Study Design, Setting and Patient Population
This is a phase II multi-centre, randomized, blinded, placebo-controlled trial of ICU
patients with early AKI with randomization stratified by sepsis. All critically ill patients
admitted to the participating ICUs will be screened for eligibility.
Operational Definitions
- Acute kidney injury (AKI) - The operational definition for early AKI will be defined and
classified according to the RIFLE criteria (and modified AKIN). The presence of early AKI
will be defined by the RIFLE class - RISK: an abrupt (within 48hr) reduction in kidney
function characterized by an relative increase in serum creatinine of >50% (1.5 fold) or
>26.5 mcmol/L from baseline or a reduction in urine output of ≤0.5 mL/kg/hr for >6 hours.
Trial Protocol
Description of Study Flow
Patients will be identified in the ICU by daily surveillance of admitted patients by the PI
and/or research coordinator or when identified by the treating ICU physician. Each patient's
eligibility will be verified by use of a one-page checklist that summarizes the inclusion and
exclusion criteria. This checklist will be included in the standardized case-report form
(CRF).
Study Intervention
Following obtainment of consent, patients will be commenced on a continuous infusion of
either the intervention (furosemide) or identical placebo (0.9% NaCl). The study protocol for
administration of furosemide by continuous infusion is adapted from the phase I study by
Ostermann et al. The study infusion bag will contain 2000mg of furosemide in 500mL of
0.9%NaCl for a final concentration of 4mg/mL. The continuous infusion will be titrated to
achieve a target urine output in the range of 1.0-2.0 mL/kg/hr. Each patient will be
administered a loading dose of 0.4 mg/kg as a separate infusion bag followed by a continuous
infusion commenced at a dose of 0.0125 ml/kg/hr. The maximum infusion rate will be
0.125ml/kg/hr. The urine output will be assessed hourly. If the target urine output has been
achieved, then the current infusion rate will be continued. If the target urine output has
not been achieved, the dose will be increased to the next infusion rate in the algorithm. If
the urine output is too brisk (>2mL/kg/hr), the dose will be maintained unless any of the
following criteria are fulfilled: decrease in mean arterial pressure <65 AND/OR addition of
or an increase in vasoactive requirements of ≥20% to achieve goal mean arterial pressure OR
central venous pressure <8 cmH2O OR central venous oxygen saturation <60% OR a cardiac index
<2.0L/min/1.73m2 (if measured). If any of these criteria are achieved, the dose will be
decreased to the next lower infusion rate in the algorithm. If any of the aforementioned
criteria have been fulfilled AND urine output remains >2mL/kg/hr for 2 consecutive hours
despite the lowest infusion rate, the treatment will be discontinued for 1 hour then resumed
at the lowest infusion rate. The fulfillment of these criteria will be brought to the
attention of the consultant ICU physician for review. At any time during the trial, if the
responsible ICU physician believes that diuretics are urgently indicated (pulmonary edema),
diuretics can be administered and this event will be documented.
All other aspects of patient management within the parameters outlined (methods of fluid
resuscitation, choice of fluids, vasoactive therapy, choice of vasoactive therapy, adjuvant
therapies such as hrAPC, intensive insulin therapy, will be at the discretion of the
consultant ICU physician.
The study drug infusion will be continued until any one of the following events occur:
the patient is initiated on RRT;
the patient dies;
the patient is discharged from the ICU;
the patient recovers kidney function; or
the patient develops a recognized adverse reaction potentially related to the study
infusion.
Methods of Randomization
The randomization sequence will be created at a single central location at the University of
Alberta Hospital (EPICORE Centre). The sequence will be stratified by the presence of a
diagnosis of sepsis.
Data Collection
Detailed clinical, physiologic, laboratory and outcome data will be collected. Data will be
collected each day on whether the primary endpoint (progression of AKI) has occurred, for
evidence of any secondary endpoints and criteria for trial discontinuation. Plasma and urine
will be collected for biomarkers studies. Any study protocol violations will be recorded. The
adjudication of protocol violations will be determined by a study investigator blinded to the
treatment allocation.
Proposed Follow-up
The investigators plan to follow all patients to determine the duration of AKI, continued
need for RRT, renal recovery and mortality until death or discharge from hospital and at 30,
60 and 90-days after randomization.
