Normothermic machine perfusion for liver transplantation: current state and future directions.

PURPOSE OF REVIEW: The number of patients on the liver transplant waitlist continues to grow and far exceeds the number of livers available for transplantation. Normothermic machine perfusion (NMP) allows for ex-vivo perfusion under physiologic conditions with the potential to significantly increase organ yield and expand the donor pool. RECENT FINDINGS: Several studies have found increased utilization of donation after cardiac death and extended criteria brain-dead donor livers with implementation of NMP, largely due to the ability to perform viability testing during machine perfusion. Recently, proposed viability criteria include lactate clearance, maintenance of perfusate pH more than 7.2, ALT less than 6000 u/l, evidence of glucose metabolism and bile production. Optimization of liver grafts during NMP is an active area of research and includes interventions for defatting steatotic livers, preventing ischemic cholangiopathy and rejection, and minimizing ischemia reperfusion injury. SUMMARY: NMP has resulted in increased organ utilization from marginal donors with acceptable outcomes. The added flexibility of prolonged organ storage times has the potential to improve time constraints and transplant logistics. Further research to determine ideal viability criteria and investigate ways to optimize marginal and otherwise nontransplantable liver grafts during NMP is warranted.

Thoraco-abdominal normothermic regional perfusion for thoracic transplantation in the United States: current state and future directions.

PURPOSE OF REVIEW: To provide an update regarding the state of thoracoabdominal normothermic regional perfusion (taNRP) when used for thoracic organ recovery. RECENT FINDINGS: taNRP is growing in its utilization for thoracic organ recovery from donation after circulatory death donors, partly because of its cost effectiveness. taNRP has been shown to yield cardiac allograft recipient outcomes similar to those of brain-dead donors. Regarding the use of taNRP to recover donor lungs, United Network for Organ Sharing (UNOS) analysis shows that taNRP recovered lungs are noninferior, and taNRP has been used to consistently recover excellent lungs at high volume centers. Despite its growth, ethical debate regarding taNRP continues, though clinical data now supports the notion that there is no meaningful brain perfusion after clamping the aortic arch vessels. SUMMARY: taNRP is an excellent method for recovering both heart and lungs from donation after circulatory death donors and yields satisfactory recipient outcomes in a cost-effective manner. taNRP is now endorsed by the American Society of Transplant Surgeons, though ethical debate continues.

Abdominal normothermic regional perfusion in the United States: current state and future directions.

PURPOSE OF REVIEW: Normothermic regional perfusion (NRP) is a novel procurement technique for donation after circulatory death (DCD) in the United States. It was pioneered by cardiothoracic surgery programs and is now being applied to abdominal-only organ donors by abdominal transplant programs. RECENT FINDINGS: Liver and kidney transplantation from thoracoabdominal NRP (TA-NRP) donors in the United States was found to have lower rates of delayed kidney graft function and similar graft and patient survival versus recipients of cardiac super rapid recovery (SRR) DCD donors. The excellent outcomes with NRP have prompted the expansion of NRP technology to abdominal transplant programs. SUMMARY: Excellent early outcomes with liver and kidney transplantation have prompted the growth of NC-NRP procurement for abdominal-only DCD donors across the US, and now requires standardization of technical and nontechnical aspects of this procedure.

Research progress on hepatic machine perfusion.

Nowadays, liver transplantation is the most effective treatment for end-stage liver disease. However, the increasing imbalance between growing demand for liver transplantation and the shortage of donor pool restricts the development of liver transplantation. How to expand the donor pool is a significant problem to be solved clinically. Many doctors have devoted themselves to marginal grafting, which introduces livers with barely passable quality but a high risk of transplant failure into the donor pool. However, existing common methods of preserving marginal grafts lead to both high risk of postoperative complications and high mortality. The application of machine perfusion allows surgeons to make marginal livers meet the standard criteria for transplant, which shows promising prospect in preserving and repairing donor livers and improving ischemia reperfusion injury. This review summarizes the progress of recent researches on hepatic machine perfusion.

Changing Trends in Liver Transplantation: Challenges and Solutions.

Despite improvements in postliver transplant outcomes through refinements in perioperative management and surgical techniques, several changing trends in liver transplantation have presented challenges. Mortality on the waitlist remains high. In the United States, Europe, and the United Kingdom, there is an increasing need for liver transplantation, primarily as a result of increased incidence of nonalcoholic steatohepatitis-related cirrhosis and cancer indications. Meanwhile, donor suitability has decreased, as donors are often older and have more comorbidities. Despite a mismatch between organ need and availability, many organs are discarded. Notwithstanding this, many solutions have been developed to overcome these challenges. Innovative techniques in allograft preservation, viability assessment, and reconditioning have allowed the use of suboptimal organs with adequate results. Refinements in surgical procedures, including live donor liver transplantations, have increased the organ pool and are decreasing the time and mortality on the waitlist. Despite many challenges, a similar number of solutions and prospects are on the horizon. This review seeks to explore the changing trends and challenges in liver transplantation and highlight possible solutions and future directions.

Heart transplant outcomes in patients with mechanical circulatory support: cold storage versus normothermic perfusion organ preservation.

OBJECTIVES: Patients with mechanical circulatory support bridged to a heart transplant (HTx) are at higher risk of postoperative graft dysfunction. In this subset, a mode of graft preservation that shortens graft ischaemia should be beneficial. METHODS: The outcomes of 38 patients on mechanical circulatory support (extracorporeal life support, left ventricular assist device and biventricular assist device) who received a HTx between 2015 and 2020 were analysed according to the method of graft preservation: cold storage (CS) group, 24 (63%) or ex vivo perfusion (EVP) group, 14 (37%). RESULTS: The median age was 57 (range 30-73) vs 64 (35-75) years (P = 0.10); 88% were men (P = 0.28); extracorporeal life support was more frequent in the CS group (54% vs 36%; P = 0.27) versus left ventricular and biventricular assist devices in the EVP group (46% vs 64%; P = 0.27). Clamping time was shorter in the EVP group (P < 0.001) and ischaemic time >4 h was higher in the CS group (P = 0.01). Thirty-day mortality was 13% (0-27%) in the CS group and 0% (P = 0.28) in the EVP group. A significantly lower primary graft failure [7% (0-23%) vs 42% (20-63%); P = 0.03] was observed in the EVP group. Survival at 1 year was 79 ± 8% (63-95%) in the CS group and 84 ± 10% (64-104%) in the EVP group (P = 0.95). CONCLUSIONS: Our results support the use of ex vivo graft perfusion in patients on mechanical circulatory support as a bridge to a HTx. This technique, by shortening graft ischaemic time, seems to improve post-HTx outcomes.

Ex situ heart perfusion: The past, the present, and the future.

Despite the advancements in medical treatment, mechanical support, and stem cell therapy, heart transplantation remains the most effective treatment for selected patients with advanced heart failure. However, with an increase in heart failure prevalence worldwide, the gap between donor hearts and patients on the transplant waiting list keeps widening. Ex situ machine perfusion has played a key role in augmenting heart transplant activities in recent years by enabling the usage of donation after circulatory death hearts, allowing longer interval between procurement and implantation, and permitting the safe use of some extended-criteria donation after brainstem death hearts. This exciting field is at a hinge point, with 1 commercially available heart perfusion machine, which has been used in hundreds of heart transplantations, and a number of devices being tested in the pre-clinical and Phase 1 clinical trial stage. However, no consensus has been reached over the optimal preservation temperature, perfusate composition, and perfusion parameters. In addition, there is a lack of objective measurement for allograft quality and viability. This review aims to comprehensively summarize the lessons about ex situ heart perfusion as a platform to preserve, assess, and repair donor hearts, which we have learned from the pre-clinical studies and clinical applications, and explore its exciting potential of revolutionizing heart transplantation.

Ex Vivo Lung Perfusion: Current Achievements and Future Directions.

There is a severe shortage in the availability of donor organs for lung transplantation. Novel strategies are needed to optimize usage of available organs to address the growing global needs. Ex vivo lung perfusion has emerged as a powerful tool for the assessment, rehabilitation, and optimization of donor lungs before transplantation. In this review, we discuss the history of ex vivo lung perfusion, current evidence on its use for standard and extended criteria donors, and consider the exciting future opportunities that this technology provides for lung transplantation.

[Advances in supercooling liver preservation].

Liver transplantation is currently the only effective treatment for end-stage liver disease. The preservation of donor liver before transplantation is important. But both traditional static cold storage and machine perfusion are limited by the preservation time, so that the allotment space of donor liver is limited, which inevitably leads to the abandonment of part of donor liver.At present, to find a preservation technology that not only guarantees the quality of donor liver but also has a longer effective preservation time is the direction of joint efforts of all clinicians. Supercooling liver preservation(SLP) to find a preservation technology that not only guarantees the quality of donor liver but also has a longer effective preservation time is the direction of joint efforts of all clinicians. SLP, a new method based on using cryoprotectants to keep donor liver under -6 ℃ and recovering the graft with subnormothermic machine perfusion that enables long-term transplantation survival following 4 days of liver preservation, made a revolutionary breakthrough in the field of liver preservation, carved out a new field for the research of liver preservation. This article reviews the latest experimental research progress of SLP in the field of liver transplantation.

Normothermic Preservation of Liver - What Does the Future Hold?

Recent years have demonstrated a surging interest in normothermic ex situ liver perfusion, with iterative experimental and clinical studies establishing this technology as providing obvious advantages over static cold storage. In particular, the safe prolongation of liver graft preservation even up to 1 week opens up possibilities of 'on circuit' interventions, which may radically change the logistics and scope of liver transplant practice. Such approaches are rife with potential, and have yet to be fully explored. Possibilities may include, but are not limited to mitochondrial enhancing strategies, steatotic graft defatting, on circuit addition of anti-aging compounds, altering graft immunogenic potential and gene silencing with siRNA, stem cell and nanoparticle therapies as well as ischemia free liver preservation. Ex situ machine perfusion technology as a platform for advanced graft modification strategies opens up the possibility of very specific, personalized transplant medicine, as well as the possibility of a future where organ grafts are re-used and repaired, providing utility to numerous successive surgical recipients, indefinitely.

What Is Hot and New in Basic and Translational Science in Liver Transplantation in 2019? Report of the Basic and Translational Research Committee of the International Liver Transplantation Society.

The International Liver Transplantation Society (ILTS) 2019 Annual Congress was held in Toronto, Canada, in May 2019. Members of the ILTS Basic and Translational Research Committee attended all sessions of the meeting and selected the most promising, innovative, and novel research presented. A total of 900 abstracts were presented at the meeting. The percentage of abstracts presented at the ILTS Congress that contains basic or translational research continues to increase, accounting for 15% of all the abstracts in 2019, up from 10% in 2018. Here, we summarize the "what's hot what's new" in 5 main themes: liver immunobiology and tolerance, ischemia/reperfusion injury and organ preservation, bioengineering and liver regeneration, hepatic primary tumor biology, and pathophysiology of liver failure.

Pumping new life into old ideas: Preservation and rehabilitation of the liver using ex situ machine perfusion.

Recent advances in machine perfusion technology have reinvigorated the field of liver transplantation with the possibilities of vastly improving the efficiency and safety of the life-saving procedure. With this improved preservation technology, transplant surgeons are now able to use previously untransplantable donor livers without significantly compromising patient outcomes. Early clinical studies demonstrate the ability to extend preservation times and assess a graft's potential viability using normothermic machine perfusion, in addition to restoring the energy supply in donor livers by supporting metabolism through circulation of vital nutrients and blood-based oxygen carriers. Future endeavors for surgeons and scientists should focus on improving criteria to assess viability, optimizing protocols for perfusion research, investigating mechanisms of poor graft viability, and targeting these mechanisms with novel therapies to improve graft function prior to transplantation. Long-term goals include extending preservation times on the scale of days to weeks, enabling long-distance organ sharing, and establishing regional organ perfusion centers to streamline the procurement, perfusion, and transplantation process.

2018 Clinical Update in Liver Transplantation.

Liver transplantation (LT) continues to be the gold standard for treating end-stage liver disease, and challenges that are posed to the anesthesiologist during transplantation are well known. Successful liver transplantation requires knowledge, recognition, and treatment of hemodynamic and metabolic disturbances by the anesthesiologist. End-stage liver disease causes unique derangements to the clotting cascade, increasing risk both for hemorrhagic and thrombotic events. Cirrhotic cardiomyopathy may be masked for years because of low systemic vascular resistance in cirrhosis, and overt heart failure can be precipitated by LT. Surveys of high-volume transplant centers show an overall transesophageal echocardiography (TEE) use rate of 95%. Guidelines on the use of TEE in LT have mirrored safety findings in several studies and suggest TEE may be used for patients with esophageal varices if the benefit outweighs the risk. This review will cover organ system dysfunction in liver cirrhosis and the implications for liver cirrhosis patients and review recent advances in pathophysiology and treatments. In addition, the authors will highlight the concept of enhanced recovery after surgery and how it pertains to the LT patient population. Lastly, the authors review recent advances in organ preservation and optimization.

Emerging technologies in organ preservation, tissue engineering and regenerative medicine: a blessing or curse for transplantation?

Since the beginning of transplant medicine in the 1950s, advances in surgical technique and immunosuppressive therapy have created the success story of modern organ transplantation. However, today more than ever, we are facing a huge discrepancy between organ supply and demand, limiting the potential for transplantation to save and improve the lives of millions. To address the current limitations and shortcomings, a variety of emerging new technologies focusing on either maximizing the availability of organs or on generating new organs and organ sources hold great potential to eventully overcoming these hurdles. These advances are mainly in the field of regenerative medicine and tissue engineering. This review gives an overview of this emerging field and its multiple sub-disciplines and highlights recent advances and existing limitations for widespread clinical application and potential impact on the future of transplantation.

Management of the brain-dead donor in the ICU: general and specific therapy to improve transplantable organ quality.

PURPOSE: To provide a practical overview of the management of the potential organ donor in the intensive care unit. METHODS: Seven areas of donor management were considered for this review: hemodynamic management; fluids and electrolytes; respiratory management; endocrine management; temperature management; anaemia and coagulation; infection management. For each subchapter, a narrative review was conducted. RESULTS AND CONCLUSIONS: Most elements in the current recommendations and guidelines are based on pathophysiological reasoning, epidemiological observations, or extrapolations from general ICU management strategies, and not on evidence from randomized controlled trials. The cardiorespiratory management of brain-dead donors is very similar to the management of critically ill patients, and the same applies to the management of anaemia and coagulation. Central diabetes insipidus is of particular concern, and should be diagnosed based on clinical criteria. Depending on the degree of vasopressor dependency, it can be treated with intermittent desmopressin or continuous vasopressin, intravenously. Temperature management of the donor is an area of uncertainty, but it appears reasonable to strive for a core temperature of > 35 °C. The indications and controversies regarding endocrine therapies, in particular thyroid hormone replacement therapy, and corticosteroid therapy, are discussed. The potential donor should be assessed clinically for infections, and screening tests for specific infections are an essential part of donor management. Although the rate of infection transmission from donor to receptor is low, certain infections are still a formal contraindication to organ donation. However, new antiviral drugs and strategies now allow organ donation from certain infected donors to be done safely.

Organ donation after circulatory death: current status and future potential.

The continuing shortage of deceased donor organs for transplantation, and the limited number of potential donors after brain death, has led to a resurgence of interest in donation after circulatory death (DCD). The processes of warm and cold ischemia threaten the viability of DCD organs, but these can be minimized by well-organized DCD pathways and new techniques of in situ organ preservation and ex situ resuscitation and repair post-explantation. Transplantation survival after DCD is comparable to donation after brain death despite higher rates of primary non-function and delayed graft function. Countries with successfully implemented DCD programs have achieved this primarily through the establishment of national ethical, professional and legal frameworks to address both public and professional concerns with all aspects of the DCD pathway. It is unlikely that expanding standard DCD programs will, in isolation, be sufficient to address the worldwide shortage of donor organs for transplantation. It is therefore likely that reliance on extended criteria donors will increase, with the attendant imperative to minimize ischemic injury to candidate organs. Normothermic regional perfusion and ex situ perfusion techniques allow enhanced preservation, assessment, resuscitation and/or repair of damaged organs as a way of improving overall organ quality and preventing the unnecessary discarding of DCD organs. This review will outline exemplar controlled and uncontrolled DCD pathways, highlighting practical and logistical considerations that minimize warm and cold ischemia times while addressing potential ethical concerns. Future perspectives will also be discussed.