Diuretic Versus Placebo in Pulmonary Embolism

Study Overview
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Brief Summary
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Pulmonary Embolism (PE) is a frequent and severe disease with an annual incidence of about 75000 cases in France and a short-term mortality rate of about 10%. Death is usually related to an acute right ventricular (RV) failure due to the increase in right ventricular afterload. Treatment of PE with RV failure consists in fluid expansion and thrombolysis in case of shock. However several studies suggest that fluid expansion may worsen acute RV failure by increasing RV dilatation and ischemia and left ventricular compression by RV dilatation. Thus, current guidelines regarding PE treatment remain unclear about the use of fluid expansion. In a preliminary study published by our group, we showed that diuretic treatment in the setting of PE with RV dilatation is safe and is associated with an increase in urine output, a decrease in heart rate and an increase in SpO2 in normotensive patients with oliguria. This may be related to the decrease of ventricular interdependence and enhancement of both LV and RV function. The main objective of the study is to evaluate the 24-hours clinical benefit of furosemide in patients referred for acute PE with RV dilatation compared to placebo. The combination of urine output and sPESI clinical parameters reflects hemodynamic status. It is relevant as it indicates the disappearance of pre-shock symptoms and is therefore associated with a lower event risk. Thus, it allows early discharge of the patients from the intensive care unit.

Official Title
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Diuretic Versus Placebo in Pulmonary Embolism With Right Ventricular Enlargement: a Double-blind Randomized Controlled Study

Conditions
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Pulmonary Embolism With Right Ventricle Enlargement

Intervention / Treatment
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* Drug: Diuretics : Furosemide
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients aged 18 years and over with Symptomatic acute pulmonary embolism with first clinical symptoms within 15 days, and objectively confirmed by CT scan RV dysfunction (≥1 criterion) confirmed by elevated BNP value or echocardiography or spiral computed tomography of the chest: Echocardiography o Right/Left ventricular end diastolic diameter > 1(apical or subcostal 4-chamber view) Computed tomography o Right/Left short-axis diameter ratio>0.9 (transverse plane) Positive Nt-proBNP (>600) or BNP>200 pg/mL One abnormal following PESI criteria Heart Rate>110/min Systolic blood pressure<100mmHg Arterial oxyhemoglobin level<90% on room air or after 5 minutes of oxygen withdrawal. Exclusion Criteria: Cardiogenic shock requiring thrombolysis Previous significant left ventricular insufficiency (LVEF<45%) Systolic blood pressure<90mmHg at admission Age ≤ 18 years Pregnancy No health insurance Patients deprived of liberty or under legal protection Creatinin clearance <30mL/min/m² hypersensibility to furosemide or its excipients functional renal insufficiency Hepatic encephalopathy Urinary tracks obstruction Hypovolemia or dehydration. Sever hypokalemia (K+ < 3mmol/L) Severe hyponatremia (Na+ < 125mmol/L) Ongoing hepatitis and hepatic insufficiency severe in patients with renal insufficiency or dialysis

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Diuretics<br> | Drug: Diuretics : Furosemide<br>* Furosemide 80mg in one single direct intra venous injection<br>|
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* Placebo in one single direct intra venous injection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Primary end point will be a combined clinical criterion, to reach the primary endpoint, patients have to meet all the following criteria: - Urine output> 0.5ml/kg/h - Normalization of clinical parameters of simplified PESI score | Normalization of clinical parameters of simplified PESI score : Heart Rate<110/min Systolic blood pressure≥100mmHg Arterial oxyhemoglobin level>90% on room air or after 5 minutes of oxygen withdrawal. | 24 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| patients have to meet all the four following criteria: - Urine output> 0.5ml/kg/h over 24 hours - Normalization of clinical parameters of simplified PESI score - Urine output | Normalization of clinical parameters of simplified PESI score : Heart Rate<110/min Systolic blood pressure≥100mmHg Arterial oxyhemoglobin level>90% on room air or after 5 minutes of oxygen withdrawal. | 48 hours | 
| - Composite criteria including death, need for catecholamine, cardiac arrest and mechanical ventilation during hospitalization and at 1 month from inclusion - NYHA score |  | In hospital and 1 month | 
| o RV/LV ratio and decrease from baseline o Systolic pulmonary pressure and decrease from baseline o Tricuspid annular plane systolic expansion (TAPSE) at o Tricuspid annular plane systolic expansion (TAPSE) variation from baseline | RV/LV ratio (diameters and surfaces) | 24 hours abd 1 month | 
| - NT-proBNP or BNP decrease at 24hours - Creatinin and liver enzymes variations at 24hours |  | 24 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pulmonary Embolism, Right Ventricle failure, Diuretics