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Liver transplantation (LT) is a high-risk surgery for hemodynamic instability and haemorrhagic shock with a high-risk of acute kidney injury (AKI). Indeed, the incidence of post-transplant AKI exceeds 50% in some series with 15% of patients requiring renal replacement therapy. Acute kidney injury after LT is a predisposing factor for chronic renal failure which is independently associated with higher morbidity and mortality.
Arginine vasopressin (AVP), an essential stress hormone released in response to hypotension, binds to AVPR1a to promote vasoconstriction. Furthermore, it may have nephroprotective effects with a preferential vasoconstriction of the post-glomerular arteriole resulting in increased glomerular filtration
The hypothesis of the present work is that low-dose arginine-vasopressin supplementation reduce posttransplant AKI in liver transplantation.
Prospective, national multicenter, double-blinded, randomized , controlled superiority trial with two parallel arms : AVP vs Norepinephrine
The primary objective is to demonstrate that intraoperative low-dose supplementation of AVP induces a reduction in posttransplant AKI after liver transplantation
Investigational medicinal product: vasopressin will be administered by continuous infusion. AVP will be used to a final concentration of 0.12 U/ml. The vasopressor infusion will be titrated to maintain an MAP of at least 65 mmHg. The study-drug infusion will be started at 5 ml/h and increased by 2.5 ml/h to achieve a maximum target rate of 30 ml/h, so that AVP doses ranged from 0.01 to 0.06 U/min.
Comparator treatment : norepinephrine will be administered by continuous infusion. Norepinephrine will be used with final concentrations of 120 microg/ml. The vasopressor infusion will be titrated to maintain an MAP of at least 65 mmHg. The study-drug infusion will be started at 5 ml/h and increased by 2.5 ml/h to achieve a maximum target rate of 30 ml/h, so that NE doses ranged from10 to 60 microg/min.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Arginine vasopressin | Experimental | low-dose arginine-vasopressin supplementation group: Vasopressin will be administered by continuous infusion. AVP will be used to a final concentration of 0.12 U/ml. The vasopressor infusion will be titrated to maintain an MAP of at least 65 mmHg. The study-drug infusion will be started at 5 ml/h and increased by 2.5 ml/h to achieve a maximum target rate of 30 ml/h, so that AVP doses ranged from 0.01 to 0.06 U/min |
|
| Norepinephrine | Active Comparator | Norepinephrine will be administered by continuous infusion. Norepinephrine will be used with final concentrations of 120 microg/ml. The vasopressor infusion will be titrated to maintain an MAP of at least 65 mmHg. The study-drug infusion will be started at 5 ml/h and increased by 2.5 ml/h to achieve a maximum target rate of 30 ml/h, so that NE doses ranged from10 to 60 microg/min. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Arginine vasopressin | Drug | low-dose arginine-vasopressin supplementation group: Vasopressin will be administered by continuous infusion. AVP will be used to a final concentration of 0.12 U/ml. The vasopressor infusion will be titrated to maintain an MAP of at least 65 mmHg. The study-drug infusion will be started at 5 ml/h and increased by 2.5 ml/h to achieve a maximum target rate of 30 ml/h, so that AVP doses ranged from 0.01 to 0.06 U/min. |
| Measure | Description | Time Frame |
|---|---|---|
| The primary objective is to compare the effect of intraoperative low-dose supplementation of AVP vs norepinephrine infusions on post-transplant Acute Kidney Injury after liver transplantation. | The stages of AKI according to AKI Network criteria (KDIGO score) determined by changes in serum creatinine and changes in urine output. | during the first 7 postoperative days |
| Measure | Description | Time Frame |
|---|---|---|
| To compare into the two arms the number of packed red blood cellsand fresh frozen plasma transfused | during the first 12 hours postoperatively | |
| To compare into the two arms the number of the Number of AKI KDIGO 1 | defined as increase in serum creatinine concentration by 1.5 to 1.9 fold or ≥0.3mg/dl (or 27 micromol/L) within 48h or urine output <0.5 ml/Kg/h over a period 6-12 h) |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Jacques DURANTEAU, Pr | Contact | 01 45 21 34 41 | +33 | jacques.duranteau@aphp.fr |
| Name | Affiliation | Role |
|---|---|---|
| Jacques DURANTEAU, Pr | Département Anesthésie-Réanimation - Université Paris-Saclay Hospital Bicêtre - Paul Brousse | Study Director |
| Gilles LEBUFFE, Pr | Service Anesthésie-Réanimation - CHU de Lille | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| URC Lariboisière-Fernand Widal-saint Louis | Recruiting | Paris | 75010 | France |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 8844239 | Background | Vincent JL, Moreno R, Takala J, Willatts S, De Mendonca A, Bruining H, Reinhart CK, Suter PM, Thijs LG. The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine. Intensive Care Med. 1996 Jul;22(7):707-10. doi: 10.1007/BF01709751. No abstract available. | |
| 25673576 |
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Prospective, national multicentre, double-blinded, randomized ,controlled superiority trial with two parallel arms
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All the clinical teams involved intraoperatively (anaesthetists, nurse anaesthetists and surgeons) and postoperatively (doctors and nurses who will take care of the patient postoperatively) and the families will ignore the allocation of treatments for the duration of the trial,except the nurse in charge of preparing the infusions ,She will ensure respect for the blind
|
| Norepinephrine | Drug | Norepinephrine will be administered by continuous infusion. Norepinephrine will be used with final concentrations of 120 microg/ml. The vasopressor infusion will be titrated to maintain an MAP of at least 65 mmHg. The study-drug infusion will be started at 5 ml/h and increased by 2.5 ml/h to achieve a maximum target rate of 30 ml/h, so that NE doses ranged from10 to 60 microg/min. |
|
| 1 during the first 7days |
| To compare into the two arms the Number of AKI KDIGO 2 | defined as increase in serum creatinine concentration by 2.0 to 2.9 fold or urine output <0.5 ml/Kg/h over a period ≥12 h) | during the first 7 postoperative |
| To compare into the Number of AKI KDIGO 3 | defined as increase in serum creatinine concentration ≥ 3 fold or ≥ 4mg/dl (or 354 micromol/L) or urine output <0.3 ml/Kg/h for ≥24h or anuria>12h) | during the first 7 postoperative |
| The need for renal replacement for replacement therapy (RRT) in ICU | during the first 7 days postoperatively and on postoperative day 30 |
| The number of patients remaining on dialysis at the end of the study | on the 30th Day |
| Average intraoperative norepinephrine concentrations | intraoperative |
| Average intraoperative concentrations of other vasopressors and inotropes (Adrenalin, Dobutamine) | intraoperative |
| Number of platelets transfused intraoperatively | during the first 12 hours postoperatively. |
| Amount of vascular filling solutions intraoperatively | During the first 12 hours postoperatively. |
| Sequential Organ Failure Assessment (SOFA score) | Sequential Organ Failure Assessment (SOFA score between 0 and 24). Zero indicates that the patient has no organ dysfunction, twenty-four is the maximum score and indicates that the patient has vinght four is the maximum score and indicates that the patient has all 6 of the organ dysfunctions explored. (respiratory, coagulatory, liver, cardiovascular, renal, and neurologic) | On the third and seventh postoperative day |
| Number of days alive outside intensive care unit | during the 30 day post-operation |
| Mortality | at 30 days |
| Daniel EYRAUD, Pr | Service Anesthésie-Réanimation -APHP Pitié-Salpêtrière | Principal Investigator |
| Emmanuel WEISS, Pr | Service Anesthésie-Réanimation - APHP hôpital Beaujon | Principal Investigator |
| Antoine DEWITTE, Pr | Service Anesthésie-Réanimation -CHU de Bordeaux centre médicochirurgical Magellan hôpital Haut Lévêque | Principal Investigator |
| Baptiste LORDIER, Pr | Service Anesthésie-Réanimation -CHU de Strasbourg Hôpital de Hautepierre | Principal Investigator |
| Alice BLET, Pr | Service Anesthésie-Réanimation - Hôpital de la Croix Rousse | Principal Investigator |
| Result |
| Hilmi IA, Damian D, Al-Khafaji A, Planinsic R, Boucek C, Sakai T, Chang CC, Kellum JA. Acute kidney injury following orthotopic liver transplantation: incidence, risk factors, and effects on patient and graft outcomes. Br J Anaesth. 2015 Jun;114(6):919-26. doi: 10.1093/bja/aeu556. Epub 2015 Feb 10. |
| 20486907 | Result | Watt KD, Pedersen RA, Kremers WK, Heimbach JK, Charlton MR. Evolution of causes and risk factors for mortality post-liver transplant: results of the NIDDK long-term follow-up study. Am J Transplant. 2010 Jun;10(6):1420-7. doi: 10.1111/j.1600-6143.2010.03126.x. Epub 2010 May 10. |
| 27841822 | Result | Hajjar LA, Vincent JL, Barbosa Gomes Galas FR, Rhodes A, Landoni G, Osawa EA, Melo RR, Sundin MR, Grande SM, Gaiotto FA, Pomerantzeff PM, Dallan LO, Franco RA, Nakamura RE, Lisboa LA, de Almeida JP, Gerent AM, Souza DH, Gaiane MA, Fukushima JT, Park CL, Zambolim C, Rocha Ferreira GS, Strabelli TM, Fernandes FL, Camara L, Zeferino S, Santos VG, Piccioni MA, Jatene FB, Costa Auler JO Jr, Filho RK. Vasopressin versus Norepinephrine in Patients with Vasoplegic Shock after Cardiac Surgery: The VANCS Randomized Controlled Trial. Anesthesiology. 2017 Jan;126(1):85-93. doi: 10.1097/ALN.0000000000001434. |
| 24652962 | Result | Pecci A, Balduini CL. Desmopressin and super platelets. Blood. 2014 Mar 20;123(12):1779-80. doi: 10.1182/blood-2014-01-551242. No abstract available. |
| 31461138 | Result | Sims CA, Holena D, Kim P, Pascual J, Smith B, Martin N, Seamon M, Shiroff A, Raza S, Kaplan L, Grill E, Zimmerman N, Mason C, Abella B, Reilly P. Effect of Low-Dose Supplementation of Arginine Vasopressin on Need for Blood Product Transfusions in Patients With Trauma and Hemorrhagic Shock: A Randomized Clinical Trial. JAMA Surg. 2019 Nov 1;154(11):994-1003. doi: 10.1001/jamasurg.2019.2884. |
| 32931198 | Result | Okazaki N, Iguchi N, Evans RG, Hood SG, Bellomo R, May CN, Lankadeva YR. Beneficial Effects of Vasopressin Compared With Norepinephrine on Renal Perfusion, Oxygenation, and Function in Experimental Septic Acute Kidney Injury. Crit Care Med. 2020 Oct;48(10):e951-e958. doi: 10.1097/CCM.0000000000004511. |
| 18305265 | Result | Russell JA, Walley KR, Singer J, Gordon AC, Hebert PC, Cooper DJ, Holmes CL, Mehta S, Granton JT, Storms MM, Cook DJ, Presneill JJ, Ayers D; VASST Investigators. Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med. 2008 Feb 28;358(9):877-87. doi: 10.1056/NEJMoa067373. |
| 19841897 | Result | Gordon AC, Russell JA, Walley KR, Singer J, Ayers D, Storms MM, Holmes CL, Hebert PC, Cooper DJ, Mehta S, Granton JT, Cook DJ, Presneill JJ. The effects of vasopressin on acute kidney injury in septic shock. Intensive Care Med. 2010 Jan;36(1):83-91. doi: 10.1007/s00134-009-1687-x. Epub 2009 Oct 20. |
| 27483065 | Result | Gordon AC, Mason AJ, Thirunavukkarasu N, Perkins GD, Cecconi M, Cepkova M, Pogson DG, Aya HD, Anjum A, Frazier GJ, Santhakumaran S, Ashby D, Brett SJ; VANISH Investigators. Effect of Early Vasopressin vs Norepinephrine on Kidney Failure in Patients With Septic Shock: The VANISH Randomized Clinical Trial. JAMA. 2016 Aug 2;316(5):509-18. doi: 10.1001/jama.2016.10485. |
| 2916660 | Result | Edwards RM, Trizna W, Kinter LB. Renal microvascular effects of vasopressin and vasopressin antagonists. Am J Physiol. 1989 Feb;256(2 Pt 2):F274-8. doi: 10.1152/ajprenal.1989.256.2.F274. |
| 11555538 | Result | Holmes CL, Patel BM, Russell JA, Walley KR. Physiology of vasopressin relevant to management of septic shock. Chest. 2001 Sep;120(3):989-1002. doi: 10.1378/chest.120.3.989. |
| 23394211 | Result | Kellum JA, Lameire N; KDIGO AKI Guideline Work Group. Diagnosis, evaluation, and management of acute kidney injury: a KDIGO summary (Part 1). Crit Care. 2013 Feb 4;17(1):204. doi: 10.1186/cc11454. |
| ID | Term |
|---|---|
| D001127 | Arginine Vasopressin |
| D009638 | Norepinephrine |
| ID | Term |
|---|---|
| D014667 | Vasopressins |
| D010909 | Pituitary Hormones, Posterior |
| D010907 | Pituitary Hormones |
| D036361 | Peptide Hormones |
| D006728 | Hormones |
| D006730 | Hormones, Hormone Substitutes, and Hormone Antagonists |
| D009479 | Neuropeptides |
| D010455 | Peptides |
| D000602 | Amino Acids, Peptides, and Proteins |
| D009842 | Oligopeptides |
| D009419 | Nerve Tissue Proteins |
| D011506 | Proteins |
| D004983 | Ethanolamines |
| D000605 | Amino Alcohols |
| D000438 | Alcohols |
| D009930 | Organic Chemicals |
| D000588 | Amines |
| D015306 | Biogenic Monoamines |
| D001679 | Biogenic Amines |
| D002395 | Catecholamines |
| D002396 | Catechols |
| D010636 | Phenols |
| D001555 | Benzene Derivatives |
| D006841 | Hydrocarbons, Aromatic |
| D006844 | Hydrocarbons, Cyclic |
| D006838 | Hydrocarbons |
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