Outcome reporting for liver transplantation machine perfusion studies: a systematic review

Defining the optimal duration for normothermic regional perfusion in the kidney donor: A porcine preclinical study.

Liver transplantation (LTX) using donors after controlled circulatory death (cDCD) is associated with poorer graft survival and increased incidence of nonanastomotic biliary strictures (NASs) compared to livers procured from brain-dead donors (DBD). The use of normothermic regional perfusion (NRP) during cDCD procurement may improve posttransplant outcomes and reduce the incidence of NAS. In Sweden, cDCD LTX was introduced through a national pilot protocol with mandatory NRP. This study aims to evaluate the outcome of cDCD LTX during the pilot period. Donor and recipient data were collected on all cDCD liver transplants during the pilot period between January 2020 to December 2022. Outcome on NAS, patient and graft survival, early allograft dysfunction, acute kidney injury, and comprehensive complication index was compared to a matched cohort of 28 patients transplanted with a DBD liver between 2018 and 2022. Eighteen patients were transplanted with a liver from a cDCD donor after using NRP. The mean functional warm ischemia time was 29 ± 6 minutes. The mean lactate reduction during NRP was 8.7 ± 2.4mmol/L, and the end NRP perfusate alanine aminotransferase was 1.4 ± 1µkat/L. When comparing recipients of cDCD liver transplant to DBD, no significant differences were observed in the incidence of NAS, patient and graft survival, comprehensive complication index, early allograft dysfunction, or acute kidney injury. Study protocol magnetic resonance cholangiopancreatography in cDCD patients showed no signs of subclinical biliary strictures. Evaluation of the Swedish national pilot of cDCD LTX with mandatory NRP shows comparable outcomes to a matched DBD cohort with 94.4% 1-year patient and graft survival and no incidence of NAS within the first year.

Liver transplantation is the only chance of cure for people with end-stage liver disease and some people with advanced liver cancers or acute liver failure. The increasing prevalence of these conditions drives demand and necessitates the increasing use of donated livers which have traditionally been considered suboptimal. Several novel machine perfusion preservation technologies have been developed, which attempt to ameliorate some of the deleterious effects of ischaemia reperfusion injury. Machine perfusion technology aims to improve organ quality, thereby improving outcomes in recipients of suboptimal livers when compared to traditional static cold storage (SCS; ice box). To evaluate the effects of different methods of machine perfusion (including hypothermic oxygenated machine perfusion (HOPE), normothermic machine perfusion (NMP), controlled oxygenated rewarming, and normothermic regional perfusion) versus each other or versus static cold storage (SCS) in people undergoing liver transplantation. We used standard, extensive Cochrane search methods. The latest search date was 10 January 2023. We included randomised clinical trials which compared different methods of machine perfusion, either with each other or with SCS. Studies comparing HOPE via both hepatic artery and portal vein, or via portal vein only, were grouped. The protocol detailed that we also planned to include quasi-randomised studies to assess treatment harms. We used standard Cochrane methods. Our primary outcomes were 1. overall participant survival, 2. quality of life, and 3. serious adverse events. Secondary outcomes were 4. graft survival, 5. ischaemic biliary complications, 6. primary non-function of the graft, 7. early allograft function, 8. non-serious adverse events, 9. transplant utilisation, and 10. transaminase release during the first week post-transplant. We assessed bias using Cochrane's RoB 2 tool and used GRADE to assess certainty of evidence. We included seven randomised trials (1024 transplant recipients from 1301 randomised/included livers). All trials were parallel two-group trials; four compared HOPE versus SCS, and three compared NMP versus SCS. No trials used normothermic regional perfusion. When compared with SCS, it was uncertain whether overall participant survival was improved with either HOPE (hazard ratio (HR) 0.91, 95% confidence interval (CI) 0.42 to 1.98; P = 0.81, I2 = 0%; 4 trials, 482 recipients; low-certainty evidence due to imprecision because of low number of events) or NMP (HR 1.08, 95% CI 0.31 to 3.80; P = 0.90; 1 trial, 222 recipients; very low-certainty evidence due to imprecision and risk of bias). No trials reported quality of life. When compared with SCS alone, HOPE was associated with improvement in the following clinically relevant outcomes: graft survival (HR 0.45, 95% CI 0.23 to 0.87; P = 0.02, I2 = 0%; 4 trials, 482 recipients; high-certainty evidence), serious adverse events in extended criteria DBD liver transplants (OR 0.45, 95% CI 0.22 to 0.91; P = 0.03, I2 = 0%; 2 trials, 156 participants; moderate-certainty evidence) and clinically significant ischaemic cholangiopathy in recipients of DCD livers (OR 0.31, 95% CI 0.11 to 0.92; P = 0.03; 1 trial, 156 recipients; high-certainty evidence). In contrast, NMP was not associated with improvement in any of these clinically relevant outcomes. NMP was associated with improved utilisation compared with SCS (one trial found a 50% lower rate of organ discard; P = 0.008), but the reasons underlying this effect are unknown. We identified 11 ongoing studies investigating machine perfusion technologies. In situations where the decision has been made to transplant a liver donated after circulatory death or donated following brain death, end-ischaemic HOPE will provide superior clinically relevant outcomes compared with SCS alone. Specifically, graft survival is improved (high-certainty evidence), serious adverse events are reduced (moderate-certainty evidence), and in donors after circulatory death, clinically relevant ischaemic biliary complications are reduced (high-certainty evidence). There is no good evidence that NMP has the same benefits over SCS in terms of these clinically relevant outcomes. NMP does appear to improve utilisation of grafts that would otherwise be discarded with SCS; however, the reasons for this, and whether this effect is specific to NMP, is not clear. Further studies into NMP viability criteria and utilisation, as well as head-to-head trials with other perfusion technologies are needed. In the setting of donation following circulatory death transplantation, further trials are needed to assess the effect of these ex situ machine perfusion methods against, or in combination with, normothermic regional perfusion.

We thank Ayorinde et al1 for their interest in our article2 and the editor for giving us the opportunity to clarify concerns. In our manuscript,2 we reported our initial experience with 46 consecutive controlled donors after circulatory death (cDCD) liver transplants (LTs) preserved with normothermic regional perfusion (NRP), presenting an 80% organ recovery rate and an outstanding low rate of complications (no cases of primary nonfunction or ischemic cholangiopathy [IC]). As the authors mentioned,1 it can be argued that the positive results could be partly justified by the short functional warm ischemia time due to premortem interventions or by a highly selected cohort. However, in the UK experience,3 they also presented excellent results with postmortem cannulation, despite a significantly longer functional warm ischemia time. Moreover, our donors cannot be considered highly selected, because our median donor age was 58 years (higher than that reported in other studies)2–4 and almost 30% were over 65 years of age. It is accepted that NRP allows a better evaluation of the graft according to liver function tests and macroscopic aspect. The authors suggest a randomized controlled trial between the rapid recovery (RR) and NRP to achieve evidence. Although it is not completely clear why NRP is beneficial, several experimental studies have demonstrated a replenishment of intracellular ATP that may help organs tolerate the subsequent cold ischemia.2,3 Moreover, RR and NRP have been recently retrospectively compared in 2 studies3,4 that demonstrate an evident benefit of NRP and even present NRP as an independent factor preventing IC. In addition, the use of NRP in Spain has significantly increased during the past years, currently being almost the only preservation system in cDCD. NRP also offers the advantage of being a relatively inexpensive technique that allows the perfusion of not only the liver but also the kidneys and pancreas and even combining with intrathoracic organ retrieval.5 Given the excellent results that we have experienced with NRP, it seems unlikely that any center would abandon NRP to perform RR and expose its recipients to a higher IC rate and graft loss. Therefore, the authors propose1 another trial comparing NRP and RR followed by ex situ machine perfusion (MP). Because NRP has shown superb results from its initial experiences,2 we do not consider NRP cDCD as marginal donors “per se,” rather donors that allow for a safe expansion of the donor pool. So, it seems to have no sense to associate MP. In our opinion, MP must still find its role in LT, although it seems to be useful in discard grafts. Our more extended experience with 83 NRP cDCD LTs has been recently presented in the International Liver Transplantation Society meeting in Toronto; primary nonfunction and IC rates remain 0% with a median follow-up of 24 months. In our opinion, although large trials would be advisable in the interest of evidence-based medicine, the results show that the benefits of NRP are so overwhelming that the adoption of the technique by worldwide active groups involved in cDCD LT is only a matter of time.

Machine perfusion techniques for liver transplantation - A meta-analysis of the first seven randomized-controlled trials

The increasing use of extended criteria donors (ECD) sets higher requirements for graft preservation. Machine perfusion (MP) improves orthotopic liver transplantation (OLT) outcomes, but its effects on different donor types remains unclear. The authors' aim was to assess the effects of hypothermic machine perfusion (HMP), normothermic machine perfusion (NMP), or normothermic regional perfusion (NRP) versus static cold storage (SCS) on different donor types. A literature search comparing the efficacy of MP versus SCS in PubMed, Cochrane, and EMBASE database was conducted. A meta-analysis was performed to obtain pooled effects of MP on ECD, donation after circulatory death (DCD), and donor after brainstem death. Thirty nine studies were included (nine randomized controlled trials and 30 cohort studies). Compared with SCS, HMP significantly reduced the risk of non-anastomotic biliary stricture (NAS) [odds ratio (OR) 0.43, 95% confidence interval (CI) 0.26-0.72], major complications (OR 0.55, 95% CI 0.39-0.78), and early allograft dysfunction (EAD) (OR 0.46, 95% CI 0.32-0.65) and improved 1-year graft survival (OR 2.36, 95% CI 1.55-3.62) in ECD-OLT. HMP also reduced primary non-function (PNF) (OR 0.40, 95% CI 0.18-0.92) and acute rejection (OR 0.62, 95% CI 0.40-0.97). NMP only reduced major complications in ECD-OLT (OR 0.56, 95% CI 0.34-0.94), without favorable effects on other complications and survival. NRP lowered the overall risk of NAS (OR 0.27, 95% CI 0.11-0.68), PNF (OR 0.43, 95% CI 0.22-0.85), and EAD (OR 0.58, 95% CI 0.42-0.80) and meanwhile improved 1-year graft survival (OR 2.40, 95% CI 1.65-3.49) in control DCD-OLT. HMP might currently be considered for marginal livers as it comprehensively improves ECD-OLT outcomes. NMP assists some outcomes in ECD-OLT, but more evidence regarding NMP-ECD is warranted. NRP significantly improves DCD-OLT outcomes and is recommended where longer non-touch periods exist.

In Situ Normothermic Regional Perfusion in Controlled Donation After Circulatory Determination Death: Organ Utilization, Outcomes, and Elusiveness of a Randomized Clinical Trial.

Machine perfusion (MP) strategies have altered the landscape of deceased donor liver procurement and preservation in recent years. Upfront costs for MP are significantly higher than those of conventional procurement/preservation techniques. We performed a systematic review to evaluate the cost-effectiveness of various MP strategies as alternatives to conventional liver procurement and preservation before liver transplantation (LT). A systematic search of MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials was performed for articles published up to February 2025, according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines. Fourteen studies reported the cost-effectiveness of MP before LT, including hypothermic oxygenated liver perfusion (n = 4), normothermic machine perfusion (n = 8), and normothermic regional perfusion (n = 2). Inflation-adjusted costs per MP run varied: normothermic machine perfusion (US$11 455-35 766), hypothermic oxygenated liver perfusion (US$6489-12 686), and normothermic regional perfusion (US$9287; single study). Six studies analyzed cost-effectiveness using real-world cohorts. All but one study found MP to be cost-effective; 5 reported overall cost savings compared with conventional procurement and static cold storage. MP influenced costs across the entire LT pathway: pre-LT (lower waitlist healthcare costs, fewer procurement "dry runs," improved organ utilization) and post-LT (shorter intensive care unit/hospital stays, reduced allograft dysfunction, need for dialysis, cholangiopathy, and retransplantation). Three studies found cost-effective improvements in quality-adjusted life years with MP. Although direct and indirect MP costs varied and were inconsistently reported, all studies based on real-world data found MP to be at least cost-neutral. Initial MP costs were offset by savings in waitlist and postoperative costs. Real-world data on the cost-effectiveness of NRP remain limited. Future clinical studies should include cost-effectiveness analysis to support institutional and policy-level investment in MP technologies.

In Italy, 20 min of continuous, flat-line electrocardiogram are required for death declaration. Despite prolonged warm ischemia time, Italian centers reported good outcomes in controlled donation after circulatory death (cDCD) liver transplantation by combining normothermic regional and end-ischemic machine perfusion (MP). The aim of this study was to evaluate the safety and feasibility of the use of septuagenarian and octogenarian cDCD donors with this approach. All cDCD older than 70 y were evaluated during normothermic regional perfusion and then randomly assigned to dual hypothermic or normothermic MP. In the period from April 2021 to December 2022, 17 cDCD older than 70 y were considered. In 6 cases (35%), the graft was not considered suitable for liver transplantation, whereas 11 (65%) were evaluated and eventually transplanted. The median donor age was 82 y, being 8 (73%) older than 80. Median functional warm ischemia and no-flow time were 36 and 28 min, respectively. Grafts were randomly assigned to ex situ dual hypothermic oxygenated MP in 6 cases (55%) and normothermic MP in 5 (45%). None was discarded during MP. There were no cases of primary nonfunction, 1 case of postreperfusion syndrome (9%) and 2 cases (18%) of early allograft dysfunction. At a median follow-up of 8 mo, no vascular complications or ischemic cholangiopathy were reported. No major differences were found in terms of postoperative hospitalization or complications based on the type of MP. The implementation of sequential normothermic regional and end-ischemic MP allows the safe use of very old donation after circulatory death donors.

Normothermic regional perfusion (NRP) and machine perfusion (MP) are variously used in many European centers to improve the outcomes after liver transplantation from donation after circulatory death (DCD). In Italy, a combination of NRP and subsequent MP has been used since the start of the activity. While NRP is mandatory for every DCD recovery, the subsequent use of MP is left to each center. We have designed a national survey to investigate practices and policies of these techniques. The questionnaire included 46 questions and was distributed to all the 21 Italian centers using an online form between June and July 2021. The overall response rate was 100%. A local NRP program for controlled Maastricht type 3 DCD was active in 11/21 (52.4%) centers. Organization and availability of personnel were perceived as the main difficulties in starting such a program. Between 2015 and 2020, 119 DCD livers were transplanted, with an overall utilization rate of 69.2%. Pump flow and gross aspect were considered the most reliable parameters in liver selection during NRP. Eight (72.7%) centers adopted subsequent hypothermic MP, 1 (9.1%) center normothermic MP, and the remaining 2 (18.2%) used both MP types. This first snapshot survey shows that NRP with subsequent MP is the most used protocol in Italy for DCD livers, although some heterogeneity exists in the type and purpose of MP between centers. Overall, this policy ensures a high utilization rate, considering the high risk of the DCD donor population in Italy.

In Italy, 20 minutes of continuous, flat-line electrocardiogram are required for death declaration, which significantly increases the risks of donation after circulatory death (DCD) LT. Despite prolonged warm ischemia time, Italian centers reported good outcomes in controlled donation after circulatory death LT by combining normothermic regional and end-ischemic machine perfusion. However, data on uncontrolled DCD (uDCD) LT performed by this approach are lacking. This was a multicenter, retrospective study performed at 3 large-volume centers comparing clinical outcomes of uncontrolled versus controlled DCD LT. The aim of the study was to assess outcomes of sequential normothermic regional perfusion and end-ischemic machine perfusion in uncontrolled DCD liver transplantation (LT). Of 153 DCD donors evaluated during the study period, 40 uDCD and 59 donation after circulatory death grafts were transplanted (utilization rate 52% vs. 78%, p = 0.004). Recipients of uDCD grafts had higher MEAF (4.9 vs. 3.5, p < 0.001) and CCI scores at discharge (24.4 vs. 8.7, p = 0.026), longer ICU stay (5 vs. 4d, p = 0.047), and a trend toward more severe AKI. At multivariate analysis, 90-day graft loss was associated with recipient BMI and lactate downtrend during normothermic regional perfusion. One-year graft survival was lower in uDCD (75% vs. 90%, p = 0.007) but became comparable when non-liver-related graft losses were treated as censors (77% vs. 90%, p = 0.100). The incidence of ischemic cholangiopathy was 10% in uDCD versus 3% in donation after circulatory death, p = 0.356. uDCD LT with prolonged warm ischemia is feasible by the sequential use of normothermic regional perfusion and end-ischemic machine perfusion. Proper donor and recipient selection are key to achieving good outcomes in this setting.

We thoroughly enjoyed the recent contribution by Ruiz et al,1 “Favorable Outcomes After Liver Transplantation With Normothermic Regional Perfusion From Donors After Circulatory Death: A Single-Center Experience,” in which they presented their results of liver transplantation following normothermic regional perfusion (NRP) from circulatory death donors (DCDs). This adds to work by our center and others suggesting that NRP improves outcomes in DCD liver transplantation, with lower rates of early allograft dysfunction, graft loss, and ischemic cholangiopathy.2-4 The authors claim that “DCD liver grafts preserved with NRP are superior to those obtained with the conventional rapid recovery technique and even comparable to donation after brainstem death grafts.” However, the absence of an appropriate control group prevents us from interpreting whether NRP was genuinely responsible for their excellent outcomes. Detractors of NRP will argue that their results reflect a highly selected cohort of donors, premortem intervention, and a short functional warm ischemia time. Definitive evidence for the efficacy of NRP in this setting would require a randomized controlled trial comparing super-rapid organ recovery and cooling versus NRP both performed after premortem donor heparinization and placement of cannulae. Although we are also proponents of NRP, high-quality evidence is now needed to demonstrate that NRP leads to meaningful incremental survival benefit and expansion of the donor pool with safe utilization of (marginal) organs, while not becoming a barrier to DCD liver transplantation, which has proven benefit to recipients.5 Numerous surgical technologies have been (over)enthusiastically and expensively adopted into mainstream practice, only for later studies to demonstrate lack of efficacy or poor long-term outcomes. Liver transplantation is potentially vulnerable to this due to the cognitive bias arising from the current focus on posttransplant survival rather than waiting list mortality,5 whereby a single poor outcome can disproportionately affect the center or surgeon mindset against DCD liver transplantation. It is important to ensure that adoption of machine perfusion technologies (including NRP) is based on robust evidence-based efficacy data and not just because they offer, what might be unnecessary, reassurance to the surgeon. In order to avoid falling into this trap, the transplant community has a responsibility at this stage to perform large-scale collaborative trials of machine perfusion before its wholesale adoption, whereby trials may become impossible to conduct due to “overwhelming evidence of efficacy.” Such trials should scientifically test the effect of NRP on overall organ offer utilization, short- and long-term transplant outcomes of all transplanted organs (including kidney and pancreas) and evaluate its role relative to other perfusion technologies and innovative donor interventions. In our opinion, given the likely reluctance of many clinicians to randomize donor livers to a standard cold perfusion and preservation arm without organ assessment before implantation, the key trial now required is one that compares NRP versus super-rapid organ recovery followed by ex situ machine perfusion to evaluate the effect of these interventions on organ utilization and clinical outcomes.

Normothermic Regional Perfusion or Normothermic Machine Perfusion in Liver Transplantation from Donation after Circulatory Death: A First Comparative Study

Heart transplantation in donation after circulatory death (DCD) relies on warm perfusion using either in situ normothermic regional perfusion (NRP) or ex situ normothermic machine perfusion. In this study, we explore an alternative: oxygenated hypothermic machine perfusion (HMP) using a novel clinically applicable perfusion system, which is compared to NRP with static cold storage (SCS). In a porcine model, a DCD setting was simulated, followed by either (1) NRP and SCS (2) NRP and HMP with the XVIVO Heart preservation system or (3) direct procurement (DPP) and HMP. After preservation, heart transplantation (HTX) was performed. After weaning from cardiopulmonary bypass (CPB), biventricular function was assessed by admittance and Swan-Ganz catheters. Only transplanted hearts in the HMP groups showed significantly increased biventricular contractility (end-systole elastance) 2 hour post-CPB (left ventricle absolute change: NRP HMP: +1.8 ± 0.56, p=0.047, DPP HMP: +1.5 ± 0.43, p=0.045 and NRP SCS: +0.97 ± 0.47 mmHg/ml, p=0.21; right ventricle absolute change: NRP HMP: +0.50 ± 0.12, p=0.025, DPP HMP: +0.82 ± 0.23, p=0.039 and NRP SCS: +0.28 ± 0.26, p=0.52) while receiving significantly less dobutamine to maintain a cardiac output >4l/min compared to SCS. Diastolic function was preserved in all groups. Post-HTX, both HMP groups showed significantly less increments in plasma troponin T compared to SCS. In DCD HTX, increased biventricular contractility post-HTX was only observed in hearts preserved with HMP. In addition, the need for inotropic support and signs of myocardial damage were lower in the HMP groups. DCD HTX can be successfully performed using DPP followed by preservation with HMP in a preclinical setting.

The limited supply and rising demand for kidney transplantation has led to the use of allografts more susceptible to ischemic reperfusion injury (IRI) and oxidative stress to expand the donor pool. Organ preservation and procurement techniques, such as machine perfusion (MP) and normothermic regional perfusion (NRP), have been developed to preserve allograft function, though their long-term outcomes have been more challenging to investigate. We performed a systematic review and meta-analysis to examine the benefits of MP and NRP compared to traditional preservation techniques. PubMed (MEDLINE), Embase, Cochrane, and Scopus databases were queried, and of 13,794 articles identified, 54 manuscripts were included (n = 41 MP; n = 13 NRP). MP decreased the rates of 12-month graft failure (OR 0.67; 95%CI 0.55, 0.80) and other perioperative outcomes such as delayed graft function (OR 0.65; 95%CI 0.54, 0.79), primary nonfunction (OR 0.63; 95%CI 0.44, 0.90), and hospital length of stay (15.5 days vs. 18.4 days) compared to static cold storage. NRP reduced the rates of acute rejection (OR 0.48; 95%CI 0.35, 0.67) compared to in situ perfusion. Overall, MP and NRP are effective techniques to mitigate IRI and play an important role in safely expanding the donor pool to satisfy the increasing demands of kidney transplantation.