Preclinical Modeling of DCD Class III Donation: Paving the Way for the Increased Use of This Challenging Donor Type

Abstract

Deceased after circulatory death (DCD) donors offer a viable solution to the current organ shortage, particularly the Maastricht Class III (arrest subsequent to cessation of life support in the hospital). Although current results from these donors are very satisfactory, the number of included donors is too low and future expansion of inclusion criteria will likely decrease organ quality, with negative consequences on the complication rate. This donor type thus represents a priority in terms of scientific exploration, so as to study it in controlled settings and prepare for future challenges. Hence, we mimicked the DCD Class III clinical conditions a Large White pig model. Herein, we detail the different strategies attempted to attain our objectives, including technical approaches such as animal positioning and ventilator settings, as well as pharmacological intervention to modulate blood pressure and heart rate. We highlight the best combination of factors to successfully reproduce DCD Class III conditions, with perfusion pressures and functional warm ischemia (hypoperfusion) closely resembling clinical situations. Finally, we detail the functional and histological impacts of these conditions. Such a model could be of critical value to explore novel management alternative for these donors, presenting a uniquely adapted platform for such therapeutics as normothermic regional circulation and/or pharmacological intervention.

Evaluation of Liver Quality after Circulatory Death versus Brain Death: A Comparative Preclinical Pig Model Study

“…(3) True DCD donation involves withdrawal of treatment, an agonal phase characterized by haemodynamic, catecholamine release and ischemic injury before asystole [42][43][44]. Reproducing in the pig is a very complex procedure, and the present study is anterior while we are developing this aspect [45]. One could also consider a limitation the fact that on several western blots (HO1, SOD1, SOD2, and HIF1) the protein signal, while different, does appear close between DCD and DBD and that the recorded difference is due to less total protein as showed by the use of StainFree technology.…”

Considerations for the use of porcine organ donation models in preclinical organ donor intervention research

“…48,59 An alternative to the hypoxic pulmonary arrest DCD model is to achieve organ hypoperfusion through a combined pharmacological and technical approach to decrease mean arterial pressure. 30,50 Although such alternative models are very reliable and reproducible, they do not account for the effect of hypoxia, specifically hypoxic pulmonary vasoconstriction, on the physiologic changes in thoracic organs during the agonal period. 29…”

“…Porcine models of DBD and DCD organ donation have been described previously 25,30,43 . The purpose of this article was to present an overview of both models with the emphasis on key conceptual and practical considerations.…”

“…In the first category (Table 2A) are studies evaluating hemodynamic, metabolic, and hormonal changes associated with brain death and the effects of brain death on donor organ function 19‐25 or pharmacologic interventions to mitigate the adverse effects of brain death 26,27 . Similarly, DCD large animal models have been developed to evaluate the impact of warm ischemia on organ donor function 28‐30 . In the second category (Table 2B) are studies that evaluate experimental methods of DBD graft preservation and technical and pharmacological modifications of DCD graft recovery 17,31,32,33,34,35,36,37,38,39,40,41 .…”

“… 26 , 27 Similarly, DCD large animal models have been developed to evaluate the impact of warm ischemia on organ donor function. 28 , 29 , 30 In the second category (Table 2B ) are studies that evaluate experimental methods of DBD graft preservation and technical and pharmacological modifications of DCD graft recovery. 17 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 In the third category (Table 2C ) are studies that combine the use of large animal models for both organ donation and organ transplantation.…”