NCT04744389

Comparison of Hypothermic Versus Normothermic Ex-vivo Preservation.

Optimization of an Evidence-based Organizational Model of Liver and Pancreas Transplant Using Cardiac Death Donors: a Pilot, Prospective, Randomized, Multicenter Study for the Comparison of Hypothermic Versus Normothermic Ex-vivo Preservation.

• Status: Unknown
• Phase: N/A
• Study type: Interventional
• Enrollment: 60 (estimated)
• Sponsor: Azienda Ospedaliero, Universitaria Pisana · Academic / Other
• Sex: All
• Age: 18 Years – 75 Years
• Healthy volunteers: Not accepted

Summary

Study groups: The study is a multicenter (Pisa and Milan), prospective, randomized study comparing D-HOPE (HMP) vs NMP in DCD and ECD-DBD (extended criteria brain-dead donors). Once a DCD or a DBD with extended criteria (ECD-DBD) meets the inclusion criteria, they are randomized as follow: 1. 20 liver grafts from DCD after normothermic regional perfusion (NRP) matching the inclusion criteria are randomized 1:1 to hypothermic machine perfusion (HMP) vs normothermic machine perfusion (NMP) and then transplanted. 2. 40 liver grafts from ECD-DBD matching the inclusion criteria are randomized 1:1 to hypothermic machine perfusion (HMP) vs normothermic machine perfusion (NMP) and then transplanted

Detailed description

The persistent mismatch between patients waiting for a liver transplant (LT) and grafts availability promoted the use of donation after circulatory death (DCD). Italian law requires 20 minutes of continous flatline electrocardiogram to declared individual's circulatory death and such a long period of warm ischemia time forced the development of protocols using abdominal normothermic regional perfusion (NRP) followed by ex-vivo graft reperfusion by means of machine perfusion technology (MP) for its potential to minimize ischemia/reperfusion damage and promote organ repair and reconditioning prior to transplantation. An extensive evaluation of all DCD donors might increase donation rate by 30%, but, while kidney transplant from DCD donors is well implemented, no definitive data exist on the optimal use of NRP and MP in liver and pancreas transplantation and an organizational model is far to be implemented. Moreover, a randomized trial comparing hypothermic vs normothermic ex-vivo perfusion has never been performed. The proposed project will perform a pilot, open, randomized, prospective trials to evaluate the sequential use of NRP followed by ex-vivo MP (hypothermic (HMP) vs normothermic (NMP)) by measuring several indicators of organ damage and recovery with the target to set up the optimal organizational model for DCD donation: 1. Twenty LT from DCD donors after NRP (considered transplantable for the acceptance criteria in use) will be randomized 1:1 to ex-vivo HMP or NMP (multicenter study together with the center in Milan) 2. 40 liver grafts from ECD-DBD matching the inclusion criteria are randomized 1:1 to hypothermic machine perfusion (HMP) vs normothermic machine perfusion (NMP) and then transplanted To assess organ damage and repair capacity, the following investigations will be performed: -biomarkers of apoptosis, necrosis, innate-mediated inflammation and its resolution, angiogenesis and thrombosis during NRP -circulating biomarkers indicating damage, proliferation, angiogenetic and tissue remodelling factors; a targeted-metabolomic and lipidomic profiling during ex-vivo HMP or NMP in the perfusate and on blood samples in the peri and post-operative period; bile composition on graft subjected to NMP. Evaluation of necrosis, apoptosis and proliferation, immunohistochemical analysis, a targeted-metabolomic and lipidomic profiling, ATP measurement, and electronic microscopy investigations will be performed on liver tissue and bile duct biopsies after NRP, before and after ex-vivo reperfusion, and immediately after reperfusion in the recipient (only for transplantable grafts) Based on the collected data a new algorithm of organ evaluation, procurement, preservation and reconditioning will be formulated and disseminated.

Conditions

• End Stage Liver DIsease

Interventions

Type	Name	Description
DEVICE	Hypothermic Machine Perfusion	The perfusion system was primed with 4 L of Belzer machine perfusion solution University of Wisconsin Machine Perfusion Solution (Bridge for Life, Ltd., Columbia, SC). The arterial and portal pressures were set at 25 mm Hg with a flow and at 3-4 mm Hg with a continuous flow, respectively. The oxygen flow was set at 0.25 L/minute. The target liver temperature was between 4°C and 10°C.
DEVICE	Normothermic Machine Perfusion	Grafts were perfused at 37°C in an OR next to the transplant OR and under medical supervision using a blood-based perfusate. Initial perfusate temperature was set at 20°C and raised by 1°C every 2 minutes. Oxygenation was provided by an anesthesia ventilator initially set at 4 L/minute with 30% fraction of inspired oxygen, and later adjusted based on perfusate pH, partial pressure of oxygen, and partial pressure of carbon dioxide. Blood gas analyses were drawn every 20 minutes during the first hour and every 30 minutes thereafter with the aim to maintain a physiological pH and ionogram result, and a partial pressure of oxygen between 200 and 250 mm Hg. Perfusate glucose, transaminases, and lactate were measured during NMP as were bile production and quality (pH, sodium, glycemia, lactate, and HCO3)

Timeline

• Start date: 2020-12-15
• Primary completion: 2022-09-30
• Completion: 2023-03-31
• First posted: 2021-02-09
• Last updated: 2022-07-26

Locations

1 site across 1 country: Italy