Development of a preclinical model of donation after circulatory determination of death for translational application

Abstract

BackgroundExtracorporeal membranous oxygenation is proposed for abdominal organ procurement from donation after circulatory determination of death (DCD). In France, the national Agency of Biomedicine supervises the procurement of kidneys from DCD, specifying the durations of tolerated warm and cold ischemia. However, no study has determined the optimal conditions of this technique. The aim of this work was to develop a preclinical model of DCD using abdominal normothermic oxygenated recirculation (ANOR). In short, our objectives are to characterize the mechanisms involved during ANOR and its impact on abdominal organs.MethodsWe used Large White pigs weighing between 45 and 55 kg. After 30 minutes of potassium-induced cardiac arrest, the descending thoracic aorta was clamped and ANOR set up between the inferior vena cava and the abdominal aorta for 4 hours. Hemodynamic, respiratory and biochemical parameters were collected. Blood gasometry and biochemistry analysis were performed during the ANOR procedure.ResultsSix ANOR procedures were performed. The surgical procedure is described and intraoperative parameters and biological data are presented. Pump flow rates were between 2.5 and 3 l/min. Hemodynamic, respiratory, and biochemical objectives were achieved under reproducible conditions. Interestingly, animals remained hemodynamically stable following the targeted protocol. Arterial pH was controlled, and natremia and renal function remained stable 4 hours after the procedure was started. Decreased hemoglobin and serum proteins levels, concomitant with increased lactate dehydrogenase activity, were observed as a consequence of the surgery. The serum potassium level was increased, owing to the extracorporeal circulation circuit.ConclusionsOur ANOR model is the closest to clinical conditions reported in the literature and will allow the study of the systemic and abdominal organ impact of this technique. The translational relevance of the pig will permit the determination of new biomarkers and protocols to improve DCD donor management.

Defining the optimal duration for normothermic regional perfusion in the kidney donor: A porcine preclinical study

“…As described previously, 25 we used a Rotaflow Maquet centrifugal pump with Softline Coating Maquet-Jostra preheparinized closed circuit (Maquet Cardiopulmonary AG, Hirrlingen, Germany) with a hollow fiber membrane oxygenator (Quadrox-D Oxygenator; Maquet). This setup is different from cardiac surgery extracorporeal pumps (typically an open circuit with a reservoir), which is not used for NRP in the clinic.…”

“…25 We explored the impact of NRP on renal injury markers and major IRI pathways such as hypoxia-inducible factor 1-alpha (HIF-1α), inflammation, and endothelial nitric oxide synthase (eNOS) activation. To this end, we adapted a previously developed porcine preclinical model to mimic kidney transplantation from DCD donor reconditioned by NRP.…”

“…To this end, we adapted a previously developed porcine preclinical model to mimic kidney transplantation from DCD donor reconditioned by NRP. 25 We explored the impact of NRP on renal injury markers and major IRI pathways such as hypoxia-inducible factor 1-alpha (HIF-1α), inflammation, and endothelial nitric oxide synthase (eNOS) activation.…”

Extra-Corporeal Membrane Oxygenation Cadaver Donors: What about Tissues Used as Allografts?

“…Regarding the animal studies, the 87% treated porcine, two bovine [ 40 , 41 ], one canine [ 41 ], and one rodent species [ 42 ]. The porcine preclinical model is the most diffused one due to size, anatomy, and cardiovascular physiology of the animal, very similar to those of human beings [ 43 ].…”

Oxygen Consumption by Warm Ischemia-Injured Porcine Kidneys in Hypothermic Static and Machine Preservation

“…Surgery has been described in detail 8,[12][13][14][15] . Briefly, after general anesthesia, midline abdominal incision, and pedicle clamping, the right kidney was removed by dissection of the vascular pedicle and ureter and transferred into a sterile bag for 60 min warm ischemia WI, and maintained at 37°C in a water bath.…”