Efficacy of Ex-situ Normothermic Perfusion Versus Cold Storage in the Transplant With Steatotic Liver Graft.

Study Overview
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Brief Summary
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Prospective, randomized, controlled clinical trial to determine the overall efficacy of normothermic machine perfusion (NMP) for steatotic liver preservation versus traditional static cold storage (SCS), in 50 liver transplant recipients with 1-year follow-up.

Detailed Description
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This is a prospective, randomized, controlled clinical trial comparing static cold storage (SCS) versus normothermic machine perfusion (NMP) for organ preservation before liver transplantation with steatotic livers (between 30 % and 60% of histologic macrovesicular steatosis), in order to: Main Objective: To compare the effect of NMP versus SCS in preventing preservation injury and graft dysfunction, as measured by highest transaminase levels during the first week after liver transplantation. Secondary Objectives: To compare graft and patient survival between the NMP and SCS steatotic livers. To compare the liver biochemical function between the NMP and SCS steatotic livers. To compare the physiological response to the reperfusion between the NMP and SCS steatotic livers. To compare the evidence of reperfusion injury between the NMP and SCS steatotic livers. To compare the evidence of ischemic cholangiopathy between the NMP and SCS steatotic livers.

Official Title
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Clinical Trial to Compare the Efficacy of Ex-situ Normothermic Perfusion With Cold Storage in the Transplant With Steatotic Liver Graft.

Conditions
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Liver Transplant

Intervention / Treatment
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* Procedure: Static cold storage (SCS)
* Device: Normothermic machine perfusion (NMP)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: LIVER DONOR: Donors older than 16 years Liver donation grafts due to brain death Steatosis confirmed by histological study (between 30% and 60% of macrovesicular steatosis) LIVER RECIPIENT: Adult patients (18 years or older) Active liver transplant waiting list candidate Able to give informed consent Exclusion Criteria: LIVER DONOR: Living donors Liver destined to the transplant split Donor age <16 years Donation after death due to asystole. When the biopsy establishes a steatosis ≥ 50%, patients who fulfill at least 3 of the following 5 risk factors will be excluded: Transaminases (AST and ALT) ≥ 200 U / L; Age ≥ 55 years; Hypernatremia ≥ 155 mEq / L; Cardiovascular risk factors, at least 2 of the following 5: DM, HTA, IMC ≥ 35, Active smoking, ischemic stroke; Days of stay in ICU ≥ 4 days with vasoactive drugs (noradrenaline or dobutamine at any dose) LIVER RECIPIENT: Age under 18 Acute/fulminant hepatic failure Transplant of more than one organ (for example, liver and kidney) Rejection of informed consent Unable to give informed consent

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Static cold storage (SCS)<br>Traditional method of organ preservation which involves flushing of cold preservation solution following complete dissection and interruption of blood supply to the donor organ. Although cold preservation slows metabolism by 10- to 12-fold, substantial anaerobic activity continues even at ice temperature. This lead to the generation of reactive oxygen species that are the basis of ischaemia-reperfusion injury, when the organ is re-exposed to oxygenated blood at the time of transplantation. This damage, exacerbated by any prior injury, limits the maximum safe preservation time of the donor organ. | Procedure: Static cold storage (SCS)<br>* The liver is flushed and cooled with specialist preservation fluid, then stored in an icebox.<br>|
| Experimental: Normothermic machine perfusion (NMP)<br>The main goal of NMP is to optimize graft preservation by mimicking physiological conditions. The perfused organ is supplied with nutrients and oxygen to maintain metabolic hemostasis. Under these conditions, ATP and glycogen reserves can be maintained or actively restored. At the same time, toxic products from the cellular milieu are continuously eliminated, so the cell-mediated injury phase of reperfusion injury can be minimized. Thus, ischemic injury is avoided and the activation of cell death cascades is prevented. This allows both hepatocellular and biliary protection. | Device: Normothermic machine perfusion (NMP)<br>* During NMP, the liver is perfused with oxygenated blood, medications and nutrients at normal body temperature to maintain a physiological milieu.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Peak of transaminases (AST and ALT) |  | Day 1 post-transplant. | 
| Peak of transaminases (AST and ALT) |  | Day 3 post-transplant. | 
| Peak of transaminases (AST and ALT) |  | Day 5 post-transplant. | 
| Peak of transaminases (AST and ALT) l |  | Day 7 post-transplant. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Primary graft failure | Primary graft failure: irreversible graft dysfunction that requires emergency hepatic replacement during the first 10 days after liver transplantation, in the absence of technical or immunological causes. | Day 10 post-transplant. | 
| Graft survival |  | Day 30 post-transplant, month 6 post-transplant, month 12 post-transplant. | 
| Patient survival |  | Day 30 post-transplant, month 6 post-transplant, month 12 post-transplant. | 
| Post-reperfusion syndrome, measured by mean arterial pressure (MAP) levels | Post-reperfusion syndrome is defined as a decrease in mean arterial pressure (MAP) of more than 30% of the baseline value for more than one minute during the first five minutes after reperfusion. This will be evaluated in the context of the use of vasopressors. | During the first 5 minutes after reperfusion | 
| Biochemical function of the liver measured by Bilirubin post-transplant levels |  | Day 1, day 3, day 5, day 7, day 30, month 6, month 12 post- transplant | 
| Biochemical function of the liver measured by GGT post-transplant levels |  | Day 1, day 3, day 5, day 7, day 30, month 6, month 12 post- transplant | 
| Biochemical function of the liver measured by AST post-transplant levels |  | Day 1, day 3, day 5, day 7, day 30, month 6, month 12 post- transplant | 
| Biochemical function of the liver measured by ALT post-transplant levels |  | Day 1, day 3, day 5, day 7, day 30, month 6, month 12 post- transplant | 
| Biochemical function of the liver measured by INR post-transplant levels |  | Day 1, day 3, day 5, day 7, day 30, month 6, month 12 post- transplant | 
| Early graft dysfunction | Defined by: Bilirubin > 10 mg / dl daily 7 after transplant INR > 1.6 on day 7 after transplantation. Peak AST and ALT > 2000 IU / L in the first 7 days after transplantation | 7 days post-transplant | 
| Intensive care stay duration |  | Day 30 | 
| Hospital stay duration |  | Day 30 | 
| Renal replacement therapy need |  | Day 30, month 6, month 12 post- transplant | 
| Intraoperative thromboelastogram result |  | In transplant surgery | 
| Histological evidence of reperfusion injury | Post-reperfusion biopsies will be compared with baseline pre-reperfusion biopsies and classified according to standard histological criteria (blind comparison to third parties). | In transplant surgery | 
| Evidence of biliary stenosis in magnetic resonance cholangiography (MRS). |  | 6 months after transplantation. |