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

Phase 3RecruitingNCT06344442

Assistance Publique - Hôpitaux de Paris304 enrolled

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.

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

Interventions

Arginine vasopressinDRUG

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.

NorepinephrineDRUG

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.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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

Outcomes

Primary Outcomes

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.

Time frame: during the first 7 postoperative days

Secondary Outcomes

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

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)

Time frame: 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)

Time frame: 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)

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)

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)

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

Mortality

Time frame: at 30 days