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| Name | Class |
|---|---|
| Erasmus Medical Center | OTHER |
| Leiden University Medical Center | OTHER |
| Universitaire Ziekenhuizen KU Leuven | OTHER |
| University Hospital, Ghent |
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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).
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Dual hypothermic oxygenated perfusion | Experimental | 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. |
|
| Care as usual | No Intervention | The donor liver is procured with a segment of 5 cm circular supratruncal aorta left attached to the coeliac trunc. The patients randomized to the control group will receive a liver graft preserved by conventional SCS without any further intervention. |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Dual hypothermic oxygenated perfusion | Procedure | Dual hypothermic oxygenated perfusion using the Liver Assist |
|
| Measure | Description | Time Frame |
|---|---|---|
| The incidence of symptomatic non-anastomotic biliary strictures (NAS) | NAS is defined as all of the following criteria:
| 6 months |
| Measure | Description | Time Frame |
|---|---|---|
| Asymptomatic NAS | Asymptomatic NAS is defined as all of the following:
|
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Robert J. Porte, MD PhD Prof | University Medical Center Groningen | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Ghent University Hospital | Ghent | De Pintelaan 185 | 9000 | Belgium | ||
| University Hospitals Leuven |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 41082480 | Derived | van Rijn R, Endo C, Kucukerbil EH, Blokzijl H, Blondeel J, Cortes Cerisuelo M, Coenraad MJ, Darwish Murad S, Doukas M, Eker H, de Haas RJ, Huurman VAL, de Meijer VE, Monbaliu D, Schurink IJ, Slangen JJG, Polak WG, de Jonge J, Porte RJ. Long-term Follow-up After Hypothermic Oxygenated Machine Perfusion in DCD Liver Transplantation: Results of a Randomized Controlled Multicenter Trial (DHOPE-DCD). Ann Surg. 2025 Nov 1;282(5):717-724. doi: 10.1097/SLA.0000000000006876. Epub 2025 Aug 5. | |
| 39853733 |
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| OTHER |
| King's College Hospital NHS Trust | OTHER |
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| Liver Assist® | Device | The Liver Assist® is the device used to give the intervention dual hypothermic perfusion. |
|
| Perfusion fluid | Procedure | The perfusion fluid is Belzer machine perfusion solution University of Wisconsin (Bridge-to-Life, Ltd., Northbrook, IL). |
|
| Glutathione | Drug | Glutathione in a dosage of 3 mmol/ is added to the perfusion fluid according to the intention of use of the perfusion fluid. |
|
| 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) | 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. | 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 | 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 | 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 | 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 | Postoperative day 0 - 7 and 1, 3, 6 months |
| Blood pressure | mm Hg | 5 min before reperfusion, at reperfusion and after 10 and 20 minutes of reperfusion |
| Heart rate | beats per minute | 5 min before reperfusion, at reperfusion and after 10 and 20 minutes of reperfusion |
| Vasopressor dosage | microgram/kg/min | 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 | 6 months |
| Postoperative complications | According to the comprehensive complication index (CCI) | 6 months |
| Renal function | Estimated glomerular filtration rate (eGFR) according to the 4-variable Modification of Diet in Renal Disease (MDRD) equation | day 7, and 1, 3, 6 months |
| Flow | ml/min | At 0, 15, 30, 45, 60, 75, 90, 105, 120 minutes after start of perfusion |
| Pressure | mm Hg | At 0, 15, 30, 45, 60, 75, 90, 105, 120 minutes after start of perfusion |
| Resistance | ml/min/mm Hg | 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 | mmol/L | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | relative levels compared to 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 | relative levels compared to 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 | relative levels compared to 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 | relative levels compared to 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 | relative levels compared to 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) | according to the Cost and Outcome analysis of Liver Transplantation (COLT) study | within 6 months after transplantation, including transplant operation |
| Health related quality of life | EQ6D questionnaire | within 6 months before transplantation and 6 months after transplantation |
| Leuven |
| Herestraat 49 |
| 3000 |
| Belgium |
| Leiden Universtiy Medical Center | Leiden | South Holland | 2333 ZA | Netherlands |
| University Medical Center Groningen | Groningen | 9700 RB | Netherlands |
| Erasmus Medical Center | Rotterdam | 3015 CE | Netherlands |
| King's College Hospital NHS Trust | London | United Kingdom |
| Derived |
| Endo C, van Rijn R, Huurman V, Schurink I, van den Berg A, Murad SD, van Hoek B, de Meijer VE, de Jonge J, van der Hilst CS, Porte RJ. Cost-effectiveness of Dual Hypothermic Oxygenated Machine Perfusion Versus Static Cold Storage in DCD Liver Transplantation. Transplantation. 2025 Feb 1;109(2):e101-e108. doi: 10.1097/TP.0000000000005232. Epub 2024 Oct 8. |
| 33626248 | Derived | van Rijn R, Schurink IJ, de Vries Y, van den Berg AP, Cortes Cerisuelo M, Darwish Murad S, Erdmann JI, Gilbo N, de Haas RJ, Heaton N, van Hoek B, Huurman VAL, Jochmans I, van Leeuwen OB, de Meijer VE, Monbaliu D, Polak WG, Slangen JJG, Troisi RI, Vanlander A, de Jonge J, Porte RJ; DHOPE-DCD Trial Investigators. Hypothermic Machine Perfusion in Liver Transplantation - A Randomized Trial. N Engl J Med. 2021 Apr 15;384(15):1391-1401. doi: 10.1056/NEJMoa2031532. Epub 2021 Feb 24. |
| 31420387 | Derived | de Vries Y, Berendsen TA, Fujiyoshi M, van den Berg AP, Blokzijl H, de Boer MT, van der Heide F, de Kleine RHJ, van Leeuwen OB, Matton APM, Werner MJM, Lisman T, de Meijer VE, Porte R. Transplantation of high-risk donor livers after resuscitation and viability assessment using a combined protocol of oxygenated hypothermic, rewarming and normothermic machine perfusion: study protocol for a prospective, single-arm study (DHOPE-COR-NMP trial). BMJ Open. 2019 Aug 15;9(8):e028596. doi: 10.1136/bmjopen-2018-028596. |
| 30866837 | Derived | van Rijn R, van den Berg AP, Erdmann JI, Heaton N, van Hoek B, de Jonge J, Leuvenink HGD, Mahesh SVK, Mertens S, Monbaliu D, Muiesan P, Perera MTPR, Polak WG, Rogiers X, Troisi RI, de Vries Y, Porte RJ. Study protocol for a multicenter randomized controlled trial to compare the efficacy of end-ischemic dual hypothermic oxygenated machine perfusion with static cold storage in preventing non-anastomotic biliary strictures after transplantation of liver grafts donated after circulatory death: DHOPE-DCD trial. BMC Gastroenterol. 2019 Mar 12;19(1):40. doi: 10.1186/s12876-019-0956-6. |
| ID | Term |
|---|---|
| D017093 | Liver Failure |
| D058625 | End Stage Liver Disease |
| D001660 | Biliary Tract Diseases |
| ID | Term |
|---|---|
| D048550 | Hepatic Insufficiency |
| D008107 | Liver Diseases |
| D004066 | Digestive System Diseases |
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| ID | Term |
|---|---|
| C115525 | newcastle organ perfusion fluid |
| D005978 | Glutathione |
| ID | Term |
|---|---|
| D009842 | Oligopeptides |
| D010455 | Peptides |
| D000602 | Amino Acids, Peptides, and Proteins |
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