Normothermic extracorporeal liver perfusion for donation after cardiac death (DCD) livers

Banan, Babak; Chung, Haniee; Xiao, Zhenyu; Tarabishy, Yaman; Jia, Jianluo; Manning, Pamela T.; Upadhya, Gundumi A.; Mohanakumar, Thalachallour; Lin, Yiing; Chapman, William C.

doi:10.1016/j.surg.2015.07.016

Cited by 31 publications

(53 citation statements)

References 21 publications

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“…We have previously shown that measurement of INR during NELP experiments is a reliable approach for the assessment of synthetic functions of the liver. (31,32) It is fast (results less than 2 minutes) and can be checked in real time. Despite ELISA kits, measuring INR is not costly, and more importantly, it is a less "subjective" and more "quantitative" marker than the bile production.…”

Section: Discussionmentioning

confidence: 99%

“…In our experiments, the vascular pressures declined after 1 hour of warm perfusion. We supplemented both the hepatic artery and the portal vein with previous projects (31,32) with providing continuous flow to both vascular limbs, we preferred to keep the system as simple as possible with using only 1 centrifugal pump. Nonetheless, we have designed a new system that will enable us to supply pulsatile and continuous flows by using only 1 centrifugal pump.…”

Section: Discussionmentioning

confidence: 99%

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Development of a normothermic extracorporeal liver perfusion system toward improving viability and function of human extended criteria donor livers

Banan¹,

Watson²,

Xu³

et al. 2016

Liver Transpl

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Donor organ shortages have led to an increased interest in finding new approaches to recover organs from extended criteria donors (ECD). Normothermic extracorporeal liver perfusion (NELP) has been proposed as a superior preservation method to reduce ischemia/reperfusion injury (IRI), precondition suboptimal grafts, and treat ECD livers so that they can be successfully used for transplantation. The aim of this study was to investigate the beneficial effects of a modified NELP circuit on discarded human livers. Seven human livers that were rejected for transplantation were placed on a modified NELP circuit for 8 hours. Perfusate samples and needle core biopsies were obtained at hourly intervals. A defatting solution that contained exendin-4 (50 nM) and L-carnitine (10 mM) was added to the perfusate for 2 steatotic livers. NELP provided normal temperature, electrolytes, and pH and glucose levels in the perfusate along with physiological vascular flows and pressures. Functional, biochemical, and microscopic evaluation revealed no additional injuries to the grafts during NELP with an improved oxygen extraction ratio (>0.5) and stabilized markers of hepatic injury. All livers synthesized adequate amounts of bile and coagulation factors. We also demonstrated a mild reduction (10%) of macroglobular steatosis with the use of the defatting solution. Histology demonstrated normal parenchymal architecture and a minimal to complete lack of IRI at the end of NELP. In conclusion, a modified NELP circuit preserved hepatocyte architecture, recovered synthetic functions, and hepatobiliary parameters of ECD livers without additional injuries to the grafts. This approach has the potential to increase the donor pool for clinical transplantation. The major limiting factor of using extended criteria donor (ECD) grafts is their greater susceptibility to injury during cold preservation and lower tolerance for ischemia/reperfusion injury (IRI) upon reperfusion. Therefore, ECD grafts have been associated with a higher risk of posttransplant complications such as primary graft nonfunction and chronic cholangiopathy.(1-4) Machine perfusion has been investigated both as a preservation method to reduce IRI in ECD livers and as a method to assess the viability and function of suboptimal grafts prior to transplantation.(5-7)Currently, there are 3 variants of liver machine perfusion that are distinguished by the perfusate temperature: hypothermic, subnormothermic, and normothermic.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Development of a normothermic extracorporeal liver perfusion system toward improving viability and function of human extended criteria donor livers

Banan¹,

Watson²,

Xu³

et al. 2016

Liver Transpl

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“…HMP acts at low metabolic activity and was suggested to protect the allografts from mitochondrial and nuclear injury and to reduce endothelial damage, as well as the alloimmune response in the recipient . NMP in turn targets the metabolically more active organ and is suggested to improve metabolism and function, as well as offering optimized viability assessment of the isolated graft. A first comparative study has been published recently, suggesting favorable effects of HMP over NMP .…”

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confidence: 99%

End‐ischemic reconditioning of liver allografts: Controlling the rewarming

et al. 2016

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Different nonhypothermic preservation modalities have shown beneficial effects in liver transplantation models. This study compares controlled oxygenated rewarming (COR) to normothermic machine perfusion (NMP) to resuscitate liver grafts following cold storage (CS). Porcine livers were preserved for 18 hours by CS. Before reperfusion, the grafts were put on a machine perfusion device (Liver Assist) for 3 hours and were randomly assigned to COR (n = 6) or NMP (n = 5) and compared to standard CS. COR was carried out with the new Custodiol-N solution, slowly increasing temperature from 8 °C to 20 °C during the first 90 minutes. NMP was carried out with diluted autologous blood at 37 °C for 3 hours. In both cases, the perfusate was oxygenated to partial pressure of oxygen > 500 mm Hg. Then liver viability was tested for 180 minutes during in vitro isolated sanguineous reperfusion. Activity of the mitochondrial caspase 9 was lower after COR. Measurement of tissue adenosine triphosphate and total adenine nucleotides at the end of the reconditioning period showed better energetic recovery after COR. COR also resulted in significantly lower enzyme leakage and higher bile production (P < 0.05) during reperfusion. This first comparison of COR and NMP as end-ischemic reconditioning modalities demonstrates superior results in terms of mitochondrial integrity resulting in better energetic recovery, less hepatocellular injury, and ultimately superior function in favor of COR. Liver Transplantation 22 1223-1230 2016 AASLD.

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“…For this reason, Banan et al incorporated a dialyzer to clear the urea and glucose in the circuit, but it would not be feasible in a portable system. Also, the costs of adding a dialyzer to the system will be $20,000–$30,000 …”

Section: Discussionmentioning

confidence: 99%

Combined liver‐kidney perfusion enhances protective effects of normothermic perfusion on liver grafts from donation after cardiac death

Zhang

et al. 2017

Liver Transpl

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It has been shown that combined liver-kidney normothermic machine perfusion (NMP) is able to better maintain the circuit's biochemical milieu. Nevertheless, whether the combined perfusion is superior to liver perfusion alone in protecting livers from donation after circulatory death (DCD) is unclear. We aimed to test the hypothesis and explored the mechanisms. Livers from 15 DCD pig donors were subjected to either static cold storage (group A), liver-alone NMP (group B), or combined liver-kidney NMP (group C). Livers were preserved for 6 hours and reperfused ex vivo for 2 hours to simulate transplantation or were transplanted in situ. During perfusion, group C showed an improved acid-base and biochemical environment in the circuit over group B. After reperfusion, the architecture of the liver grafts was best preserved in group C, followed by group B, then group A, as shown by the histology and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling staining of both hepatocytes and biliary epithelium. Ki-67 staining showed substantial hepatocyte proliferation and biliary epithelial regeneration after perfusion in group B and group C. Group C produced more bile in the reperfusion phase than those in group A and group B, with more physiological bile composition and less severe biliary epithelium injury. Von Willebrand factor-positive endothelial cells and E-selectin expression decreased in both group B and group C. Combined liver-kidney NMP not only produced more adenosine triphosphate, protected the nitric oxide signaling pathway, but also diminished oxidative stress (high mobility group box-1 protein and 8-hydroxy-2-deoxy guanosine levels) and inflammatory cytokine (IL6 and IL8) release when compared with liver-alone NMP and CS. In addition, the 7-day survival rate of liver transplant recipients was higher in group C than that in groups A and B. In conclusion, combined liver-kidney NMP can better protect DCD livers from warm ischemia and reperfusion injury probably by maintaining the stability of the internal environment and by abolishing oxidative stress injury.Liver Transplantation 24 67-79 2018 AASLD.

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Normothermic extracorporeal liver perfusion for donation after cardiac death (DCD) livers

Cited by 31 publications

References 21 publications

Development of a normothermic extracorporeal liver perfusion system toward improving viability and function of human extended criteria donor livers

Development of a normothermic extracorporeal liver perfusion system toward improving viability and function of human extended criteria donor livers

End‐ischemic reconditioning of liver allografts: Controlling the rewarming

Combined liver‐kidney perfusion enhances protective effects of normothermic perfusion on liver grafts from donation after cardiac death

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