Liver Damage
Conditions
Keywords
ECD liver transplant allografts, Hypothermic machine perfusion, Cold storage preservation, liver transplant, portable bypass system, machine perfusion preservation, extended criteria liver
Brief summary
This is a study comparing a technique of continuous circulation to the liver as a means of preventing liver damage during transportation to the transplant hospital. This new technique of Machine Perfusion (MP) will be compared to the standard technique where the liver is maintained in a bag of solution on ice without circulation. The investigators will evaluate and compare the outcomes of the transplants with the new technique to the standard technique. There will be 24 MP patient's in the study. The investigators have previously used this technique with success in 20 human liver transplant patients. The investigators think there will be a benefit in terms of less damage to and better function of the donor liver which will result in faster recovery for the patients. This protective effect may allow us to successfully transplant more patients and prevent people from dying while waiting for a liver transplant.
Detailed description
It is our hypothesis that liver machine perfusion will increase the safe utilization of the existing supply of extended criteria donor (ECD) livers by (1) increasing the quality and duration of preservation thereby reducing the clinical effects reperfusion injury (2) improving early outcomes in patients receiving ECD liver allografts (3) developing reliable markers for pretransplant assessment of the potential graft (4) giving surgeons more confidence when transplanting ECD livers and (5) allowing an avenue for ex vivo manipulation of the liver to protect or restore a transiently injured liver. The proposed study is a matched cohort design. Potential subjects will be recruited from the Center for Liver Disease and Transplantation (CLDT) active Liver Transplant Waiting List. The Principal Investigator as well as the CoInvestigators, are all actively involved in the pre transplant evaluation process. Patients who are on the Waiting List and have provided written consent to receive an ECD graft will be recruited for this trial. Subjects will be matched with 24 historical control patients who received similar cold stored ECD grafts. Subjects will be matched on known covariates including donor age, donation after cardiac death, steatosis, both warm and cold ischemia times, recipient age, Model End-Stage Liver Disease (MELD) score and disease etiology. Subjects will be noncritically ill, not in an intensive care unit, and have a MELD \< 35 in order to minimize the variability in outcome in the sickest patients. All subjects must provide written informed consent and meet the inclusion and exclusion criteria. Subjects will be followed for one year post transplantation, in conjunction with their routine liver transplant followup appointments. Retention of subjects for this trial will not be a challenge, in that the followup visit time points (postoperative days 1 through the discharge date, 7, 14, 30, 90, 180 and 365) are all consistent with our standard of care.
Interventions
DEVICEThe Medtronic Portable Bypass System (PBS®)
Will be used for machine perfusion of liver grafts.
Sponsors
Columbia University
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 90 Years
Healthy volunteers
No
Inclusion criteria
* Signed written informed IRB consent by patient or patient's legally appointed representative. * Be at least 18 years of age; male or female. * Listed with UNOS for liver transplantation. * Organ declined by at least one transplant center * Extended criteria donor as defined by: * Presence of hepatitis C antibody * Donation after Cardiac Death (DCD) * Severe Hypernatremia: donor serum sodium \>165 meq/L for at least 12 hours prior to procurement * Donor age ≥65 years * Presence of significant steatosis \>25% macrovesicular by biopsy * Evidence of significant donor ischemic injury * Current donor serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) \>1000 IU/L * Ischemic injury evidenced by prolonged hypotension, high pressor requirement and/or rising serum liver function tests or one test more than five times the upper limit of normal (AST, ALT, or Total Bilirubin)
Exclusion criteria
* Patients in whom the donor liver will be subjected to less than 4 hours of cold ischemia (surgeon desires immediate implantation) * Patient hospitalized in intensive care unit (ICU) at time of transplantation and/or physiologic MELD score \>35 * Dual organ recipient * ABO incompatibility * Retransplantation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Patient Survival at One Year Post-Transplantation | Post-Operative Day 1 to Day 365 | — |
| Graft Survival at One Year Post-Transplantation | Post-Operative Day 1 to Day 365 | Analysis was based on the amount of liver allografts in each cohort that were deemed to be clinically functional at 1 year post-transplantation (i.e. no re-transplantation required). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Post-Operative Complications | 1 Month Post-Transplantation | Incidence of Retransplants or Hepatic Artery Thrombosis (HAT) within 1 month post-transplantation |
| Incidence of Bile Leaks | Post-Operative Day 1 to Day 365 | Incidence of bile leaks. |
| Incidence of Re-Operation For Bleeding | Post-Operative Day 1 to Day 365 | Incidence of patients who required re-operation for a bleeding event |
| Incidence of Hernia Events Within 1 Year Post-Transplantation | Post-Operative Day 1 to Day 365 | — |
| Incidence of Primary Graft Nonfunction | Post-Operative Day 1 to Day 7 | Incidence of Primary Graft Nonfunction (PNF), defined as follows: * Relisted for orthotopic liver transplantation (OLT) within 7 days of OLT, not for vascular thromboses * Alanine aminotransferase (ALT) \>2000 and one or both of: acidosis with pH \<7.3 or lactate \>2X (two times) normal * International normalized ratio (INR) \>2.5 |
| Time With Stent (Days) | Post-Operative Day 1 to Day 365 | Measure of biliary complications as evidenced by mean time with stent (in days). |
| Incidence of Biliary Strictures | Post-Operative Day 1 to Day 365 | Incidence of biliary strictures. |
| Incidence of Endoscopic Retrograde Cholangiopancreatographies (ERCPs) | Post-Operative Day 1 to Day 365 | Incidence of endoscopic retrograde cholangiopancreatographies (ERCPs) |
| Hospital Length of Stay (Index Transplant Hospitalization) | First admission after transplant | Length of transplant hospital stay post-transplantation (Index Transplant Hospitalization) |
| Incidence of Early Allograft Dysfunction (EAD) | Within the first 7 days post-transplantation | Incidence of Early Allograft Dysfunction (EAD), defined as follows: * Bilirubin \>10 on post-operative day (POD)#7 * International normalized ratio (INR) \>1.6 on POD#7 * Transaminase level (aspartate aminotransferase (AST) or alanine aminotransferase (ALT)) \>2000 within the first 7 days |
Countries
United States
Participant flow
Recruitment details
24 liver recipients who received extended criteria donor (ECD) liver transplant allografts were recruited for our treatment group over a span of 2 years. As a high-volume, major NY transplant center with approximately 270 adult patients on our Liver Transplant Waiting List and 45-50% receiving ECD grafts, we were able to meet our enrollment goal.
Participants by arm
| Arm | Count |
|---|---|
| Matched Control Group This study had a matched cohort design. Treatment subjects were matched with 25 historical control patients who received similar cold stored extended criteria donor (ECD) grafts. Subjects were matched on known covariates including donor age, donation after cardiac death, steatosis, both warm and cold ischemia times, recipient age, Model for End-Stage Liver Disease (MELD) score and disease etiology. Additional analyses were performed on historical control blood and/or tissue samples previously collected and stored in the study's sample repository. | 25 |
| Experimental: Hypothermic Machine Perfusion Group Group 24 subjects were treated with the Medtronic Portable Bypass System (PBS®) with Model 550 Bioconsole, and the BioCal® blood temperature control module was used for machine perfusion of liver grafts. These products are commercially available and are used in clinical practice for cardiopulmonary bypass and extracorporeal membrane oxygenation. The Medtronic system utilizes an atraumatic centrifugal pump that can deliver the flow rates approximating portal venous flow in human livers, and it has modules for online membrane oxygenation, and electronic flow measurement. | 24 |
| Total | 49 |
Baseline characteristics
| Characteristic | Matched Control Group | Experimental: Hypothermic Machine Perfusion Group Group | Total |
|---|---|---|---|
| Age, Customized 18-21 years | 0 participants | 0 participants | 0 participants |
| Age, Customized 22-29 years | 0 participants | 0 participants | 0 participants |
| Age, Customized 30-39 years | 0 participants | 1 participants | 1 participants |
| Age, Customized 40-49 years | 3 participants | 3 participants | 6 participants |
| Age, Customized 50-59 years | 11 participants | 9 participants | 20 participants |
| Age, Customized 60-69 years | 8 participants | 9 participants | 17 participants |
| Age, Customized 70-79 years | 3 participants | 2 participants | 5 participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 11 Participants | 3 Participants | 14 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 13 Participants | 18 Participants | 31 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 3 Participants | 4 Participants |
| Race/Ethnicity, Customized Black or African American | 7 participants | 5 participants | 12 participants |
| Race/Ethnicity, Customized Multiracial | 0 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized Other | 2 participants | 5 participants | 7 participants |
| Race/Ethnicity, Customized White | 16 participants | 14 participants | 30 participants |
| Sex: Female, Male Female | 10 Participants | 8 Participants | 18 Participants |
| Sex: Female, Male Male | 15 Participants | 16 Participants | 31 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 25 | 6 / 24 |
| other Total, other adverse events | 0 / 25 | 0 / 24 |
| serious Total, serious adverse events | 11 / 25 | 6 / 24 |
Outcome results
Primary
Graft Survival at One Year Post-Transplantation
Analysis was based on the amount of liver allografts in each cohort that were deemed to be clinically functional at 1 year post-transplantation (i.e. no re-transplantation required).
Time frame: Post-Operative Day 1 to Day 365
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Matched Control Group | Graft Survival at One Year Post-Transplantation | 23 grafts |
| Experimental: Hypothermic Machine Perfusion Group | Graft Survival at One Year Post-Transplantation | 23 grafts |
Primary
Patient Survival at One Year Post-Transplantation
Time frame: Post-Operative Day 1 to Day 365
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Matched Control Group | Patient Survival at One Year Post-Transplantation | 19 participants |
| Experimental: Hypothermic Machine Perfusion Group | Patient Survival at One Year Post-Transplantation | 19 participants |
Secondary
Hospital Length of Stay (Index Transplant Hospitalization)
Length of transplant hospital stay post-transplantation (Index Transplant Hospitalization)
Time frame: First admission after transplant
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Matched Control Group | Hospital Length of Stay (Index Transplant Hospitalization) | 16.5 days |
| Experimental: Hypothermic Machine Perfusion Group | Hospital Length of Stay (Index Transplant Hospitalization) | 10 days |
Secondary
Incidence of Bile Leaks
Incidence of bile leaks.
Time frame: Post-Operative Day 1 to Day 365
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Matched Control Group | Incidence of Bile Leaks | 3 events |
| Experimental: Hypothermic Machine Perfusion Group | Incidence of Bile Leaks | 0 events |
Secondary
Incidence of Biliary Strictures
Incidence of biliary strictures.
Time frame: Post-Operative Day 1 to Day 365
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Matched Control Group | Incidence of Biliary Strictures | 10 events |
| Experimental: Hypothermic Machine Perfusion Group | Incidence of Biliary Strictures | 2 events |
Secondary
Incidence of Early Allograft Dysfunction (EAD)
Incidence of Early Allograft Dysfunction (EAD), defined as follows: * Bilirubin \>10 on post-operative day (POD)#7 * International normalized ratio (INR) \>1.6 on POD#7 * Transaminase level (aspartate aminotransferase (AST) or alanine aminotransferase (ALT)) \>2000 within the first 7 days
Time frame: Within the first 7 days post-transplantation
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Matched Control Group | Incidence of Early Allograft Dysfunction (EAD) | 9 participants |
| Experimental: Hypothermic Machine Perfusion Group | Incidence of Early Allograft Dysfunction (EAD) | 5 participants |
Secondary
Incidence of Endoscopic Retrograde Cholangiopancreatographies (ERCPs)
Incidence of endoscopic retrograde cholangiopancreatographies (ERCPs)
Time frame: Post-Operative Day 1 to Day 365
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Matched Control Group | Incidence of Endoscopic Retrograde Cholangiopancreatographies (ERCPs) | 35 events |
| Experimental: Hypothermic Machine Perfusion Group | Incidence of Endoscopic Retrograde Cholangiopancreatographies (ERCPs) | 7 events |
Secondary
Incidence of Hernia Events Within 1 Year Post-Transplantation
Time frame: Post-Operative Day 1 to Day 365
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Matched Control Group | Incidence of Hernia Events Within 1 Year Post-Transplantation | 2 hernia events |
| Experimental: Hypothermic Machine Perfusion Group | Incidence of Hernia Events Within 1 Year Post-Transplantation | 4 hernia events |
Secondary
Incidence of Post-Operative Complications
Incidence of Retransplants or Hepatic Artery Thrombosis (HAT) within 1 month post-transplantation
Time frame: 1 Month Post-Transplantation
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Matched Control Group | Incidence of Post-Operative Complications | Retransplant | 0 participants |
| Matched Control Group | Incidence of Post-Operative Complications | HAT | 1 participants |
| Experimental: Hypothermic Machine Perfusion Group | Incidence of Post-Operative Complications | Retransplant | 1 participants |
| Experimental: Hypothermic Machine Perfusion Group | Incidence of Post-Operative Complications | HAT | 1 participants |
Secondary
Incidence of Primary Graft Nonfunction
Incidence of Primary Graft Nonfunction (PNF), defined as follows: * Relisted for orthotopic liver transplantation (OLT) within 7 days of OLT, not for vascular thromboses * Alanine aminotransferase (ALT) \>2000 and one or both of: acidosis with pH \<7.3 or lactate \>2X (two times) normal * International normalized ratio (INR) \>2.5
Time frame: Post-Operative Day 1 to Day 7
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Matched Control Group | Incidence of Primary Graft Nonfunction | 2 participants |
| Experimental: Hypothermic Machine Perfusion Group | Incidence of Primary Graft Nonfunction | 1 participants |
Secondary
Incidence of Re-Operation For Bleeding
Incidence of patients who required re-operation for a bleeding event
Time frame: Post-Operative Day 1 to Day 365
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Matched Control Group | Incidence of Re-Operation For Bleeding | 5 participants |
| Experimental: Hypothermic Machine Perfusion Group | Incidence of Re-Operation For Bleeding | 2 participants |
Secondary
Time With Stent (Days)
Measure of biliary complications as evidenced by mean time with stent (in days).
Time frame: Post-Operative Day 1 to Day 365
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Matched Control Group | Time With Stent (Days) | 86 days |
| Experimental: Hypothermic Machine Perfusion Group | Time With Stent (Days) | 66.5 days |