scholarly journals Thrombolytic Therapy During ex-vivo Normothermic Machine Perfusion of Human Livers Reduces Peribiliary Vascular Plexus Injury

2021 ◽  
Vol 8 ◽  
Author(s):  
Omar Haque ◽  
Siavash Raigani ◽  
Ivy Rosales ◽  
Cailah Carroll ◽  
Taylor M. Coe ◽  
...  
Keyword(s):  
Hepatic Artery ◽  
Biliary Complications ◽  
Machine Perfusion ◽  
Biliary Injury ◽  
Vascular Plexus ◽  
Liver Model ◽  
Increased Risk ◽  
Normothermic Machine Perfusion ◽  
Human Livers ◽  
D Dimer

Background: A major limitation in expanding the use of donation after circulatory death (DCD) livers in transplantation is the increased risk of graft failure secondary to ischemic cholangiopathy. Warm ischemia causes thrombosis and injury to the peribiliary vascular plexus (PVP), which is supplied by branches of the hepatic artery, causing higher rates of biliary complications in DCD allografts.Aims/Objectives: We aimed to recondition discarded DCD livers with tissue plasminogen activator (tPA) while on normothermic machine perfusion (NMP) to improve PVP blood flow and reduce biliary injury.Methods: Five discarded DCD human livers underwent 12 h of NMP. Plasminogen was circulated in the base perfusate prior to initiation of perfusion and 1 mg/kg of tPA was administered through the hepatic artery at T = 0.5 h. Two livers were split prior to perfusion (S1, S2), with tPA administered in one lobe, while the other served as a control. The remaining three whole livers (W1-W3) were compared to seven DCD control liver perfusions (C1-C7) with similar hepatocellular and biliary viability criteria. D-dimer levels were measured at T = 1 h to verify efficacy of tPA. Lactate, total bile production, bile pH, and difference in biliary injury scores before and after perfusion were compared between tPA and non-tPA groups using unpaired, Mann-Whitney tests.Results: Average weight-adjusted D-dimer levels were higher in tPA livers in the split and whole-liver model, verifying drug function. There were no differences in perfusion hepatic artery resistance, portal vein resistance, and arterial lactate between tPA livers and non-tPA livers in both the split and whole-liver model. However, when comparing biliary injury between hepatocellular and biliary non-viable whole livers, tPA livers had significantly lower PVP injury scores (0.67 vs. 2.0) and mural stroma (MS) injury scores (1.3 vs. 2.7).Conclusion: This study demonstrates that administration of tPA into DCD livers during NMP can reduce PVP and MS injury. Further studies are necessary to assess the effect of tPA administration on long term biliary complications.

scholarly journals Machine Perfusion: Cold versus Warm, versus Neither. Update on Clinical Trials

2020 ◽  
Vol 40 (03) ◽  
pp. 264-281 ◽  
Author(s):  
E. Bonaccorsi-Riani ◽  
I.M.A. Brüggenwirth ◽  
J.E. Buchwald ◽  
S. Iesari ◽  
P.N. Martins
Keyword(s):  
Liver Transplantation ◽  
Clinical Trials ◽  
Ex Situ ◽  
Machine Perfusion ◽  
Correct Trial ◽  
Gold Standard Method ◽  
Liver Preservation ◽  
Mature Phase ◽  
Normothermic Machine Perfusion ◽  
Human Livers

AbstractMachine perfusion (MP) preservation is potentially one of the most significant improvements in the field of liver transplantation in the last 20 years, and it has been considered a promising strategy for improved preservation and ex situ evaluation of extended criteria donor (ECD) organs. However, MP preservation adds significant cost and logistical considerations to liver transplantation. MP protocols are mainly classified according to the perfusion temperature with hypothermic machine perfusion (HMP) and normothermic machine perfusion (NMP) being the two categories most studied so far. After extensive preclinical work, MP entered the clinical setting, and there are now several studies that demonstrated feasibility and safety. However, because of the limited quality of clinical trials, there is no compelling evidence of superiority in preservation quality, and liver MP is still considered experimental in most countries. MP preservation is moving to a more mature phase, where ongoing and future studies will bring new evidence in order to confirm their superiority in terms of clinical outcomes, organ utilization, and cost-effectiveness. Here, we present an overview of all preclinical MP studies using discarded human livers and liver MP clinical trials, and discuss their results. We describe the different perfusion protocols, pitfalls in MP study design, and provide future perspectives. Recent trials in liver MP have revealed unique challenges beyond those seen in most clinical studies. Randomized trials, correct trial design, and interpretation of data are essential to generate the data necessary to prove if MP will be the new gold standard method of liver preservation.

scholarly journals Methaemoglobinaemia Can Complicate Normothermic Machine Perfusion of Human Livers

2021 ◽  
Vol 8 ◽  
Author(s):  
Samuel J. Tingle ◽  
Ibrahim Ibrahim ◽  
Emily R. Thompson ◽  
Lucy Bates ◽  
Ashwin Sivaharan ◽  
...  
Keyword(s):  
Methylene Blue ◽  
Blood Gas Analysis ◽  
Gas Analysis ◽  
Machine Perfusion ◽  
Matched Cohort ◽  
Blood Gas ◽  
Viability Test ◽  
Normothermic Machine Perfusion ◽  
Delivery Platform ◽  
Human Livers

Background: Although liver normothermic machine perfusion is increasingly used clinically, there are few reports of complications or adverse events. Many centers perform liver NMP to viability test suboptimal grafts, often for prolonged periods. In addition, several researchers are investigating NMP as a drug delivery platform, which usually necessitates prolonged perfusion of otherwise non-viable liver grafts. We describe two instances of methaemoglobinaemia during NMP of suboptimal livers.Methods: The NMP of eight human livers rejected for transplantation is described. Methaemoglobinaeima developed in two; one perfused using generic Medtronic™ perfusion equipment and one using the OrganOx Metra®.Results: The first liver (53 years DBD) developed methaemoglobinaemia (metHb = 2.4%) after 13 h of NMP, increasing to metHb = 19% at 16 h. Another liver (45 years DBD) developed methaemoglobinaemia at 25 h (metHb = 2.8%), which increased to metHb = 28.2% at 38 h. Development of methaemoglobinaemia was associated with large reductions in oxygen delivery and oxygen extraction. Both livers were steatotic and showed several suboptimal features on viability testing. Delivery of methylene blue failed to reverse the methaemoglobinaemia. Compared to a matched cohort of steatotic organs, livers which developed methaemoglobinaemia showed significantly higher levels of hemolysis at 12 h (prior to development of methaemoglobinaemia).Conclusions: Methaemglobinaemia is a complication of NMP of suboptimal liver grafts, not limited to a single machine or perfusion protocol. It can occur within 13 h (a timepoint frequently surpassed when NMP is used clinically) and renders further perfusion futile. Therefore, metHb should be monitored during NMP visually and using blood gas analysis.

scholarly journals Production of Physiologically Relevant Quantities of Hemostatic Proteins During Ex Situ Normothermic Machine Perfusion of Human Livers

2018 ◽  
Vol 24 (9) ◽  
pp. 1298-1302 ◽  
Author(s):  
Shanice A. Karangwa ◽  
Jelle Adelmeijer ◽  
Alix P. M. Matton ◽  
Vincent E. de Meijer ◽  
Ton Lisman ◽  
...  
Keyword(s):  
Ex Situ ◽  
Machine Perfusion ◽  
Normothermic Machine Perfusion ◽  
Human Livers

Lipid metabolism and functional assessment of discarded human livers with steatosis undergoing 24 hours of normothermic machine perfusion

2018 ◽  
Vol 24 (2) ◽  
pp. 233-245 ◽  
Author(s):  
Qiang Liu ◽  
Ahmed Nassar ◽  
Laura Buccini ◽  
Giuseppe Iuppa ◽  
Basem Soliman ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Functional Assessment ◽  
Machine Perfusion ◽  
Normothermic Machine Perfusion ◽  
Human Livers

scholarly journals Subnormothermic Machine Perfusion of Steatotic Livers Results in Increased Energy Charge at the Cost of Anti-Oxidant Capacity Compared to Normothermic Perfusion

Metabolites ◽  
2019 ◽  
Vol 9 (11) ◽  
pp. 246 ◽  
Author(s):  
Negin Karimian ◽  
Siavash Raigani ◽  
Viola Huang ◽  
Sonal Nagpal ◽  
Ehab O. A. Hafiz ◽  
...  
Keyword(s):  
Energy Charge ◽  
Redox Status ◽  
High Energy ◽  
Ex Situ ◽  
Machine Perfusion ◽  
Normothermic Perfusion ◽  
Normothermic Machine Perfusion ◽  
Anti Oxidant ◽  
Human Livers ◽  
The Cost

There continues to be significant debate regarding the most effective mode of ex situ machine perfusion of livers for transplantation. Subnormothermic (SNMP) and normothermic machine perfusion (NMP) are two methods with different benefits. We examined the metabolomic profiles of discarded steatotic human livers during three hours of subnormothermic or normothermic machine perfusion. Steatotic livers regenerate higher stores of ATP during SNMP than NMP. However, there is a significant depletion of available glutathione during SNMP, likely due to an inability to overcome the high energy threshold needed to synthesize glutathione. This highlights the increased oxidative stress apparent in steatotic livers. Rescue of discarded steatotic livers with machine perfusion may require the optimization of redox status through repletion or supplementation of reducing agents.

scholarly journals Metabolic and lipidomic profiling of steatotic human livers during ex situ normothermic machine perfusion guides resuscitation strategies

PLoS ONE ◽  
2020 ◽  
Vol 15 (1) ◽  
pp. e0228011 ◽  
Author(s):  
Siavash Raigani ◽  
Negin Karimian ◽  
Viola Huang ◽  
Anna M. Zhang ◽  
Irene Beijert ◽  
...  
Keyword(s):  
Ex Situ ◽  
Machine Perfusion ◽  
Normothermic Machine Perfusion ◽  
Human Livers
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