Dual Hypothermic Oxygenated Machine Perfusion Research Articles

Full-left/Full-right Liver Splitting With Middle Hepatic Vein and Caval Partition During Dual Hypothermic Oxygenated Machine Perfusion.

Split liver transplantation is a valuable means of mitigating organ scarcity but requires significant surgical and logistical effort. Ex vivo splitting is associated with prolonged cold ischemia, with potentially negative effects on organ viability. Machine perfusion can mitigate the effects of ischemia-reperfusion injury by restoring cellular energy and improving outcomes. We describe a novel technique of full-left/full-right liver splitting, with splitting and reconstruction of the vena cava and middle hepatic vein, with dual arterial and portal hypothermic oxygenated machine perfusion. The accompanying video depicts the main surgical passages, notably the splitting of the vena cava and middle hepatic vein, the parenchymal transection, and the venous reconstruction. The left graft was allocated to a pediatric patient having methylmalonic aciduria, whereas the right graft was allocated to an adult patient affected by hepatocellular carcinoma and cirrhosis. This technique allows ex situ splitting, counterbalancing prolonged ischemia with the positive effects of hypothermic oxygenated machine perfusion on graft viability. The venous outflow is preserved, safeguarding both grafts from venous congestion; all reconstructions can be performed ex situ, minimizing warm ischemia. Moreover, there is no need for highly skilled surgeons to reach the donor hospital, thereby simplifying logistical aspects.

Prolonged hypothermic machine perfusion enables daytime liver transplantation – an IDEAL stage 2 prospective clinical trial

Liver transplantation is traditionally performed around the clock to minimize organ ischemic time. However, the prospect of prolonging preservation times holds the potential to streamline logistics and transform liver transplantation into a semi-elective procedure, reducing the need for nighttime surgeries. Dual hypothermic oxygenated machine perfusion (DHOPE) of donor livers for 1-2h mitigates ischemia-reperfusion injury and improves transplant outcomes. Preclinical studies have shown that DHOPE can safely extend the preservation of donor livers for up to 24h. We conducted an IDEAL stage 2 prospective clinical trial comparing prolonged (≥4h) DHOPE to conventional (1-2h) DHOPE for brain-dead donor livers, enabling transplantation the following morning. Liver allocation to each group was based on donor hepatectomy end times. The primary safety endpoint was a composite of all serious adverse events (SAE) within 30 days after transplantation. The primary feasibility endpoint was defined as the number of patients assigned and successfully receiving a prolonged DHOPE-perfused liver graft. Trial registration at: WHO International Clinical Trial Registry Platform, number NL8740. Between November 1, 2020 and July 16, 2022, 24 patients were enrolled. The median preservation time was 14.5h (interquartile range [IQR], 13.9-15.5) for the prolonged group (n=12) and 7.9h (IQR, 7.6-8.6) for the control group (n=12; p=0.01). In each group, three patients (25%; 95% CI 3.9-46%, p=1) experienced a SAE. Markers of ischemia-reperfusion injury and oxidative stress in both perfusate and recipients were consistently low and showed no notable discrepancies between the two groups. All patients assigned to either the prolonged group or control group successfully received a liver graft perfused with either prolonged DHOPE or control DHOPE, respectively. This first-in-human clinical trial demonstrates the safety and feasibility of DHOPE in prolonging the preservation time of donor livers to enable daytime transplantation. The ability to extend the preservation window to up to 20h using hypothermic oxygenated machine preservation at a 10°C temperature has the potential to reshape the landscape of liver transplantation. University Medical Center Groningen, the Netherlands.

Impact of Hypothermic Oxygenated Machine Perfusion on Hepatocellular Carcinoma Recurrence after Liver Transplantation.

Machine perfusion may be able to mitigate ischemia-reperfusion injury (IRI), which increases hepatocellular carcinoma (HCC) recurrence after liver transplantation (LT). This study aimed to investigate the impact of dual-hypothermic oxygenated machine perfusion (D-HOPE) on HCC recurrence in LT. A single-center retrospective study was conducted from 2016 to 2020. Pre- and postoperative data of HCC patients undergoing LT were analyzed. Recipients of a D-HOPE-treated graft were compared to those of livers preserved using static cold storage (SCS). The primary endpoint was recurrence-free survival (RFS). Of 326 patients, 246 received an SCS-preserved liver and 80 received a D-HOPE-treated graft (donation after brain death (DBD), n = 66; donation after circulatory death (DCD), n = 14). Donors of D-HOPE-treated grafts were older and had higher BMI. All DCD donors were treated by normothermic regional perfusion and D-HOPE. The groups were comparable in terms of HCC features and estimated 5-year RFS according to the Metroticket 2.0 model. D-HOPE did not reduce HCC recurrence (D-HOPE 10%; SCS 8.9%; p = 0.95), which was confirmed using Bayesian model averaging and inverse probability of treatment weighting-adjusted RFS analysis. Postoperative outcomes were comparable between groups, except for lower AST and ALT peak in the D-HOPE group. In this single-center study, D-HOPE did not reduce HCC recurrence but allowed utilizing livers from extended criteria donors with comparable outcomes, improving access to LT for patients suffering from HCC.

A Real-time Prediction Biomarker for Early Allograft Dysfunction before Liver Transplantation during End-ischemic Dual Hypothermic Oxygenated Machine Perfusion

A Real-time Prediction Biomarker for Early Allograft Dysfunction before Liver Transplantation during End-ischemic Dual Hypothermic Oxygenated Machine Perfusion

313.6: Early Graft Disfunction After Hypothermic Oxygenated Machine Perfusion of ECD Criteria Liver Grafts: No Longer A Clinical Issue?

Introduction: Early allograft disfunction (EAD) continues to be an important issue in liver transplantation, varying from 15 to 30%. This rate is particularly high in case of extended criteria donor (ECD) grafts due to significant ischemia-reperfusion injury leading to EAD. This injury is substantially reduced by thermoregulated oxygenated machine perfusion. The aim of the paper was to assess the use of hypothermic oxygenated machine perfusion (HOPE) in ECD liver grafts in a high-volume liver transplantation center using a specific protocol. Method: Grafts with >30% macrosteatosis and with multiple ECD (at least 2 criteria) were perfused using dual HOPE (hepatic artery and portal vein perfusion), while HOPE (portal vein perfusion only) was used for the remaining ECD grafts. The main criteria to establish graft improvement were the improvement of arterial and portal perfusion flows, with lactate under 3 mmol/L throughout the procedure. Results: Between February 2016 and February 2022, 26 ECD liver grafts were harvested from DBD (donation after brain death) donors and benefitted from HOPE. Dual HOPE was used in 8 grafts (30.7%). Criteria for graft improvement were met in all grafts except 5 (19.2%), where lactate was over 3 mmol/L, with a median of 3.6 (range 3.5-6.1). The median follow-up was 5 months (range 2-44). No EAD was encountered. Conclusion: By using a combined protocol of HOPE and dual HOPE, ECD liver grafts may be safely used by avoiding early graft dysfunction.

Sequential hypothermic and normothermic machine perfusion enables safe transplantation of high-risk donor livers

Ex situ normothermic machine perfusion (NMP) is increasingly used for viability assessment of high‐risk donor livers, whereas dual hypothermic oxygenated machine perfusion (DHOPE) reduces ischemia‐reperfusion injury. We aimed to resuscitate and test the viability of initially‐discarded, high‐risk donor livers using sequential DHOPE and NMP with two different oxygen carriers: an artificial hemoglobin‐based oxygen carrier (HBOC) or red blood cells (RBC). In a prospective observational cohort study of 54 livers that underwent DHOPE‐NMP, the first 18 procedures were performed with a HBOC‐based perfusion solution and the subsequent 36 procedures were performed with an RBC‐based perfusion solution for the NMP phase. All but one livers were derived from extended criteria donation after circulatory death donors, with a median donor risk index of 2.84 (IQR 2.52–3.11). After functional assessment during NMP, 34 livers (63% utilization), met the viability criteria and were transplanted. One‐year graft and patient survival were 94% and 100%, respectively. Post‐transplant cholangiopathy occurred in 1 patient (3%). There were no significant differences in utilization rate and post‐transplant outcomes between the HBOC and RBC group. Ex situ machine perfusion using sequential DHOPE‐NMP for resuscitation and viability assessment of high‐risk donor livers results in excellent transplant outcomes, irrespective of the oxygen carrier used.

Outcome of liver transplantation with grafts from brain-dead donors treated with dual hypothermic oxygenated machine perfusion, with particular reference to elderly donors

Prompted by the utilization of extended criteria donors, dual hypothermic oxygenated machine perfusion (D‐HOPE) was introduced in liver transplantation to improve preservation. When donors after neurological determination of death (DBD) are used, D‐HOPE effect on graft outcomes is unclear. To assess D‐HOPE value in this setting and to identify ideal scenarios for its use, data on primary adult liver transplant recipients from January 2014 to April 2021 were analyzed using inverse probability of treatment weighting, comparing outcomes of D‐HOPE‐treated grafts (n = 121) with those preserved by static cold storage (n = 723). End‐ischemic D‐HOPE was systematically applied since November 2017 based on donor and recipient characteristics and transplant logistics. D‐HOPE use was associated with a significant reduction of early allograft failure (OR: 0.24; 0.83; p = .024), grade ≥3 complications (OR: 0.57; p = .046), comprehensive complication index (−7.20 points; p = .003), and improved patient and graft survival. These results were confirmed in the subset of elderly donors (>75‐year‐old). Although D‐HOPE did not reduce the incidence of biliary complications, its use was associated with a reduced severity of ischemic cholangiopathy. In conclusion, D‐HOPE improves postoperative outcomes and reduces early allograft loss in extended criteria DBD grafts.

Normothermic Regional Perfusion and Hypothermic Oxygenated Machine Perfusion for Livers Donated After Controlled Circulatory Death With Prolonged Warm Ischemia Time: A Matched Comparison With Livers From Brain-Dead Donors.

Prolonged warm ischemia time (WIT) has a negative prognostic value in liver transplantation (LT) using grafts procured after circulatory death (DCD). To assess the value of abdominal normothermic regional perfusion (A-NRP) associated with dual hypothermic oxygenated machine perfusion (D-HOPE) in controlled DCD LT, prospectively collected data on LTs performed between January 2016 and July 2021 were analyzed. Outcome of controlled DCD LTs performed using A-NRP + D-HOPE (n = 20) were compared to those performed with grafts procured after brain death (DBD) (n = 40), selected using propensity-score matching. DCD utilization rate was 59.5%. In the DCD group, median functional WIT, A-NRP and D-HOPE time was 43, 246, and 205 min, respectively. Early outcomes of DCD grafts recipients were comparable to those of matched DBD LTs. In DCD and DBD group, incidence of anastomotic biliary complications and ischemic cholangiopathy was 15% versus 22% (p = 0.73) and 5% versus 2% (p = 1), respectively. One-year patient and graft survival was 100% versus 95% (p = 0.18) and 90% versus 95% (p = 0.82). In conclusion, the association of A-NRP + D-HOPE in DCD LT with prolonged WIT allows achieving comparable outcomes to DBD LT.

Prolonged dual hypothermic oxygenated machine preservation (DHOPE-PRO) in liver transplantation: study protocol for a stage 2, prospective, dual-arm, safety and feasibility clinical trial

IntroductionEnd-ischaemic preservation of a donor liver by dual hypothermic oxygenated machine perfusion (DHOPE) for 2 hours prior to transplantation is sufficient to mitigate ischaemia-reperfusion damage and fully restore cellular energy...

How to Preserve Liver Grafts From Circulatory Death With Long Warm Ischemia? A Retrospective Italian Cohort Study With Normothermic Regional Perfusion and Hypothermic Oxygenated Perfusion.

Donation after circulatory death (DCD) in Italy, given its 20-min stand-off period, provides a unique bench test for normothermic regional perfusion (NRP) and dual hypothermic oxygenated machine perfusion (D-HOPE). We coordinated a multicenter retrospective Italian cohort study with 44 controlled DCD donors, who underwent NRP, to present transplant characteristics and results. To rank our results according to the high donor risk, we matched and compared a subgroup of 37 controlled DCD livers, preserved with NRP and D-HOPE, with static-preserved controlled DCD transplants from an established European program. In the Italian cohort, D-HOPE was used in 84% of cases, and the primary nonfunction rate was 5%. Compared with the matched comparator group, the NRP + D-HOPE group showed a lower incidence of moderate and severe acute kidney injury (stage 2: 8% versus 27% and stage 3: 3% versus 27%; P = 0.001). Ischemic cholangiopathy remained low (2-y proportion free: 97% versus 92%; P = 0.317), despite the high-risk profile resulting from the longer donor warm ischemia in Italy (40 versus 18 min; P < 0.001). These data suggest that NRP and D-HOPE yield good results in DCD livers with prolonged warm ischemia.

Machine Perfusion of Donation After Circulatory Death Liver and Lungs Before Combined Liver-lung Transplantation.

Shortage of deceased donor organs for transplantation has led to the increased use of organs from donation after circulatory death (DCD) donors. There are currently no reports describing outcomes after multiorgan transplantation with DCD livers. The use of DCD organs for multiorgan transplantation can be enhanced if the detrimental effects of prolonged cold ischemia and subsequent ischemia-reperfusion injury are overcome. We present a case in which the liver and lungs of a DCD donor were preserved using ex situ machine perfusion for combined liver-lung transplantation. The recipient was a 19-year-old male patient requiring bilateral lung transplantation for severe progressive pleural parenchymal fibroelastosis and portal hypertension with portal vein thrombosis. The donor liver was preserved with dual hypothermic oxygenated machine perfusion, whereas the lungs were perfused using ex vivo lung perfusion. With ex vivo lung perfusion, total preservation time of right and left lung reached 17 and 21 h, respectively. Now, 2 y after transplantation, liver function is normal and lung function is improving. To conclude, we suggest that combined transplantation of DCD liver and lungs is feasible when cold ischemia is reduced with ex situ machine perfusion preservation.

Evaluation of the ex vivo liver viability using a nuclear magnetic resonance relaxation time-based assay in a porcine machine perfusion model

There is a dearth of effective parameters for selecting potentially transplantable liver grafts from expanded-criteria donors. In this study, we used a nuclear magnetic resonance (NMR) relaxation analyzer-based assay to assess the viability of ex vivo livers obtained via porcine donation after circulatory death (DCD). Ex situ normothermic machine perfusion (NMP) was utilized as a platform for viability test of porcine DCD donor livers. A liver-targeted contrast agent, gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA), was injected into the perfusate during NMP, and the dynamic biliary excretion of the Gd-EOB-DTPA was monitored by measuring the longitudinal relaxation time (T1). The longitudinal relaxation rate (R1) of the bile was served as a parameter. The delay of increase in biliary R1 during early stage of NMP indicated the impaired function of liver grafts in both warm and cold ischemia injury, which was correlated with the change of alanine aminotransferase. The preservative superiority in cold ischemia of dual hypothermic oxygenated machine perfusion could also be verified by assessing biliary R1 and other biochemical parameters. This study allows for the dynamic assessment of the viability of porcine DCD donor livers by combined usage of ex situ NMP and NMR relaxation time based assay, which lays a foundation for further clinical application.

Ex Situ Dual Hypothermic Oxygenated Machine Perfusion for Human Split Liver Transplantation.

After transport using static cold storage, a 51-year-old brain death donor liver underwent end-ischemic DHOPE. During DHOPE, the donor liver was maintained <10 °C and oxygenated with a Po2 of >106 kPa. An ex situ ERL/LLS split was performed with continuing DHOPE throughout the procedure to avoid additional ischemia time. Total cold ischemia times for the LLS and ERL were 205 minutes and 468 minutes, respectively. Both partial grafts were successfully transplanted at 2 different transplant centers. Peak aspartate aminotransferase and alanine aminotransferase were 172 IU/L and 107 IU/L for the LLS graft, and 839 IU/L and 502 IU/L for the ERL graft, respectively. The recipient of the LLS experienced an episode of acute cellular rejection. The ERL transplantation was complicated by severe acute pancreatitis with jejunum perforation requiring percutaneous drainage and acute cellular rejection. No device-related adverse events were observed. Liver splitting during continuous DHOPE preservation is feasible, has the potential to substantially shorten cold ischemia time and may optimize transplant logistics. Therefore liver splitting with DHOPE can potentially improve utilization of split liver transplantation.

A Randomized Controlled Trial of Dual Hypothermic Oxygenated Machine Perfusion in Donation after Circulatory Death Liver Transplantation

Purpose: Transplantation of livers from donation after circulatory death (DCD) donors is associated with an increased risk of non-anastomotic biliary strictures (NAS). Hypothermic oxygenated machine perfusion of livers may reduce the incidence of biliary complications, but data from prospective controlled studies are lacking. Method: In this multicenter, controlled trial we randomly assigned patients undergoing transplantation of a DCD liver to receive that liver after dual hypothermic oxygenated machine perfusion or conventional static cold storage alone (control group). The primary end point was the occurrence of NAS within 6 months after transplantation. Secondary end points included other graft-related and general complications. Results: A total of 156 patients were enrolled; 78 participants received a machine perfused liver and 78 received a liver after static cold storage only. NAS occurred in 6% of the patients in the machine perfusion group and 18% of the controls (risk ratio, 0.36; 95%CI, 0.14-0.94; P= 0.03). Post-reperfusion syndrome occurred in 13% of the recipients of a machine perfused liver and in 27% of the controls (risk ratio, 0.43; 95%CI, 0.20-0.91; P = 0.03). Early allograft dysfunction occurred in 26% of machine perfused livers vs. 40% of controls (risk ratio 0.61; 95%CI, 0.39-0.96; P = 0.03). Cumulative number of treatments for NAS was almost 4-fold lower after machine perfusion, compared to controls. There were no significant differences in adverse events. Conclusion: In this randomized trial, hypothermic oxygenated machine perfusion led to a lower risk of NAS, post-reperfusion syndrome and early allograft dysfunction after DCD liver transplantation than conventional static cold storage.

Perfusate Analysis During Dual Hypothermic Oxygenated Machine Perfusion of Liver Grafts: Correlations With Donor Factors and Early Outcomes.

Liver graft viability assessment has long been considered a limit of hypothermic oxygenated machine perfusion (HOPE). Aim of this study was assessing correlations of easily available perfusate parameters (PP) (aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, glucose, lactate, and pH) with graft features and outcome. In the period October 2018-February 2020, perfusate samples were obtained every 30 minutes during 50 dual-HOPE (D-HOPE) procedures. Correlations of PP with graft factors, 90-day graft loss, early allograft dysfunction (EAD), L-GrAFT score, acute kidney injury, and comprehensive complication index were analyzed using Pearson coefficient, receiver-operating characteristics analysis and by univariable and multivariable regression. Median D-HOPE time was 122 minutes. All parameters were normalized to liver weight. Only macrovesicular steatosis (MaS) significantly impacted PP levels and slope. Grafts with ≥30% MaS exhibited significantly different PP values and slope. Graft loss and EAD rate were 2% (n = 1) and 26% (n = 13). All PP except lactate correlated with EAD, 90-minute alanine aminotransferase showing the highest area under the receiver-operating characteristics curve (0.84). However, at multivariable analysis, the only factor independently associated with EAD was MaS (odds ratio, 5.44; confidence interval, 1.05-28.21; P = 0.04). Ninety minutes lactate dehydrogenase had the strongest correlation with L-GrAFT (R = 0.70; P < 0.001). PP correlated poorly with comprehensive complication index and grades 2-3 acute kidney injury rate. PP were predictive of graft function after transplant, but their association with graft survival and clinical outcomes requires further evaluation. MaS influenced levels of PP and was the only independent predictor of EAD.

Extended hypothermic oxygenated machine perfusion enables ex situ preservation of porcine livers for up to 24 hours.

Background & AimsEnd-ischemic hypothermic oxygenated machine perfusion (HOPE) of the donor liver for 1–2 h mitigates ischemia-reperfusion injury during subsequent liver transplantation. Extended preservation time may be preferred to facilitate difficult recipient hepatectomy or to optimize logistics. We therefore investigated whether end-ischemic dual HOPE (DHOPE) could extend preservation time for up to 24 h using a porcine liver reperfusion model.MethodsFollowing 30 min warm ischemia, porcine livers were subjected to 2 h static cold storage (SCS), followed by 2 h, 6 h, or 24 h DHOPE (n = 6 per group). Subsequent normothermic reperfusion was performed for 4 h using autologous blood. Two livers preserved by 24 h SCS served as additional controls. A proof of principle confirmation was carried out in 2 discarded human livers subjected to extended DHOPE. Hepatocellular and cholangiocyte injury and function were assessed. Oxidative stress levels and histology were compared between groups.ResultsPerfusion flows remained stable during DHOPE, regardless of duration. After normothermic reperfusion, livers perfused for 24 h by DHOPE had similar lactate clearance, blood pH, glucose, and alanine aminotransferase levels, and biliary pH, bicarbonate, and LDH levels, as livers perfused for 2 h and 6 h. Levels of malondialdehyde and high-mobility group box 1 in serum and liver parenchyma were similar for all groups. Histological analysis of bile ducts and liver parenchyma revealed no differences between the groups. Extended DHOPE in discarded human livers preserved hepatocellular and cholangiocyte function and histology after reperfusion. In contrast, livers preserved by 24 h SCS were non-functioning.ConclusionExtended end-ischemic DHOPE enabled successful preservation of porcine and discarded human donor livers for up to 24 h. Extended DHOPE enables safe extension of preservation time, which may facilitate allocation and transplantation from a logistical perspective, and further expand the donor pool.Lay summaryIt has been suggested that preserving liver grafts with a technique called (dual) hypothermic oxygenated machine perfusion ([D]HOPE) leads to better outcomes after transplantation than if livers are stored on ice, especially if an organ is of lesser quality. In this study, we showed that DHOPE could be used to preserve liver grafts for up to 24 h. This extended procedure could be used globally to facilitate transplantation and expand the donor pool.

Hypothermic oxygenated machine perfusion enables 24-hour Ex situ preservation of porcine donation after circulatory death livers

Background: End-ischemic hypothermic oxygenated machine perfusion reduces ischemia-reperfusion injury of donor livers during storage and transplantation. However, it is unknown whether this technique also supports an extension of the ex situ preservation time. We aimed to determine whether liver grafts from donation after circulatory death (DCD) porcine donors can be effectively preserved up to 24-hours using dual hypothermic oxygenated machine perfusion (DHOPE). Methods Porcine DCD livers were subjected to 2h static cold storage (SCS), followed by 2, 6, or 24 hours DHOPE (n=6 per group), using Belzer UW solution. Hepatocellular and bile duct viability were tested during 4h normothermic ex situ reperfusion with autologous blood. DCD livers preserved by 24h SCS (n=2) served as controls. Results: In all three study groups, portal venous and arterial flows remained stable during DHOPE. After normothermic reperfusion, there were no significant differences in lactate clearance, blood pH, glucose, and alanine aminotransferase levels among the DHOPE-preserved levels. All DHOPE-preserved livers produced bile and there were no significant differences in biliary pH, HCO3-, and LDH between the groups at 4h after reperfusion. Moreover, levels of malondialdehyde and HMGB-1 (markers for oxidative stress) in serum and liver parenchyma were similar for all DHOPE-preserved livers. Levels of cell-free DNA, a marker of cell death, were similar between the groups. Histological analysis of bile ducts and liver parenchyma also revealed no differences. In contrast, liver preserved by 24h SCS did not produce bile after reperfusion and turned bluish with reducing portal and arterial flows, representative for a non-viable liver. Histology revealed massive cellular necrosis. Conclusion: While 24h SCS preservation of DCD liver grafts lead to non-viable livers after warm reperfusion, DHOPE enabled successful ex situ preservation of donor livers up to 24h. If confirmed with human liver grafts, this technique can facilitate logistics of allocation and transplantation. Illustrative example of a porcine liver at the end of 24-hour DHOPE (A), and at the end of reperfusion after 24-hour DHOPE (B) or 24-hourSCS (C)

Transplantation of high-risk donor livers after resuscitation and viability assessment using a combined protocol of oxygenated hypothermic, rewarming and normothermic machine perfusion: study protocol for a prospective, single-arm study (DHOPE-COR-NMP trial)

IntroductionExtended criteria donor (ECD) livers are increasingly accepted for transplantation in an attempt to reduce the gap between the number of patients on the waiting list and the available number...

Study protocol for a multicenter randomized controlled trial to compare the efficacy of end-ischemic dual hypothermic oxygenated machine perfusion with static cold storage in preventing non-anastomotic biliary strictures after transplantation of liver grafts donated after circulatory death: DHOPE-DCD trial

BackgroundThe major concern in liver transplantation of grafts from donation after circulatory death (DCD) donors remains the high incidence of non-anastomotic biliary strictures (NAS). Machine perfusion has been proposed as an alternative strategy for organ preservation which reduces ischemia-reperfusion injury (IRI). Experimental studies have shown that dual hypothermic oxygenated machine perfusion (DHOPE) is associated with less IRI, improved hepatocellular function, and better preserved mitochondrial and endothelial function compared to conventional static cold storage (SCS). Moreover, DHOPE was safely applied with promising results in a recently performed phase-1 study. The aim of the current study is to determine the efficacy of DHOPE in reducing the incidence of NAS after DCD liver transplantation.MethodsThis is an international multicenter randomized controlled trial. Adult patients (≥18 yrs. old) undergoing transplantation of a DCD donor liver (Maastricht category III) will be randomized between the intervention and control group. In the intervention group, livers will be subjected to two hours of end-ischemic DHOPE after SCS and before implantation. In the control group, livers will be subjected to care as usual with conventional SCS only. Primary outcome is the incidence of symptomatic NAS diagnosed by a blinded adjudication committee. In all patients, magnetic resonance cholangiography will be obtained at six months after transplantation.DiscussionDHOPE is associated with reduced IRI of the bile ducts. Whether reduced IRI of the bile ducts leads to lower incidence of NAS after DCD liver transplantation can only be examined in a randomized controlled trial.Trial registrationThe trial was registered in Clinicaltrials.gov in September 2015 with the identifier NCT02584283.

Pretransplant sequential hypo- and normothermic machine perfusion of suboptimal livers donated after circulatory death using a hemoglobin-based oxygen carrier perfusion solution.

Ex situ dual hypothermic oxygenated machine perfusion (DHOPE) and normothermic machine perfusion (NMP) of donor livers may have a complementary effect when applied sequentially. While DHOPE resuscitates the mitochondria and increases hepatic adenosine triphosphate (ATP) content, NMP enables hepatobiliary viability assessment prior to transplantation. In contrast to DHOPE, NMP requires a perfusion solution with an oxygen carrier, for which red blood cells (RBC) have been used in most series. RBC, however, have limitations and cannot be used cold. We, therefore, established a protocol of sequential DHOPE, controlled oxygenated rewarming (COR), and NMP using a new hemoglobin‐based oxygen carrier (HBOC)‐based perfusion fluid (DHOPE‐COR‐NMP trial, NTR5972). Seven livers from donation after circulatory death (DCD) donors, which were initially declined for transplantation nationwide, underwent DHOPE‐COR‐NMP. Livers were considered transplantable if perfusate pH and lactate normalized, bile production was ≥10 mL and biliary pH > 7.45 within 150 minutes of NMP. Based on these criteria five livers were transplanted. The primary endpoint, 3‐month graft survival, was a 100%. In conclusion, sequential DHOPE‐COR‐NMP using an HBOC‐based perfusion fluid offers a novel method of liver machine perfusion for combined resuscitation and viability testing of suboptimal livers prior to transplantation.