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A randomized trial of normothermic preservation in liver transplantation


Liver transplantation is a highly successful treatment, but is severely limited by the shortage in donor organs. However, many potential donor organs cannot be used; this is because sub-optimal livers do not tolerate conventional cold storage and there is no reliable way to assess organ viability preoperatively. Normothermic machine perfusion maintains the liver in a physiological state, avoids cooling and allows recovery and functional testing. Here we show that, in a randomized trial with 220 liver transplantations, compared to conventional static cold storage, normothermic preservation is associated with a 50% lower level of graft injury, measured by hepatocellular enzyme release, despite a 50% lower rate of organ discard and a 54% longer mean preservation time. There was no significant difference in bile duct complications, graft survival or survival of the patient. If translated to clinical practice, these results would have a major impact on liver transplant outcomes and waiting list mortality.

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Change history

  • 23 April 2018

    The Source Data files originally published with this article were missing for Extended Data Figures 3 and 4. This has now been corrected.


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This study was performed by the Consortium for Organ Preservation in Europe (COPE). We thank the European Commission for their support through the Seventh Framework Programme. The following organisations, groups and individuals also made substantial contributions without which this trial could not have been completed successfully: NHS Blood and Transplant; the Surgical Intervention Trials Unit, University of Oxford; the Clinical Trials and Research Governance unit, University of Oxford; Centre for Evidence in Transplantation, Royal College of Surgeons of England; the Liver Transplant Coordinators, anaesthetists and liver unit physicians at the Queen Elizabeth Hospital, Birmingham, Addenbrooke’s Hospital, Cambridge, King’s College Hospital, London, the Royal Free Hospital London, Hospital Clinic, Barcelona, University Hospitals, Leuven, University Hospital, Essen; M. Soo, S. Morrish, C. Morris, L. Randle, R. Macedo Arantes, R. Morovat, A. Elsharkawy, G. Hirschfield, P. Muiesan, J. Isaac, J. Grayer, B. Buchholz, H. Vilca-Melendez, A. Zamalloa, D. Chasiotis, S. Khorsandi, B. Davidson, D. Sharma, A. Esson, D. Monbaliu, S. Mertens, S. Swoboda, J. Neuhaus, T. Benkö, V. Molina, R. Kumar, A. Bradley, M. Laspeyres, B. Patel, A. Mukwamba, S. Banks, the COPE Transplant Technicians, the Specialist Nurses in Organ Donation and, of course, all of the donors and their families. This study was funded by a European Commission Seventh Framework Programme (FP7) Grant (No 305934).

Reviewer information

Nature thanks S. Schneeberger, S. G. Tullius and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Author information

D.N., S.R.K., R.J.P., C.C.C. and P.J.F. designed this study with help from other authors. R.J.P is Coordinator of the COPE Consortium. M.Z.A. and R.J.P. oversaw the collection of samples and establishment of the trial biobank. D.N., C.D.L.C., A.W., H.M., M.T.P.R.P., D.M., W.J., N.H., C.I., M.M., R.R., A.J.B., C.J.E.W., I.J., J.P., P.K., A.Pau., M.P. and J.C.G.-V. were responsible for the clinical conduct of the study at the respective trial sites. D.N., S.R.K., V.C. and S.J.D. were responsible for statistical design and analysis. L.R. and C.C.C. provided device support and expertise to all trial sites. D.N., S.U., A.Pal. and J.K. were responsible for MRCP image analysis. P.M., S.R.K. and S.J.D. provided governance oversight to ensure the study adhered to all regulatory and ethical requirements. All authors reviewed the manuscript.

Competing interests

P.J.F. is a co-founder, chief medical officer and consultant to OrganOx Limited and also holds shares in the company. C.C.C. is a co-founder, chief technical officer and consultant to OrganOx Limited and also holds shares in the company. Neither P.J.F. nor C.C.C. were involved in the selection, recruitment or transplantation of patients in this study.

Correspondence to David Nasralla or Constantin C. Coussios or Peter J. Friend.

Extended data figures and tables

  1. Extended Data Fig. 1 Forest plot for subgroup analysis of peak AST by donor type.

    Geometric mean ratio and 95% confidence interval are reported for each subgroup and overall for all groups. DBD group, n = 87 NMP, n = 80 SCS; DCD group, n = 33 NMP, n = 20 SCS.

  2. Extended Data Fig. 2 Post-reperfusion syndrome.

    a, Kaplan–Meier plot for one-year survival of patients with two-sided log-rank test. b, Kaplan–Meier plot for one-year graft survival with two-sided log-rank test.

  3. Extended Data Fig. 3 Machine perfusion parameters during NMP.

    a, Hepatic artery flow during NMP. b, Portal vein flow during NMP. c, Perfusate pH during NMP. d, Bile production during NMP. ad, Data are mean ± s.d. of each time point. Actual values are shown in the table. n = 87. Source data

  4. Extended Data Fig. 4 Perfusate lactate levels during NMP.

    Scatter graph with trend line showing perfusate lactate levels at different time points during NMP for all transplanted livers. n = 94. Source data

  5. Extended Data Fig. 5 NMP device and circuit.

    a, OrganOx metra (generation 1). The NMP device used in the trial. b, OrganOx metra NMP circuit. The liver is perfused via the hepatic artery and portal vein. It drains via the inferior vena cava to a centrifugal pump through which the perfusate passes, via a heat exchanger/oxygenator, to a reservoir or directly into the hepatic artery. The perfusate in the reservoir drains under gravity into the portal vein.

  6. Extended Data Table 1 Detailed breakdown of reasons for discard of NMP livers
  7. Extended Data Table 2 Post-reperfusion syndrome analysis
  8. Extended Data Table 3 Extended primary outcome analysis
  9. Extended Data Table 4 Characteristics and perfusate analysis of livers included in NMP liver quality model development
  10. Extended Data Table 5 Adverse events analysis
  11. Extended Data Table 6 Detailed breakdown of adverse events in each trial arm

Supplementary information

  1. Supplementary Information

    Clinical Trail Protocol. The full trial protocol for a multicentre randomised controlled trial to compare the efficacy of ex-vivo normothermic machine perfusion with static cold storage in human liver transplantation.

  2. Reporting Summary

  3. Supplementary Information

    Statistical Analysis Plan. A comprehensive description of the statistical methodology applied to the trial data.

  4. Supplementary Information

    Final Statistical Report. The full report from trial statisticians reporting trial outcomes available at 1 year following completion of recruitment.

  5. Supplementary Information

    Primary Non-Function Serious Adverse Event. Clinical trial source document submitted to the trial Data Monitoring Committee providing a narrative description of the events surrounding the transplantation of a normothermic machine perfused liver which resulted in primary non-function of the organ.

  6. Supplementary Information

    Device Error Serious Adverse Event. Clinical trial source document submitted to the trial Data Monitoring Committee providing a narrative description of the events surrounding the normothermic machine perfusion of a liver in which a device error led to the organ being discarded.

Source data

  1. Source data for Extended data figures 3a-e

  2. Source data for Extended data figure 4b

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Further reading

Fig. 1: Image of liver during normothermic machine perfusion.
Fig. 2: CONSORT diagram.
Extended Data Fig. 1: Forest plot for subgroup analysis of peak AST by donor type.
Extended Data Fig. 2: Post-reperfusion syndrome.
Extended Data Fig. 3: Machine perfusion parameters during NMP.
Extended Data Fig. 4: Perfusate lactate levels during NMP.
Extended Data Fig. 5: NMP device and circuit.


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