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. 2022 Apr 4;9:100077. doi: 10.1016/j.sipas.2022.100077

Role of normothermic machine perfusion in liver transplantation: Current trends and outcomes

Mahmoudreza Moein 1,†, Jonathan Capelin 1, Joseph F Toth 1, Dylan Tylor 1, Zoe M Weiss 1, Bhavani G Murugesan 1, Reza F Saidi 1,†,⁎
PMCID: PMC11750010  PMID: 39845073

Abstract

Background

Liver transplantation is the only known curative treatment option for end-stage liver diseases and failure; however, there is an imbalance between the number of available liver organs for transplant and the number of patients as recipients due to a shortage of suitable organs. In recent years, ex vivo liver machine perfusion has been introduced to liver transplantation to expand the donor organ pool. Studies showed that using normothermic machine perfusion can increase the pool of transplantable discarded livers and is a promising strategy to improve graft resilience and performance further.

Methods

A systematic literature search of PubMed and ClinicalTrials.gov registry was performed. A three-stage independent screening method was applied. Inclusion criteria for this review were published prospective, retrospective, clinical trials, and systematic reviews studies using normothermic machine perfusion devices.

Results

Twenty-two articles on normothermic liver machine perfusion with patients and graft survival rate were identified. These studies have demonstrated the safety and efficacy of normothermic liver machine perfusion for discarded liver preservation in both standard and expanded criteria donors following patients and graft follow-ups. The overall number of livers that went under NMP was 568 in all the studies in which 503 of the livers were transplanted (88.6%). The 30,90,180 days and 1-year patients and grafts survival rates were promising.

Conclusion

Normothermic machine perfusion is a novelty method recently being used in liver transplantation and can lead to the expansion of the liver donor pool by revitalizing discarded livers. Our study was able to show the promising outcomes for both patients and grafts, which were achieved in many human clinical studies around the world using normothermic machine perfusion as a method of liver preservation and revitalization.

Keywords: Liver, transplant, normothermic machine perfusion, discarded, outcomes, survival

Nomenclature

ECD

Extended criteria donors

DCD

Donation after cardiac death

IRI

Ischemic reperfusion injury

SCS

Static cold storage

MP

Machine perfusion

NMP

Normothermic machine perfusion

SNMP

Sub normothermic machine perfusion

HMP

Hypothermic machine perfusion

PRISMA-P

Preferred reporting items for systematic reviews and meta-analysis for protocol 2015

D-HOPE

Dual hypothermic oxygenated machine perfusion

PNF

Primary non function

EAD

Early allograft dysfunction

AST

Aspartate aminotransferase

Introduction

Liver transplantation (LT) is a lifesaving treatment for selected patients with end-stage liver disease, primary liver cancer, and fulminant hepatic failure. The incidence of liver disease has increased around 500% during the last 4-5 decades. [1], [2], [3]

LT has a 5-year patient and graft survival rate of more than 80%. However, organ shortage remains a global problem that eliminates about 11% of patients on waiting lists due to death or worsening conditions. [4], [5], [6] The United States Organ Procurement and Transplantation Network 2016 national data found that 1,104 patients died while waiting for a liver transplant, and a further 1,317 were removed from the list as their eligibility for the transplantation was changed. [6] The global shortage in donor organ pools has driven centers to use extended criteria donors (ECD), including elderly and donation after cardiac death (DCD), as well as organs from donors with actively infected hepatitis C virus. [6]

The rate of organ donations has increased over the last decade mainly because of including high-risk, so-called 'marginal donors' such as DCD and old donors. [7] Many studies showed that marginal organs have greater vulnerability to ischemia-reperfusion injury (IRI), an inevitable process during organ transplantation. [4,[8], [9], [10]] Revitalizing the discarded and marginal livers can expand the donor pool available liver allograft for transplantation.

Static cold storage in a specialized preservation solution is the standard technique for preserving donor organs between recovery and implantation. Although studies show that static cold storage has promising results for optimal donor organs, it is less suitable for marginal and high-risk organs. The reason is that marginal organs have a greater tendency for ischemia-reperfusion injuries, and there is no way for organ viability assessment in this group. Investigators worldwide are working on new preservation methods to expand the donor criteria and organ pools by improving the viability of high-risk organs without compromising outcomes. [7,[11], [12], [13]]

Normothermic machine perfusion (NMP) of the liver is a new technology developed to reduce ischemic damage and provide better organ preservation than static cold storage techniques. The most important advantages of NMP include the following:

  • 1.-

    Reducing the chance of ischemia/reperfusion injury.

  • 2.-

    The ability of liver function assessment prior to the transplantation.

  • 3.-

    Improvement of transplant logistics.

  • 4.-

    The ability for interventions and using medications to recondition the liver. [14]

The purpose of introducing NMP for use in clinical practice was to minimize IRI and its effects on the liver graft, enabling successful preservation and functional testing of the organ especially marginal and high-risk livers, improving the logistics of transplantation by prolonging the preservation time up to 24 hours, and at the end, increasing the number of livers transplanted. [4] This effort leads to a liver donor pool expansion by the resuscitation of the discarded liver with normothermic machine perfusion, which was excluded by donation criteria. [15]

NMP can maintain the metabolic activity of the liver at the body temperature and remove the harmful substances produced following ischemic injuries of grafts.[16,17] Several animal experiments and clinical trials have shown that compared to SCS, NMP shows a higher level of liver grafts protection.[16,18,19]

Another important advantage of normothermic perfusion over static cold storage preservation and hypothermic perfusion is the ability of full metabolic support and the possibility to assess graft viability and functionality prior to the transplantation. In addition, pharmacological conditioning and intervention are possible during NMP, which can help to increase the viability of the organ.[20,21]

This systematic review aims to provide a summary of the literature on normothermic liver machine perfusion, focusing on patients and graft survival rate and a possible new direction in the future of liver preservation and transplantation.

Methods

Search strategy

A systematic literature review was performed following the Preferred Reporting Items for Systematic reviews and Meta-Analyses for Protocols 2015 (PRISMA-P) (Fig. 1). A wide-ranging screening of the National Library of Medicine Database and google scholar was performed on September 8, 2021, and last updated on December 4, 2021, to identify literature on liver preservation using normothermic machine perfusion (NMP) survival rate. The following search queries were performed:

  • 1.-

    "Liver transplant AND Machine AND human."

  • 2.-

    " Liver transplant AND normothermic AND human."

Fig. 1.

Fig 1

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Flowchart of the performed systematic literature research

Additionally, the ClinicalTrials.gov registry of the US National Library of Medicine was searched on September 8, 2021, for the following MeSH terms:

“Normothermic Machine Perfusion AND Liver Transplantation”

Inclusion and Exclusion criteria

Articles meeting inclusion criteria for this review were published prospective, retrospective, clinical trials, and systematic reviews studies using normothermic machine perfusion device for organ preservation in liver transplantation. Letters and video articles were excluded. Also, follow-up studies on sub-normothermic, hypothermic, or normothermic, which reported no further information on postoperative outcomes of the respective recipients, were excluded.

Data extraction

A three-stage independent screening method was applied by one of the authors (MM). In discordance, the corresponding author RS was consulted, and the consensus was made via discussion. During stage one of data extraction, the titles and abstracts of all retrieved records were reviewed, and unsuitable studies were excluded. During stage two, full-text articles of the remaining studies were read carefully and assessed for inclusion criteria, and studies without clinical trials were excluded.

During stage three, Articles without patients’ post-operation survival rates were excluded. Extracted data were reviewed and analyzed by both authors.

Results

A systematic literature search of the National Library of Medicine database identified 2665 records. Based on to title and abstract, 2483 papers were excluded, and 182 articles went for complete text analysis. Of these, 114 publications did not meet the inclusion criteria. The remaining 68 articles all worked on the effect of normothermic machine perfusion on liver preservation. Finally, based on the inclusion criteria, 22 articles that had patients and graft survival rates after using normothermic machine perfusion to preserve liver function were included in this systematic review.

The overall number of livers that went under NMP were 568 in all the studies which 503 of the livers were transplanted (88.6%) . The 30 days patients and graft survival rate were obtained in 265 transplants, and it was from 90-100 %.[7,11,16,[22], [23], [24], [25],[27], [28], [29], [30], [31],33,35,[37], [38], [39]] The 90 days patients and graft survival rate were obtained in 134 transplants, and it was from 94-100 %. [11,16,[22], [23], [24], [25],30,31,33,35,37,39] The 180 days patients and graft survival rate were obtained in 103 transplants, and it was from 89-100 %. [7,11,[22], [23], [24],30,31,33,37,39] The one-year patients survival rate was obtained in 325 transplants, and it was from 81-100% [11,19,23,26,28,32,36,38,39] and the one-year graft survival rate was obtained in 294 transplants, and it was from 81-100%.[11,19,23,26,[32], [34],36,38,39]

Mergental et al.'s study showed that normothermic machine perfusion could be used as a liver viability assessment modality to predict the long-term outcome of the grafted liver that was preserved with normothermic machine perfusion. They were able to follow up their patients for 24 months, and the patients and graft survival rate was 86.4% after 12 months and 81.2% at the 24 months. [39]

Nasralla et al. was the first randomized clinical trial for assessing normothermic machine perfusion function and its survival outcome, with the largest number of cases. They were able to transplant 121 livers out of 137 livers preserved with normothermic machine perfusion, and the patient survival rate was 95.8%, and graft survival rate was 95% after 12 months follow up. The causes of graft failure in the NMP transplanted livers were hepatic artery thrombosis (n = 2), ischemic cholangiopathy (n = 1), non-thrombotic infarction (n = 1), inferior vena cava occlusion (n = 1) and PNF (n = 1). Nasralla et al.'s study showed a significant reduction in peak AST and EAD rates, both clinically accepted biomarkers for the long-term patient and graft survival rates. They were also able to show that the amount of reduction in peak AST and EAD was accelerated in the context of improving organ utilization and longer organ preservation. [19] Liu et al.'s study showed that not only using fresh frozen plasma in normothermic machine perfusion is feasible and safe, but also it reduces the incidence of EAD.

One of their patients died of intracranial hemorrhage on postoperative months 8 with normal liver function. In 12-35 months post-operation, their study survival rate was 95.24% for patients and 100% for the grafts. [32]

Seidita et al.'s study was the only study that was able to follow up the patients for 3 years, and the 3 years patient and graft survival rate was 82%.[37]

Below is a summarized patient and graft survival rate chart [Fig 2]. Charts A, B, C, D show the patients' and grafts survival rates after 30,90,180 days and 1-year follow-ups. [Fig. 3] shows the number of cases in each study that went under NMP and the number of perfused livers that were transplanted.

Fig. 2.

Fig 2:

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(A) 30 days patient and graft survival rate, (B) 90 days patient and graft survival rate, (C) 180 days patient and graft survival rate, (D) 1- year patient and graft survival rate.

Fig. 3.

Fig 3:

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*Total number of livers went under normothermic machine perfusion (Total number of livers were transplanted after normothermic machine perfusion preservation).

Discussion

Organ preservation is a significant step to improve transplantation outcomes. During the past decade, there have been many studies on the organ functionality out of the body and how to help preserve it. Many studies showed that a dynamic intervention by perfusion not only expanded the donor pool but also it can help to improve the organ quality before transplantation, which resulted in a better long-term outcome. [40]. The most significant challenge facing the field of organ transplantation today is increasing the number of allografts available for transplant. Various approaches have been implemented to expand the organ donor pool, including increased live donation, a national effort to expand deceased donor donation, split organ donation, paired donor exchange, national sharing models, and greater use of expanded criteria donors. [41]

The first technique introduced for preserving donor organs was static cold storage (SCS) which is currently still the standard technique. SCS offers a simple and effective solution, and it is the standard method being used due to its accessibility and simplicity, but it cannot answer the demand for organ transplantation. Optimized organ preservation can help expand the donor pool by optimizing and improving the function of so-called marginal livers. In recent years, the focus of many studies has been to develop a modality for better and optimized organ preservation and conditioning.

Machine Perfusion (MP) has been introduced as a promising modality to improve marginal organs functionality. Compared to the SCS, MP can prolong the storage time and limit the damages during the cold ischemia phase. It can also reverse some of these damages and provide a similar body physiologic condition to help the organ continue its functionality. [42], [43], [44]

Machine perfusion can resuscitate the discarded livers and suppress some inflammatory responses, which minimizes post-transplant complications and better long-term outcomes. As a result, many previously discarded livers become usable, which leads to donor organ pool expansion and helps increase the number of liver transplantation, which is necessary to overcome the imbalance between the number of recipients in waiting lists and the number of available donors’ livers.

Currently, there are 3 main subtypes for liver machine perfusion techniques:

  • 1.-

    Normothermic machine perfusion (NMP)

  • 2.-

    Sub normothermic machine perfusion (SNMP)

  • 3.-

    Hypothermic machine perfusion (HMP)

Sub-normothermic and hypothermic machine perfusion (SNMP and HMP) of the liver needs a red blood cell-free solution containing oxygen, which can be delivered separately via the portal vein or the portal vein and hepatic artery together at the same time (dual hypothermic oxygenated perfusion, D-HOPE). Hypothermic machine perfusion has some intrinsic safety, and also studies showed that it could lower the risk of the post-reperfusion syndrome and early allograft dysfunction, but on the other side, liver metabolism would be suppressed, and the liver cannot produce bile during hypothermic machine perfusion preservation method.[46,47]

Normothermic Machine perfusion (NMP) is a new technology modality that has been used recently in liver preservation with the potential to be a game-changer in liver transplantation, especially in discarded livers and extending the donation criteria. Normothermic machine perfusion can restore and maintain normal liver function at body temperature. [[45], [46]] NMP also allows the surgeon and transplant team to assess liver function and predict the quality of the donor organ by considering some metabolic and dynamic parameters and safety of the organ for transplantation which is the most significant advantage of NMP compared to the traditional SCS technique. [6]

The importance of these function assessments and outcome predictions shows itself in marginal and currently discarded livers that hold the most promise for the liver transplantation pool expansion.

During ex vivo normothermic MP (NMP), the liver perfuses with an oxygenated red blood cell-based perfusion solution at the average body temperature (35.5–37.5°C), which simulates the normal body physiology. One of the significant advantages of this method is the ability to add different compounds, nutrition, and even medications to the solution to improve the liver functionality and the outcome of the transplantation. [46]

In the present review, we demonstrated the long-term outcome of patients and grafts survival rate using NMP before transplantation. Although the number of cases and the duration of follow-ups are limited as NMP is a newly used method for liver preservation, the current data is promising. Nasralla et al. demonstrated a 50% lower rate of organ discard with NMP than with cold storage (CS), despite longer warm ischemic and total preservation times[19]. In their study, Mac Conmara et al. showed that NMP technology is associated with significantly reduced rates of liver discard in the United States. According to their research, the percentage of the discarded liver after cold storage preservation was 13.3% and 3.5 % in the NMP group, which shows a 9.8% reduction in the number of discarded livers in NMP.[48] Interestingly, this reduction was seen even though NMP donor profiles had more significant risk factors for a potential discard. The positive impact of NMP on liver utilization and functionality resulted in some discussion and arguments throughout the Unites States for the possible chance of integrating this practice into the current clinical strategies.

Although the results from all the studies about the efficacy of normothermic machine perfusion in liver preservation are promising in terms of patients' and graft survival rates, some limitations still need further assessments and investigations. Randomized clinical trials can eliminate important biases in the studies, which results in more accurate data collection and outcomes. Due to the shortage of overall available livers for transplantation and the limited number of liver transplant centers, designing a randomized clinical trial needs a strict plan and the collaboration of liver transplant centers for a multi-institutional project. Also, there are some logistic limitations for the normothermic machines. Currently, a few companies make normothermic machines and have different protocols and settings for their devices. Still, some studies are needed to establish the best setting for the NMP, which can improve the overall outcome of patients and grafts survival rates and reduce post transplants complications.

In conclusion, normothermic machine perfusion is a newly used technology in the liver transplant field with a great potential to expand the donor pool by extending the donor criteria, especially for discarded livers. The constant challenges of persistent organ shortage and ongoing donor demographic changes threaten the quality and quantity of the available liver grafts. Integrating this new technology in practice can help to overcome these challenges. Considering the novelty of this new technique, it is still critical to continue observing the underlying mechanisms that lead to the clinical changes and the possibility of expanding the use of this technique for treatment and reconditioning of marginal and discarded donor livers. [49]

The article was revised for grammar and language errors by two different software and all the errors were corrected.

Author Contributions

Both authors have contributed equally to study conception and design, data collection, and manuscript drafting.

Conflict of interest

Authors declare that they do not have any personal or financial conflicts of interest.

Funding statement

The authors declare that there was no source of funding for this project.

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