Reperfusion Injury
Conditions
Keywords
Liver, Transplantation, Ischemia-reperfusion, Effectiveness
Brief summary
The purpose of this study is to establish the effectiveness of the combined drug approach (anti-thrombin III, infliximab, apotransferrin, human recombinant erythropoietin beta, C1-inhibitor, glutathione, alfa-tocopherol, melatonin and epoprostenol)aimed to reduce ischemia-reperfusion injury during liver transplantation in eligible recipients.
Detailed description
This unicentric, investigator-driven, open-label randomized clinical trial with 2 parallel arms was conducted in Belgium from September 2013 through February 2018, with 1-year follow-up. Adults wait-listed for a first solitary full-size liver transplant were screened for eligibility. Exclusion criteria were acute liver failure, kidney failure, contraindication to treatment, participation in another trial, refusal, technical issues, and death while awaiting transplant. Included patients were enrolled and randomized at the time of liver offer. Data were analyzed from May 20, 2019, to May 27, 2020. Participants were randomized to a combined drug approach with standard of care (static cold storage) or standard of care only (control group). In the combined drug approach group, following static cold preservation, donor livers were infused with epoprostenol (ex situ, portal vein); recipients were given oral α-tocopherol and melatonin prior to anesthesia and intravenous antithrombin III, infliximab, apotransferrin, recombinant erythropoietin-β, C1-inhibitor, and glutathione during the anhepatic and reperfusion phase. The primary outcome was the posttransplant peak serum aspartate aminotransferase (AST) level within the first 72 hours. Secondary end points were the frequencies of postreperfusion syndrome, ischemia-reperfusion injury score, early allograft dysfunction, surgical complications, ischemic cholangiopathy, acute kidney injury, acute cellular rejection, and graft and patient survival.
Interventions
DRUGAntithrombin-III
DRUGInfliximab
DRUGApotransferrin
DRUGC1-Inhibitor
DRUGGlutathione
DRUGAlfa-tocopherol
DRUGMelatonin
DRUGEpoprostenol
Sponsors
Universitaire Ziekenhuizen KU Leuven
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Patients suffering from irreversible liver failure eligible for liver transplantation according to Eurotransplant guidelines. 2. Patients \> 18 years of age at time of listing on Eurotransplant waiting list for liver transplantation in University Hospitals Leuven, Belgium.
Exclusion criteria
1. Patients who refuse to participate in the study. 2. History of hypersensitivity to one/several component(s) of the combined drug approach. 3. Conditions that prevent the use of the combined drug approach: * Administration of heparin at therapeutic dose pre-operatively, * Congestive heart failure, * History of seizure, poorly controlled arterial hypertension, myocardial infarction or stroke in the month preceding the liver transplantation, venous thromboembolic disease, * Unstable angina pectoris, * Sepsis, abcesses or opportunistic infections, * History of infliximab treatment, * Use of vitamin K antagonist anticoagulation. 4. Mental conditions rendering the subject incapable to understand the nature, scope, and consequences of the trial. 5. Combined organ transplantation. 6. Re-transplantation. 7. Patients that are dialysis-dependent prior to the liver transplantation.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Peak Aspartate Aminotransferase Within First 72h Post Transplant | within 72 hours following liver transplantation | peak AST is defined as the highest value of serum AST within 72 hours following liver transplantation |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Graft Loss | 3 and 12 months after liver transplantation | graft loss at 3 and 12 months after liver transplantation |
| Recipient Death | 3 and 12 months after liver transplantation | recipient death at 3 and 12 months after liver transplantation |
| Early Graft Dysfunction | within first 7 days | early graft dysfunction as defined by Olthoff |
| Number of Participants Developing Biliary Strictures | within 12 months post transplantation | Biliary strictures are the narrowing of the intrahepatic or extrahepatic biliary ductal system. Here we report the number of participants developing biliary strictures within 12 months post transplantation by MRCP (magnetic resonance cholangiopancreatography) |
| Ischemia Reperfusion Injury Score | One hour post reperfusion | Ischemia Reperfusion Injury score 1h post reperfusion by using the Suzuki score and Monbaliu et al. The score ranges from 0 (no injury) to 4 (severe injury). |
| Patients With at Least 1 Severe Surgical Complications | within 1 year after liver transplantation | The ranking of surgical complications will be done by using Clavien-Dindo classification Grade I Any deviation from the normal post-operative course not requiring surgical, endoscopic or radiological intervention. This includes the need for certain drugs (e.g. antiemetics, antipyretics, analgesics, diuretics and electrolytes), treatment with physiotherapy and wound infections that are opened at the bedside Grade II Complications requiring drug treatments other than those allowed for Grade I complications; this includes blood transfusion and total parenteral nutrition (TPN) Grade III Complications requiring surgical, endoscopic or radiological intervention Grade IV Life-threatening complications; this includes CNS complications (e.g. brain haemorrhage, ischaemic stroke, subarachnoid haemorrhage) which require intensive care, but excludes transient ischaemic attacks (TIAs) Grade V Death of the patient A severe surgical complication is defined as Grade III or higher. |
| Non-anastomotic Biliary Stricture | 1 year | Non-anastomotic biliary stricture at 1 year |
| Acute Kidney Injury Score | 48h | An acute kidney injury score of 1 indicates risk; 2, injury; and 3, failure. According to RIFLE (Risk, Injury, Failure, Loss of kidney function, and End-stage kidney disease) Minimum score is 0 meaning there is no injury, maximum score is 3 meaning failure of the organ. |
| Post-Reperfusion Syndrome | first 5 minutes following graft reperfusion | Post-reperfusion syndrome defined as a 30% decrease of mean systemic blood pressure for more than 1 minute during the first 5 minutes following graft reperfusion |
| Graft Rejection | till 1 year after transplantation | a liver biopsy will be taken after transplantation and in case of clinical suspicion of acute rejection |
Other
| Measure | Time frame | Description |
|---|---|---|
| Intensive Care Unit Length of Stay (Recipient) | During hospital stay for liver transplantation | Intensive Care Unit stay immediately after liver transplantation (not after rehospitalization) |
Countries
Belgium
Participant flow
Pre-assignment details
Of 143 enrolled participants, 93 were randomized. Reasons for exclusion of enrolled participants was : * Patients deceased before transplantation (on waiting list) * Patients not eligible anymore for transplantation * Included in other clinical trials * Change from single liver transplantation to combined transplantation (liver-kidney)
Participants by arm
| Arm | Count |
|---|---|
| Combined Drug Approach the group receives a combination of drugs
Antithrombin-III
Infliximab
Apotransferrin
Human recombinant erythropoietin
C1-Inhibitor
Glutathione
Alfa-tocopherol
Melatonin
Epoprostenol | 38 |
| Controls the group do not receive a combination of drugs, but a placebo (sodium chloride solution)
Sodium chloride solution | 36 |
| Total | 74 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Did not receive intervention | 15 | 4 |
Baseline characteristics
| Characteristic | Controls | Total | Combined Drug Approach |
|---|---|---|---|
| Age, Continuous | 60 years | 60 years | 59 years |
| Brain death duration | 14.3 hours | 13.5 hours | 13.3 hours |
| Cold ischemia time | 5.8 hours | 5.8 hours | 5.8 hours |
| Donor age | 59 years | 59 years | 57 years |
| Donor cause of death Anoxia | 2 Participants | 2 Participants | 0 Participants |
| Donor cause of death Cerebrovascular accident | 11 Participants | 31 Participants | 20 Participants |
| Donor cause of death Other | 12 Participants | 24 Participants | 12 Participants |
| Donor cause of death Trauma | 11 Participants | 17 Participants | 6 Participants |
| Donor hepatectomy duration | 32.5 minutes | 34 minutes | 34.5 minutes |
| Donor type Donation after Brain Death | 23 Participants | 49 Participants | 26 Participants |
| Donor type Donation after Circulatory Death | 13 Participants | 25 Participants | 12 Participants |
| Implantation duration | 38.5 Minutes | 39.0 Minutes | 39.5 Minutes |
| Indication for liver transplant Cholestatic disease | 4 participants | 8 participants | 4 participants |
| Indication for liver transplant Chronic liver disease | 18 participants | 43 participants | 25 participants |
| Indication for liver transplant Cryptogenic | 0 participants | 1 participants | 1 participants |
| Indication for liver transplant Ethyl | 18 participants | 41 participants | 23 participants |
| Indication for liver transplant HBV | 0 participants | 2 participants | 2 participants |
| Indication for liver transplant HCC | 12 participants | 30 participants | 18 participants |
| Indication for liver transplant HCV | 0 participants | 2 participants | 2 participants |
| Indication for liver transplant Metabolic disease | 3 participants | 7 participants | 4 participants |
| Indication for liver transplant Nonalcoholic Steatohepatitis | 10 participants | 12 participants | 2 participants |
| Intensive Care Unit Length of stay (donor) | 4 days | 4 days | 3 days |
| Model for End-Stage Liver Disease score (MELD) | 13.8 score on a scale | 13.6 score on a scale | 13.2 score on a scale |
| Race (NIH/OMB) American Indian or Alaska Native | — | 0 Participants | — |
| Race (NIH/OMB) Asian | — | 0 Participants | — |
| Race (NIH/OMB) Black or African American | — | 0 Participants | — |
| Race (NIH/OMB) More than one race | — | 0 Participants | — |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | — | 0 Participants | — |
| Race (NIH/OMB) Unknown or Not Reported | — | 0 Participants | — |
| Race (NIH/OMB) White | — | 0 Participants | — |
| Sex: Female, Male Female | 11 Participants | 21 Participants | 10 Participants |
| Sex: Female, Male Male | 25 Participants | 53 Participants | 28 Participants |
| Type of preservation solution HTK (Histidine-tryptophan-ketoglutarate) | 5 Participants | 11 Participants | 6 Participants |
| Type of preservation solution IGL-1 (Institut Georges Lopez-1) | 25 Participants | 50 Participants | 25 Participants |
| Type of preservation solution Other | 1 Participants | 1 Participants | 0 Participants |
| Type of preservation solution UW (University of Wisconsin) | 5 Participants | 12 Participants | 7 Participants |
| Warm ischemia time if Donation after Circulatory Death | 16 minutes | 17 minutes | 17 minutes |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 4 / 36 | 3 / 36 |
| other Total, other adverse events | 33 / 36 | 31 / 36 |
| serious Total, serious adverse events | 6 / 36 | 4 / 36 |
Outcome results
Primary
Peak Aspartate Aminotransferase Within First 72h Post Transplant
peak AST is defined as the highest value of serum AST within 72 hours following liver transplantation
Time frame: within 72 hours following liver transplantation
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Combined Drug Approach | Peak Aspartate Aminotransferase Within First 72h Post Transplant | 1262.9 U/L |
| Controles | Peak Aspartate Aminotransferase Within First 72h Post Transplant | 1451.2 U/L |
Secondary
Acute Kidney Injury Score
An acute kidney injury score of 1 indicates risk; 2, injury; and 3, failure. According to RIFLE (Risk, Injury, Failure, Loss of kidney function, and End-stage kidney disease) Minimum score is 0 meaning there is no injury, maximum score is 3 meaning failure of the organ.
Time frame: 48h
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Combined Drug Approach | Acute Kidney Injury Score | RIFLE 0 | 27 Participants |
| Combined Drug Approach | Acute Kidney Injury Score | RIFLE 1 | 4 Participants |
| Combined Drug Approach | Acute Kidney Injury Score | RIFLE 2 | 2 Participants |
| Combined Drug Approach | Acute Kidney Injury Score | RIFLE 3 | 1 Participants |
| Controles | Acute Kidney Injury Score | RIFLE 3 | 0 Participants |
| Controles | Acute Kidney Injury Score | RIFLE 0 | 31 Participants |
| Controles | Acute Kidney Injury Score | RIFLE 2 | 3 Participants |
| Controles | Acute Kidney Injury Score | RIFLE 1 | 1 Participants |
Secondary
Early Graft Dysfunction
early graft dysfunction as defined by Olthoff
Time frame: within first 7 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Combined Drug Approach | Early Graft Dysfunction | 13 Participants |
| Controles | Early Graft Dysfunction | 17 Participants |
Secondary
Graft Loss
graft loss at 3 and 12 months after liver transplantation
Time frame: 3 and 12 months after liver transplantation
Population: Death-censored graft survival
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Combined Drug Approach | Graft Loss | 3-months | 2 Participants |
| Combined Drug Approach | Graft Loss | 12-months | 3 Participants |
| Controles | Graft Loss | 3-months | 0 Participants |
| Controles | Graft Loss | 12-months | 0 Participants |
Secondary
Graft Rejection
a liver biopsy will be taken after transplantation and in case of clinical suspicion of acute rejection
Time frame: till 1 year after transplantation
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Combined Drug Approach | Graft Rejection | 9 Participants |
| Controles | Graft Rejection | 8 Participants |
Secondary
Ischemia Reperfusion Injury Score
Ischemia Reperfusion Injury score 1h post reperfusion by using the Suzuki score and Monbaliu et al. The score ranges from 0 (no injury) to 4 (severe injury).
Time frame: One hour post reperfusion
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Combined Drug Approach | Ischemia Reperfusion Injury Score | 2 score |
| Controles | Ischemia Reperfusion Injury Score | 2 score |
Secondary
Non-anastomotic Biliary Stricture
Non-anastomotic biliary stricture at 1 year
Time frame: 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Combined Drug Approach | Non-anastomotic Biliary Stricture | 4 Participants |
| Controles | Non-anastomotic Biliary Stricture | 2 Participants |
Secondary
Number of Participants Developing Biliary Strictures
Biliary strictures are the narrowing of the intrahepatic or extrahepatic biliary ductal system. Here we report the number of participants developing biliary strictures within 12 months post transplantation by MRCP (magnetic resonance cholangiopancreatography)
Time frame: within 12 months post transplantation
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Combined Drug Approach | Number of Participants Developing Biliary Strictures | 13 Participants |
| Controles | Number of Participants Developing Biliary Strictures | 10 Participants |
Secondary
Patients With at Least 1 Severe Surgical Complications
The ranking of surgical complications will be done by using Clavien-Dindo classification Grade I Any deviation from the normal post-operative course not requiring surgical, endoscopic or radiological intervention. This includes the need for certain drugs (e.g. antiemetics, antipyretics, analgesics, diuretics and electrolytes), treatment with physiotherapy and wound infections that are opened at the bedside Grade II Complications requiring drug treatments other than those allowed for Grade I complications; this includes blood transfusion and total parenteral nutrition (TPN) Grade III Complications requiring surgical, endoscopic or radiological intervention Grade IV Life-threatening complications; this includes CNS complications (e.g. brain haemorrhage, ischaemic stroke, subarachnoid haemorrhage) which require intensive care, but excludes transient ischaemic attacks (TIAs) Grade V Death of the patient A severe surgical complication is defined as Grade III or higher.
Time frame: within 1 year after liver transplantation
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Combined Drug Approach | Patients With at Least 1 Severe Surgical Complications | 10 Participants |
| Controles | Patients With at Least 1 Severe Surgical Complications | 8 Participants |
Secondary
Post-Reperfusion Syndrome
Post-reperfusion syndrome defined as a 30% decrease of mean systemic blood pressure for more than 1 minute during the first 5 minutes following graft reperfusion
Time frame: first 5 minutes following graft reperfusion
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Combined Drug Approach | Post-Reperfusion Syndrome | 7 Participants |
| Controles | Post-Reperfusion Syndrome | 6 Participants |
Secondary
Recipient Death
recipient death at 3 and 12 months after liver transplantation
Time frame: 3 and 12 months after liver transplantation
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Combined Drug Approach | Recipient Death | 3 months | 3 Participants |
| Combined Drug Approach | Recipient Death | 12 months | 4 Participants |
| Controles | Recipient Death | 3 months | 1 Participants |
| Controles | Recipient Death | 12 months | 3 Participants |
Other Pre-specified
Intensive Care Unit Length of Stay (Recipient)
Intensive Care Unit stay immediately after liver transplantation (not after rehospitalization)
Time frame: During hospital stay for liver transplantation
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Combined Drug Approach | Intensive Care Unit Length of Stay (Recipient) | 3 Days |
| Controles | Intensive Care Unit Length of Stay (Recipient) | 4 Days |