Rationale: Recent publications report good results of controlled donation after circulatory death (DCD) Maastricht category III liver transplantation when strict donor-recipient matching is applied and ischemia times are kept to a minimum. However a major concern remains the high rate of biliary complications after transplantation of DCD livers. Non-anastomotic biliary strictures (NAS) occur in 29% of patients receiving a DCD graft whereas the incidence of NAS in recipients of donation after brain death (DBD) liver grafts is 11%. NAS are associated with higher morbidity and increased cost of liver transplantation. Injury to the biliary epithelium and the peribiliary vascular plexus occurring during donor warm ischemia and static cold storage (SCS) has been identified as a major risk factor for development of NAS. Machine perfusion has been proposed as an alternative strategy for organ preservation, offering the opportunity to improve the quality of the organ by providing oxygen to the graft. Experimental studies have shown that end-ischemic dual hypothermic oxygenated machine perfusion (DHOPE) helps liver grafts to recover from ischemia by restoring mitochondrial function. Moreover, DHOPE has been shown to provide better preservation of peribiliary vascular plexus of the bile ducts, which could be an important step forward in reducing the incidence of NAS after transplantation. Objective: To study the efficacy of end-ischemic DHOPE in reducing the incidence of NAS within six months after controlled DCD (Maastricht category III) liver transplantation. Study design: An international, multicenter, prospective, randomized, controlled, interventional, clinical trial with a two parallel arm approach (treatment/control). Study population: Adult patients (≥18 yrs old) undergoing a liver transplantation with a liver graft procured from a controlled DCD donor (Maastricht category III) with a body weight ≥40 kg. Intervention: In the intervention group liver grafts will be subjected to two hours of hypothermic, oxygenated perfusion at the end of SCS and before implantation. In the control group donor liver grafts will be preserved in accordance to standard practice by SCS only. Main study parameters/endpoints: The incidence and severity of symptomatic NAS as diagnosed by an Adjudication committee (who are blinded for the group assignment) by means of magnetic resonance cholangiopancreatography (MRCP).
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
PREVENTION
Masking
DOUBLE
Enrollment
157
Dual hypothermic oxygenated perfusion using the Liver Assist
The Liver Assist® is the device used to give the intervention dual hypothermic perfusion.
The perfusion fluid is Belzer machine perfusion solution University of Wisconsin (Bridge-to-Life, Ltd., Northbrook, IL).
Glutathione in a dosage of 3 mmol/ is added to the perfusion fluid according to the intention of use of the perfusion fluid.
Ghent University Hospital
Ghent, De Pintelaan 185, Belgium
University Hospitals Leuven
Leuven, Herestraat 49, Belgium
Leiden Universtiy Medical Center
Leiden, South Holland, Netherlands
University Medical Center Groningen
Groningen, Netherlands
Erasmus Medical Center
Rotterdam, Netherlands
King's College Hospital NHS Trust
London, United Kingdom
The incidence of symptomatic non-anastomotic biliary strictures (NAS)
NAS is defined as all of the following criteria: * any irregularities or narrowing of the lumen of the intra- or extrahepatic donor bile ducts, but not at the anastomosis * which are diagnosed by cholangiogram (preferably by MRCP) * in the presence of a patent hepatic artery demonstrated by Doppler ultrasonography and if necessary, by computed tomography angiography * and as assessed by the Adjudication Committee * when imaging is indicated by clinical signs (i.e., jaundice, cholangitis) or elevation of cholestatic laboratory parameters in blood samples taken during follow-up
Time frame: 6 months
Asymptomatic NAS
Asymptomatic NAS is defined as all of the following: * irregularities or narrowing of the lumen of the intra- or extrahepatic donor bile ducts, but not at the anastomosis * which are diagnosed by cholangiogram (preferably by MRCP) * in the presence of a patent hepatic artery demonstrated by Doppler ultrasonography and if necessary, by computed tomography angiography * in the absence of clinical signs (i.e., jaundice, cholangitis) or elevation of cholestatic laboratory parameters in blood samples taken during follow-up
Time frame: 6 months
The severity of NAS
Severity and location of NAS is based on assessment of the images of the MRCP obtained in all patients at six months after transplantation (time window of 15 days) which will be performed based on a scoring system described by Buis et. al. And required treatment for NAS (i.e. ursodeoxycholic acid, ERCP, retransplantation)
Time frame: 6 months
The location of NAS
Assessment of the images of the MRCP obtained in all patients at six months after transplantation (time window of 15 days) which will be performed based on a scoring system described by Buis et. al.
Time frame: 6 months
Graft (censored and uncensored for patient death) survival
Time frame: 7 days, 1, 3 , 6, and 12 months after transplantation
Patient survival
Time frame: 7 days, 1, 3 , 6, and 12 months after transplantation
Primary non-function
Defined as liver failure requiring retransplantation or leading to death within seven days after transplantation without any identifiable cause such as surgical problems, hepatic artery thrombosis, portal vein thrombosis and acute rejection
Time frame: 7 days
Initial poor function
Defined as a modification of the Olthoff criteria: Prothrombin time/ international normalized ratio (INR) \>1.6 and or serum total bilirubin \>10 mg/dL on postoperative day 7
Time frame: 7 days
Biochemical analysis of graft function and ischemia-reperfusion injury
serum levels of alanine aminotransferase (ALT), AST, alkaline phosphatase (AlkP), gamma-glutamyl transferase (γGT), and total bilirubin
Time frame: Postoperative day 0 - 7 and 1, 3, 6 months
Blood pressure
mm Hg
Time frame: 5 min before reperfusion, at reperfusion and after 10 and 20 minutes of reperfusion
Heart rate
beats per minute
Time frame: 5 min before reperfusion, at reperfusion and after 10 and 20 minutes of reperfusion
Vasopressor dosage
microgram/kg/min
Time frame: 5 min before reperfusion, at reperfusion and after 10 and 20 minutes of reperfusion
Length of stay
Length of initial ICU and initial hospital stay is determined in days of admission following liver transplantation. Duration of follow-up hospital stay is determined in days of hospital admission after discharge and up to six months after liver transplantation
Time frame: 6 months
Postoperative complications
According to the comprehensive complication index (CCI)
Time frame: 6 months
Renal function
Estimated glomerular filtration rate (eGFR) according to the 4-variable Modification of Diet in Renal Disease (MDRD) equation
Time frame: day 7, and 1, 3, 6 months
Flow
ml/min
Time frame: At 0, 15, 30, 45, 60, 75, 90, 105, 120 minutes after start of perfusion
Pressure
mm Hg
Time frame: At 0, 15, 30, 45, 60, 75, 90, 105, 120 minutes after start of perfusion
Resistance
ml/min/mm Hg
Time frame: At 0, 15, 30, 45, 60, 75, 90, 105, 120 minutes after start of perfusion
(In selected centers) value of perfusate's pH
Time frame: At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion
(In selected centers) value of perfusate's sodium
mmol/L
Time frame: At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion
(In selected centers) value of perfusate's potassium
mmol/L
Time frame: At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion
(In selected centers) value of perfusate's bicarbonate
mmol/l
Time frame: At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion
(In selected centers) value of perfusate's lactate
mmol/l
Time frame: At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion
(In selected centers) value of perfusate's alanine transaminase (ALT)
U/L
Time frame: At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion
(In selected centers) value of perfusate's aspartate transaminase (AST)
U/L
Time frame: At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion
(In selected centers) value of perfusate's alkaline phosphatase (AlkP)
U/L
Time frame: At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion
(In selected centers) value of perfusate's gamma glutamyltransferase (γGT)
U/L
Time frame: At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion
(In selected centers) value of perfusate's urea
mmol/L
Time frame: At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion
(In selected centers) value of perfusate's total bilirubin
umol/l
Time frame: At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion
(In selected centers) value of perfusate's thrombomodulin
pg/dl
Time frame: At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion
(In selected centers) value of perfusate's high mobility group box-1 (HMBG) protein
μg/mL
Time frame: At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion
(In selected centers) value of perfusate's cytochrome C
Time frame: At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion
(In selected centers) level of miRNA CDmiR-30e in perfusate
relative levels compared to perfusate
Time frame: At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion
(In selected centers) level of miRNA CDmiR-222 in perfusate
relative levels compared to perfusate
Time frame: At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion
(In selected centers) level of miRNA CDmiR-296 in perfusate
relative levels compared to perfusate
Time frame: At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion
(In selected centers) level of miRNA HDmiR-122 in perfusate
relative levels compared to perfusate
Time frame: At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion
(In selected centers) level of miRNA HDmiR-148a in perfusate
relative levels compared to perfusate
Time frame: At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion
Histopathological status liver and bile ducts (in selected centers)
Time frame: Within 0 to 30 minutes before perfusion, at 2 hours of perfusion, and at 1 hour after reperfusion
New onset diabetes after transplantation
* Symptoms of diabetes and random plasma glucose ≥11.1 mmol/L. Symptoms include polyuria, polydipsia, and unexplained weight loss. OR * Fasting plasma glucose ≥7.0 mmol/L. Fasting is defined as no caloric intake for at least eight hours. OR * Two-hour plasma glucose ≥11.1 mmol/L during an oral glucose tolerance test. The test should be performed as described by the WHO, using a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water.
Time frame: 90 days
Costs of treatment (in selected centers)
according to the Cost and Outcome analysis of Liver Transplantation (COLT) study
Time frame: within 6 months after transplantation, including transplant operation
Health related quality of life
EQ6D questionnaire
Time frame: within 6 months before transplantation and 6 months after transplantation
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