Role of Active Deresuscitation After Resuscitation: (RADAR-Canada)

Role of Active Deresuscitation After Resuscitation: The RADAR-Canada Pilot Clinical Trial

The RADAR-Canada trial is a pilot RCT undertaken to assess the acceptability of, compliance with, and biologic consequences of a deresuscitation protocol designed to expedite the removal of excess interstitial fluid in patients who remain in a positive fluid balance following admission to an intensive care unit (ICU).

Study Overview

• Status: Not yet recruiting
• Conditions: Sepsis; Critical Illness; Trauma; ARDS; Fluid Overload
• Intervention / Treatment: Drug: Furosemide Injection; Drug: Metolazone Tablets

Detailed Description

Background: Over the course of an acute illness, critically ill patients typically receive substantial volumes of intravenous fluids, administered for resuscitation, maintenance, and as diluents for medications. A positive fluid balance is associated with adverse clinical outcomes. Whether active reversal of a positive fluid balance through fluid restriction and diuresis will improve outcomes is uncertain.

Methods: The Role of Active Deresuscitation After Resuscitation (RADAR) trial is a pilot study to determine the feasibility of a larger trial powered for clinically important outcomes, the acceptability of a deresuscitation protocol, and the impact of a trial on stability of practice patterns. RADAR is an open label pilot trial that will recruit 120 patients from 10 to 12 active sites in Canada. Eligible patients will be 18 years or older, mechanically ventilated >48 hours but in the ICU for less than five days, and in a calculated positive fluid balance of > three liters. Patients will be randomized to either usual care or a deresuscitation protocol incorporating a fluid minimization strategy and diuresis.

Results and Discussion: Evidence that recruited patients will be managed according to the trial protocol, with a withdrawal rate of less than 5%, a compliance rate of >75% and a crossover rate of <10% will establish the acceptability of the protocol. A mean difference in fluid balance between groups of more than three liters 72 hours after enrolment will establish the feasibility of the protocol. Analyses of clinical effects will be secondary analyses. Survival to day 90 following randomization will be measured, and other clinical measures will provide estimates of rates of key outcomes to inform the design of a definitive, adequately powered trial.

• Study Type: Interventional
• Enrollment (Estimated): 120
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Laura Romero, RN; Phone Number: 416-864-6060; Email: Laura.Romero@unityhealth.to
• Study Contact Backup: Name: Michael Sklar, MD; Phone Number: 416-864-6060; Email: Michael.Sklar@unityhealth.to

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5B 1W8
      • Unity Health Toronto
      • Contact: John C Marshall, MD; Phone Number: 4168645225; Email: john.marshall@unityhealth.to

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Age 18 years or older
2. Mechanically ventilated for > 48 hours
3. Calculated volume accumulation > 3 liters since ICU admission or pitting edema in at least two sites (arms, legs, or trunk)
4. Admitted to ICU for ≤ five days
5. Informed consent obtained from patient or alternate decision-maker

Exclusion Criteria:

1. Lack of consent from patient or substitute decision maker or from responsible physician 2. Active bleeding (defined as > 2 units transfused RBC in past 24 hours) 3. Hemodynamic instability (defined as use of vasopressors >0.1 µg/kg/minute norepinephrine or equivalent, or increase in vasopressor dose over past 6 hours) 4. Currently receiving dialysis, or plans to initiate dialysis imminently 5. P/F ratio < 75 6. Subarachnoid hemorrhage 7. Severe traumatic brain injury with admission GCS <8 8. Diabetic ketoacidosis or hyperosmolar state 9. Acute cardiac failure or cardiogenic shock 10. Suspected or established diabetes insipidus 11. Allergy to furosemide 12. High probability of death within 24 hours

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Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Active deresuscitation; Fluid minimization: clinical and research teams will review all intravenous orders and attempt to reduce fluids to 10-15 ml/hr.; Active deresuscitation:; Administer bolus furosemide 0.5 mg/kg bid or tid; Target daily negative fluid balance as follows: Calculated positive balance: < 3 liters -600 - -800 ml/24 hours 3-6 liters 0.8 - 1.2 liters/24 hours 6- 10 liters 1.2 - 2.0 liters/24 hours >10 liters >2.0 liters/24 hours; If bolus furosemide fails to achieve these goals, results in hypotension or tachycardia, or at the discretion of the attending intensivist, start furosemide infusion titrated on an hourly basis to achieve above goals; If single agent ineffective, consider addition of metolazone	Drug: Furosemide Injection; o.5 mg/kg bid or tid IV; Drug: Metolazone Tablets; Diuretic as needed
No Intervention: Usual care; Care at the discretion of the attending team.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Efficacy: Mean cumulative fluid balance	Total fluid input (mL) - output (mL) in each group	72 hours following randomization
Compliance with deresuscitation protocol	Daily fluid balance in mL >10 liters, target >2.0 liters/24 hours	Each 24 hours over first week
Acceptability of protocol	Percentage of eligible patients who consent to randomization	Day 1

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
All cause mortality	Deaths	90 days following randomization
New onset organ dysfunction	Change in aggregate Multiple Organ Dysfunction (MOD) score from baseline, where the range is 0 - 25, and higher values indicate more severe organ dysfunction	7 days following randomization
Organ support-free days	Days alive and free from respiratory or hemodynamic support	28 days following randomization

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Inflammatory and renal biomarkers - change from baseline values	including, but not limited to IL-6, sTNFr1, ICAM, HCO3-, protein C, CRP) or markers of AKI (including, but not limited to N-GAL, KIM-1, TIMP2-IGFBP-7, cystatin C	3 days following randomization

Collaborators and Investigators

• Sponsor: Unity Health Toronto
• Collaborators: Canadian Institutes of Health Research (CIHR)
• Investigators: Principal Investigator: John C Marshall, MD, Unity Health Toronto

Study record dates

Study Major Dates

• Study Start (Estimated): May 1, 2024
• Primary Completion (Estimated): March 31, 2025
• Study Completion (Estimated): June 30, 2025

Study Registration Dates

• First Submitted: February 26, 2024
• First Submitted That Met QC Criteria: March 16, 2024
• First Posted (Actual): March 22, 2024

Study Record Updates

• Last Update Posted (Actual): March 22, 2024
• Last Update Submitted That Met QC Criteria: March 16, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: sepsis; critical illness; acute respiratory distress syndrome; multiple trauma
• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Critical Illness; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Natriuretic Agents; Membrane Transport Modulators; Diuretics; Sodium Chloride Symporter Inhibitors; Sodium Potassium Chloride Symporter Inhibitors; Furosemide; Metolazone
• Other Study ID Numbers: 4588

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No