Effect of Nitric Oxide (NO) on Ischemic/Reperfusion Injury During Extended Donor Criteria (EDC) Liver Transplantation

Study Overview
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Brief Summary
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In this study, the researchers propose to investigate the efficacy of inhaled nitric oxide to prevent ischemia-reperfusion (I/R) hepatocyte injury in patients who receive extended donor criteria(EDC)liver grafts based on changes in proteomic and metabolomic markers following revascularization of the donor graft. In reviewing the literature, no uniform extended criteria donor classification exists. The characteristics most associated with liver graft failure appear to be cold ischemia time greater than 10 hours, warm ischemia time greater than 40 minutes, donor age > 55 years of age, donor hospitalization > 5 days, a donation after cardiac death (DCD) graft, and a split graft. The researchers will exclude warm ischemia time as this is impossible to predict prior to the transplantation. Any donor meeting at least one of the other criteria will be classified as an EDC donor. Hypothesis 1: Inhaled nitric oxide will improve overall outcome of liver recipients after EDC liver transplantation Suppression of oxidative injury will improve graft function postoperatively as measured by International Normalized Ratio (INR) bilirubin, transaminases, and duration of hospital stay. Hypothesis 2: The mechanisms of therapeutic efficacy of inhaled nitric oxide is based on reduction in post-reperfusion oxidative injury as readily measured by the detectable changes in the protein and metabolic profiles in plasma of patients treated with inhaled-NO Nuclear Magnetic Resonance (NMR)-based metabolic markers (xanthine end-products, lactate, and hepatic osmolytes) that are consistent with acute liver injury will be decreased in NO-treated recipients. Protein markers of reperfusion injury (argininosuccinate synthase (ASS) and estrogen sulfotransferase (EST-1) will be greater in the plasma of patients who are not treated with inhaled-NO Reduced oxidative injury will be reflected by a decrease in the number of mitochondrial peroxiredoxins isoforms and the number that are oxidized in NO-treated liver recipients.

Official Title
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Investigation of the Effect of Nitric Oxide on Ischemic Reperfusion Injury During Extended Donor Criteria Liver Transplantation

Conditions
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Liver Transplantation, Ischemia/Reperfusion Injury, Oxidative Injury

Intervention / Treatment
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* Drug: Nitric Oxide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18 - 69 years of age moderate to severe liver disease (MELD score 22 to 30) is receiving a extended donor criteria liver graft Exclusion Criteria: undergoing multi-organ transplant 70 years or older diagnosed with hepatocarcinoma diagnosed with either hepatopulmonary syndrome or pulmonary hypertension pregnant

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 69 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: No nitric oxide<br>This arm will not receive nitric oxide, but will receive other standard inhaled anesthetics | |
| Experimental: Nitric Oxide<br>Will receive Nitric oxide and other standard inhaled anesthetics | Drug: Nitric Oxide<br>* Inhalation - 40 ppm, at the initiation of anesthesia to the end of surgery<br>* Other names: INOmax;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To Determine if Inhaled Nitric Oxide Has Beneficial Effects on Overall Outcome After Extended Criteria Donor (EDC) Liver Transplantation |  | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To Construct a Plasma Metabolic/Protein Profile of I/R Injury in Transplanted Livers |  | 3 years | 
| To Examine the Effects of Nitric Oxide on Protein Synthesis and Metabolism Following Extended Criteria Donor Liver Transplantation |  | 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Extended Donor Criteria