Ischemia/Reperfusion Injury, Liver Transplantation, Oxidative Injury
Conditions
Keywords
Extended Donor Criteria
Brief summary
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.
Interventions
DRUGNitric Oxide
Inhalation - 40 ppm, at the initiation of anesthesia to the end of surgery
Sponsors
University of Colorado, Denver
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 69 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| To Determine if Inhaled Nitric Oxide Has Beneficial Effects on Overall Outcome After Extended Criteria Donor (EDC) Liver Transplantation | 3 years |
Secondary
| Measure | 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 |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| No Nitric Oxide This arm will not receive nitric oxide, but will receive other standard inhaled anesthetics | 5 |
| Nitric Oxide Will receive Nitric oxide and other standard inhaled anesthetics
Nitric Oxide: Inhalation - 40 ppm, at the initiation of anesthesia to the end of surgery | 7 |
| Total | 12 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Blood drawn using incorrect test tube; sample invalid | 1 | 0 |
Baseline characteristics
| Characteristic | No Nitric Oxide | Nitric Oxide | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 0 Participants | 1 Participants |
| Age, Categorical Between 18 and 65 years | 4 Participants | 7 Participants | 11 Participants |
| BMI | 26.59 kg/m^2 STANDARD_DEVIATION 5.01 | 27.1 kg/m^2 STANDARD_DEVIATION 5.83 | 26.89 kg/m^2 STANDARD_DEVIATION 5.51 |
| Diagnosis Bone mets | 0 participants | 1 participants | 1 participants |
| Diagnosis Cirrhosis | 5 participants | 3 participants | 8 participants |
| Diagnosis Fatty Liver (NASH) | 1 participants | 0 participants | 1 participants |
| Diagnosis HCC | 2 participants | 4 participants | 6 participants |
| Diagnosis Hepatitis C | 4 participants | 4 participants | 8 participants |
| Diagnosis Hepatoma | 1 participants | 4 participants | 5 participants |
| Diagnosis Metabolic Disease (METDIS) - Alpha-1-Antitrypsin Deficiency (A-1-A) | 0 participants | 1 participants | 1 participants |
| Diagnosis Primary Sclerosing Cholangitis (PSC) | 0 participants | 1 participants | 1 participants |
| Model for End-Stage Liver Disease Score | 26.2 units on a scale STANDARD_DEVIATION 5.42 | 27.14 units on a scale STANDARD_DEVIATION 3.64 | 26.75 units on a scale STANDARD_DEVIATION 4.5 |
| Sex: Female, Male Female | 1 Participants | 2 Participants | 3 Participants |
| Sex: Female, Male Male | 4 Participants | 5 Participants | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 5 | 0 / 7 |
| serious Total, serious adverse events | 0 / 5 | 0 / 7 |
Outcome results
Primary
To Determine if Inhaled Nitric Oxide Has Beneficial Effects on Overall Outcome After Extended Criteria Donor (EDC) Liver Transplantation
Time frame: 3 years
Population: The outcome measure data are unavailable. This study was terminated when the P.I. left the university. Research Administration and the study team have made numerous unsuccessful attempts to obtain the outcome measure data.
Secondary
To Construct a Plasma Metabolic/Protein Profile of I/R Injury in Transplanted Livers
Time frame: 3 years
Population: The outcome measure data are unavailable. This study was terminated when the P.I. left the university. Research Administration and the study team have made numerous unsuccessful attempts to obtain the outcome measure data.
Secondary
To Examine the Effects of Nitric Oxide on Protein Synthesis and Metabolism Following Extended Criteria Donor Liver Transplantation
Time frame: 3 years
Population: The outcome measure data are unavailable. This study was terminated when the P.I. left the university. Research Administration and the study team have made numerous unsuccessful attempts to obtain the outcome measure data.