Combined Hypothermic and Normothermic Machine Perfusion Improves Functional Recovery of Extended Criteria Donor Livers

Abstract

Hypothermic oxygenated perfusion (HOPE) and normothermic perfusion are seen as distinct techniques of ex situ machine perfusion of the liver. We aimed to demonstrate the feasibility of combining both techniques and whether it would improve functional parameters of donor livers into transplant standards. Ten discarded human donor livers had either 6 hours of normothermic perfusion (n = 5) or 2 hours of HOPE followed by 4 hours of normothermic perfusion (n = 5). Liver function was assessed according to our viability criteria; markers of tissue injury and hepatic metabolic activity were compared between groups. Donor characteristics were comparable. During the hypothermic perfusion phase, livers down-regulated mitochondrial respiration (oxygen uptake, P = 0.04; partial pressure of carbon dioxide perfusate, P = 0.04) and increased adenosine triphosphate levels 1.8-fold. Following normothermic perfusion, those organs achieved lower tissue expression of markers of oxidative injury (4-hydroxynonenal, P = 0.008; CD14 expression, P = 0.008) and inflammation (CD11b, P = 0.02; vascular cell adhesion molecule 1, P = 0.05) compared with livers that had normothermic perfusion alone. All livers in the combined group achieved viability criteria, whereas 40% (2/5) in the normothermic group failed (P = 0.22). In conclusion, this study suggests that a combined protocol of hypothermic oxygenated and normothermic perfusions might attenuate oxidative stress, tissue inflammation, and improve metabolic recovery of the highest-risk donor livers compared with normothermic perfusion alone.

Transient Cold Storage Prior to Normothermic Liver Perfusion May Facilitate Adoption of a Novel Technology

“…There may also be a benefit in a period of hypothermic machine perfusion prior to NMP or in controlled rewarming as was shown by Boteon et al wherein livers that had been cold stored for prolonged periods benefited from 2 hours of hypothermic oxygenated machine perfusion (HOPE) before NMP. Although these livers were not transplanted, HOPE and NMP livers achieved lower tissue expression markers of oxidative injury and inflammation as well as enhanced metabolic recovery compared with livers subjected directly to NMP …”

“…The median donor risk index (DRI) was 1.87 years (range, 1.06-3.20 years), and median donor liver index (DLI) was 1.33 (0.6-3.38). The median recipient age was 58 years (25-73 years) with a median Model for End-Stage Liver Disease (MELD) score of 14 (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24). For the DCD livers, the median fWIT was 16 minutes (12-28 minutes), and the median UK-DCD risk score (31) was 7 (4-11).…”

“…However, experimental evidence suggests that rapid rewarming after a period of cooling can induce cellular injury . Work in a porcine model comparing continuous NMP with a post–static cold storage normothermic machine perfusion (pSCS‐NMP) approach demonstrated how livers that were subjected to pSCS‐NMP had increased markers of hepatocellular injury, sinusoidal endothelial cell dysfunction, and Kupffer cell injury .…”

“…However, experimental evidence suggests that rapid rewarming after a period of cooling can induce cellular injury. (11,12) Work in a porcine model comparing continuous NMP with a post-static cold storage normothermic machine perfusion (pSCS-NMP) approach demonstrated how livers that were subjected to pSCS-NMP had increased markers of hepatocellular injury, sinusoidal endothelial cell dysfunction, and Kupffer cell injury. (13) Conversely, 2 clinical studies investigating NMP of discarded or high-risk human livers have demonstrated evidence that pSCS-NMP can be implemented without any apparent detriment to the graft (when using physiological oxygen tensions), (1,14,15) and the end-ischemic approach has been used successfully in hypothermic machine perfusion studies.…”

Pretransplant sequential hypo- and normothermic machine perfusion of suboptimal livers donated after circulatory death using a hemoglobin-based oxygen carrier perfusion solution

“…Machine perfusion, was recently introduced in clinical practice using two different temperature protocols: hypothermic (4-12°C) or normothermic (37°C) machine perfusion. 9,10 Different perfusion solutions have been used for (D)HOPE and NMP. Normothermic machine perfusion (NMP) allows for ex situ functional testing of (extended criteria) donor livers prior to transplantation and suboptimal donor livers have been successfully transplanted after NMP.…”