Fluid Removal Protocol for Fluid Overload

(RADAR-Canada Trial)

Overseen By Michael Sklar, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Unity Health Toronto

Disqualifiers: Dialysis, Brain injury, Cardiac failure, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 1 week

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a special fluid removal strategy for ICU patients with fluid overload, a condition where the body retains too much water. Researchers aim to determine if a combination of furosemide (Lasix, a diuretic) and metolazone (Zaroxolyn, another diuretic) can more effectively eliminate this excess fluid. The trial includes two groups: one receiving usual care and another receiving the experimental treatment. Eligible participants have been on a ventilator for over two days and exhibit noticeable swelling or fluid build-up since entering the ICU. As a Phase 2 trial, this research focuses on assessing the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What prior data suggests that this protocol is safe for fluid removal in ICU patients?

Research has shown that furosemide, a common diuretic that helps remove excess fluid from the body, is generally safe for very sick patients. Some studies suggest it can aid in short-term survival and kidney recovery. However, uncertainty remains about its potential serious side effects. Safety concerns often involve changes in blood levels of potassium and magnesium, essential minerals for the body.

Metolazone, another diuretic, is approved by the FDA to treat fluid buildup in conditions like heart failure and kidney disease. Research indicates that using metolazone with furosemide does not increase the risk of death or serious illness compared to using furosemide alone. This combination effectively manages excess fluid.

Both furosemide and metolazone have been used in medical practice for many years, indicating they are generally well-tolerated. However, like any medication, they may have side effects, which should be discussed with healthcare providers. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about this trial because it explores a detailed fluid removal protocol aiming to address fluid overload more effectively. Unlike standard treatments that often rely solely on diuretics like furosemide, this approach includes active deresuscitation to achieve precise fluid balance targets. By potentially adding metolazone and adjusting the furosemide dosage dynamically, the protocol seeks to optimize fluid reduction without causing side effects like hypotension or tachycardia. This trial could offer insights into a more tailored and responsive strategy for managing fluid overload, which is a common challenge in critical care settings.

What evidence suggests that this fluid removal protocol is effective for fluid overload?

Studies have shown that furosemide effectively removes excess fluid in conditions like congestive heart failure, which often cause fluid buildup. It increases urination, reducing fluid retention. In this trial, one arm involves active deresuscitation using furosemide, with metolazone added if necessary. Metolazone aids in eliminating more salt and water, potentially leading to noticeable weight loss and reduced swelling. Together, these medications may help balance fluid levels in the body, though results can vary among individuals. ^{3 6 7 8 9}

Who Is on the Research Team?

John C Marshall, MD

Principal Investigator

Unity Health Toronto

Are You a Good Fit for This Trial?

This trial is for ICU patients who still have too much fluid in their body after initial treatment. It's not clear what the specific inclusion or exclusion criteria are, but typically, participants would need to be stable enough for additional interventions and without conditions that could skew results.

Inclusion Criteria

I have significant swelling in two or more areas or have accumulated over 3 liters of fluid since being in ICU.

I was in the ICU for 5 days or less.

Informed consent obtained from patient or alternate decision-maker

Exclusion Criteria

I have had a bleeding in the space around my brain.

Lack of consent from patient or substitute decision maker or from responsible physician

I had a severe brain injury with a low score on the coma scale.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1 week

Treatment

Participants are randomized to either usual care or a deresuscitation protocol incorporating a fluid minimization strategy and diuresis

1 week

Daily monitoring in ICU

Follow-up

Participants are monitored for safety and effectiveness after treatment

90 days

What Are the Treatments Tested in This Trial?

Interventions

• Furosemide
• Metolazone

Trial Overview The RADAR-Canada trial is testing a protocol using Furosemide (a diuretic injection) and Metolazone (diuretic tablets) to see if they can help remove excess fluid from patients more quickly than usual care.

How Is the Trial Designed?

Group I: Active deresuscitation Experimental Treatment 2 Interventions

* 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

Group II: Usual care Active Control 1 Intervention

Care at the discretion of the attending team.

Furosemide is already approved in European Union, United States, Canada, Japan, China for the following indications:

Approved in European Union as Lasix for:

• Hypertension
• Edema associated with congestive heart failure
• Liver cirrhosis
• Renal disease
• Nephrotic syndrome

Approved in United States as Lasix for:

• Edema associated with congestive heart failure
• Liver cirrhosis
• Renal disease
• Nephrotic syndrome
• Acute pulmonary edema

Approved in Canada as Lasix for:

• Edema associated with congestive heart failure
• Liver cirrhosis
• Renal disease
• Nephrotic syndrome
• Hypertension

Approved in Japan as Lasix for:

• Edema associated with congestive heart failure
• Liver cirrhosis
• Renal disease
• Nephrotic syndrome

Approved in China as Lasix for:

• Edema associated with congestive heart failure
• Liver cirrhosis
• Renal disease
• Nephrotic syndrome
• Hypertension

Who Is Running the Clinical Trial?

Unity Health Toronto

Lead Sponsor

Trials

572

Recruited

470,000+

Canadian Institutes of Health Research (CIHR)

Collaborator

Trials

1,417

Recruited

26,550,000+

Citations

1. ncbi.nlm.nih.gov ncbi.nlm.nih.gov/books/NBK499921/

Furosemide - StatPearls - NCBI Bookshelf The Food and Drug Administration (FDA) has approved furosemide to treat conditions with volume overload and edema secondary to congestive heart failure ...

2. emcrit.org emcrit.org/ibcc/diurese/

Diuretics & Deresuscitation More effective diuresis generally depends on giving furosemide more frequently (rather than necessarily in higher doses). Depending on the ...

3. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0736467925002665

Pilot Study Identifying Predictive Factors of Diuretic ... Median urine volume per 40 mg i.v. furosemide was 625 mL (IQR 350, 1075 mL). Treatment failure—defined as 6-h urine volume < 600 mL—was observed in 25.8% (26/ ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9192894/

Loop diuretics in adult intensive care patients with fluid overload The evidence is very uncertain about the effect of loop diuretics on mortality and serious adverse events in adult ICU patients with fluid overload.

5. ajkd.org ajkd.org/article/S0272-6386%2821%2901019-2/fulltext

Diuretics in States of Volume Overload: Core Curriculum ... Separately, clinical trials highlight improved outcomes in some states of volume overload, such as loop diuretics and sodium/glucose ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7048112/

Impact of protocolized diuresis for de-resuscitation in the ... Using a diuresis protocol for volume de-resuscitation, we demonstrated a significant decrease in net cumulative fluid balance at 72 h following ...

7. kireports.org kireports.org/article/S2468-0249(22)01501-7/fulltext

Efficacy, Safety, and Tolerability of Oral Furosemide Among ... Safety outcomes included the following: (i) serum potassium less than 3.2 mEq/l, (ii) serum magnesium less than 0.8 mg/dl, (iii) serum ...

8. ccforum.biomedcentral.com ccforum.biomedcentral.com/articles/10.1186/s13054-020-2798-6

Association between furosemide administration and outcomes ... Furosemide administration was associated with improved short-term survival and recovery of renal function in critically ill patients with AKI.

9. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0883944120306079

A narrative review of pharmacologic de-resuscitation in the ... Despite evidence highlighting harms of fluid overload, minimal guidance exists on counteraction via utilization of diuretics in the de-resuscitation phase.