Ex situ normothermic machine perfusion of donor livers using a haemoglobin-based oxygen carrier: a viable alternative to red blood cells

Abstract

Dear Editors, With interest, we have read the systematic review by Eshmuminov et al. regarding porcine and human liver normothermic machine perfusion (NMP) [1]. The authors focused on studies using red blood cells (RBC) as oxygen carrier in the perfusion fluid and excluded studies using perfusion solutions based on artificial oxygen carriers. In their review, the authors state 'We excluded studies using artificial oxygen carriers. Results of studies with synthetic haemoglobinbased oxygen carriers (HBOC) were disappointing, even with stopping of the ongoing clinical trials by FDA due to safety reasons'. We found this paragraph misleading as it suggests that studies on liver NMP using an HBOC have provided disappointing results. This, however, is not true. The German review article quoted by Eshmuminov et al. to support their statement does not mention the use of HBOC for ex situ NMP [2]. Potential side effects, such as described after in vivo clinical transfusion, are less likely to occur when an HBOC-based perfusion solution is used for ex situ NMP of donor livers, because the donor liver is extensively flushed prior to implantation. Moreover, although HBOC may not be as effective as RBC in treating severe anaemia in clinical trials, postmarketing experience in South Africa has recently resulted in FDA-approved clinical application for life-threatening anaemia in patients unable or unwilling to undergo RBC transfusion [3,4].Several groups have reported experience with an HBOC-201 (HbO 2 therapeutics)-based perfusion fluid for ex situ liver machine perfusion, all of which showed favourable results [5][6][7]. Fontes et al. were the first to report on the use of an HBOC-based perfusion fluid in machine perfusion [5]. Subnormothermic machine perfusion was compared with static cold storage in a porcine liver transplantation model [5]. The machine perfusion group had a higher survival rate, better graft function and decreased reactive oxygen species (ROS) formation after reperfusion. Both Laing et al. from Birmingham and our group have reported a preclinical study on the efficacy of NMP with an HBOC-based perfusion solution using discarded human livers [6,7]. Laing et al. described improved vascular flow and decreased ROS formation after NMP with HBOC, compared to NMP with RBC [6]. We reported improved vascular flow, increased hepatic ATP concentration and increased bile production during NMP using an HBOCbased perfusion fluid, compared to NMP with RBC [7].Based on the aforementioned studies and some unique properties of HBOC, such as the availability and the ability to be used at low temperatures, a clinical trial has been initiated in our centre to investigate the viability of high-risk donor livers using ex situ machine perfusion (www.trialregister.nl; NTR5972). Thus far, six extended criteria donor livers that were initially declined for transplantation nationwide were successfully transplanted after dual hypothermic machine perfusion, followed by controlled oxygenated rewarming and subsequent NMP, each phase using...

Twelve-hour Normothermic Liver Perfusion in a Rat Model: Characterization of the Changes in the Ex-situ Bio-molecular Phenotype and Metabolism

“…Indeed, our previous metabolic investigation of rat livers ex situ-perfused for 4 h using a perfusion uid supplemented with the non-cellular hemoglobin Oxyglobin®, disclosed improved lactate clearance, higher ATP tissue content, and lower succinate tissue and perfusate concentration in livers subjected to OxCbased NMP compared to those perfused in the absence of OxC. The present study shows that this compound, similar to the one used in clinical setting 31,32 , can effectively deliver oxygen and consequently support liver cell metabolism during prolonged NMP, as attested by analysis of DO2, VO2, and pO2.…”

Twelve-hour normothermic liver perfusion in a rat model: characterization of the changes in the ex-situ bio-molecular phenotype and metabolism

“…Indeed, our previous metabolic investigation of rat livers ex situ-perfused for 4 h using a perfusion fluid supplemented with the non-cellular hemoglobin Oxyglobin®, disclosed improved lactate clearance, higher ATP tissue content, and lower succinate tissue and perfusate concentration in livers subjected to OxC-based NMP compared to those perfused in the absence of OxC. The present study shows that this compound, similar to the one used in clinical setting 22 , 23 , can effectively deliver oxygen and consequently support liver cell metabolism during prolonged NMP, as attested by analysis of DO2, VO2, and pO2. Moreover, the use of an artificial OxC enabled to fulfill the 3R principles 24 , 25 of preclinical research without adding possible confounding factors to biological analyses.…”

Oxygen Transport during Ex Situ Machine Perfusion of Donor Livers Using Red Blood Cells or Artificial Oxygen Carriers

“…In this trial suboptimal livers were continuously perfused and oxygenated, which increased the utilization of initially discarded donor organs. An advantage of HBOC-201 is that it can be used during the HMP phase which avoids the need to change the perfusion fluid when one switches from hypothermia to normothermia [55,57,60]. After MP, the perfused organ is flushed, leaving only minimal amounts of HBOC-201 to reach the recipient.…”