Sequential Hypo- and Normo-thermic Perfusion to Preserve Extended Criteria Donor Livers for Transplantation

Study Overview
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Brief Summary
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Hypothermic machine perfusion (HMP) has been shown to be beneficial to preserve extended criteria donor (ECD) livers for transplantation. Normothermic machine perfusion (NMP) had the same benefits and also the convenience on liver quality assessment. The investigators proposed to do sequential HMP (1-4 hours) and NMP (1-14 hours) on 15 ECD human livers by using an institutional-developed perfusion device for liver transplantation.

Detailed Description
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Liver transplantation is a successful therapy on the patients with end-stage liver disease, however is limited by the shortage of donor organs. Donor criteria were expanded in the past decades, however the extended criteria donor (ECD) livers may induce a higher risk of complications. Static cold storage (SCS) is the standard procedure for ex vivo liver preservation for about 4 decades, but has the limitation on preserving ECD livers and especially the inconvenience to evaluate liver quality prior to transplantation. Hypothermic (4-8 Celsius degree) machine perfusion (HMP) and Normothermic (35-37 Celsius degree) machine perfusion (NMP) have been shown to be beneficial to preserve extended criteria donor (ECD) livers respectively. NMP also had the convenience on liver quality assessment. The investigators had an institutional-developed device for liver NMP used on 25 patients with the FDA's IDE approval. In the present study the investigators are proposing to expand the use of the device on sequential HMP (1-4 hours) and NMP (1-14 hours) on 15 ECD human livers. This will be a single center prospective pilot study. The liver metabolism and hydrodynamics during perfusion will be recorded. The transplant procedure and post-transplant care will follow the clinical standard of care. The follow-up period is 12 months after transplantation. The primary end point will be the rate of patient survival and primary non function (PNF) within 30 days after transplantation, while the secondary end points will be: Early Allograft Dysfunction (EAD), 6 months patient and graft survival, peak liver function tests in the first 7 days after transplantation, surgical outcomes (operative time, transfusion requirement etc.), rate of post-transplant kidney failure, assessment of histological ischemia reperfusion (liver and bile duct), rate of vascular complications, rate of biliary complications, hospital and ICU length of stay, rejection rate, infection rate, the ability to predict function based on on-pump viability markers, and the incidence of adverse effect (AE).

Official Title
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Assess Safety and Feasibility of Sequential Hypothermic Oxygenated Machine Perfusion and Normothermic Machine Perfusion to Preserve Extended Criteria Donor Livers for Transplantation

Conditions
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Liver Transplantation

Intervention / Treatment
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* Device: Liver Machine Perfusion (MP) device


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients undergoing liver transplantation Age 18 or older at the time of transplantation Willingness and ability to comply with the study procedures Signed Informed Consent Form Exclusion Criteria: Recipient of partial grafts (split and living donors) Mentally or legally incapacitated subjects Inability to understand the procedures due to language barriers Multiorgan transplant

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: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Fifteen extended criteria donor livers will undergo sequential hypothermic and normothermic machine perfusion preservation prior to transplantation.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Liver perfusion<br>Device: Liver Machine Perfusion (MP) Device The liver grafts will be preserved at hypothermic and normothermic temperature on the institutional-developed Liver MP Device, and have continuous perfusion with oxygen supply in the ex vivo organ preservation phase. | Device: Liver Machine Perfusion (MP) device<br>* Donor livers will have ex vivo continuous perfusion on the institutional-developed Liver MP device. The temperature of liver grafts will be controlled during perfusion.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| patient survival at 1 month post-transplant | Patient survival will be recorded at 1 month post transplantation. | 1 month post-transplant | 
| graft survival at 1 month post-transplant | graft survival will be recorded at 1 month post transplantation. The allograft will be considered lost if a patient has a primary non function (PNF), liver re-transplant or in the event of patient death. | 1 month post-transplant | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| rate of post-transplant early allograft dysfunction (EAD) | EAD is defined as the presence of one or more of the following previously defined postoperative laboratory analyses reflective of liver injury and function: bilirubin ≥10mg/dL on post-operative day (POD) 7, international normalized ratio (INR) ≥1.6 on POD 7, and alanine or aspartate aminotransferases (ALT or AST) >2000 IU/L within the first 7 days. | in the first 7 days after transplantation | 
| patient survival at 6 month post-transplant | patient survival will be recorded at 6 months post transplantation. | 6 month post-transplant | 
| graft survival at 6 month post-transplant | graft survival will be recorded at 6 month post transplantation. The allograft will be considered lost if a patient has a primary non function (PNF), liver re-transplant or in the event of patient death. | 6 month post-transplant | 
| Estimated blood loss at transplant surgery | Estimated blood loss (ml) during transplant surgery | during surgery | 
| peak alanine aminotransferases in the first 7 days after transplantation | peak level (U/L) of alanine aminotransferases in the first 7 days after transplantation | in the first 7 days after transplantation | 
| peak aspartate aminotransferases in the first 7 days after transplantation | peak level (U/L) of aspartate aminotransferases in the first 7 days after transplantation | in the first 7 days after transplantation | 
| total bilirubin on post-operative day 7 | total bilirubin (mg/dL) on post-operative day 7 | on post-operative day 7 | 
| international normalized ratio on post-operative day 7 | international normalized ratio on post-operative day 7 | on post-operative day 7 | 
| Hospital length of stay | Length of stay (days) in the hospital at the time for transplantation | up to 36 weeks | 
| ICU length of stay | Length of stay (days) in ICU at the time after liver transplantation | up to 36weeks |