Renal Replacement Therapy for Acute Kidney Injury in Intensive Care Unit Clinical Trial
Official title:
Artificial Kidney Initiation in Kidney Injury, a Multicenter Randomised Trial
The best timing for renal replacement therapy (RRT) in intensive care unit (ICU) patients
with acute kidney injury (AKI) is unknown. The investigators will conduct a multicenter
prospective randomized open-label trial to compare two strategies in ICU patients
(mechanically ventilated and/or receiving catecholamine infusion) with severe AKI defined as
RIFLE F classification. These patients will be randomly allocated to one of the following
strategies:
1. an "early" strategy where RRT is started immediately when a RIFLE F status is
documented
2. a "delayed" strategy where RRT (in patients who also present RIFLE F renal failure) is
started only in case of occurrence of one or more of the following events ("Alert
Criteria"): oliguria or anuria lasting for more than 72 hours after randomization,
serum urea concentration > 40 mmol /L, serum potassium concentration > 6 mmol /L, serum
potassium concentration > 5.5 mmol /L that persists despite well-conducted medical
treatment with at least sodium bicarbonate and / or glucose-insulin infusion, arterial
pH < 7.15 in the context of pure metabolic acidosis (PaCO2 <35 mmHg) or in the context
of mixed acidosis with PaCO2> 50 mmHg without possibility of lowering this PaCO2 value,
acute overload pulmonary edema generating severe hypoxemia requiring oxygen flow>
5L/min in spontaneously breathing patients or FiO2> 50% in mechanically (invasive or
noninvasive) ventilated to maintain SpO2> 95%, despite diuretic therapy.
The primary endpoint is overall survival, measured from the date of randomization to the
date of death, regardless of the cause. The minimum duration of each patient's follow-up
will be 60 days.
Background:
Acute kidney injury (AKI) is a common complication in intensive care unit (ICU) patients.
Renal replacement therapy (RRT) is the major supportive treatment of AKI. Despite progress
in RRT management, mortality remains high and the timing of its initiation remains open to
debate when no metabolic disorder (severe hyperkalemia or metabolic acidosis) or major fluid
overload threaten short-term prognosis. Such abnormalities mandate RRT and are non-inclusion
criteria of our study. Whereas many studies have focused on RRT modalities, no prospective
randomized study has evaluated the criteria for initiating RRT in ICU in the absence of the
above-mentioned life-threatening disorders. In other words, whether duration of
oliguria/anuria and/or value of serum urea/creatinine are an adequate indication for RRT is
unknown. Given the lack of high quality data, it is not surprising that survey of practices
showed wide variation in the timing of RRT initiation and that no precise guidelines could
be drawn by expert recommendation as to the optimal start of RRT, making a randomised
controlled study of timing of RRT both desirable and ethical.
Objective:
The main objective of this study is to compare two strategies of RRT initiation in terms of
overall survival in ICU patients (mechanically ventilated and/or receiving catecholamine
infusion) with severe AKI defined as RIFLE F classification. These patients will be randomly
allocated to one of the following strategies:
1. an "early" strategy where RRT is started immediately when a RIFLE F status is
documented
2. a "delayed" strategy where RRT (in patients who also present RIFLE F renal failure) is
started only in case of occurrence of one or more of the following events ("Alert
Criteria"): oliguria or anuria lasting for more than 72 hours after randomization,
serum urea concentration > 40 mmol /L, serum potassium concentration > 6 mmol /L, serum
potassium concentration > 5.5 mmol /L that persists despite well-conducted medical
treatment with at least sodium bicarbonate and / or glucose-insulin infusion, arterial
pH < 7.15 in the context of pure metabolic acidosis (PaCO2 <35 mmHg) or in the context
of mixed acidosis with PaCO2> 50 mmHg without possibility of lowering this PaCO2 value,
acute overload pulmonary edema generating severe hypoxemia requiring oxygen flow>
5L/min in spontaneously breathing patients or FiO2> 50% in mechanically (invasive or
noninvasive) ventilated to maintain SpO2> 95%, despite diuretic therapy.
Design:
Prospective, multicenter, randomized, open-label trial comparing two RRT initiation
strategies in terms of overall survival.
Primary endpoint:
Overall survival, measured from the date of randomization to the date of death, regardless
of the cause. The minimum duration of each patient's follow-up will be 60 days.
Secondary endpoints:
Survival rate at day 28, percentage of patients requiring who did not require RRT in the
"delayed" strategy, time until cessation of RRT therapy, rate of adverse events potentially
related to the AKI or to RRT (e.g; RRT catheter-related complications, hemorrhage due to
anticoagulation required for RRT etc…), rate of nosocomial infections, number of
ventilator-free days of RRT-free days and of vasopressors free days, length of stay in ICU
and hospital, rate of limitations of treatment for futility, total cost of consumables
(including RRT catheters and lines among others) related to RRT between day 1 and day 28.
Number of subjects required:
We hypothesized that the "delayed" strategy would prove beneficial to the patients and would
translate into increased survival. The study is designed to prove superiority (and not
noninferiority) of this strategy over the "early" one.
The 60 days survival rate with the "early" strategy is estimated to be 45%. It is necessary
to include 620 patients (310 per arm) to obtain a power of 90% to detect a survival
improvement of 14% at day 60 with the "delayed" strategy (log-rank two tailed test, global
significance level of 5%), with two blind interim analyses by independent observers at 90
and 180 deaths (group sequential approach of O'Brien-Fleming), and a estimated dropout rate
of 10%.
Duration of study:
Inclusion: 18 months Minimum participation of each patient: 60 days Analysis and report: 10
months
;
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment