A Multicenter Randomized Controlled Trial to Compare the Efficacy of End-ischemic Dual Hypothermic Oxygenated Perfusion With Standard Static Cold Storage of Liver Grafts Donated After Circulatory Death in Preventing Biliary Complications
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 发起方
- 入组人数
- 157
- 试验地点
- 6
- 主要终点
- The incidence of symptomatic non-anastomotic biliary strictures (NAS)
研究概览
简要总结
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).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Prevention
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 100 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Adult patients (≥ 18 years old)
- •Signed informed consent
- •Willing and able to attend follow-up examinations
- •Donor liver graft from a controlled donation after circulatory death (Maastricht category III)
- •Donors with a body weight ≥40 kg
排除标准
- •Simultaneous participation in another clinical trial that might possibly influence this trial
- •Mental conditions rendering the subject incapable to understand the nature, scope and consequences of the trial
- •Listed for liver transplantation due to fulminant liver failure or retransplantation because of primary non-function
- •Recipient positive test for HIV
- •Donor positive for HIV antigen, hepatitis B core antibody, hepatitis B surface antigen, or hepatitis C antibody
- •Simultaneous transplantation of another organ
- •Patients with contra-indications for MRCP (i.e. pacemaker)
研究组 & 干预措施
Dual hypothermic oxygenated perfusion
The liver is procured with a segment of supratruncal aorta. The intervention is restricted to the liver graft after arrival in the transplant center and before implantation. The donor liver is subjected to 2 hours of hypothermic oxygenated perfusion via the portal vein and the supratruncal aorta applied by the Liver Assist®. Before perfusion, the liver is flushed via the portal vein with 1 L Belzer machine perfusion solution. The perfusion is pressure controlled and set to a mean of 25 mmHg (arterial) and 5 mm Hg (portal). The perfusion fluid is 4 L Belzer machine perfusion solution with additional 3 mmol/L glutathione. The perfusion fluid is 12°C, when the temperature is set at 10°C. The oxygen flow is set at 0.5 mL/min of 100% oxygen on each of the two membrane oxygenators.
干预措施: Dual hypothermic oxygenated perfusion (Procedure)
Dual hypothermic oxygenated perfusion
The liver is procured with a segment of supratruncal aorta. The intervention is restricted to the liver graft after arrival in the transplant center and before implantation. The donor liver is subjected to 2 hours of hypothermic oxygenated perfusion via the portal vein and the supratruncal aorta applied by the Liver Assist®. Before perfusion, the liver is flushed via the portal vein with 1 L Belzer machine perfusion solution. The perfusion is pressure controlled and set to a mean of 25 mmHg (arterial) and 5 mm Hg (portal). The perfusion fluid is 4 L Belzer machine perfusion solution with additional 3 mmol/L glutathione. The perfusion fluid is 12°C, when the temperature is set at 10°C. The oxygen flow is set at 0.5 mL/min of 100% oxygen on each of the two membrane oxygenators.
干预措施: Liver Assist® (Device)
Dual hypothermic oxygenated perfusion
The liver is procured with a segment of supratruncal aorta. The intervention is restricted to the liver graft after arrival in the transplant center and before implantation. The donor liver is subjected to 2 hours of hypothermic oxygenated perfusion via the portal vein and the supratruncal aorta applied by the Liver Assist®. Before perfusion, the liver is flushed via the portal vein with 1 L Belzer machine perfusion solution. The perfusion is pressure controlled and set to a mean of 25 mmHg (arterial) and 5 mm Hg (portal). The perfusion fluid is 4 L Belzer machine perfusion solution with additional 3 mmol/L glutathione. The perfusion fluid is 12°C, when the temperature is set at 10°C. The oxygen flow is set at 0.5 mL/min of 100% oxygen on each of the two membrane oxygenators.
干预措施: Perfusion fluid (Procedure)
Dual hypothermic oxygenated perfusion
The liver is procured with a segment of supratruncal aorta. The intervention is restricted to the liver graft after arrival in the transplant center and before implantation. The donor liver is subjected to 2 hours of hypothermic oxygenated perfusion via the portal vein and the supratruncal aorta applied by the Liver Assist®. Before perfusion, the liver is flushed via the portal vein with 1 L Belzer machine perfusion solution. The perfusion is pressure controlled and set to a mean of 25 mmHg (arterial) and 5 mm Hg (portal). The perfusion fluid is 4 L Belzer machine perfusion solution with additional 3 mmol/L glutathione. The perfusion fluid is 12°C, when the temperature is set at 10°C. The oxygen flow is set at 0.5 mL/min of 100% oxygen on each of the two membrane oxygenators.
干预措施: Glutathione (Drug)
结局指标
主要结局
The incidence of symptomatic non-anastomotic biliary strictures (NAS)
时间窗: 6 months
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
次要结局
- Asymptomatic NAS(6 months)
- The severity of NAS(6 months)
- The location of NAS(6 months)
- Graft (censored and uncensored for patient death) survival(7 days, 1, 3 , 6, and 12 months after transplantation)
- Patient survival(7 days, 1, 3 , 6, and 12 months after transplantation)
- Primary non-function(7 days)
- Initial poor function(7 days)
- Biochemical analysis of graft function and ischemia-reperfusion injury(Postoperative day 0 - 7 and 1, 3, 6 months)
- Blood pressure(5 min before reperfusion, at reperfusion and after 10 and 20 minutes of reperfusion)
- Heart rate(5 min before reperfusion, at reperfusion and after 10 and 20 minutes of reperfusion)
- Vasopressor dosage(5 min before reperfusion, at reperfusion and after 10 and 20 minutes of reperfusion)
- Length of stay(6 months)
- Postoperative complications(6 months)
- Renal function(day 7, and 1, 3, 6 months)
- Flow(At 0, 15, 30, 45, 60, 75, 90, 105, 120 minutes after start of perfusion)
- Pressure(At 0, 15, 30, 45, 60, 75, 90, 105, 120 minutes after start of perfusion)
- Resistance(At 0, 15, 30, 45, 60, 75, 90, 105, 120 minutes after start of perfusion)
- (In selected centers) value of perfusate's pH(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(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(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(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(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)(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)(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)(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)(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(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(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(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(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(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(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(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(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(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(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)(Within 0 to 30 minutes before perfusion, at 2 hours of perfusion, and at 1 hour after reperfusion)
- New onset diabetes after transplantation(90 days)
- Costs of treatment (in selected centers)(within 6 months after transplantation, including transplant operation)
- Health related quality of life(within 6 months before transplantation and 6 months after transplantation)
研究者
Robert J. Porte
Prof. dr.
University Medical Center Groningen