Impact of Back-to-Base Normothermic Machine Perfusion on Complications and Costs: A Multi-Center, Real-World Risk-Matched Analysis.

OBJECTIVE: Assess cost and complication outcomes after liver transplantation (LT) using normothermic machine perfusion (NMP). SUMMARY BACKGROUND DATA: End-ischemic NMP is often used to aid logistics, yet its' impact on outcomes after LT remains unclear, as does its' true impact on costs associated with transplantation. METHODS: Deceased donor liver recipients at two centers (1/1/2019-6/30/2023) were included. Retransplants, splits and combined grafts were excluded. End-ischemic NMP (OrganOx-Metra®) was implemented 10/2022 for extended-criteria DBDs, all DCDs and logistics. NMP-cases were matched 1:2 with cold storage controls (SCS) using the Balance-of-Risk (DBD-grafts) and UK-DCD Score (DCD-grafts). RESULTS: Overall, 803 transplantations were included, 174 (21.7%) receiving NMP. Matching was achieved between 118 NMP-DBDs with 236 SCS; and 37 NMP-DCD with 74 corresponding SCS. For both graft types, median inpatient comprehensive complications index (CCI) values were comparable between groups. DCD-NMP grafts experienced reduced cumulative 90-day CCI (27.6 vs. 41.9, P=0.028). NMP also reduced the need for early relaparotomy and renal-replacement-therapy, with subsequently less-frequent major complications (Clavien-Dindo >IVa). This effect was more pronounced in DCD-transplants. NMP had no protective effect on early biliary complications. Organ acquisition/preservation costs were higher with NMP, yet NMP-treated grafts had lower 90-day pre-transplant costs in context of shorter waiting-list times. Overall costs were comparable for both cohorts. CONCLUSIONS: This is the first risk-adjusted outcome and cost analysis comparing NMP and SCS. In addition to logistical benefits, NMP was associated with a reduction in relaparotomy and bleeding in DBD-grafts, and overall complications and post-LT renal-replacement for DCDs. While organ acquisition/preservation was more costly with NMP, overall 90-day-healthcare costs-per-transplantation were comparable.

The Impact of Normothermic Machine Perfusion and Acuity Circles on Waitlist Time, Mortality and Cost in Liver Transplantation: A Multi-Center Experience.

BACKGROUND: Ex-situ normothermic machine perfusion (NMP) helps increase the use of extended criteria donor livers. However, the impact of an NMP program on waitlist times and mortality has not been evaluated. METHODS: Adult patients listed for liver transplant (LT) at two academic centers 1/1/2015-9/1/2023 were included (n=2773) to allow all patients >6-months follow-up from listing. Routine NMP was implemented on 10/14/2022. Waitlist outcomes were compared from pre-NMP pre-acuity-circles (n=1,460), pre-NMP with acuity circles (n=842) and with NMP (n=381). RESULTS: Median waitlist time was 79days (IQR 20-232 d) at baseline, 49days (7-182) with acuity circles, and 14days (5-56) with NMP (p<0.001). The rate of transplant-per-100-person-years improved from 61-per-100-person-years to 99-per-100-person-years with acuity circles, and 194-per-100-person-years with NMP (p<0.001). Crude mortality without transplant decreased from 18.3% (n=268/1460), to 13.3% (n=112/843), to 6.3% (n=24/381) p<0.001) with NMP. Incidence of mortality without LT was 15-per-100-person-years before acuity circles, 19-per-100 with acuity circles, and 9-per-100-person-years after NMP (p<0.001). Median MELD at LT was lowest with NMP, but MELD at listing was highest in this era (p<0.0001). Median DRI of transplanted livers at baseline was 1.54 (1.27-1.82), 1.66 (1.42-2.16) with acuity circles, and 2.06 (1.63-2.46) with NMP (p<0.001). Six-month post-LT survival was not different between eras (p=0.322). The total cost of healthcare while waitlisted was lowest in the NMP era ($53,683 vs. $32,687 vs. $23,688, p<0.001); cost-per-day did not differ between eras (p=0.152). CONCLUSION: Implementation of a routine NMP program was associated with reduced waitlist time and mortality without compromising short-term survival after liver transplant despite increased use of riskier grafts. Routine NMP use enables better waitlist management with reduced healthcare costs.

Acute rejection after liver transplantation with machine perfusion versus static cold storage: A systematic review and meta-analysis.

BACKGROUND AND AIMS: Acute cellular rejection (ACR) is a frequent complication after liver transplantation. By reducing ischemia and graft damage, dynamic preservation techniques may diminish ACR. We performed a systematic review to assess the effect of currently tested organ perfusion (OP) approaches versus static cold storage (SCS) on post-transplant ACR-rates. APPROACH AND RESULTS: A systematic search of Medline, Embase, Cochrane Library, and Web of Science was conducted. Studies reporting ACR-rates between OP and SCS and comprising at least 10 liver transplants performed with either hypothermic oxygenated perfusion (HOPE), normothermic machine perfusion, or normothermic regional perfusion were included. Studies with mixed perfusion approaches were excluded. Eight studies were identified (226 patients in OP and 330 in SCS). Six studies were on HOPE, one on normothermic machine perfusion, and one on normothermic regional perfusion. At meta-analysis, OP was associated with a reduction in ACR compared with SCS [OR: 0.55 (95% CI, 0.33-0.91), p =0.02]. This effect remained significant when considering HOPE alone [OR: 0.54 (95% CI, 0.29-1), p =0.05], in a subgroup analysis of studies including only grafts from donation after cardiac death [OR: 0.43 (0.20-0.91) p =0.03], and in HOPE studies with only donation after cardiac death grafts [OR: 0.37 (0.14-1), p =0.05]. CONCLUSIONS: Dynamic OP techniques are associated with a reduction in ACR after liver transplantation compared with SCS. PROSPERO registration: CRD42022348356.

The role of ischaemia-reperfusion injury and liver regeneration in hepatic tumour recurrence.

The risk of cancer recurrence after liver surgery mainly depends on tumour biology, but preclinical and clinical evidence suggests that the degree of perioperative liver injury plays a role in creating a favourable microenvironment for tumour cell engraftment or proliferation of dormant micro-metastases. Understanding the contribution of perioperative liver injury to tumour recurrence is imperative, as these pathways are potentially actionable. In this review, we examine the key mechanisms of perioperative liver injury, which comprise mechanical handling and surgical stress, ischaemia-reperfusion injury, and parenchymal loss leading to liver regeneration. We explore how these processes can trigger downstream cascades leading to the activation of the immune system and the pro-inflammatory response, cellular proliferation, angiogenesis, anti-apoptotic signals, and release of circulating tumour cells. Finally, we discuss the novel therapies under investigation to decrease ischaemia-reperfusion injury and increase regeneration after liver surgery, including pharmaceutical agents, inflow modulation, and machine perfusion.