Ex Situ Organ Preservation: The Temperature Paradigm

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Currently, over 116 500 patients are waiting for a lifesaving organ in the United States.1 A promising alternative to increase the source of organs is the use of grafts from donors after Circulatory death (DCD). At present, DCD lungs, livers, and kidneys with minimal warm ischemic time are considered and successfully used for transplantation. However, it has been documented that liver grafts from DCD (compared with donors after brain death) have a higher incidence of primary nonfunction and a worse 1- and 3-year graft survivals.2
Current research is directed at techniques to improve practices for organ preservation, storage, and assessment of organ viability pretransplantation. One of them is ex situ perfusion of organs, a concept introduced in the early 1900s by Charles Lindbergh and Alexis Carrel, when Locke’s solution was used to preserve kidneys and vessels.3
Kakizaki et al4 describe the results of a subnormothermic ex vivo liver perfusion (SELP) rat model and concluded that even 30 minutes of room temperature (22.5 ± 2.5°C) perfusion after cold storage resuscitated DCD liver grafts from ischemia-reperfusion injury and improved the viability of livers. This conclusion was made on liver function parameter measurements in the perfusate and pro/inflammatory cytokine studies. This study adds support to the growing practice of ex-vivo organ perfusion at the time of organ procurement or after cold storage. Future studies should evaluate longer perfusion with oxygen delivery to match oxygen requirements.
Perfusion for hours allows assessment of function, which is particularly important in DCD organs subjected to prolonged ischemia during the agonal period. In addition, ex vivo perfusion “washes out” toxic products of ischemic and reperfusion injury, as postulated by the authors. Although this study used clear perfusate, prolonged ex vivo organ perfusion to document organ function (and likelihood of transplant success) must be done at normothermia (37 ± 0.5°C) and requires an oxygen carrier, “Red blood cells (RBC)” are the best oxygen carrier in our experience.5,6
Kakizaki et al, first procured liver grafts from DCD rats with 7 minutes of agonal time and 30 minutes of warm ischemia. These grafts were then flushed and cold stored in University of Wisconsin (UW) solution for 6 hours. Then SELP is a single-pass perfusion (non-recirculating) with Krebs-Henseleit Buffer (KHB) at a pressure of 7 mm Hg via the portal vein only. Carbogen (95% O2 and 5% CO2) was bubbled into the KHB to achieve a pO2 of 525 ± 25 mm Hg. During SELP, the authors measured bile production, lactate levels, and hepatic oxygen consumption; however, these values are not as accurate due to decreased organ metabolic rate at room temperature. To assess organ function and viability, Kakizaki et al performed a second study where the organs were perfused for 60 minutes at normothermia with the goal of measuring liver transaminases, oxygen consumption, and bile production.
To compare Kakizaki et al's work with current normothermic liver perfusion techniques, it is important to summarize the current system used in the US clinical trial on normothermic liver ex-situ perfusion (OrganOx metra liver device). This is a close system with dual perfusion (hepatic artery and portal vein).7 The system includes: (1) an automated pump for hepatic artery perfusion (10Fr cannula) targeting perfusion pressures of 67.5 ± 7.5 mm Hg, (2) gravity perfusion via the portal vein (20Fr cannula), and (3) hepatic blood outflow collected via the Inferior vena cava at a pressure of −1 to 2 mm Hg. Additional systems components include: a membrane oxygenator for gas exchange, a heat exchanger, and a set of valves and flow sensors that control and continuously monitor physiological parameters.
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