A reproducible extended ex-vivo normothermic machine liver perfusion protocol utilising improved nutrition and targeted vascular flows

IF 5.4 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
George Clarke, Jingwen Mao, Angus Hann, Yiyu Fan, Amita Gupta, Anisa Nutu, Erwin Buckel Schaffner, Kayani Kayani, Nicholas Murphy, Mansoor N. Bangash, Anna L. Casey, Isla Wootton, Alexander J. Lawson, Bobby V. M. Dasari, M. Thamara P. R. Perera, Hynek Mergental, Simon C. Afford
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Abstract

Normothermic machine perfusion of donor livers has become standard practice in the field of transplantation, allowing the assessment of organs and safe extension of preservation times. Alongside its clinical uses, there has been expanding interest in extended normothermic machine perfusion (eNMP) of livers as a potential vehicle for medical research. Reproducible extended normothermic machine perfusion has remained elusive due to its increased complexity and monitoring requirements. We set out to develop a reproducible protocol for the extended normothermic machine perfusion of whole human livers. Human livers declined for transplantation were perfused using a blood-based perfusate at 36 °C using the Liver Assist device (XVIVO, Sweden), with continuous veno-venous haemofiltration in-parallel. We developed the protocol in a stepwise fashion. Perfusion techniques utilised included: targeted physiological vascular flows, phosphate replacement (to prevent hypophosphataemia), N-acetylcysteine (to prevent methaemoglobin accumulation), and the utilisation of sodium lactate as both a nutritional source and real-time measure of hepatocyte function. All five human livers perfused with the developed protocol showed preserved function with a median perfusion time of 168 h (range 120–184 h), with preserved viability throughout. Livers can be reproducibly perfused in excess of 120 (range 121–184) hours with evidence of preserved hepatocyte and cholangiocyte function. Clarke et al. present a reproducible protocol for the extended normothermic machine perfusion of human livers. Function and are preserved in five human livers perfused between 121–184 h. Circulating blood through human livers at normal body temperature allows transplant surgeons to assess the function of the liver and safely extend the time it is out of the body prior to transplantation. Extending this perfusion of livers beyond 24 h has proven difficult. We evaluated improved techniques to circulate blood through the liver. We found the improved techniques could enable a machine to be used to reliably perfuse livers for more than 24 h, whilst preserving the function of the liver. Our improved method included varying the blood flow according to liver size and removing waste products from the circulating blood. Using our method could enable more livers to be used successfully in transplant operations, reducing the waiting times for people requiring liver transplantation and improving their quality of life.

Abstract Image

利用改进的营养和定向血管流量,实现可重复的扩展体外常温机器肝脏灌注方案。
背景:对供体肝脏进行常温机器灌注已成为移植领域的标准做法,可对器官进行评估并安全延长保存时间。在临床应用的同时,人们对延长肝脏常温机器灌注(eNMP)作为医学研究的潜在工具的兴趣也在不断扩大。由于其复杂性和监测要求的增加,可重复的延长常温机器灌注仍然难以实现。方法:使用肝脏辅助设备(XVIVO,瑞典)在 36 °C的温度下使用基于血液的灌注液灌注衰竭的用于移植的人类肝脏,同时进行连续的静脉血液滤过。我们以循序渐进的方式制定了方案:灌注技术包括:有针对性的生理血管流量、磷酸盐置换(防止低磷血症)、N-乙酰半胱氨酸(防止高铁血红蛋白积累),以及利用乳酸钠作为营养源和肝细胞功能的实时测量。采用所制定的方案灌注的五个人肝均显示功能保持完好,中位灌注时间为 168 小时(120-184 小时不等),整个过程中的存活率保持完好:结论:肝脏可重复灌注超过 120 小时(范围为 121-184 小时),且有证据表明肝细胞和胆管细胞功能得以保留。
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