Low-dose Arginine-vasopressin Supplementation on Post-transplant Acute Kidney Injury After Liver Transplantation (AVENIR Trial)

Official title

Effect of Low-dose Arginine-vasopressin Supplementation on Post-transplant Acute Kidney Injury After Liver Transplantation

Overview

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.

Detailed description

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.

Interventions

• Drug Arginine vasopressin
  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.
• Drug Norepinephrine
  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.

Primary outcome measures

• 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. [Time frame: during the first 7 postoperative days]

Secondary outcome measures (12)

• To compare into the two arms the number of packed red blood cellsand fresh frozen plasma transfused [Time frame: during the first 12 hours postoperatively]
• To compare into the two arms the number of the Number of AKI KDIGO 1 [Time frame: 1 during the first 7days]
• To compare into the two arms the Number of AKI KDIGO 2 [Time frame: during the first 7 postoperative]
• To compare into the Number of AKI KDIGO 3 [Time frame: during the first 7 postoperative]
• The need for renal replacement for replacement therapy (RRT) in ICU [Time frame: during the first 7 days postoperatively and on postoperative day 30]
• The number of patients remaining on dialysis at the end of the study [Time frame: on the 30th Day]
• Average intraoperative norepinephrine concentrations [Time frame: intraoperative]
• Average intraoperative concentrations of other vasopressors and inotropes (Adrenalin, Dobutamine) [Time frame: intraoperative]
• Number of platelets transfused intraoperatively [Time frame: during the first 12 hours postoperatively.]
• Amount of vascular filling solutions intraoperatively [Time frame: During the first 12 hours postoperatively.]
• Sequential Organ Failure Assessment (SOFA score) [Time frame: On the third and seventh postoperative day]
• Number of days alive outside intensive care unit [Time frame: during the 30 day post-operation]

Eligibility criteria

Inclusion criteria

• Age ≥ 18 years
• Any adult patient with a scheduled liver transplantation
• All participants will need to be given clear information about the study and give signed informed consent.
• Person affiliated to the Social Security

Exclusion criteria

• Super-emergency for liver transplantation or fulminant hepatitis
• Patient listed for or receiving simultaneous liver-kidney transplantation (SLKT)
• Patients with end-stage renal disease (chronic eGFR < 15 mL/min/1.73 m2 or requiring extra-renal purification before liver transplantation
• Patient with epilepsy
• Hypersensitivity to arginine-vasopressin and to its excipients
• Patient refusal
• Patients for whom it is impossible to give informed consent (language barrier)
• Adults under guardianship or trusteeship, persons deprived of their liberty
• Patient enrolled in another interventional clinical study
• Pregnancy or breastfeeding

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

France · 1 center

• URC Lariboisière-Fernand Widal-saint Louis — Paris

Publications

• 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. PMID 8844239
• 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. PMID 25673576
• 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. PMID 20486907
• 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. V PMID 27841822
• 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. PMID 24652962
• 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. PMID 31461138
• 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. PMID 32931198
• 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. PMID 18305265

Identifiers

NCT: NCT06344442 · APHP220827

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗