Liver transplantation represents an effective treatment for patients with end-stage liver disease. However, patient access to this lifesaving procedure continues to be limited by the lack of organs resulting into high mortality rates while awaiting transplantation.1 Attempts to expand the donor pool during the last decade using marginal organs and partial grafts have reached a plateau. At the same time, organ discard rates (organs procured but never transplanted) continue to remain mainly related to the poor quality of donor organs.1 In 2014, more than 25% of all livers procured in the United States were discarded after procurement owing to concerns of primary graft nonfunction.1 Clearly, many of those organs represent missed opportunities as (i) most of these livers were working perfectly well in the donor before procurement, and (ii) the decision to discard these organs was most likely based on the surgeon’s “gut feeling,” as objective and scientific criteria to accept (or discard) a liver are largely lacking.
The work from Nasralla and colleagues2 recently published in “Nature” is a clear “game changer” in addressing those key issues. In one of the most elegant and calculated evolutions from bench-to-bed-side research, the University of Oxford group designed a randomized, controlled study to test the potential of normothermic machine preservation (NMP). This technology is based on the rationale that the deleterious effects of cold injury and ischemia sustained by the graft during static cold storage (SCS) can be ameliorated by perfusing organs at physiologic temperatures with a preservation solution able to deliver oxygen, nutrients, and, potentially, medications. Extensive preclinical work3-5 has demonstrated that NMP is superior to SCS in preserving and potentially resuscitating severely injured grafts. Most importantly, research shows6,7 that this preservation modality holds the potential to assess organ quality guiding clinicians during the difficult decision of organ acceptance.
Over a period of almost 2 years, 334 livers offered for transplantation to 8 European Centers were randomized to either conventional SCS preservation or NMP.2 Sixty-four livers were subsequently excluded from the study (with organs from donation after cardiac deaths [DCDs] donors not progressing to circulatory arrest during the allotted time interval, recipient consent not obtained or donors not eligible to the study protocol). In the SCS arm, organs were stored and transplanted according to standard practice. Livers in the NMP arm were connected to the NMP machine (OrganOx Metra; OrganOx Limited, Oxford, England, UK) after retrieval and perfused through the hepatic artery and portal vein with a blood-based oxygenated perfusion solution until surgery.2
The primary endpoint of the study was the difference in peak serum aspartate transaminase (AST) during the first week after transplant.2 Median peak AST in the NMP group was reduced by 49.4% when compared with the SCS group (488.1 vs 964.9; interquartile range, 408.9-582.8 vs 794.5-1172.0 IU/L) despite NMP livers having had longer functional warm ischemia times (DCDs), longer overall preservation times, and fewer organ discards. The greatest benefit in reduction in AST levels was observed in the DCD group (73.3% reduction compared with 40.2% of donation after brain death [DBD] livers. Notably, the primary outcome data for NMP DCD livers were superior to those of both DCD and DBD livers preserved under SCS conditions.2
In addition, the authors collected a number of very relevant secondary outcomes.2 Early allograft dysfunction, defined as any one of the following clinical indicators: bilirubin >170 μmol/L on day 7 after transplant; international normalized ratio (INR) > 1.6 by day 7, and peak-AST > 2000 IU/L. The odds of NMP livers developing early allograft dysfunction were 74% lower compared with the SCS arm (10.1% versus 29.9%). Although the trial has not been designed to demonstrate that NMP can prolong preservation time, median total preservation time was longer for NMP compared with SCS livers (11:54 hrs vs. 7:45 hrs; P < 0.001).2 This difference was likely based on an increasing operator confidence during the trial. Post reperfusion syndrome8 was more likely to occur in SCS livers (33.0% vs 12.4% in NMP grafts). The rate of anastomotic (NMP 8.6%; SCS 10.8%) and nonanastomotic (NMP 43.2%; SCS 45.9%) biliary strictures was comparable in both arms, with 1 patient in each group developing severe ischemic cholangiopathy. There were no differences in the length of time recovering in the ICU or of the overall hospital length of stay. One-year patient and graft survival were comparable between arms (patient survival: NMP 94.9% vs 95.8% in SCS; graft survival: NMP 95% vs 96% in SCS).
In one of the most elegant and calculated evolutions from bench-to-bed-side research, the University of Oxford group designed a randomized, controlled study to test the potential of normothermic machine preservation.
Viability assessment during preservation was a major focus of this trial. Because of the low graft failure rate, no marker (either alone or as a composite measure) was identified as an absolute predictor of viability. Interestingly, 18 successfully transplanted livers produced little to no bile during perfusion. One liver presented with a highly increased lactate (>4 for the duration of NMP) and low pH; this graft went on to develop primary nonfunction. Baseline enzyme levels in the perfusate (soon after connecting the organ to the device) predicted the enzyme release in the posttransplant phase. However, the most striking secondary outcomes of all was the difference in organ discard rates with 24.1% for the SCS group compared to 11.7% for the NMP group (P = 0.008) resulting in 20% (!) more transplants performed in the NMP arm (121 vs. 101).2
If confirmed by future studies, this study would represent a monumental milestone in our field. In addition to the benefits of NMP on organ quality less obvious aspects may have contributed to the success. Research in the field of decision-making behavior9 shows that decisions made under stressful conditions, such as the one encountered during acceptance of a marginal organ, have a tendency to be less rational. Moreover, decisions made under time pressure have a tendency to prefer lower risk choices while spending more time debating the negative consequences. As a result, risk-adverse people tend to make more conservative choices and risk takers tend to make riskier decisions, with neither approach representing an ideal scenario. Providing the accepting surgeon more time and data on organ quality (though the design of the study did not allow the surgeon to discard an organ based on viability assessment), NMP may have also improved the decision making process. After all, improving pH, lactate levels, and bile productions represent very powerful indicators of organ quality reassuring transplant caregivers.
In conclusion, this well-designed and conducted randomized, controlled study represents a major achievement in the field of liver transplantation. Normothermic machine preservation appears to be a powerful preservation technology and a promising organ assessment platform that has the potential to increase organ utilization dramatically. Future studies will need to confirm these findings, expand them to other organs, refine perfusion protocols, and test the potential of NMP in reconditioning severely injured grafts.
1. Fayek SA, Quintini C, Chavin KD, et al. The current state of liver transplantation in the United States: perspective from American Society of Transplant Surgeons (ASTS) scientific studies committee and endorsed by ASTS council. Am J Transplant
. 2016;16:3093–3104 Organ Procurement and Transplantation Network National Data. [cited 2016 Jul 15]. Available from: https://optn.transplant.hrsa
2. Nasralla D, Coussios CC, Mergental H, et al. A randomized trial of normothermic preservation in liver transplantation. Nature
3. Brockmann J, Reddy S, Coussios C, et al. Normothermic perfusion: a new paradigm for organ preservation. Ann Surg
4. Xu H, Berendsen T, Kim K, et al. Excorporeal normothermic machine perfusion resuscitates pig DCD livers with extended warm ischemia. J Surg Res
5. Liu Q, Nassar A, Farias K, et al. Sanguineous normothermic machine perfusion improves hemodynamics and biliary epithelial regeneration in donation after cardiac death porcine livers. Liver Transpl
6. Mergental H, Perera MT, Laing RW, et al. Transplantation of declined liver allografts following normothermic ex-situ evaluation. Am J Transplant
7. Watson CJE, Kosmoliaptsis V, Pley C, et al. Observations on the ex situ perfusion of livers for transplantation. Am J Transplant
. 2018; Published online February 8, 2018. doi:10.1111/ajt.14687.
8. Hilmi I, Horton CN, Planinsic RM, et al. The impact of postreperfusion syndrome on short-term patient and liver allograft outcome in patients undergoing orthotopic liver transplantation. Liver Transpl
9. Gok K, Atsan N. Decision-making under stress and its implications for managerial decision-making: a review of literature. Int J Bus Soc Res