Perfusion settings and additives in liver normothermic machine perfusion with red blood cells as oxygen carrier. A systematic review of human and porcine perfusion protocols

Eshmuminov, Dilmurodjon; Leoni, Filippo; Schneider, Marcel; Becker, Dustin; Muller, Xavier; Onder, Christopher H.; Hefti, Max; Schüler, Martin; Dutkowski, Philipp; Graf, Rolf; Rohr, Philipp Rudolf von; Clavien, Pierre‐Alain; Borrego, Lucía Bautista

doi:10.1111/tri.13306

Cited by 38 publications

(44 citation statements)

References 84 publications

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“…Moreover, the analysis of the perfusate may help to evaluate organ viability even in hypothermic conditions, and the infusion of therapeutic agents -e.g. nutrition, mesenchymal stromal cells (MSC) and extracellular vesicles releasing by MSC, anti-inflammatory and anti-apoptotic additives -might be a simple implement of the perfusion system in use [42][43][44][45] .…”

Section: Discussionmentioning

confidence: 99%

Hypothermic Oxygenated New Machine Perfusion System in Liver and Kidney Transplantation of Extended Criteria Donors:First Italian Clinical Trial

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Angeletti

et al. 2020

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With the aim to explore innovative tools for organ preservation, especially in marginal organs, we hereby describe a clinical trial of ex-vivo hypothermic oxygenated perfusion (HOPE) in the field of liver (Lt) and kidney transplantation (Kt) from extended criteria Donors (ecD) after brain death. A matched-case analysis of donor and recipient variables was developed: 10 HOPE-ECD livers and kidneys (HOPE-L and HOPE-K) were matched 1:3 with livers and kidneys preserved with static cold storage (ScS-L and ScS-K). Hope and ScS groups resulted with similar basal characteristics, both for recipients and donors. Cumulative liver and kidney graft dysfunction were 10% (HOPE L-K) vs. 31.7%, in ScS group (p = 0.05). Primary non-function was 3.3% for SCS-L vs. 0% for HOPE-L. No primary nonfunction was reported in HOPE-K and SCS-K. Median peak aspartate aminotransferase within 7-days post-LT was significantly higher in SCS-L when compared to HOPE-L (637 vs.344 U/L, p = 0.007). Graft survival at 1-year post-transplant was 93.3% for SCS-L vs. 100% of HOPE-L and 90% for SCS-K vs. 100% of HOPE-K. Clinical outcomes support our hypothesis of machine perfusion being a safe and effective system to reduce ischemic preservation injuries in Kt and in Lt.

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Section: Discussionmentioning

confidence: 99%

Hypothermic Oxygenated New Machine Perfusion System in Liver and Kidney Transplantation of Extended Criteria Donors:First Italian Clinical Trial

Ravaioli

Pace

Angeletti

et al. 2020

Sci Rep

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“…We first perfused pig livers with a hyperglycemic perfusate (perfusate glucose >10 mmol l −1 ) at fixed insulin injection rates (0.9 U h −1 ). Although glucose is not the primary energy source for hepatocytes 10 , perfusion protocols available in the literature 4,5,11,12 have used this approach. For example, the pioneering randomized controlled trial of normothermic liver perfusion in humans also reported high glucose levels in the perfusate (>10 mmol l −1 ) at a constant insulin injection rate (7 U h −1 ) 5 .…”

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An integrated perfusion machine preserves injured human livers for 1 week

et al. 2020

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tandard preservation of donor livers is performed by flushing the organ with a cold solution at the time of procurement, which is followed by static storage on ice. This approach reduces liver metabolic activity, allowing safe storage for up to 12-18 h (refs. 1,2). Recently, the combination of supercooling with subzero storage (−4 °C) and hypothermic, as well as subnormothermic, machine perfusion achieved an extension of the preservation time of human livers up to 27 h (ref. 2). By contrast, human livers can also be kept metabolically fully active for up to 24 h by supplying normothermic blood or oxygenated fluids in a controlled environment by machine perfusion 1,3-5. The possibility of repairing poor-quality livers sufficiently to enable transplantation requires preserving metabolically active livers 1,3 for several days. Accordingly, the need for long-term organ preservation technology has been endorsed by multiple private and governmental initiatives 1. However, currently used normothermic machine perfusion technologies have been used only for a relatively short time period (for example, a median perfusion time of 9 h (ref. 5)), to successfully maintain hemodynamics, perfusate oxygenation and temperature. We sought to extend perfusion time beyond 24 h by engineering a perfusion machine that recapitulates additional core body functions that are critical to liver health. We chose 7-d as a target because this time period has been shown to offer a credible time frame for inducing clinically relevant liver regeneration in patients undergoing complex liver resection 6-8. Under physiologic conditions, the liver, which constitutes 2.5% of body weight, receives 25% of the blood output of the heart and performs >5,000 functions 9. It has a unique dual vascular supply with high-pressure, oxygen-rich arterial blood entering through the hepatic artery and low-pressure, oxygen-reduced portal vein blood draining the abdominal viscera. Its high metabolic activity produces waste products that are excreted in the bile or removed by hepatic macrophages or the kidneys. The metabolic profile is largely controlled by pancreatic hormones, including insulin and glucagon. Our perfusion technology, developed in the "Liver4Life project", includes automated control of glucose levels by injection of insulin and glucagon, a dialysis membrane for waste-product removal, regulation of oxygenation and liver movement to prevent pressure necrosis. Results Liver perfusion machine. Our perfusion machine (Fig. 1a,b) recapitulates blood supply through the two vascular entries of the liver, the hepatic artery and portal vein. The hepatic artery is supplied with oxygen-rich blood at elevated pressure (mean arterial pressure (MAP) ≥ 65 mmHg) in a pulsatile manner (Fig. 1c), whereas the portal vein receives blood at low pressure (around 5-10 mmHg) with a reduced oxygen content (venous blood, non-pulsatile). The system maintains oxygen saturation of 65% in the vena cava by continuously adjusting oxygen content in the portal vein (Fig. 1d). In vivo, nutr...

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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.

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

et al. 2018

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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...

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Perfusion settings and additives in liver normothermic machine perfusion with red blood cells as oxygen carrier. A systematic review of human and porcine perfusion protocols

Cited by 38 publications

References 84 publications

Hypothermic Oxygenated New Machine Perfusion System in Liver and Kidney Transplantation of Extended Criteria Donors:First Italian Clinical Trial

Hypothermic Oxygenated New Machine Perfusion System in Liver and Kidney Transplantation of Extended Criteria Donors:First Italian Clinical Trial

An integrated perfusion machine preserves injured human livers for 1 week

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

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