Furosemide Injection for Cardio-Renal Syndrome

Overseen By Christopher W McIntyre, MD

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: London Health Sciences Centre Research Institute and Lawson Research Institute of St. Joseph's

Must be taking: Loop diuretics

Must not be taking: Additional diuretics

Disqualifiers: Liver disease, Pregnancy, Kidney malformation, others

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

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 2

50 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to improve treatment for individuals with both heart failure and kidney disease who experience fluid buildup despite taking diuretics, which help the body eliminate excess water. The researchers seek to determine if measuring the salt content in the kidneys can predict a person's response to these medications. Participants should have heart failure, be on a specific dose of diuretics, and still exhibit signs of fluid overload, such as leg swelling or difficulty breathing when lying down. As an unphased trial, this study offers participants the chance to contribute to groundbreaking research that could lead to better treatment options.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you must already be taking loop diuretics like furosemide or bumetanide. You cannot take additional diuretics other than spironolactone, epleronone, metolazone, or finerenone.

What prior data suggests that this method is safe for measuring kidney sodium content in patients with cardio-renal syndrome?

Research has shown that high doses of furosemide injections are generally safe for individuals with cardio-renal syndrome, a condition where heart and kidney problems occur together. One study found that high doses of furosemide did not harm kidney function in most individuals with this condition. Another study suggested that furosemide is safe and effective for those unresponsive to standard treatments for swelling and kidney failure. Overall, furosemide has been well-tolerated, with few reports of serious side effects in these cases. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Furosemide Injection is unique because it targets patients with diuretic resistance, a challenging group where standard diuretics often fall short. While most treatments for cardio-renal syndrome rely on oral diuretics, Furosemide Injection provides a direct approach to tackle fluid overload. Researchers are excited because this method may offer more immediate relief from symptoms like edema and congestion, potentially improving quality of life for patients who haven't responded well to traditional therapies.

What evidence suggests that Furosemide Injection might be an effective treatment for cardio-renal syndrome?

Research has shown that high doses of furosemide can ease symptoms and improve the quality of life for people with severe heart failure. It helps the body eliminate excess fluid, which can also lead to weight loss. In heart failure patients with kidney disease, studies found that furosemide injections noticeably improve symptoms and aid in weight loss. Although some individuals may not respond as well to the treatment, furosemide remains effective for many. Most patients experience improvement without major side effects. ^{3 6 7 8 9}

Who Is on the Research Team?

Christopher W McIntyre, MD

Principal Investigator

Western University

Are You a Good Fit for This Trial?

This trial is for adults over 18 with a certain level of kidney function, diagnosed with heart failure and experiencing fluid overload despite taking diuretics like furosemide. They must be able to consent and not have conditions that exclude them from MRI scans or other specific health issues.

Inclusion Criteria

My water pills are not working as expected.

Willing and able to provide consent

I have been diagnosed with heart failure.

Exclusion Criteria

I have liver disease affecting my kidneys.

Your blood potassium level is too low.

I have chronic kidney disease due to a kidney malformation.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

Initial Study Visit

Participants undergo a combined proton (1H) and 23Na MRI scan of their kidneys, complete a questionnaire, and have various measurements taken.

1 day

1 visit (in-person)

Second Study Visit for Diuretic Resistant Patients

Participants with diuretic resistance receive an additional intravenous dose of diuretic and undergo a second MRI scan.

1 day

1 visit (in-person)

Follow-up

Participants are monitored for changes in kidney sodium content and response to diuretic therapy.

1-2 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Furosemide Injection

Trial Overview The study tests if measuring kidney sodium content using MRI can predict how well patients with heart failure and kidney disease respond to diuretics. It compares this response in those resistant to diuretics before and after an extra dose of the medication.

How Is the Trial Designed?

Group I: Furosemide Injection Experimental Treatment 1 Intervention

Patients with diuretic resistance: The presence of diuretic resistance, defined as having clinical signs of fluid overload despite diuretic therapy (this information is routinely collected at each clinical visit). "Fluid overload" is defined as the presence of at least two of the following clinical features: * Peripheral or sacral oedema * Jugular venous distension ≥ 7 cm * Radiographic pulmonary oedema or pleural effusion * Enlarged liver or ascites * Pulmonary rales, paroxysmal nocturnal dyspnoea, or orthopnoea * Point of Care UltraSound (POCUS) evidence of congestion. Inferior Vena Cava diameter \>2.5 cm and/or failure to collapse at least 50% with sharp inspiration

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

Approved in United States as Lasix for:

• Edema
• Hypertension
• Hypercalcemia
• Nephrotic syndrome

Approved in European Union as Lasix for:

• Oedema
• Hypertension
• Hypercalcaemia

Approved in Canada as Lasix for:

• Edema
• Hypertension
• Hypercalcemia

Who Is Running the Clinical Trial?

London Health Sciences Centre Research Institute and Lawson Research Institute of St. Joseph's

Lead Sponsor

Trials

686

Recruited

427,000+

London Health Sciences Centre OR Lawson Research Institute of St. Joseph's

Lead Sponsor

Trials

668

Recruited

424,000+

London Health Sciences Centre Research Institute OR Lawson Research Institute of St. Joseph's

Lead Sponsor

Trials

678

Recruited

421,000+

Lawson Health Research Institute

Lead Sponsor

Trials

684

Recruited

432,000+

Published Research Related to This Trial

Subcutaneously administered furosemide showed significant diuretic effects in a pilot study with 12 healthy volunteers, indicating it can effectively increase urine output compared to a placebo.

The study found that the most common side effects were minor, such as transient burning and stinging at the injection site, suggesting that this method of administration is relatively safe.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Diuretic effects of subcutaneous furosemide in human volunteers: a randomized pilot study. Verma, AK., da Silva, JH., Kuhl, DR.[2013]

In a four-year study of 533 hospitalized patients receiving furosemide, 39.8% experienced adverse reactions (ARs), with the most common being electrolyte disturbances and extracellular volume depletion, indicating a significant incidence of ARs associated with this medication.

While the overall frequency of severe ARs was low, they were notably higher in patients with liver cirrhosis, suggesting that these patients require careful monitoring when treated with furosemide.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Furosemide-induced adverse reactions during hospitalization. Naranjo, CA., Busto, U., Cassis, L.[2013]

In a study of 456 critically ill children in the pediatric intensive care unit, furosemide use was associated with significantly less fluid accumulation but did not reduce the incidence of acute kidney injury (AKI).

However, furosemide exposure was linked to a higher mortality rate, suggesting that while it may help manage fluid overload, it could also increase the risk of death in this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association Between Furosemide Exposure and Clinical Outcomes in a Retrospective Cohort of Critically Ill Children. Dai, X., Chen, J., Li, W., et al.[2021]

In a study involving 20 patients with severe heart failure, continuous infusion of high-dose furosemide resulted in significantly greater urinary volume (2,860 ml) and sodium excretion (210 mmol) compared to a bolus injection (2,260 ml and 150 mmol, respectively), indicating higher efficacy in diuresis.

The continuous infusion method also led to fewer side effects, as short-term hearing loss was only reported in patients receiving the bolus injection, suggesting that continuous infusion may be a safer option for managing severe heart failure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Diuretic efficacy of high dose furosemide in severe heart failure: bolus injection versus continuous infusion. Dormans, TP., van Meyel, JJ., Gerlag, PG., et al.[2022]

In three patients with chronic heart failure who experienced severe symptoms despite standard treatments, high-dose continuous intravenous administration of loop diuretics provided relief, suggesting a potential solution for diuretic-resistant heart failure.

Proper monitoring and management of hydration status in chronic heart failure patients can enhance their prognosis and quality of life, indicating the importance of individualized treatment approaches.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Failing diuretics in severe chronic heart failure]. Dormans, TP., Gerlag, PG., Smits, P.[2007]

High doses of furosemide (up to 720 mg orally and even higher intravenously) were administered to patients with severe edema due to conditions like nephrotic syndrome and renal failure, showing effectiveness in achieving satisfactory diuresis.

The study suggests that using high doses of furosemide is both safe and effective for patients with edema and renal failure that do not respond to standard treatments, as evidenced by positive outcomes in multiple cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Experiences with high doses of furosemide in renal disease and resistant edematous states. Silverberg, DS., Ulan, RA., Baltzan, MA., et al.[2018]

In a study involving 42 patients with chronic renal insufficiency, continuous intravenous infusion of furosemide resulted in significantly greater sodium and urine volume excretion compared to bolus administration, indicating a more effective diuretic response.

The continuous infusion method led to a higher fractional excretion of sodium, suggesting that it may be a better option for managing fluid balance in patients with advanced chronic renal insufficiency.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The comparison of the diuretic and natriuretic efficacy of continuous and bolus intravenous furosemide in patients with chronic kidney disease. Sanjay, S., Annigeri, RA., Seshadri, R., et al.[2013]

A 2-year-old cat treated with subcutaneous furosemide for congestive heart failure developed circular, crusted skin lesions at injection sites, marking the first reported case of dermatologic adverse effects from this treatment in cats.

Switching to a different brand of furosemide resolved the skin issues while effectively managing the cat's lung edema, highlighting the need for awareness of potential skin reactions in feline patients receiving subcutaneous furosemide.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dermatologic adverse effect of subcutaneous furosemide administration in a cat. Mazzoldi, C., Aspidi, F., Romito, G.[2023]

In a study of 17,068 hospitalized patients, 13.9% received furosemide, primarily for congestive heart failure, indicating its common use in managing cardiovascular conditions.

While 10.1% of furosemide recipients experienced adverse reactions, serious life-threatening effects were rare, suggesting that furosemide is generally safe, especially when potassium supplements are used to mitigate hypokalemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical toxicity of furosemide in hospitalized patients. A report from the Boston Collaborative Drug Surveillance Program. Greenblatt, DJ., Duhme, DW., Allen, MD., et al.[2019]

In a study of 22,374 hospitalized patients, the use of furosemide was linked to an increased risk of hospital-acquired acute kidney injury (HA-AKI), with the total daily dose being the most significant risk factor identified.

A prognostic nomogram was developed to predict the likelihood of AKI in patients receiving furosemide, showing a high predictive accuracy of 77.40%, which can help clinicians make better treatment decisions based on individual patient factors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hospitalized patients received furosemide undergoing acute kidney injury: the risk and prediction tool. Guan, C., Li, C., Xu, L., et al.[2023]

Angiotensin II infusion significantly increased natriuresis and diuresis in conscious rabbits, but it reduced the effectiveness of furosemide, a diuretic, in promoting natriuresis, indicating a potential interaction that diminishes furosemide's response.

The study found that while angiotensin II decreased renal plasma flow and altered furosemide's pharmacodynamics, it did not affect the glomerular filtration rate, suggesting that the interaction primarily impacts how furosemide works rather than how it is processed by the kidneys.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Furosemide dynamics in conscious rabbits: modulation by angiotensin II. Homsy, W., Marleau, S., du Souich, P.[2019]

In a study of 266 stable outpatients with heart failure and reduced ejection fraction, higher daily doses of furosemide were linked to worse long-term survival, with a significant increase in mortality risk for doses above 40 mg/day.

Patients receiving intermediate (41-80 mg/day) and high (>80 mg/day) doses of furosemide had hazard ratios of 4.1 and 19.8 for mortality, respectively, indicating that furosemide may be detrimental in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Furosemide Prescription During the Dry State Is a Predictor of Long-Term Survival of Stable, Optimally Medicated Patients With Systolic Heart Failure. Sargento, L., Simões, AV., Longo, S., et al.[2018]

In a study of 35 patients with severe chronic congestive heart failure, high doses of furosemide (250 to 4000 mg/d) effectively improved symptoms, led to significant weight reduction (average of 11 kg), and enhanced quality of life.

The mean survival after starting high-dose furosemide therapy was 11.3 months, and in cases where this therapy failed, long-term intermittent hemofiltration further extended survival by an average of 3 months, indicating the potential for these treatments to prolong life in patients with refractory heart failure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High-dose furosemide in the treatment of refractory congestive heart failure. Gerlag, PG., van Meijel, JJ.[2013]

Citations

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Systematic Review on the Management of Diuretic Resistance ... Both treatments led to similar weight loss at 96 h, the primary outcome, but dapagliflozin was associated with a numerically lower diuretic efficiency (weight ...

2. withpower.com withpower.com/trial/phase-cardio-renal-syndrome-9-2020-ced69

Furosemide Injection for Cardio-Renal Syndrome Research shows that high-dose furosemide can help reduce symptoms and improve quality of life in patients with severe heart failure by promoting weight loss and ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5933583/

A perspective on diuretic resistance in chronic congestive ... All patients showed improvement in symptoms and weight reduction with no significant side effects.

4. sciencedirect.com sciencedirect.com/science/article/pii/S0753332222014470

Review Diuretic resistance in patients with kidney disease The main causes and coping strategies of diuretic resistance in patients with kidney diseases were described in detail in this report.

5. jacc.org jacc.org/doi/10.1016/j.jacc.2019.12.059

Diuretic Therapy for Patients With Heart Failure Clinical trial data suggest that such changes are usually transient and associated with similar or even better long-term outcomes in the setting ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC3010630/

Therapeutic Options for the Management of the Cardiorenal ... Safety and efficacy of out patient nesiritide in patients with advanced heart failure. Results of the serial infusion of nesiritide (FUSION II) trial.

7. onlinejcf.com onlinejcf.com/article/S1071-9164(09)00608-3/fulltext

High Dose Intravenous Furosemide for the Management ... Conclusion: High dose of IV furosemide therapy was effective and safe in the majority of acute CRS as it had no negative impact on renal function. Furthermore, ...

8. clinicaltrials.gov clinicaltrials.gov/study/NCT00982423?term=LASIX&viewType=Table&rank=7

NCT00982423 | The Effects of Decreasing the Lasix Dose ... The investigators' objective is to define the effects of decreasing the furosemide dose on heart, kidney and humoral function in people with compensated ...

9. ahajournals.org ahajournals.org/doi/10.1161/CIR.0000000000000664

Cardiorenal Syndrome: Classification, Pathophysiology ... On the basis of the analyses highlighted above, high-dose intermittent furosemide appears to be safe and effective in AHF. Whether diuretics ...