Comparison of Hypothermic Versus Normothermic Ex-vivo Preservation.

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

UNKNOWN

Clinical Phase

NA

Total Enrollment

60 participants

Study Classification

INTERVENTIONAL

Study Start Date

2020-12-15

Study Completion Date

2023-03-31

Brief Summary

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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

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Detailed Description

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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

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End Stage Liver DIsease

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

SINGLE

Participants

Study Groups

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Hypothermic Machine Perfusion

uDCD and cDCD after Normothermic Regional Perfusion matching the inclusion criteria, ECD matching the inclusion criteria, uDCD and cDCD exceeding the inclusion criteria.

Group Type EXPERIMENTAL

Hypothermic Machine Perfusion

Intervention Type DEVICE

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.

Normothermic Machine Perfusion

uDCD and cDCD after Normothermic Regional Perfusion matching the inclusion criteria, ECD matching the inclusion criteria, uDCD and cDCD exceeding the inclusion criteria.

Group Type EXPERIMENTAL

Normothermic Machine Perfusion

Intervention Type DEVICE

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)

Interventions

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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.

Intervention Type 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)

Intervention Type DEVICE

Other Intervention Names

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Hypothermic machine perfusion (HMP) Normothermic machine perfusion (NMP)

Eligibility Criteria

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Inclusion Criteria

DCD:

* no absolute contraindications as per Italian National Transplant center (CNT)
* donor age ≤70 years
* witnessed and documented cardiac arrest
* macro-vescicular steatosis \<30% at liver biopsy
* necrosis \<5% at liver biopsy
* fibrosis \<2 as per Ishak's score at liver biopsy
* arteriolar thickening \<60% at liver biopsy
* WIT ≤160 minutes
* ALT \<1000 UI/L during NRP
* downward trend lactate during NRP

DBD:

* no absolute contraindications as per Italian National Transplant center (CNT)
* donor age \> 70 years
* macro-steatosis between 30 and 50% at liver biopsy

* Subject must be greater than or equal to 18 years of age.
* Subject with end-stage liver disease who is actively listed for primary liver transplantation
* Subject, or a legally authorized representative, has given informed consent to participate in the study

Exclusion Criteria

DCD:

* absolute contraindications as per Italian National Transplant center (CNT)
* donor age \>70 years
* macro-vescicular steatosis \>30% at liver biopsy
* necrosis \>5% at liver biopsy
* fibrosis \>2 as per Ishak's score at liver biopsy
* severe macroangiopathy (arteriolar thickening \>60% at liver biopsy)
* WIT \>160 minutes
* ALT \>1000 UI/L during NRP
* uptrend lactate during NRP

DBD:

* absolute contraindications as per Italian National Transplant center (CNT)
* donor age \< 70 years
* macro-steatosis between \> 50% at liver biopsy

RECIPIENTS

* Subject is currently listed as a UNOS status 1A.
* Subject is requiring oxygen therapy via ventilator/respiratory support.
* Subject is planned to undergo simultaneous solid organ transplant.
* Subject is pregnant at the time of transplant.
* Subject MELD score 25 or higher
* Subject receives re-transplantation of liver.
* Any medical conditions contro-indicating the use of DCD grafts at transplant surgeon/hepatologist evaluation

Minimum Eligible Age

18 Years

Maximum Eligible Age

75 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No