicenter, real-world risk-matched analysis. Annals of Surgery, 280(2), 300-310.
US cost analysis of end-ischemic NMP using the metra compared to SCS livers based on results from 2 centers. While organ recovery costs were more with NMP, overall healthcare costs were similar due to the reduction in complications seen with the metra.
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Infection and Prophylaxis During Normothermic Liver Perfusion: Audit of Incidence and Pharmacokinetics of Antimicrobial Therapy
Qureshi, S., Elliott, H., Noel, A., Swift, L., Fear, C., Webster, R., Brown, N. M., Gaurav, R., Butler, A. J., & Watson, C. J. E. (2024). Infection and prophylaxis during normothermic liver perfusion: Audit of incidence and pharmacokinetics of antimicrobial therapy. Transplantation, 108(6), 1376-1382.
Review of 210 metra perfusions and the microorganisms cultured. Also demonstrates drug levels of meropenem and fluconazole in the perfusate of livers on the metra, with recommendations for antimicrobial prophylaxis.
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Bile Chemistry During Ex Situ Normothermic Liver Perfusion Does Not Always Predict Cholangiopathy
Watson, C. J. E., Gaurav, R., Swift, L., Fear, C., Allison, M. E. D., Upponi, S. S., Brais, R., & Butler, A. J. (2024). Bile chemistry during ex situ normothermic liver perfusion does not always predict cholangiopathy. Transplantation, 108(11), 2040-2047.
Review of bile chemistry of 200 perfused livers showing what is normal chemistry and comments on assessing bile duct viability by looking at bile chemistry.
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D-dimer Release From Livers During Ex Situ Normothermic Perfusion and After In Situ Normothermic Regional Perfusion: Evidence for Occult Fibrin Burden Associated With Adverse Transplant Outcomes and Cholangiopathy
Watson, C. J. E., MacDonald, S., Bridgeman, C., Brais, R., Upponi, S. S., Foukaneli, T., Swift, L., Fear, C., Selves, L., Kosmoliaptsis, V., Allison, M., Hogg, R., Saeb Parsy, K., Thomas, W., Gaurav, R., & Butler, A. J. (2023). D-dimer release from livers during ex situ normothermic perfusion and after in situ normothermic regional perfusion: Evidence for occult fibrin burden associated with adverse transplant outcomes and cholangiopathy. Transplantation, 107(11), 2019-2029.
Demonstration of the presence of d-dimers in the perfusate of DBD and DCD livers undergoing perfusion. High levels were associated with graft failure and cholangiopathy. (D-dimers are breakdown products of fibrin). Supports theory that intravascular fibrin is the cause of post transplant cholangiopathy.
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Normothermic machine perfusion of donor livers for transplantation in the United States – a randomized controlled trial
Chapman, W. C., Barbas, A. S., D'Alessandro, A. M., Vianna, R., Kubal, C. A., Abt, P., Sonnenday, C., Barth, R., Alvarez-Casas, J., Yersiz, H., Eckhoff, D., Cannon, R., Genyk, Y., Sher, L., Singer, A., Feng, S., Roll, G., Cohen, A., Doyle, M. B., Sudan, D. L., Al-Adra, D., Khan, A., Subramanian, V., Abraham, N., Olthoff, K., Tekin, A., Berg, L., Coussios, C., Morris, C., Randle, L., Friend, P., & Knechtle, S. J. (2023). Normothermic machine perfusion of donor livers for transplantation in the United States: A randomized controlled trial. Annals of Surgery, 278(5), e912-e921.
Report of the US multicentrer study of NMP comparing 191 livers preserved with SCS and 192 undergoing NMP; 136 NMP and 130 SCS livers were transplanted. NMP livers had less early allograft dysfunction (non-significant) overall, much more apparent in DCD livers where the incidence was highest in SCS livers, andsignificnatly less post reperfusion syndrome than SCS livers.
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Mitochondrial respiration during normothermic liver machine perfusion predicts clinical outcome
Meszaros, A. T., Hofmann, J., Buch, M. L., Cardini, B., Dunzendorfer-Matt, T., Nardin, F., Blumer, M. J., Fodor, M., Hermann, M., Zelger, B., Otarashvili, G., Schartner, M., Weissenbacher, A., Oberhuber, R., Resch, T., Troppmair, J., Öfner, D., Zoller, H., Tilg, H., Gnaiger, E., Hautz, T., & Schneeberger, S. (2022). Mitochondrial respiration during normothermic liver machine perfusion predicts clinical outcome. EBioMedicine, 85, 104311.
Study of 50 livers undergoing NMP on the metra examining integrity of mitchondrial function by serial biopsies and showing a wide variability in mitchondrial respiration at the end of cold storage, but stable levels of function during NMP. The preservation of mitchondrial respiration predicted outcome post transplant.
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Predicting Early Allograft Function After Normothermic Machine Perfusion
Watson, C. J. E., Gaurav, R., Fear, C., Swift, L., Selves, L., Ceresa, C. D. L., Upponi, S. S., Brais, R., Allison, M., Macdonald-Wallis, C., Taylor, R., & Butler, A. J. (2022). Predicting early allograft function after normothermic machine perfusion. Transplantation, 106(12), 2391-2398.
Multivariate analysis of 154 metra perfused livers looking at perfusate chemistry which predicts better early allograft function as measured by the Model for Early Allograft Function (MEAF) score. ALT and lactate measured at 2 hours were the biggest predictors, followed by the need for bicarbonate to maintain pH.
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The Actual Operative Costs of Liver Transplantation and Normothermic Machine Perfusion in a Canadian Setting
Webb, A. N., Izquierdo, D. L., Eurich, D. T., Shapiro, A. M. J., & Bigam, D. L. (2021). The actual operative costs of liver transplantation and normothermic machine perfusion in a Canadian setting. Pharmacoeconomics Open, 5(2), 311-318.
Canadian study detemrmining the actual cost of recovering recovering livers in and out of province as a prelude to a cost effectiveness study of NMP.
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Transplantation of discarded livers following viability testing with normothermic machine perfusion
Mergental, H., Laing, R. W., Kirkham, A. J., Perera, M. T. P. R., Boteon, Y. L., Attard, J., Barton, D., Curbishley, S., Wilkhu, M., Neil, D. A. H., Hübscher, S. G., Muiesan, P., Isaac, J. R., Roberts, K. J., Abradelo, M., Schlegel, A., Ferguson, J., Cilliers, H., Bion, J., Adams, D. H., Morris, C., Friend, P. J., Yap, C., Afford, S. C., & Mirza, D. F. (2020). Transplantation of discarded livers following viability testing with normothermic machine perfusion. Nature Communications, 11, 2939.
UK study of 22 livers declined by all UK centres that were assessed on the metra and transplanted, with 100% 90 day graft survival. Results were similar to a contemporay cohort of standard livers, although later follow up reported biliary complications in DCD livers reflecting study protocol not assessing bile for bile duct viability.
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Clinical Implementation of Prolonged Liver Preservation and Monitoring Through Normothermic Machine Perfusion in Liver Transplantation
Cardini, B., Oberhuber, R., Fodor, M., Hautz, T., Margreiter, C., Resch, T., Scheidl, S., Maglione, M., Bösmüller, C., Mair, H., Frank, M., Augustin, F., Griesmacher, A., Schennach, H., Martini, J., Breitkopf, R., Eschertzhuber, S., Pajk, W., Obwegeser, A., Tilg, H., Watson, C., Öfner, D., Weissenbacher, A., & Schneeberger, S. (2020). Clinical implementation of prolonged liver preservation and monitoring through normothermic machine perfusion in liver transplantation. Transplantation, 104(9), 1917-1928.
Single centre report of early NMP experience where 34 livers underwent NMP, with 25 successfully transplanted. Graft and pateint survival 88% at 20 months. Preservation times up to 38h reported, and daytime surgery became routine.
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A randomized trial of normothermic preservation in liver transplantation
Nasralla D, Coussios CC, Mergental H, et al. Consortium for Organ Preservation in Europe. Nature. 2018;557(7703):50–56.
The first randomised controlled trial comparing machine perfusion technology with static cold storage in human liver transplantation. In this trial, the ³Ô¹ÏºÚÁÏÍø metra was transported to and from the donor centre to minimise cold storage time.
Compared with static cold storage, the ³Ô¹ÏºÚÁÏÍø metra achieved a 50% lower level of graft injury despite a 50% lower rate of organ discard and a 54% longer mean preservation time.
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References:
UK/US MD-040-13-1 - September 2022