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

Trial Summary

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 data supports the effectiveness of the drug 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 reducing fluid buildup. This suggests that furosemide may be effective in managing fluid-related issues in cardio-renal syndrome as well. ^{1 2 3 4 5}

Is Furosemide Injection generally safe for humans?

Furosemide is generally considered safe for humans, but it can cause some side effects like electrolyte imbalances (changes in the levels of minerals in the blood) and fluid depletion. Serious side effects are uncommon and usually occur in very sick patients or those with liver disease. It's important to monitor patients closely, especially if they have other health issues. ^{6 7 8 9 10}

How does the drug Furosemide Injection differ from other treatments for cardio-renal syndrome?

Furosemide Injection is unique because it can be administered in high doses and through continuous infusion, which may be beneficial for patients with severe heart failure or those who are resistant to standard diuretic treatments. This method of administration can help manage fluid overload more effectively compared to traditional oral or bolus injection methods. ^{1 3 11 12 13}

What is the purpose of this trial?

Diuretic therapy is the cornerstone of the management of fluid overload in heart failure. Resistance to diuretic therapy is the most common reason for treatment failure in patients affected by the combination of heart failure and kidney disease. Currently, there is no way of predicting whether heart failure patients will develop resistance to diuretic therapy and what dose of diuretic is necessary to overcome diuretic resistance. Answering these questions would allow doctors to be able to prescribe an accurate dose of diuretic therapy to prevent diuretic resistance and potential side effects of an excessive diuretic dose. With magnetic resonance imaging, it is possible to measure the kidney sodium (salt) content and observe the diuretic response in patients with heart failure and kidney disease. The investigators speculate that measuring kidney sodium content will allow to predict diuretic response in these patients. The aim of this study is to compare the kidney sodium content in patients with chronic cardiorenal syndrome with and without diuretic resistance. Secondly, in a sample of patients with diagnosed diuretic resistance,the aim will be to observe the changes in kidney sodium content induced by an additional dose of diuretic therapy and to observe whether these changes are associated with a response to diuretic therapy.

Research Team

Christopher W McIntyre, MD

Principal Investigator

Western University

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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 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 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]

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]

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]

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]

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 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]

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]

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 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]

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]

References

1. United States pubmed.ncbi.nlm.nih.gov

Diuretic effects of subcutaneous furosemide in human volunteers: a randomized pilot study. [2013]

2. United States 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. [2018]

3. Netherlands pubmed.ncbi.nlm.nih.gov

[Failing diuretics in severe chronic heart failure]. [2007]

4. United States pubmed.ncbi.nlm.nih.gov

High-dose furosemide in the treatment of refractory congestive heart failure. [2013]

5. Australia 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. [2013]

6. United States pubmed.ncbi.nlm.nih.gov

Clinical toxicity of furosemide in hospitalized patients. A report from the Boston Collaborative Drug Surveillance Program. [2019]

7. Libya pubmed.ncbi.nlm.nih.gov

Dermatologic adverse effect of subcutaneous furosemide administration in a cat. [2023]

8. England pubmed.ncbi.nlm.nih.gov

Hospitalized patients received furosemide undergoing acute kidney injury: the risk and prediction tool. [2023]

9. United States pubmed.ncbi.nlm.nih.gov

Furosemide-induced adverse reactions during hospitalization. [2013]

10. Switzerland pubmed.ncbi.nlm.nih.gov

Association Between Furosemide Exposure and Clinical Outcomes in a Retrospective Cohort of Critically Ill Children. [2021]

11. United States pubmed.ncbi.nlm.nih.gov

Furosemide dynamics in conscious rabbits: modulation by angiotensin II. [2019]

12. United States pubmed.ncbi.nlm.nih.gov

Diuretic efficacy of high dose furosemide in severe heart failure: bolus injection versus continuous infusion. [2022]

13. Canada pubmed.ncbi.nlm.nih.gov

Experiences with high doses of furosemide in renal disease and resistant edematous states. [2018]