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The purpose of this study is to determine whether the Tacrolimus added to histidine-tryptophan-ketoglutarate (HTK) solution given through intraportal and intraarterial infusion during back-table procedure is capable of reducing the degree of early allograft liver dysfunction, as assessed by postoperative levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), during first 7 postoperative days and by serum and histochemical markers of liver injury and inflammation.
Early allograft liver dysfunction remains a significant complication of cadaveric liver transplantation with resource consuming and costly treatment, increased risk of multiorgan failure and 6-months mortality.
Ischemic reperfusion injury (IRI) is a main reason for early allograft liver dysfunction. Inflammatory response to brain death in donor can precipitate the extent of dysfunction after reperfusion in recipient (1). Clear inflammatory pathways in response to IRI have been reported to be associated with early allograft liver dysfunction (2,3). It was shown that ex vivo intraportal tacrolimus perfusion suppressed inflammation and immune response in the transplanted liver on a genome-wide basis (4).
We hypothesize that Tacrolimus added to HTK solution given through intraportal and intraarterial back-table infusion is capable of reducing the degree of early allograft liver dysfunction, as assessed by incidence of postreperfusion hyperfibrinolysis, postoperative levels of AST,ALT, during 1-7 postoperative days as well as serum and histochemical markers of liver injury and inflammation compared to no intraportal and intraarterial back-table infusion.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Tacrolimus + HTK | Experimental | During back-table operation 1000 ml of HTK solution cooled to 2-4˚C containing 20 ng/ml Tacrolimus would be given through intraportal (under gravity pressure of 40 cm H2O) and intraarterial infusion (under pressure of 40-50 mm Hg) followed by intraportal infusion of 200 ml 5% solution of Albumin containing 20 ng/ml Tacrolimus under gravity pressure of 40 cm H2O. |
|
| HTK | No Intervention | During back-table operation 1000 ml of HTK solution cooled to 2-4˚C would be given through intraportal (under gravity pressure of 40 cm H2O) and intraarterial infusion (under pressure of 40-50 mm Hg) followed by intraportal infusion of 200 ml 5% solution of Albumin under gravity pressure of 40 cm H2O. |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Tacrolimus | Drug | 1000 ml of HTK solution (Custodiol, Dr. Franz Köhler Chemie GmBH) cooled to 2-4˚C containing 20 ng/ml Tacrolimus would be given through intraportal (under gravity pressure of 40 cm H2O) and intraarterial infusion (under pressure of 40-50 mm Hg) followed by intraportal infusion of 200 ml 5% solution of Albumin containing 20 ng/ml Tacrolimus under gravity pressure of 40 cm H2O. |
| Measure | Description | Time Frame |
|---|---|---|
| Early Allograft Dysfunction | Protocol is restricted to liver transplants performed with classic technique with sequential portal-arterial reperfusion. Early allograft dysfunction will be assessed on the basis of highest levels of AST and ALT during 1-7 postoperative days. | 1-7 postoperative days after liver transplant procedure |
| Measure | Description | Time Frame |
|---|---|---|
| Ischemic Reperfusion Injury of the Liver Allograft | Protocol is restricted to liver transplants performed with classic technique with sequential portal-arterial reperfusion. A wedge resection of small (5x5mm) part of liver segment-III will be sampled at 2 hours after venous reperfusion. Rate of necrosis, inflammation, vascular thrombosis, cluster of differentiation (CD) 68 and High mobility group box 1 protein (HMGB1) staining will be assessed thereafter. |
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Inclusion Criteria:
age 15-65 years macrovesicular steatosis < 40% (macroscopy or biopsy) sodium <165 mmol/l ICU stay and ventilation < 11 days cold ischemia time < 13 hours AST < 200 U/l ALT < 200 U/l bilirubin < 50 μmol/l application of norepinephrine is allowed
Exclusion Criteria:
Recipient:
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| Name | Affiliation | Role |
|---|---|---|
| Aliaksei E Shcherba, PhD | RSPC for tissue and organ transplantation | Principal Investigator |
| Oleg O Rumo, MD PhD | RSPC for organ and tissue transplantation, Minsk 9th clinic | Study Chair |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| RSPC for organ and tissue transplantation, Minsk 9th clinic | Minsk | 220116 | Belarus |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 22006860 | Background | Friedman BH, Wolf JH, Wang L, Putt ME, Shaked A, Christie JD, Hancock WW, Olthoff KM. Serum cytokine profiles associated with early allograft dysfunction in patients undergoing liver transplantation. Liver Transpl. 2012 Feb;18(2):166-76. doi: 10.1002/lt.22451. | |
| 12827549 | Background | Busuttil RW, Tanaka K. The utility of marginal donors in liver transplantation. Liver Transpl. 2003 Jul;9(7):651-63. doi: 10.1053/jlts.2003.50105. |
| Label | URL |
|---|---|
| Related Info | View source |
| ID | Type | URL | Comment |
|---|---|---|---|
| 10.15825/1995-1191-2015-3-24 | Clinical Study Report | View IPD |
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| ID | Title | Description |
|---|---|---|
| FG000 | Tacrolimus + HTK | During back-table operation 1000 ml of HTK solution cooled to 2-4˚C containing 20 ng/ml Tacrolimus would be given through intraportal (under gravity pressure of 40 cm H2O) and intraarterial infusion (under pressure of 40-50 mm Hg) followed by intraportal infusion of 200 ml 5% solution of Albumin containing 20 ng/ml Tacrolimus under gravity pressure of 40 cm H2O. Tacrolimus: 1000 ml of HTK solution (Custodiol, Dr. Franz Köhler Chemie GmBH) cooled to 2-4˚C containing 20 ng/ml Tacrolimus would be given through intraportal (under gravity pressure of 40 cm H2O) and intraarterial infusion (under pressure of 40-50 mm Hg) followed by intraportal infusion of 200 ml 5% solution of Albumin containing 20 ng/ml Tacrolimus under gravity pressure of 40 cm H2O. |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| liver biopsy taken at 2 hours after portal reperfusion |
| Inflammatory Response to Reperfusion | Protocol is restricted to liver transplants performed with classic technique with sequential portal-arterial reperfusion. After unclamping portal vein but before unclamping the inferior vena cava and after venting of first 100 ml of blood a 5 ml sample of blood (code is "HV") from a tube inserted into caval suture line will be taken. Another 5 ml sample of blood (code is "C") will be taken by puncture of one of hepatic veins 20 min later. Samples (5 ml each) of peripheral blood will be taken on 1st and 3d postoperative day (POD). P-selectin, interleukin-6, interleukin-8, tumor necrosis factor alfa (TNF-a) and macrophage inflammatory protein 1 alpha (MIP-1a) will be determined in samples "HV" and "C". Interleukin-8, elastase, TNF-a and vascular endothelial growth factor (VEGF) will be determined in samples of 1st and 3d POD. | 0 and 20 min after portal reperfusion, 1 and 3 postoperative day |
| Postreperfusion Hyperfibrinolysis | Protocol is restricted to liver transplants performed with classic technique with sequential portal-arterial reperfusion. Peripheral blood samples will be taken 15 min and 2 hours after portal reperfusion. Hyperfibrinolysis will be diagnosed by Thromboelastometry (ROTEM) if one or more following criteria are met: LI30<85% or ML>15% or LI60<85% or A10 in Extem is by 15% is less then A10 in Aptem. | 15 min and 2 hours after portal reperfusion |
| 18825712 | Background | Ilmakunnas M, Tukiainen EM, Rouhiainen A, Rauvala H, Arola J, Nordin A, Makisalo H, Hockerstedt K, Isoniemi H. High mobility group box 1 protein as a marker of hepatocellular injury in human liver transplantation. Liver Transpl. 2008 Oct;14(10):1517-25. doi: 10.1002/lt.21573. |
| 21672049 | Background | Kristo I, Wilflingseder J, Kainz A, Marschalek J, Wekerle T, Muhlbacher F, Oberbauer R, Bodingbauer M. Effect of intraportal infusion of tacrolimus on ischaemic reperfusion injury in orthotopic liver transplantation: a randomized controlled trial. Transpl Int. 2011 Sep;24(9):912-9. doi: 10.1111/j.1432-2277.2011.01284.x. Epub 2011 Jun 14. |
| 20677285 | Background | Olthoff KM, Kulik L, Samstein B, Kaminski M, Abecassis M, Emond J, Shaked A, Christie JD. Validation of a current definition of early allograft dysfunction in liver transplant recipients and analysis of risk factors. Liver Transpl. 2010 Aug;16(8):943-9. doi: 10.1002/lt.22091. |
| Result | Shcherba A.E., Minou A.F., Efimov D.J., Korotkov S.V., LebedzO.A., Dzyadzko A.M., Karitka A., Santotski E.O., Rummo O.O.//Influence of Back Table Portal And Arterial Flushing with HTK and Tacrolimus on the Incidence of Liver Graft Dysfunction. Materials of "Avantguardia in the HPB - surgery and Liver transplantation: When East meets West". Volume 61, June 2014, Supplement 1.- P. S13-14. |
| 25044812 | Result | Abstracts of the ILTS 20(th) Annual International Congress, June 3-7, 2014, London, United Kingdom. Liver Transpl. 2014 Jun;20 Suppl 1:S1-399. doi: 10.1002/lt.23901. No abstract available. |
| FG001 | HTK Solution Only | During back-table operation 1000 ml of HTK solution cooled to 2-4˚C would be given through intraportal (under gravity pressure of 40 cm H2O) and intraarterial infusion (under pressure of 40-50 mm Hg) followed by intraportal infusion of 200 ml 5% solution of Albumin under gravity pressure of 40 cm H2O. |
| COMPLETED |
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| NOT COMPLETED |
|
Not provided
| ID | Title | Description |
|---|---|---|
| BG000 | Tacrolimus + HTK | During back-table operation 1000 ml of HTK solution cooled to 2-4˚C containing 20 ng/ml Tacrolimus would be given through intraportal (under gravity pressure of 40 cm H2O) and intraarterial infusion (under pressure of 40-50 mm Hg) followed by intraportal infusion of 200 ml 5% solution of Albumin containing 20 ng/ml Tacrolimus under gravity pressure of 40 cm H2O. Tacrolimus: 1000 ml of HTK solution (Custodiol, Dr. Franz Köhler Chemie GmBH) cooled to 2-4˚C containing 20 ng/ml Tacrolimus would be given through intraportal (under gravity pressure of 40 cm H2O) and intraarterial infusion (under pressure of 40-50 mm Hg) followed by intraportal infusion of 200 ml 5% solution of Albumin containing 20 ng/ml Tacrolimus under gravity pressure of 40 cm H2O. |
| BG001 | HTK Only | During back-table operation 1000 ml of HTK solution cooled to 2-4˚C would be given through intraportal (under gravity pressure of 40 cm H2O) and intraarterial infusion (under pressure of 40-50 mm Hg) followed by intraportal infusion of 200 ml 5% solution of Albumin under gravity pressure of 40 cm H2O. |
| BG002 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants | Participants |
| ||||||||||||||||||
| Age, Continuous | Mean | Inter-Quartile Range | years |
| |||||||||||||||||
| Gender | Count of Participants | Participants |
| ||||||||||||||||||
| Region of Enrollment | Number | participants |
|
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Early Allograft Dysfunction | Protocol is restricted to liver transplants performed with classic technique with sequential portal-arterial reperfusion. Early allograft dysfunction will be assessed on the basis of highest levels of AST and ALT during 1-7 postoperative days. | Posted | Count of Participants | Participants | 1-7 postoperative days after liver transplant procedure |
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| Secondary | Ischemic Reperfusion Injury of the Liver Allograft | Protocol is restricted to liver transplants performed with classic technique with sequential portal-arterial reperfusion. A wedge resection of small (5x5mm) part of liver segment-III will be sampled at 2 hours after venous reperfusion. Rate of necrosis, inflammation, vascular thrombosis, cluster of differentiation (CD) 68 and High mobility group box 1 protein (HMGB1) staining will be assessed thereafter. | Not Posted | liver biopsy taken at 2 hours after portal reperfusion | Participants | ||||||||||||||||||||||||||||||||||
| Secondary | Inflammatory Response to Reperfusion | Protocol is restricted to liver transplants performed with classic technique with sequential portal-arterial reperfusion. After unclamping portal vein but before unclamping the inferior vena cava and after venting of first 100 ml of blood a 5 ml sample of blood (code is "HV") from a tube inserted into caval suture line will be taken. Another 5 ml sample of blood (code is "C") will be taken by puncture of one of hepatic veins 20 min later. Samples (5 ml each) of peripheral blood will be taken on 1st and 3d postoperative day (POD). P-selectin, interleukin-6, interleukin-8, tumor necrosis factor alfa (TNF-a) and macrophage inflammatory protein 1 alpha (MIP-1a) will be determined in samples "HV" and "C". Interleukin-8, elastase, TNF-a and vascular endothelial growth factor (VEGF) will be determined in samples of 1st and 3d POD. | Not Posted | 0 and 20 min after portal reperfusion, 1 and 3 postoperative day | Participants | ||||||||||||||||||||||||||||||||||
| Secondary | Postreperfusion Hyperfibrinolysis | Protocol is restricted to liver transplants performed with classic technique with sequential portal-arterial reperfusion. Peripheral blood samples will be taken 15 min and 2 hours after portal reperfusion. Hyperfibrinolysis will be diagnosed by Thromboelastometry (ROTEM) if one or more following criteria are met: LI30<85% or ML>15% or LI60<85% or A10 in Extem is by 15% is less then A10 in Aptem. | Not Posted | 15 min and 2 hours after portal reperfusion | Participants |
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Tacrolimus + HTK | During back-table operation 1000 ml of HTK solution cooled to 2-4˚C containing 20 ng/ml Tacrolimus would be given through intraportal (under gravity pressure of 40 cm H2O) and intraarterial infusion (under pressure of 40-50 mm Hg) followed by intraportal infusion of 200 ml 5% solution of Albumin containing 20 ng/ml Tacrolimus under gravity pressure of 40 cm H2O. Tacrolimus: 1000 ml of HTK solution (Custodiol, Dr. Franz Köhler Chemie GmBH) cooled to 2-4˚C containing 20 ng/ml Tacrolimus would be given through intraportal (under gravity pressure of 40 cm H2O) and intraarterial infusion (under pressure of 40-50 mm Hg) followed by intraportal infusion of 200 ml 5% solution of Albumin containing 20 ng/ml Tacrolimus under gravity pressure of 40 cm H2O. | 8 | 12 | 0 | 0 | ||
| EG001 | HTK Solution | During back-table operation 1000 ml of HTK solution cooled to 2-4˚C would be given through intraportal (under gravity pressure of 40 cm H2O) and intraarterial infusion (under pressure of 40-50 mm Hg) followed by intraportal infusion of 200 ml 5% solution of Albumin under gravity pressure of 40 cm H2O. | 20 | 22 | 0 | 0 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Early allograft dysfunction | Hepatobiliary disorders | Systematic Assessment | defined due to Olthoff criteria (2010) |
| |
| Death | Surgical and medical procedures | Systematic Assessment |
|
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Aliaksej Shcherba | Republican scientific and practical center for organ and tissue transplantation | +375293330689 | aleina@tut.by |
| ID | Term |
|---|---|
| D016559 | Tacrolimus |
| ID | Term |
|---|---|
| D018942 | Macrolides |
| D007783 | Lactones |
| D009930 | Organic Chemicals |
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| >=65 years |
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| Male |
|