Mr Keno Mentor, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion:
This unblinded randomised trial compared the outcomes of liver transplantation following either normothermic machine perfusion (NMP) or static cold storage (SCS). The study employed a ‘device-to-donor’ methodology where the Organox metra device is transported to the site of organ retrieval, which the authors highlight is logistically more challenging. 266 livers were included in the analysis. The primary endpoint was early allograft dysfunction (EAD), defined as abnormal liver parameters 7 days after transplantation. There was no significant difference in EAD between the 2 groups. Although the difference in EAD was numerically greater when using an as treated or sub-group analysis of higher risk groups (high DRI, DCD donor), this to failed to reach statistical significance. The authors reached conclusions similar to that of previous European trials – NMP is a safe modality and shows potential to improve outcomes in marginal organs.
Expert Review
Reviewer:
Mr Simon Knight, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Clinical Impact Rating
3
Review:
The use of machine preservation technologies in liver transplantation has been gaining pace over recent years, with centres using a mixture of normothermic machine perfusion (NMP), hypothermic oxygenated machine perfusion (HOPE) and normothermic regional perfusion (NRP). Machine preservation has the potential to resuscitate the liver, reverse retrieval-related injury, allow longer safe preservation times and enable viability assessment prior to implant. In particular, NMP allows functional assessment of the liver with well-defined parameters predicting early allograft function (1). The first multicentre randomised controlled trial (RCT) of normothermic machine perfusion in Europe was published in 2018, and demonstrated a significant (50%) reduction in the incidence of early allograft dysfunction (EAD) in machine perfused livers, despite longer preservation times (2). These results were replicated in a US study (using a different NMP device), which also demonstrated a significant reduction in the incidence of EAD with NMP (3). Whilst not specifically designed to demonstrate differences in organ utilisation, both studies also showed a reduction in organ discard rates, particularly for donation after cardiac death (DCD) livers. In a recent publication in the Annals of Surgery, Chapman and colleagues report the results of the large multicentre US experience of NMP (4). They used a protocol very similar to that followed in the European RCT. Livers were randomised to either conventional static cold storage (SCS) or NMP, with perfusion initiated at the donor hospital and the liver transported on the device to the implanting centre. In contrast to the European study, the trial did not meet its primary endpoint of demonstrating an overall reduction in EAD. Per-protocol analysis showed similar trends to the prior European and US studies, with greater reduction in EAD rates seen with NMP in DCD and high donor-risk index (DRI) subgroups. Interestingly, there was evidence of a learning curve, with a reduction in EAD rates in the NMP arm following enhanced training during the study. Unlike the previous two RCTs, there was no difference in transplant rate between the arms. One important point to note is that all three RCTs used NMP in a “device-to-donor” configuration, with initiation of NMP at the donor hospital and transport on the device. This has significant logistical challenges, particularly in countries like the US where travel distances are longer and travel by plane is more common. In reality, most centres using NMP routinely in the UK and Europe are using NMP in a “back-to-base” configuration, with transport of the liver under SCS and initiation of perfusion in the recipient centre. Whilst small studies suggest that this does not compromise outcomes for the majority of livers (5), there is no large-scale RCT evidence to support the back-to-base NMP perfusion strategy that many centres are employing. Overall, whilst this study demonstrates a smaller effect size than previous RCTs, it does confirm that the technology is safe and that the main benefit of this technology appears to be for more marginal (high DRI and DCD) livers. References 1. Watson CJE, Gaurav R, Fear C et al. Predicting Early Allograft Function After Normothermic Machine Perfusion. Transplantation 2022; 106: 2391. 2. Nasralla D, Coussios CC, Mergental H et al. A randomized trial of normothermic preservation in liver transplantation. Nature 2018; 557: 50. 3. Markmann JF, Abouljoud MS, Ghobrial RM et al. Impact of Portable Normothermic Blood-Based Machine Perfusion on Outcomes of Liver Transplant: The OCS Liver PROTECT Randomized Clinical Trial. JAMA Surgery 2022; 157: 189. 4. Chapman WC, Barbas AS, D’Alessandro AM et al. Normothermic Machine Perfusion of Donor Livers for Transplantation in the United States - A Randomized Controlled Trial. Annals of Surgery 2023; 5. Ceresa CDL, Nasralla D, Watson CJE et al. Transient Cold Storage Prior to Normothermic Liver Perfusion May Facilitate Adoption of a Novel Technology. Liver Transplantation: Official Publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society 2019; 25: 1503.
Aims:
The aim of this study was to investigate the effectiveness of normothermic machine preservation (NMP) versus static cold storage (SCS) in the prevention of preservation-related graft injury.
Interventions:
Donor livers were randomised to undergo either NMP or SCS.
Participants:
383 donor livers were randomised out of which 266 donor livers were transplanted.
Outcomes:
The primary endpoint was early allograft dysfunction (EAD). Secondary endpoints included graft survival, patient survival, incidence of postreperfusion syndrome, biochemical liver function, biliary complications, histological evidence of ischemia-reperfusion injury, feasibility and safety, health economics and organ utilization.
Follow Up:
12 months
OBJECTIVE:
To compare conventional low-temperature storage of transplant donor livers [static cold storage (SCS)] with storage of the organs at physiological body temperature [normothermic machine perfusion (NMP)].
BACKGROUND:
The high success rate of liver transplantation is constrained by the shortage of transplantable organs (eg, waiting list mortality >20% in many centers). NMP maintains the liver in a functioning state to improve preservation quality and enable testing of the organ before transplantation. This is of greatest potential value with organs from brain-dead donor organs (DBD) with risk factors (age and comorbidities), and those from donors declared dead by cardiovascular criteria (donation after circulatory death).
METHODS:
Three hundred eighty-three donor organs were randomized by 15 US liver transplant centers to undergo NMP (n = 192) or SCS (n = 191). Two hundred sixty-six donor livers proceeded to transplantation (NMP: n = 136; SCS: n = 130). The primary endpoint of the study was "early allograft dysfunction" (EAD), a marker of early posttransplant liver injury and function.
RESULTS:
The difference in the incidence of EAD did not achieve significance, with 20.6% (NMP) versus 23.7% (SCS). Using exploratory, "as-treated" rather than "intent-to-treat," subgroup analyses, there was a greater effect size in donation after circulatory death donor livers (22.8% NMP vs 44.6% SCS) and in organs in the highest risk quartile by donor risk (19.2% NMP vs 33.3% SCS). The incidence of acute cardiovascular decompensation at organ reperfusion, "postreperfusion syndrome," as a secondary outcome was reduced in the NMP arm (5.9% vs 14.6%).
CONCLUSIONS:
NMP did not lower EAD, perhaps related to the inclusion of lower-risk liver donors, as higher-risk donor livers seemed to benefit more. The technology is safe in standard organ recovery and seems to have the greatest benefit for marginal donors.
Mr John Fallon, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion:
This small unblinded randomised trial was conducted in a single high volume transplant centre in China by the group who have been pioneering the ischaemia-free liver transplant technique since its fist publication in 2018. Images and videos of their technique have been included in their 3 publications on their reports and protocols. The IFLT cohort was n=32 and the CLT n=33, of these 2 (6%) in the IFLT experience EAD and 8 (24%) in the CLT (p=0.044) which was the primary endpoint. In some of the secondary endpoints they found significant improvement with IFLT: peak ALT and ASK at 7 days, total bilirubin, post-op lactate positive perfusate microbial culture and non-anastomotic strictures at 12 months. When scrutinising these strictures, there were 2 in IFLT (one mild and one moderate) and 9 in CLT (five mild and four moderate) none of which required intervention. The marked reduction in post-reperfusion syndrome is important 3 (9%) in IFLT and 21 (64%) in CLT given the risk of post-reperfusion cardiac arrest. They found no significant differences in primary non-function, over-all hospital stay, anastomotic stenosis (though the rate was higher in IFLT) and, graft and patient survival. They present an impressive success given the complexity of the procedure, however this is its key limitation. Despite the improvement in EAD, strictures and post-reperfusion syndrome there was no measurable benefit in patient or graft survival within the first year and none of the strictures require intervention. It was done in a set of low risk DBD donors, a cohort in which similar benefits have been seen with NMP alone. There are technical limitations, it was performed with a liver assist device which is not transportable, thus donor and recipient must be in the same location. The technique is of interest and a great technical achievement, but a study of larger numbers with a wider range of DBD donors and longer-term follow-up is required.
Expert Review
Reviewer:
Mr John O'Callaghan, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Review:
This is a very interesting randomised controlled trial in liver transplantation that has the potential to significantly change practice and improve transplant outcomes. 68 liver transplant recipients from donation after brain death were randomised to standard treatment or for an “Ischemia-Free Liver Transplant” (IFLT). The trial was conducted at a single hospital in China. The study was adequately randomised, but the clinical team could not be blinded to the intervention, understandably. For the intervention group, the Liver Assist device (Organ assist, The Netherlands) was used to establish in situ normothermic perfusion. The liver was then procured and moved to the reservoir of the Liver Assist for ex situ normothermic machine perfusion and moved to the recipient locality for transplant. For the liver implantation to the recipient, the anastomoses of the inferior vena cava, portal vein, and hepatic artery were performed under continuous in situ normothermic machine perfusion. Machine perfusion was discontinued after the donor liver had been revascularized. Then the biliary tract was reconstructed. There was therefore zero cold ischemic time for the IFLT group. Mean cold ischaemic time in the standard care group was approximately 7 hours, and mean normothermic perfusion time in the IFLT group was approximately 7 hours. The primary outcome was Early Allograft Dysfunction (EAD) and this was significantly reduced by IFLT (6% versus 24%), as were peak ALT, AST and bilirubin levels. Post-reperfusion syndrome was dramatically reduced, from 64% to 9%. Non-anastomotic biliary strictures were also significantly reduced (8% versus 36%), although this was recorded as seen on protocol MRCP. This clinical trial has shown a dramatic reduction in the ischemia reperfusion injury of transplant livers through the novel use of technology to remove the cold ischemic phase of the organ preservation period. The donor liver is kept warm and perfused all through the process of procurement from the donor body, preservation outside the body, and during the implant into the recipient up until the moment of reperfusion with the recipient’s blood. The technique clearly improved early transplant function. The reduction in non-anastomotic strictures was largely asymptomatic, so it remains to be seen if this technique can significantly reduce the risk of symptomatic strictures in higher risk livers.
Aims:
To compare outcomes in the novel technique of ischaemia-free liver transplantation (IFLT) to conventional liver transplantation (CLT).
Interventions:
The technique being tested is IFLT compared with CLT. IFLT is a complex technique in which during DBD donation the perfusion cannulas of a Liver Assist can be placed in the donor liver prior to cessation of donor circulation. The arterial canula placed via the splenic artery, portal vein via and vein graft and the outflow canula into the infra-hepatic cava. The perfusion can then seamlessly be transferred from donor circulation to NMP, the liver is then procured and continued NMP until implantation. The supra-hepatic caval (piggyback), portal vein and hepatic arterial anastomoses are then performed in the recipient while NMP continues, and once completed the NMP cannulas are removed, and hepatic perfusion transferred from NMP to recipient without interruption of perfusion.
Participants:
65 adult whole liver-only transplant recipients.
Outcomes:
The primary endpoint was early allograft dysfunction (EAD) within 7 days as defined by the Olthoff criteria. The secondary endpoints included primary non-function, post-reperfusion syndrome, biliary complications, post-reperfusion lactate, post-transplant LFTs, patient and graft survival at 1,6, & 12 months, ITU stay and overall hospital stay.
Follow Up:
12 months
BACKGROUND & AIMS:
Ischemia-reperfusion injury (IRI) has thus far been considered as an inevitable component of organ transplantation, compromising outcomes, and limiting organ availability. Ischemia-free organ transplantation is a novel approach designed to avoid IRI, with the potential to improve outcomes.
METHODS:
In this randomized-controlled clinical trial, recipients of livers from donors after brain death were randomly assigned to receive either an ischemia-free or a 'conventional' transplant. The primary endpoint was the incidence of early allograft dysfunction. Secondary endpoints included complications related to graft IRI.
RESULTS:
Out of 68 randomized patients, 65 underwent transplants and were included in the analysis. 32 patients received ischemia-free liver transplantation (IFLT), and 33 received conventional liver transplantation (CLT). Early allograft dysfunction occurred in two recipients (6%) randomized to IFLT and in eight (24%) randomized to CLT (difference -18%; 95% CI -35% to -1%; p = 0.044). Post-reperfusion syndrome occurred in three recipients (9%) randomized to IFLT and in 21 (64%) randomized to CLT (difference -54%; 95% CI -74% to -35%; p <0.001). Non-anastomotic biliary strictures diagnosed with protocol magnetic resonance cholangiopancreatography at 12 months were observed in two recipients (8%) randomized to IFLT and in nine (36%) randomized to CLT (difference, -28%; 95% CI -50% to -7%; p = 0.014). The comprehensive complication index at 1 year after transplantation was 30.48 (95% CI 23.25-37.71) in the IFLT group vs. 42.14 (95% CI 35.01-49.26) in the CLT group (difference -11.66; 95% CI -21.81 to -1.51; p = 0.025).
CONCLUSIONS:
Among patients with end-stage liver disease, IFLT significantly reduced complications related to IRI compared to a conventional approach.
CLINICAL TRIAL REGISTRATION:
chictr.org. ChiCTR1900021158.
IMPACT AND IMPLICATIONS:
Ischemia-reperfusion injury has thus far been considered as an inevitable event in organ transplantation, compromising outcomes and limiting organ availability. Ischemia-free liver transplantation is a novel approach of transplanting donor livers without interruption of blood supply. We showed that in patients with end-stage liver disease, ischemia-free liver transplantation, compared with a conventional approach, led to reduced complications related to ischemia-reperfusion injury in this randomized trial. This new approach is expected to change the current practice in organ transplantation, improving transplant outcomes, increasing organ utilization, while providing a clinical model to delineate the impact of organ injury on alloimmunity.
Mr John O'Callaghan, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion:
This is an interesting and well-conducted trial in ECD liver transplantation. Livers were randomised to standard static cold storage (SCS) or to a period of Hypothermic Oxygenated Perfusion (HOPE), using the Vitasmart device (Bridge to Life, DG, USA). Organs in the HOPE group had a period of SCS of 4-5 hours on average prior to starting HOPE for 2-3 hours on average. No organ was discarded during perfusion. The study was single centre and designed with a prior power calculation to determine sample size. The primary endpoint was Early Allograft Dysfunction (EAD) using a well-established composite definition. There was a significant reduction in EAD with HOPE compared to SCS (13% versus 35%) and also a significant reduction in re-transplantation (0% versus 11%). This form of HOPE, using just portal vein perfusion in ECD liver transplantation, is associated with better early allograft function, which is very likely to impact on longer term function and graft survival.
Expert Review
Reviewer:
Mr Simon Knight, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Clinical Impact Rating
4
Review:
The shortage of suitable donors to meet demand has resulted in increasing use of extended criteria donor (ECD) organs to try to address the mismatch. ECD donor organs are known to be more at risk of adverse post-operative outcomes due to increased vulnerability to ischaemia-reperfusion injury. In attempts to counter this additional risk, there has been a great deal of interest in novel perfusion technologies to recondition, repair and assess grafts prior to transplant. Such technologies can be used in the donor (normothermic regional perfusion, NRP) or ex-vivo (hypothermic oxygenated perfusion, HOPE or normothermic machine perfusion, NMP). The technologies differ in their simplicity/ease of use, ability to assess organ viability and the duration of safe perfusion. In a recent paper in the American Journal of Transplantation, Ravaioli and colleagues report a single centre randomised controlled trial of HOPE after static cold storage (SCS) versus SCS alone in ECD liver grafts (1). 110 recipients were randomised and followed for a median of 473 days. The authors report a significant reduction in the risk of the primary endpoint of early allograft dysfunction with HOPE, from 35% to 13%. This reduction is similar in magnitude to that seen in previous studies of NMP (2) and HOPE in DCD livers (3). Unlike in these previous studies there was no difference in incidence of biliary complications, most likely as this study does not include DCD livers which are at higher risk for ischaemic-type biliary lesions. Perhaps the most striking finding is that graft survival was significantly higher in the HOPE arm of the study, a finding not seen in the larger multicentre studies of HOPE or NMP. A detailed breakdown of causes and timings of graft loss is not provided, making the role of perfusion in this finding difficult to interpret. Another interesting finding is the numerically lower incidence of acute rejection in HOPE livers. This has been seen previously with use of HOPE in kidney transplantation (4), and may offer at least a partial explanation for the difference in graft survival seen. Overall, these findings support previous studies in both liver and kidney transplantation that HOPE is a safe, simple and effective method of preservation which may be beneficial in marginal donor organs. References 1. Ravaioli M, Germinario G, Dajti G et al. Hypothermic oxygenated perfusion in extended criteria donor liver transplantation-A randomized clinical trial. American Journal of Transplantation: Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons 2022; 2. Nasralla D, Coussios CC, Mergental H et al. A randomized trial of normothermic preservation in liver transplantation. Nature 2018; 557: 50. 3. van Rijn R, Schurink IJ, de Vries Y et al. Hypothermic Machine Perfusion in Liver Transplantation - A Randomized Trial. The New England Journal of Medicine 2021; 384: 1391. 4. Jochmans I, Brat A, Davies L et al. Oxygenated versus standard cold perfusion preservation in kidney transplantation (COMPARE): a randomised, double-blind, paired, phase 3 trial. Lancet (London, England) 2020; 396: 1653.
Aims:
The aim of this study was to compare the effect of hypothermic oxygenated perfusion (HOPE) versus static cold storage (SCS) in extended criteria donor (ECD) liver transplantation.
Interventions:
Participants undergoing transplantation of an ECD liver graft were randomly assigned to receive a liver after HOPE or after SCS alone.
Participants:
135 potential ECD liver grafts were randomised, of which 110 were used for liver transplantation.
Outcomes:
The primary outcome was the incidence of early allograft dysfunction (EAD). The secondary outcome were patient survival, graft survival, the early allograft failure simplified estimation (EASE) risk score, and the rate of graft or other graft-related complications.
Follow Up:
1 year
Hypothermic Oxygenated Perfusion (HOPE) of the liver can reduce the incidence of early allograft dysfunction (EAD) and failure in extended criteria donors (ECD) grafts, although data from prospective studies are very limited. In this monocentric, open-label study, from December 2018 to January 2021, 110 patients undergoing transplantation of an ECD liver graft were randomized to receive a liver after HOPE or after static cold storage (SCS) alone. The primary endpoint was the incidence of EAD. The secondary endpoints included graft and patient survival, the EASE risk score, and the rate of graft or other graft-related complications. Patients in the HOPE group had a significantly lower rate of EAD (13% vs. 35%, p = .007) and were more frequently allocated to the intermediate or higher risk group according to the EASE score (2% vs. 11%, p = .05). The survival analysis confirmed that patients in the HOPE group were associated with higher graft survival one year after LT (p = .03, log-rank test). In addition, patients in the SCS group had a higher re-admission and overall complication rate at six months, in particular cardio-vascular adverse events (p = .04 and p = .03, respectively). HOPE of ECD grafts compared to the traditional SCS preservation method is associated with lower dysfunction rates and better graft survival.
Mr John O'Callaghan, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion:
This paper reports the long-term outcome from hearts randomised in the randomised PROCEED II study at a single centre. Previous publications of the PROCEED II study have already shown non-inferior short-term outcomes comparing perfusion on the OCS device to cold storage on ice. The study as a whole included 130 patients randomised in a 1:1 fashion, and this single-centre follow up reports on only 38. As such, this latest report is underpowered to identify all but the most obvious of clinical differences and the authors acknowledge this limitation. Follow-up in this cohort of 38 was acceptable, at 92%, which equates to 3 lost-to follow up. Recipients in the cold-storage arm were significantly older, by 8 years. There was no significant difference in overall survival at median follow up of 8.4 years and no difference in cardiac allograft vasculopathy. The study outcomes should be viewed in the context of a highly selected donor and recipient population, with any potential benefits more likely to show themselves when using extended criteria donors.
Expert Review
Reviewer:
Mr Simon Knight, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Clinical Impact Rating
2
Review:
Utilisation of deceased donor cardiothoracic organs is typically lower than those of abdominal organs (1). This has led to interest in methods for ex-vivo preservation and viability assessment, which have the potential to prolong preservation times, recondition organs and improve outcomes by allowing assessment prior to transplantation. The first randomised controlled trial of normothermic ex-vivo cardiac preservation (PROCEED II) was reported in the Lancet in 2015 (2). The study randomised 130 transplant recipients to receive a heart either stored using conventional static cold storage (SCS) or preserved using the Organ Care System (OCS) perfusion device. The authors reported non-inferiority of perfused hearts, with no measurable difference in patient or graft survival despite longer overall preservation times in the OCS group. Of note, 5 hearts were discarded due to preservation parameters in the OCS group, but despite the potential advantages of discarding suboptimal organs, there was no measured clinical benefit (3). All hearts in the study had to be suitable for either arm and were relatively low-risk, meaning that any impact on organ utilisation cannot be assessed. In a recent paper published in Clinical Transplantation, Chen and colleagues report long-term outcomes in 38 patients from a single participating centre from the trial (4). Eight-year survival was numerically lower in the OCS group (57.9% vs. 73.7%, p=0.24) but not meeting statistical significance in this small sample. The apparent excess mortality in the OCS group seemed mainly related to events that are difficult to attribute to the preservation method (e.g. CMV infection or malignancy), supported by a lack of difference in the rate of graft-related mortality (84.2% in both groups). In contrast to the survival data, there was numerically higher freedom from coronary allograft vasculopathy (CAV; 89.5% vs. 67.8%) and non-fatal major cardiac events (89.5% vs. 67.5%) in the OCS group. Differences in CAV rate may relate to the shorter cold-ischaemic times in the OCS group, reducing ischaemia reperfusion injury. Overall, the small sample size means that firm conclusions are difficult to draw and this study is unlikely to have a significant impact on clinical practice. It would perhaps have been more useful to compile long-term outcomes from all patients in the original study to increase statistical power and see if the trends seen here were borne out in other centre’s data. Use of the OSC device is feasible and likely safe, but there is limited evidence of clinical benefit in standard-risk hearts. Whether ex-vivo perfusion will have a greater utility in preservation and viability assessment of hearts from more marginal donors remains to be seen. References 1. NHS Blood and Transplant. NHSBT Annual Activity Report 2020/21 [Internet]. [cited 2022 Apr 13] Available from: https://nhsbtdbe.blob.core.windows.net/umbraco-assets-corp/24053/activity-report-2020-2021.pdf 2. Ardehali A, Esmailian F, Deng M et al. Ex-vivo perfusion of donor hearts for human heart transplantation (PROCEED II): a prospective, open-label, multicentre, randomised non-inferiority trial. Lancet (London, England) 2015; 385: 2577. 3. Freed DH, White CW. Donor heart preservation: straight up, or on the rocks? The Lancet 2015; 385: 2552. 4. Chen Q, Singer-Englar T, Kobashigawa JA et al. Long-term outcomes after heart transplantation using ex vivo allograft perfusion in standard risk donors: A single-center experience. Clinical Transplantation 2022; : e14591.
Aims:
This study aimed to assess the long-term outcomes of heart transplant patients that received allografts preserved using the Organ Care System (OCS) versus standard cold storage (CS).
Interventions:
Participants were randomised to receive allografts preserved with either CS or OCS.
Participants:
38 heart transplant candidates.
Outcomes:
The primary outcomes were 8-year overall survival and freedom from cardiac allograft-related death up to 8 years. Secondary outcomes were 8-year freedom from cardiac allograft vasculopathy (CAV), freedom from non-fatal major adverse cardiac events and freedom from rejections.
Follow Up:
8 years
INTRODUCTION:
The Organ Care System (OCS) is an ex vivo perfusion platform for donor heart preservation. Short/mid-term post-transplant outcomes after its use are comparable to standard cold storage (CS). We evaluated long-term outcomes following its use.
METHODS:
Between 2011 and 2013, 38 patients from a single center were randomized as a part of the PROCEED II trial to receive allografts preserved with CS (n = 19) or OCS (n = 19). Endpoints included 8-year survival, survival free from graft-related deaths, freedom from cardiac allograft vasculopathy (CAV), non-fatal major adverse cardiac events (NF-MACE), and rejections.
RESULTS:
Eight-year survival was 57.9% in the OCS group and 73.7% in the CS group (p = .24). Freedom from CAV was 89.5% in the OCS group and 67.8% in the CS group (p = .13). Freedom from NF-MACE was 89.5% in the OCS group and 67.5% in the CS group (p = .14). Eight-year survival free from graft-related death was equivalent between the two groups (84.2% vs. 84.2%, p = .93). No differences in rejection episodes were observed (all p > .5).
CONCLUSIONS:
In select patients receiving OCS preserved allografts, late post-transplant survival trended lower than those transplanted with an allograft preserved with CS. This is based on a small single-center series, and larger numbers are needed to confirm these findings.
Mr John O'Callaghan, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion:
This is an interesting and well-conducted, multicentre study in liver transplantation using a normothermic preservation machine (OCS). The study was adequately randomised and, understandably, clinicians could not be blinded to the group allocation, the comparator being standard cold storage on ice. However, good steps were taken to re-randomise patients if a first liver was subsequently not suitable for transplant. The donor population for inclusion was selected on the basis of at least one of the following criteria: 40 years of age or older; expected total cross-clamp/cold ischemic time of 6 or more hours; DCD donors if 55 years or younger; or macrosteatotic livers (≤40%). The primary endpoint was early allograft dysfunction (EAD) using the Olthoff definition. Mean perfusion time on the machine was 117 minutes, 152/155 preserved in this way were transplanted. However, there was a significantly higher proportion of DCD livers transplanted from the OCS group than the cold storage group (51% versus 26%). There were 298 patients included in the modified intention to treat analysis, which showed a significant decrease in EAD when the OCS machine was used compared to standard cold storage. Short term patient and graft survival was equivalent but ischaemic biliary lesions were significantly reduced with OCS by 6 and 12 months (2.6% versus 9.9%) and recipients experienced fewer incidences of severe reperfusion injury.
Expert Review
Reviewer:
Mr John O'Callaghan, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Clinical Impact Rating
5
Review:
This is a well-conducted, multicentre study in liver transplantation using a normothermic preservation machine (The OCS Liver from TransMedics, MA, USA). The study took place over a period of approximately three years at 20 centres in the USA. The study targeted organs that had risk factors for early allograft dysfunction (EAD), such as older donor age, moderate steatosis, or anticipated long cold ischaemic time. The study was adequately randomised and, understandably, clinicians could not be blinded to the group allocation. If a liver was found to be not suitable for transplantation, then the recipient was randomised a second time. This, to some extent, mediates any potential bias that might be introduced when clinicians could not be easily blinded to the preservation method. Mean perfusion time on the machine was 117 minutes. The total preservation time for machine perfused livers was on average longer than the control group at 455 minutes compared to 339 minutes. Approximately 10% of livers randomised to OCS cross over to the other arm and were preserved with cold storage instead due to: accessory vessels, vascular reconstruction, or liver haematoma. However, the results from the intention to treat analysis were very similar to the per protocol analysis regardless, suggesting that there was no systematic bias introduced. Reassuringly 98% of livers preserved on the machine were successfully transplanted; those not transplanted were not used following assessment on the machine, showing poor lactate clearance or fibrosis on biopsy. There was a significantly higher proportion of DCD livers transplanted from the machine perfusion group than the cold storage group (51% versus 26%). The analysis showed a significant decrease in early allograft dysfunction (EAD, using the Olthoff definition) when the OCS machine was used. Short term patient and graft survival was equivalent but ischaemic biliary lesions were significantly reduced with OCS by 6 and 12 months (2.6% versus 9.9%). This study shows the safety of this technology in liver preservation and how it can potentially give greater confidence to transplant livers following DCD or marginal DBD. Despite the greater proportion of DCD livers in the OCS machine group, and the longer overall preservation time, there was a lower incidence of severe reperfusion injury, EAD and ischaemic biliary lesions. This study adds weight to the improved preservation possible with normothermic machines, and the confidence in organ viability when using this platform.
Aims:
The aim of this study was to investigate liver transplant outcomes associated with portable normothermic machine perfusion preservation of livers obtained from deceased donors.
Interventions:
Participants were randomised to either the Organ Care System (OCS) group or ischemic cold storage (ICS) group.
Participants:
300 recipients receiving donor livers preserved using ICS or the OCS.
Outcomes:
The primary effectiveness outcome was the incidence of early allograft dysfunction (EAD). Secondary outcomes were extent of reperfusion syndrome, OCS Liver ex vivo assessment capability of donor allografts, incidence of ischemic biliary complications (IBCs) at 6 and 12 months, and overall patient survival posttransplant. The primary safety outcome was the number of severe adverse events related to the liver graft within 30 days following transplantation.
Follow Up:
12 months
IMPORTANCE:
Ischemic cold storage (ICS) of livers for transplant is associated with serious posttransplant complications and underuse of liver allografts.
OBJECTIVE:
To determine whether portable normothermic machine perfusion preservation of livers obtained from deceased donors using the Organ Care System (OCS) Liver ameliorates early allograft dysfunction (EAD) and ischemic biliary complications (IBCs).
DESIGN, SETTING, AND PARTICIPANTS:
This multicenter randomized clinical trial (International Randomized Trial to Evaluate the Effectiveness of the Portable Organ Care System Liver for Preserving and Assessing Donor Livers for Transplantation) was conducted between November 2016 and October 2019 at 20 US liver transplant programs. The trial compared outcomes for 300 recipients of livers preserved using either OCS (n = 153) or ICS (n = 147). Participants were actively listed for liver transplant on the United Network of Organ Sharing national waiting list.
INTERVENTIONS:
Transplants were performed for recipients randomly assigned to receive donor livers preserved by either conventional ICS or the OCS Liver initiated at the donor hospital.
MAIN OUTCOMES AND MEASURES:
The primary effectiveness end point was incidence of EAD. Secondary end points included OCS Liver ex vivo assessment capability of donor allografts, extent of reperfusion syndrome, incidence of IBC at 6 and 12 months, and overall recipient survival after transplant. The primary safety end point was the number of liver graft-related severe adverse events within 30 days after transplant.
RESULTS:
Of 293 patients in the per-protocol population, the primary analysis population for effectiveness, 151 were in the OCS Liver group (mean [SD] age, 57.1 [10.3] years; 102 [67%] men), and 142 were in the ICS group (mean SD age, 58.6 [10.0] years; 100 [68%] men). The primary effectiveness end point was met by a significant decrease in EAD (27 of 150 [18%] vs 44 of 141 [31%]; P = .01). The OCS Liver preserved livers had significant reduction in histopathologic evidence of ischemia-reperfusion injury after reperfusion (eg, less moderate to severe lobular inflammation: 9 of 150 [6%] for OCS Liver vs 18 of 141 [13%] for ICS; P = .004). The OCS Liver resulted in significantly higher use of livers from donors after cardiac death (28 of 55 [51%] for the OCS Liver vs 13 of 51 [26%] for ICS; P = .007). The OCS Liver was also associated with significant reduction in incidence of IBC 6 months (1.3% vs 8.5%; P = .02) and 12 months (2.6% vs 9.9%; P = .02) after transplant.
CONCLUSIONS AND RELEVANCE:
This multicenter randomized clinical trial provides the first indication, to our knowledge, that normothermic machine perfusion preservation of deceased donor livers reduces both posttransplant EAD and IBC. Use of the OCS Liver also resulted in increased use of livers from donors after cardiac death. Together these findings indicate that OCS Liver preservation is associated with superior posttransplant outcomes and increased donor liver use.
Mr John O'Callaghan, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion:
This is a good quality and fair sized randomised controlled trial in renal transplantation. Patients received alemtuzumab induction therapy and then were maintained on prednisolone and tacrolimus. In the study arm, patients also received autologous mesenchymal stem cell (MSC) infusions and then had tacrolimus minimisation and subsequent withdrawal. The intention was to see if fibrosis could be reduced through tacrolimus withdrawal, using MSCs to reduce the risk of rejection in this context. Randomisation was performed by an online system and is likely to be truly random, however the nature of the intervention means that the study was not easily blinded and there is the potential for bias. However, pathologists examining the biopsies were blinded to the allocation and used standardised scoring, which is an important strength of the study. Withdrawals and dropouts are adequately described and the statistical methods are appropriate. The analysis was however not by strict intention-to-treat; one in 12 patients allocated to the study arm had abnormal MSC growth and could not receive that intervention so were excluded from the analysis for example. There were 4 patients in the control arm who refused to have a follow up biopsy and so were also excluded. These seem small numbers, but in a small trial are significant. The overall fibrosis scores and progression of fibrosis was the same in both arms of the study. Renal function was similar and risk of acute rejection was similarly low between the study arms. There was a significantly higher number of Tregs in the MSC group. A post hoc analysis of 5-year outcomes is presented, but does not indicate any significant differences. The study was too small to identify any significant difference in graft or patient survival. In conclusion, the use of MSC was safe within this study and was not associated with increased risk of rejection when combined with tacrolimus withdrawal.
Expert Review
Reviewer:
Mr John O'Callaghan, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Clinical Impact Rating
4
Review:
This study from the Netherlands is a good quality randomised controlled trial in renal transplantation and it supports the ongoing investigation of mesenchymal stem cells (MSC) as a potential component of immune suppression regimens. Renal transplant recipients in the trial received alemtuzumab induction therapy and then were maintained on prednisolone and tacrolimus. In the study arm patients also received two infusions of autologous mesenchymal stem cells (MSCs) and then progressed to tacrolimus minimisation and subsequent withdrawal. The intention was to see if fibrosis could be reduced through tacrolimus withdrawal, using MSCs to safely reduce the risk of rejection in this context. The study was necessarily open-label to the patient and clinicians. However, pathologists examining the biopsies were blinded to the allocation and used standardised scoring, this is an important strength of the study. Blinded assessment of biopsy scores was similar for both groups and showed similar progression over 24 weeks. There was only one episode of acute rejection in the MSC group on for-cause biopsy and none in the control arm. This was present in a patient on reduced immune suppression due to BK virus infection. There was no graft or patient loss in either arm, but the study was too small to really assess for these outcomes. Protocol biopsies showed a mixture of TCMR and ABMR in 3-4 patients in each study group during the study period. There were no serious adverse events directly related to the infusion of MSCs and the overall adverse event rate was similar between the study arms. Whilst there was no statistically significant difference between the groups in terms of most leukocyte cell lines quantified, there was a significant increase in Tregs in the MSC group that persisted up to 52 weeks after transplantation. The study was too small to identify any significant difference in graft or patient survival, particularly at later timepoints. In conclusion, the use of MSC was safe within this study and was not associated with increased risk of rejection when combined with tacrolimus withdrawal. Whilst there was no apparent difference in fibrosis on biopsy scores, the increase in Tregs is intriguing and there is a potential to see improved GFR at longer follow up in a larger study. This is an exciting potential avenue to improve long-term allograft survival and warrants further exploration in a larger study.
Aims:
The aim of this post hoc analysis was to investigate the effect of mesenchymal stromal cell (MSC) therapy with early tacrolimus withdrawal in renal transplant patients.
Interventions:
Participants in the original trial were randomised to either MSC plus early tacrolimus withdrawal or to standard tacrolimus dose.
Participants:
70 living donor kidney transplant recipients.
Outcomes:
The primary outcome was quantitative assessment of interstitial fibrosis. The secondary outcomes were patient death, graft loss, acute rejection, renal function, adverse events, and immunological responses.
Follow Up:
5 years
After renal transplantation, there is a need for immunosuppressive regimens which effectively prevent allograft rejection, while preserving renal function and minimizing side effects. From this perspective, mesenchymal stromal cell (MSC) therapy is of interest. In this randomized prospective, single-center, open-label trial, we compared MSCs infused 6 and 7 weeks after renal transplantation and early tacrolimus withdrawal with a control tacrolimus group. Primary end point was quantitative evaluation of interstitial fibrosis in protocol biopsies at 4 and 24 weeks posttransplant. Secondary end points included acute rejection, graft loss, death, renal function, adverse events, and immunological responses. Seventy patients were randomly assigned of which 57 patients were included in the final analysis (29 MSC; 28 controls). Quantitative progression of fibrosis failed to show benefit in the MSC group and GFR remained stable in both groups. One acute rejection was documented (MSC group), while subclinical rejection in week 24 protocol biopsies occurred in seven patients (four MSC; three controls). In the MSC group, regulatory T cell numbers were significantly higher compared to controls (p = .014, week 24). In conclusion, early tacrolimus withdrawal with MSC therapy was safe and feasible without increased rejection and with preserved renal function. MSC therapy is a potentially useful approach after renal transplantation.
Mr John O'Callaghan, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion:
This is a well-conducted, multicenter randomised controlled trial (RCT) that took place across 6 transplant centres in 3 European countries, and included 160 patients. Livers from donation after circulatory death were randomised by a centralised, computerised system, with stratification for centre and recipient Primary Sclerosing Cholangitis. The livers were randomised to either static cold storage, or static cold storage followed by minimum 2 hours perfusion in the Liver Assist device from Organ Assist, which provides dual oxygenated cold perfusion. Median perfusion time in the study was short (2 hours 12 minutes) but this meant that the overall cold ischaemic time was longer in the perfused group (8 hours 44 minutes versus 6 hours 49 minutes). The study found a significant reduction in symptomatic, non-anastomotic, biliary strictures associated when livers were perfused (6% versus 18%). Importantly, radiologists were blinded to group allocation and scans were reviewed by two radiologists independently, with discrepancies reviewed by a third. There was also a significant reduction in the risk of post-reperfusion syndrome with perfused livers. There was one case of primary non-function in the control group and none in the study group. There was no significant difference in early allograft dysfunction. This well-conducted study clearly shows that a short period of oxygenated hypothermic perfusion of DCD livers can reduce the incidence of non-anastomotic biliary strictures compared to static cold storage alone, despite a longer overall period of cold storage.
Expert Review
Reviewer:
Mr Simon Knight, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Clinical Impact Rating
5
Review:
The period of warm ischaemia experienced by livers from donors after circulatory death (DCD) is associated with increased incidence of non-anastomotic biliary strictures, requiring intervention and in some cases retransplantation. The largest increase in transplantation over recent years has come from the DCD donor pool, and so there is interest in interventions to reduce bile-duct injury and improve outcomes. Oxygenated machine preservation may restore mitochondrial function and reduce the ischaemia reperfusion injury, with the potential to reduce bile-duct injury resulting from the transplant process. In this multicentre trial, van Rijn et al. randomized livers from controlled DCD donors to conventional static cold storage or hypothermic oxygenated machine perfusion (HOPE). The primary endpoint was the incidence of symptomatic non-anastomotic biliary strictures up to 6 months post-transplant, which were subsequently confirmed on protocol magnetic resonance cholangiopancreatography (MRCP) by blinded radiologists. The authors demonstrate a significant reduction in the incidence of non-anastomotic strictures, along with reductions in post-reperfusion syndrome and early allograft dysfunction. There are obvious parallels between this study and the recent phase III trial of normothermic machine preservation (NMP) of the liver (1). The benefits of the two technologies appear similar, with similar magnitude in the effect on reperfusion injury and allograft dysfunction. The NMP study did not demonstrate a statistically significant difference in the incidence of biliary strictures, although the numerical difference was similar to the present study in the smaller DCD cohort. Perhaps the largest distinction between HOPE and NMP is not clinical outcome, but logistics. HOPE is a much more straightforward technology, not requiring a red-cell perfusate and with less monitoring required during perfusion. The potential for liver injury resulting from device malfunction is also lower as the liver is stored cold. However, the maximum perfusion time is shorter – NMP allows for perfusion for up to 24 hours, offering obvious logistical advantages in operating theatre management with the potential for daytime operating and multiple transplants. It will be interesting to see the results of future studies comparing the two technologies head-to-head, in particular exploring the effects on organ utilization from DCD donors. References 1. Nasralla D, Coussios CC, Mergental H, Akhtar MZ, Butler AJ, Ceresa CDL, Chiocchia V, Dutton SJ, García-Valdecasas JC, Heaton N, Imber C, Jassem W, Jochmans I, Karani J, Knight SR, Kocabayoglu P, Malagò M, Mirza D, Morris PJ, Pallan A, Paul A, Pavel M, Perera MTPR, Pirenne J, Ravikumar R, Russell L, Upponi S, Watson CJE, Weissenbacher A, Ploeg RJ, Friend PJ; Consortium for Organ Preservation in Europe. A randomized trial of normothermic preservation in liver transplantation. Nature. 2018 May;557(7703):50-56.
Aims:
The aim of this study was to compare the effect of hypothermic oxygenated machine perfusion with that of static cold preservation in recipients of liver transplants from donors after circulatory death.
Interventions:
Participants were randomised to either the machine-perfusion group or the control group.
Participants:
160 liver transplant patients aged ≥ 18 years.
Outcomes:
The primary outcome was the occurrence of nonanastomotic biliary strictures during a period of 6 months following transplantation. The secondary endpoints were graft-related and general complications.
Follow Up:
1 year
BACKGROUND:
Transplantation of livers obtained from donors after circulatory death is associated with an increased risk of nonanastomotic biliary strictures. Hypothermic oxygenated machine perfusion of livers may reduce the incidence of biliary complications, but data from prospective, controlled studies are limited.
METHODS:
In this multicenter, controlled trial, we randomly assigned patients who were undergoing transplantation of a liver obtained from a donor after circulatory death to receive that liver either after hypothermic oxygenated machine perfusion (machine-perfusion group) or after conventional static cold storage alone (control group). The primary end point was the incidence of nonanastomotic biliary strictures within 6 months after transplantation. Secondary end points included other graft-related and general complications.
RESULTS:
A total of 160 patients were enrolled, of whom 78 received a machine-perfused liver and 78 received a liver after static cold storage only (4 patients did not receive a liver in this trial). Nonanastomotic biliary strictures occurred in 6% of the patients in the machine-perfusion group and in 18% of those in the control group (risk ratio, 0.36; 95% confidence interval [CI], 0.14 to 0.94; P = 0.03). Postreperfusion syndrome occurred in 12% of the recipients of a machine-perfused liver and in 27% of those in the control group (risk ratio, 0.43; 95% CI, 0.20 to 0.91). Early allograft dysfunction occurred in 26% of the machine-perfused livers, as compared with 40% of control livers (risk ratio, 0.61; 95% CI, 0.39 to 0.96). The cumulative number of treatments for nonanastomotic biliary strictures was lower by a factor of almost 4 after machine perfusion, as compared with control. The incidence of adverse events was similar in the two groups.
CONCLUSIONS:
Hypothermic oxygenated machine perfusion led to a lower risk of nonanastomotic biliary strictures following the transplantation of livers obtained from donors after circulatory death than conventional static cold storage. (Funded by Fonds NutsOhra; DHOPE-DCD ClinicalTrials.gov number, NCT02584283.).
Dr Liset Pengel, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion:
The well-designed, multicentre, double-blind, randomised controlled trial compared oxygenated hypothermic machine perfusion (HMP) with standard (non-oxygenated) HMP in kidney pairs from DCD donors aged 50 and over with sites in Belgium, The Netherlands and United Kingdom. Kidneys from each pair were randomised according to a computer-generated sequence. Blinding was ensured by using empty dummy oxygen bottles in the standard HMP arm and all health care professionals and transplant recipients were blinded to the allocation. The sample size calculation showed that 81 pairs were needed to provide 90% power to show an 8 ml/min/1.73m² difference in the primary outcome estimated GFR. The primary analysis, based on intention-to-treat and ony including only kidney pairs for which both grafts were functioning at 12 months, showed no significant difference in eGFR. A sensitivity analysis that accounted for failed grafts and patient death showed a significantly higher eGFR in the oxygenated group. Graft failure was significantly lower in the oxygenated HMP group as was the number of biopsy-proven rejection episodes. The authors conclude that oxygenated HMP has the potential to improve clinical outcomes and reduce health-care costs.
Expert Review
Reviewer:
Mr John O'Callaghan, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Review:
The publication of this recent paper revisits the addition of oxygen to hypothermic machine perfusion (HMP). The trial was conducted across 19 European transplant centres in three countries (Belgium, the Netherlands and the United Kingdom). The trial was of a robust design, with double‐blinding, effective randomization and intention‐to‐treat analysis. In order to maximize the potential benefit, only donors over the age of 50 from Donation after Circulatory Death were included, and initially, they were analysed in paired fashion, one being allocated to receive oxygen and the other without. Possibly because of this analysis method, there was not significant evidence of improved GFR at 12 months after transplantation; kidney pairs where one kidney was lost or not transplanted could not be included in this analysis. However, graft failure at 12 months was significantly higher in the group without oxygen (10% vs. 3%) and severe complications were also significantly higher (11% vs. 8%). When including in the analysis kidneys from pairs where one kidney failed, GFR at 12 months was also significantly better for the group receiving oxygen. One standout, and unexpected result, was the significant reduction in acute rejection seen in the oxygenated group as well (14% vs. 26%). It is speculated that this may be related to the improved GFR at 12 months. This study demonstrates potential important clinical benefits of oxygenated HMP over standard HMP in this study cohort. The device used for perfusion was the Kidney Assist Transporter (Organ Assist BV, Groningen, the Netherlands), and no changes to perfusion settings were made once started. Machine perfusion was not possible in only 5% of kidneys retrieved and deemed suitable for transplantation at that point. The process of oxygenated perfusion is therefore straightforward and suitable for the majority of kidneys. Perfusion was maintained from retrieval to implantation, which may prove to be a logistical challenge for some centres or programmes, when transport of the machine has to be considered. The median cold ischaemic time was 10–11 h. It is unclear whether the potential benefit would be present with a shorter period of oxygenated perfusion after a period of either static cold storage or nonoxygenated cold perfusion. However, the addition of supplemental oxygen to HMP can be a simple process with the right equipment, is safe, feasible for many kidneys and may have significant clinical benefits.
Aims:
This study aimed to determine if supplemental oxygen during hypothermic machine perfusion (HMP) led to improvements in the outcome of kidneys donated following circulatory death.
Interventions:
One kidney from each donor was randomised to either oxygenated hypothermic machine perfusion (HMPO2) or HMP without oxygenation.
Participants:
197 kidney pairs were randomised.
Outcomes:
The primary endpoint was the estimated glomerular filtration rate (eGFR) at 12 months post-transplant. The secondary endpoints included patient survival and graft survival up at 12 months, primary non function, delayed graft function, renal function according to CKD-EPI and MDRD equations, acute rejection and safety outcomes.
Follow Up:
12 months
BACKGROUND:
Deceased donor kidneys are preserved in cold hypoxic conditions. Providing oxygen during preservation might improve post-transplant outcomes, particularly for kidneys subjected to greater degrees of preservation injury. This study aimed to investigate whether supplemental oxygen during hypothermic machine perfusion (HMP) could improve the outcome of kidneys donated after circulatory death.
METHODS:
This randomised, double-blind, paired, phase 3 trial was done in 19 European transplant centres. Kidney pairs from donors aged 50 years or older, donated after circulatory death, were eligible if both kidneys were transplanted into two different recipients. One kidney from each donor was randomly assigned using permuted blocks to oxygenated hypothermic machine perfusion (HMPO2), the other to HMP without oxygenation. Perfusion was maintained from organ retrieval to implantation. The primary outcome was 12-month estimated glomerular filtration rate (eGFR) using the Chronic Kidney Disease Epidemiology Collaboration equation in pairs of donated kidneys in which both transplanted kidneys were functioning at the end of follow-up. Safety outcomes were reported for all transplanted kidneys. Intention-to-treat analyses were done. This trial is registered with the ISRCTN Registry, ISRCTN32967929, and is now closed.
FINDINGS:
Between March 15, 2015, and April 11, 2017, 197 kidney pairs were randomised with 106 pairs transplanted into eligible recipients. 23 kidney pairs were excluded from the primary analysis because of kidney failure or patient death. Mean eGFR at 12 months was 50·5 mL/min per 1·73 m2 (SD 19·3) in the HMPO2 group versus 46·7 mL/min per 1·73m2 (17·1) in HMP (mean difference 3·7 mL/min per 1·73m2, 95% CI -1·0 to 8·4; p=0·12). Fewer severe complications (Clavien-Dindo grade IIIb or more) were reported in the HMPO2 group (46 of 417, 11%, 95% CI 8% to 14%) than in the HMP group (76 of 474, 16%, 13% to 20%; p=0·032). Graft failure was lower with HMPO2 (three [3%] of 106) compared with HMP (11 [10%] of 106; hazard ratio 0·27, 95% CI 0·07 to 0·95; p=0·028).
INTERPRETATION:
HMPO2 of kidneys donated after circulatory death is safe and reduces post-transplant complications (grade IIIb or more). The 12-month difference in eGFR between the HMPO2 and HMP groups was not significant when both kidneys from the same donor were still functioning 1-year post-transplant, but potential beneficial effects of HMPO2 were suggested by analysis of secondary outcomes.
Mr Simon Knight, Centre for Evidence in Transplantation, The Royal College of Surgeons of England.
Conclusion:
This small placebo-controlled study investigated the role of somatostatin in reducing the portal venous pressure during liver transplantation in patients with portal hypertension. Use of somatostatin resulted in a significant reduction in the hepatic venous portal gradient compared to placebo. No difference was seen in the severity of the ischaemia-reperfusion injury or in clinical outcomes. This study is interesting, but ultimately underpowered to detect any differences in meaningful clinical outcomes. It does, however, provide strong justification for a larger study of the use of somatostatin in this group, and also possibly in patients with portal hypertension undergoing liver resection. How it compares to standard surgical management of portal hypertension (e.g. shunting or splenic vein ligation) is also unclear and would need further study.
Expert Review
Reviewer:
Prof. Edward K. Geissler, PhD, University Hospital Regensburg, Department of Surgery, University of Regensburg, Regensburg, Germany
Conflicts of Interest:
No
Clinical Impact Rating
4
Review:
Somatostatin was administered to liver transplant recipients with severe portal hypertension from the time of transplant surgery until post-op day 5, in a 2:1 randomized (somatostatin: n=18 vs. placebo: n=11) double-blinded trial. Administration of somatostatin was safe in these portal hypertensive recipients, and there was 55% hemodynamic response rate, fulfilling the targeted endpoint; nearly a 30% decrease in hepatic venous portal gradient and portal flow was observed. Arterial flow to the graft was also preserved. No substantial effects on systemic hemodynamics developed with somatostatin treatment, and there was no evidence of late complications or apparent issues with graft or patient survival. Somatostatin could provide a valuable option in cases of small-for-size liver allografts, where surgical techniques are often needed to reduce graft perfusion. The temporary lowering of liver perfusion with somatostatin could also be useful in cases of substantial liver tumor resections. Finally, there was an apparent, albeit non-significant, decreased biliary stenosis incidence with somatostatin, warranting additional investigations. Therefore, this trial shows that somatostatin reduces the hepatic venous portal gradient while maintaining arterial flow to the liver in a liver transplant setting, potentially providing a pharmacological treatment to benefit allograft recipients, and oncology patients, experiencing clinically significant portal hypertension.
Aims:
To investigate the safety and efficacy of somatostatin (SST) as liver inflow modulator in patients with end-stage liver disease (ESLD) and clinically significant portal hypertension (CSPH) undergoing liver transplantation (LT).
Interventions:
Patients were randomized (2:1) to receive SST or placebo. Hepatic and systemic hemodynamics were measured, along with liver function tests and clinical outcomes. Ischemia-reperfusion injury (IRI) was analyzed through histological and protein expression analysis. Blood samples were taken daily for the first 7 postoperative days (PODs) and at POD 14. Further samples were obtained as required according to the patient’s clinical condition.
Participants:
33 adult liver transplant recipients with ESLD and CSPH.
Outcomes:
The primary endpoint was the hemodynamic response (defined as a 20% reduction of hepatic venous portal gradient (HVPG) in response to the SST bolus). Secondary endpoints included hemodynamic response, liver function tests and clinical outcomes in the short and long-term period.
Follow Up:
Median follow-up of 55.9 months (IQR 50.4–78).
OBJECTIVE: To investigate the safety and efficacy of somatostatin as liver inflow modulator in patients with end-stage liver disease (ESLD) and clinically significant portal hypertension (CSPH) undergoing liver transplantation (LT) (ClinicalTrials.gov number,01290172).
BACKGROUND: In LT, portal hyperperfusion can severely impair graft function and survival, mainly in cases of partial LT.
METHODS: Thirty-three patients undergoing LT for ESLD and CSPH were randomized double-blindly to receive somatostatin or placebo (2:1). The study drug was administered intraoperatively as 5-mL bolus (somatostatin: 500 mug), followed by a 2.5 mL/h infusion (somatostatin: 250 mug/h) for 5 days. Hepatic and systemic hemodynamics were measured, along with liver function tests and clinical outcomes. The ischemia-reperfusion injury (IRI) was analyzed through histological and protein expression analysis.
RESULTS: Twenty-nine patients (18 receiving somatostatin, 11 placebo) were included in the final analysis. Ten patients responded to somatostatin bolus, with a significant decrease in hepatic venous portal gradient (HVPG) and portal flow of -28.3% and -29.1%, respectively. At graft reperfusion, HVPG was lower in patients receiving somatostatin (-81.7% vs -58.8%; P = 0.0084), whereas no difference was observed in the portal flow (P = 0.4185). Somatostatin infusion counteracted the decrease in arterial flow (-10% vs -45%; P = 0.0431). There was no difference between the groups in the severity of IRI, incidence of adverse events, long-term complications, graft, and patient survival.
CONCLUSIONS: Somatostatin infusion during LT in patients with CSPH is safe, reduces the HVPG, and preserves the arterial inflow to the graft. This study establishes the efficacy of somatostatin as a liver inflow modulator.
Mr John O'Callaghan, Centre for Evidence in Transplantation, The Royal College of Surgeons of England.
Conclusion:
This is a very interesting study comparing T3 with T4 infusions in brain dead donors prior to cardiac allograft retrieval. Whilst the randomisation process was fair and the allocation concealment maintained, the infusions were not blinded to the study clinicians. The study was not powered for the number of hearts transplanted, but for the proportion of hearts with normalised Left Ventricular Ejection Fraction (LVEF) after infusion. Based on previous cases, the authors assumed a normalisation rate of 85% versus 44% using data from different time-periods to power their study. However, during the study, both arms had a normalisation rate of approximately 50%. During this study baseline T3 and T4 levels were not low in donors prior to infusions starting. More hearts from donors receiving T3 were ultimately transplanted, however there were significant differences in the baseline characteristics of the groups that may explain this phenomenon: younger donors, less with left ventricular hypertrophy, more blood group O donors. Overall this study is likely to be underpowered to test the hypothesis, and cardiac stunning seemed to resolve regardless of free T3 levels after infusion.
Expert Review
Reviewer:
David A. Baran, MD, FACC, FSCAI System Director, Advanced Heart Failure, Transplant and MCS Professor of Medicine, Eastern Virginia Medical School (Cardiology) Sentara Heart Hospital | 600 Gresham Dr | Norfolk, VA 23507 docbaran@gmail.com
Conflicts of Interest:
No
Clinical Impact Rating
4
Review:
Dhar and colleagues report the results of a prospective randomized trial of T3 versus T4 in the management of brain dead potential organ donors with hemodynamic instability despite protocol based fluid resuscitation. The authors are to be commended for performing donor research which is sorely lacking and is also quite challenging to perform. In all, they studied 37 donors out of 387 donors during a 2 year time period (9.6 %). The majority of donors were either too young or old (< 18 years or > 50 years old), or unable to randomize in less than 12 hours following brain death declaration. Of 387 donors, 71 were eligible for a run-in phase of the trial, and 52 % were actually randomized. Unfortunately, through the play of chance and small numbers, there were significant imbalances in baseline characteristics of the groups with the T3 group being younger with a better PaO2:FiO2 ratio. The authors found that hearts were more likely to be transplanted in the T3 group as well as lungs, but these differences did not meet statistical significance once adjusted for donor age and PaO2:FiO2 ratio. The improvement in left ventricular ejection fraction and reduction in vasopressor dose was comparable between groups as well. It is unclear why results on a cardiac trial would be adjusted for the PaO2:FiO2 ratio and in this case, it contributed to designating this a negative trial, perhaps avoidably so. Overall, the study was overtly underpowered especially to compare two treatments which both may have benefit compared to no hormonal therapy. The study illustrates the tremendous difficulty associated with donor research, even with an organ procurement organization that brings donors to a dedicated organ retrieval facility (so there is no variation between local donor hospitals). Future studies may consider removing the obstacles to enrollment such as the limitation of starting study drug within 12 hours of arrival at the procurement facility, and basing enrollment on donor left ventricular dysfunction rather than simply blood pressure and volume status. Other relevant questions remain including the utility of higher doses of T4 and T3, as well as a longer period of drug treatment. In conclusion, this intriguing study suggests that more work is warranted on the effect of thyroid hormone supplementation to increase the number of suitable donor hearts.
Aims:
To determine whether T3 infusion can improve cardiac performance, haemodynamic stability, and result in more hearts transplanted than standard T4 therapy in haemodynamically unstable heart-eligible brain dead (BD) organ donors.
Interventions:
Donors underwent echocardiography, within 12 hours of brain death and were randomised to T3 or T4 infusion for 8 hours.
Participants:
37 BD donors were randomised (n=16 T3 vs n=21 T4).
Outcomes:
Primary outcomes were assessed as incidence of myocardial dysfunction, improvement in left ventricular ejection fraction (LVEF) after 8 hours of treatment and proportion of donors with abnormal LVEF who achieve recovery to normal LVEF. Secondary outcomes comprised proportion of hearts that could be successfully transplanted, improvement in haemodynamic parameters and the change in free T3 and free T4 levels between groups after infusion.
Follow Up:
8 hours
RATIONALE:
Brain-dead (BD) organ donors frequently exhibit hemodynamic instability and/or reversible cardiac dysfunction. Retrospective studies have suggested that thyroid hormone may stabilize hemodynamics and enhance myocardial recovery. Intravenous levothyroxine (T4) is most frequently utilized but studies have suggested that triiodothyronine (T3) may be superior. We performed a randomized comparative-effectiveness trial to address this uncertainty in donor management.
METHODS:
All heart-eligible donors managed at a single OPO underwent standardized fluid resuscitation. If not weaned off vasopressors, donors underwent echocardiography (within 12 hours of BD) and were randomized to T3 or T4 infusion for eight hours.
RESULTS:
A total of 37 BD donors were randomized (16 T3 vs 21 T4). Baseline ejection fraction (EF) was comparable (median 38% vs 45%, P = 0.87) as was vasopressor dosage (6 vs 12 μg/min of norepinephrine, NE, P = 0.12). Reduction in NE dose and proportion weaned off vasopressors was similar and LVEF improved in both groups (repeat EF: 50% vs 52.5%, P = 0.38) with almost half attaining EF ≥55%. Although more hearts were transplanted in the T3 group (10/16 vs 6/21, P = 0.04), this difference did not persist after adjusting for baseline imbalances in age and PF ratio.
CONCLUSIONS:
Infusion of T3 does not appear to confer significant hemodynamic or cardiac benefits over T4 for hemodynamic unstable BD organ donors.
CET Conclusion