Hemodynamics Effects of Fludrocortisone on the Pressor Response to Noradrenaline Septic Shock Patients

Study Overview
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Brief Summary
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The benefit of low-dose steroids in septic shock is still debated today, especially with mineralocorticoids. Fludrocortisone is a synthetic mineralocorticoid, an analogue of aldosterone, which has shown, in combination with hydrocortisone, a favorable effect on the mortality of septic shock patients with relative adrenal insufficiency. In a previous study in healthy volunteers, we showed for the first time that fludrocortisone at a dose of 400 μg per day significantly improved the pressor response to phenylephrine. These results confirm the observations reported in rats with endotoxin shock, where fludrocortisone was shown to significantly increase blood pressure and contractile response to phenylephrine. These encouraging results argue for a potential vascular beneficial effect of fludrocortisone and need to be confirmed in a population of septic shock patients. In this context, we aimed to evaluate the effect of oral administration of 100 μg every 6 hours of fludrocortisone on vascular responsiveness to noradrenaline in septic shock patients.

Detailed Description
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Patients admitted to medical and surgical intensive care units with septic shock who meet the selection criteria may be offered participation in the study. The consent is signed either by the patient or his or her relative/legal representative if he or she is not capable or the patient is included according to the emergency procedure in the absence of a relative. The patient is managed according to the usual procedures for patients in septic shock. After collection of the initial workup and basal measurements, the physician randomizes (=includes) the patient into one of 2 arms : the patient receives either fludrocortisone (400 μg per day), administered in 1 dose of 100 μg every 6 hours, i.e., 2 tablets of 50 μg per dose, or the placebo

Official Title
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Evaluation of the Hemodynamics Effects of Fludrocortisone on the Pressor Response to Noradrenaline in Septic Shock Patients

Conditions
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Septic Shock

Intervention / Treatment
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* Drug: Fludrocortisone
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age > 18 years Patient with septic shock for less than 48 hours, defined by the combination of: Sepsis defined as organ dysfunction caused by an inappropriate host response to infection (increase in SOFA score of at least 2 points secondary to infection), Persistent hypotension requiring vasopressor drugs to maintain mean arterial pressure ≥ 65 mmHg, Hemodynamic stability for >30 min with mean arterial pressure ≥ 65 mmHg and noradrenaline dose ≤ 0.5 μg/kg/min, Consent signed by the patient, family member, or legal representative or inclusion under emergency procedure, Negative to a diagnostic test for SARS-CoV2 less than 72 hours old; the test used must be on the the list published on the Ministry of Solidarity and Health website Non-inclusion Criteria: Current treatment with steroids or other treatment that may affect the hypothalamic-pituitary-adrenal axis, Anesthetic induction with etomidate within 6 hours prior to randomization given its selective inhibitory effect on 11 β-hydroxylase, Known hypersensitivity to fludrocortisone (or any of its excipients), or to tetracosactide (Synacthen®), Disturbed gastric emptying (gastric residue > 500 ml) in the absence of an alternative route of administration available (naso-jejunal tube or jejunostomy), Pregnant or nursing woman, Patient participating in another trial, possibly interfering with the study procedures, Person not affiliated to a social security system, Known situation of deprivation of freedom (safeguard of justice), guardianship or curatorship, Patient with a life expectancy of less than 24 hours. Patient with known or suspected SARS-CoV2 pneumonia Exclusion criteria: Patients under court protection will be excluded as soon as the investigator is aware of their status. Hemodynamic worsening with noradrenaline dose >1.5 μg/kg/min before evaluation of the primary end point. Catecholamine withdrawal before evaluation of the primary end point.

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 |
| --- | --- |
| Experimental: Fludrocortisone<br>100 μg every 6 hours of fludrocortisone per os A pharmacokinetic study is performed in this arm | Drug: Fludrocortisone<br>* 100 μg every 6 hours of fludrocortisone per os<br>* Other names: Flucortac;|
| Placebo Comparator: Control<br>100 μg every 6 hours of placebo per os | Drug: Placebo<br>* 100 μg every 6 hours of placebo per os<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean arterial blood pressure (mmHg) | Mean arterial blood pressure (mmHg) after a dose escalation of norepinephrine in increments of 0.2 μg/kg/min to a maximum dose of 1.5 μg/kg/min. | 1,5 hours after the second administration of fludrocortisone or placebo (7,5 hours) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Heart rate | Heart rate | Baseline, before the first administration of the drug (fludrocortisone/placebo) | 
| Heart rate | Heart rate | 1,5 hours after the second administration of fludrocortisone or placebo (7,5 hours) | 
| Heart rate | Heart rate | After the 3rd administration of fludrocortisone or placebo (12 hours) | 
| Heart rate | Heart rate | After the 4th administration of fludrocortisone or placebo (18 hours) | 
| arterial pressure | Mean arterial pressure, systolic arterial pressure, diasystolic arterial pressure | Baseline, before the first administration of the experimental drug (fludrocortisone/placebo) | 
| arterial pressure | Mean arterial pressure, systolic arterial pressure, diasystolic arterial pressure | 1,5 hours after the second administration of fludrocortisone or placebo (7,5 hours) | 
| arterial pressure | Mean arterial pressure, systolic arterial pressure, diasystolic arterial pressure | After the 3rd administration of fludrocortisone or placebo (12 hours) | 
| arterial pressure | Mean arterial pressure, systolic arterial pressure, diasystolic arterial pressure | After the 4th administration of fludrocortisone or placebo (18 hours) | 
| Cardiac output | Cardiac output | Baseline, before the first administration of the experimental drug (fludrocortisone/placebo) | 
| Cardiac output | Cardiac output | 1,5 hours after the second administration of fludrocortisone or placebo (7,5 hours) | 
| Cardiac output | Cardiac output | After the 3rd administration of fludrocortisone or placebo (12 hours) | 
| Cardiac output | Cardiac output | After the 4th administration of fludrocortisone or placebo (18 hours) | 
| Cardiac index | Cardiac index | Baseline, before the first administration of the experimental drug (fludrocortisone/placebo) | 
| Cardiac index | Cardiac index | 1,5 hours after the second administration of fludrocortisone or placebo (7,5 hours) | 
| Cardiac index | Cardiac index | After the 3rd administration of fludrocortisone or placebo (12 hours) | 
| Cardiac index | Cardiac index | After the 4th administration of fludrocortisone or placebo (18 hours) | 
| Indexed Systemic Vascular Resistances (ISVR) | Indexed Systemic Vascular Resistances (ISVR) | Baseline, before the first administration of the experimental drug (fludrocortisone/placebo) | 
| Indexed Systemic Vascular Resistances (ISVR) | Indexed Systemic Vascular Resistances (ISVR) | 1,5 hours after the second administration of fludrocortisone or placebo (7,5 hours) | 
| Indexed Systemic Vascular Resistances (ISVR) | Indexed Systemic Vascular Resistances (ISVR) | After the 3rd administration of fludrocortisone or placebo (12 hours) | 
| Indexed Systemic Vascular Resistances (ISVR) | Indexed Systemic Vascular Resistances (ISVR) | After the 4th administration of fludrocortisone or placebo (18 hours) | 
| Indexed Global Telediastolic Volume (IGVT) | Indexed Global Telediastolic Volume (IGVT) | Baseline, before the first administration of the experimental drug (fludrocortisone/placebo) | 
| Indexed Global Telediastolic Volume (IGVT) | Indexed Global Telediastolic Volume (IGVT) | 1,5 hours after the second administration of fludrocortisone or placebo (7,5 hours) | 
| Indexed Global Telediastolic Volume (IGVT) | Indexed Global Telediastolic Volume (IGVT) | After the 3rd administration of fludrocortisone or placebo (12 hours) | 
| Indexed Global Telediastolic Volume (IGVT) | Indexed Global Telediastolic Volume (IGVT) | After the 4th administration of fludrocortisone or placebo (18 hours) | 
| Ejection Volume Variability (EVV) | Ejection Volume Variability (EVV) | Baseline, before the first administration of the experimental drug (fludrocortisone/placebo) | 
| Ejection Volume Variability (EVV) | Ejection Volume Variability (EVV) | 1,5 hours after the second administration of fludrocortisone or placebo (7,5 hours) | 
| Ejection Volume Variability (EVV) | Ejection Volume Variability (EVV) | After the 3rd administration of fludrocortisone or placebo (12 hours) | 
| Ejection Volume Variability (EVV) | v | After the 4th administration of fludrocortisone or placebo (18 hours) | 
| Extravascular Pulmonary Water (EVW) | Extravascular Pulmonary Water (EVW) | Baseline, before the first administration of the experimental drug (fludrocortisone/placebo) | 
| Extravascular Pulmonary Water (EVW) | Extravascular Pulmonary Water (EVW) | 1,5 hours after the second administration of fludrocortisone or placebo (7,5 hours) | 
| Extravascular Pulmonary Water (EVW) | Extravascular Pulmonary Water (EVW) | After the 3rd administration of fludrocortisone or placebo (12 hours) | 
| Extravascular Pulmonary Water (EVW) | Extravascular Pulmonary Water (EVW) | After the 4th administration of fludrocortisone or placebo (18 hours) | 
| Mortality | Percentage of deceased patients | Day 28 | 
| Mortality | Percentage of deceased patients | Day 90 | 
| Length of stay in intensive care unit | Length of stay in intensive care unit | Day 90 | 
| Length of stay in care unit | Length of stay in care unit | Day 90 | 
| Time to wean from catecholamines | Time to wean from catecholamines | Day 90 | 
| Duration of mechanical ventilation (MV) | Duration of mechanical ventilation (MV) | Day 90 | 
| Inflammation markers | IFNγ, TNF α, IL1β, IL6, IL10 dosage | Baseline, before the first administration of the experimental drug (fludrocortisone/placebo) | 
| Inflammation markers | IFNγ, TNF α, IL1β, IL6, IL10 dosage | 1,5 hours after the second administration of fludrocortisone or placebo (7,5 hours) | 
| natremia dosage | blood sodium | Baseline, before the first administration of the experimental drug (fludrocortisone/placebo) | 
| natremia dosage | blood sodium | 1,5 hours after the second administration of fludrocortisone or placebo (7,5 hours) | 
| urinary sodium dosage | urinary sodium | Baseline, before the first administration of the experimental drug (fludrocortisone/placebo) | 
| urinary sodium dosage | urinary sodium | 1,5 hours after the second administration of fludrocortisone or placebo (7,5 hours) | 
| kalemia dosage | blood potassium | Baseline, before the first administration of the experimental drug (fludrocortisone/placebo) | 
| kalemia dosage | blood potassium | 1,5 hours after the second administration of fludrocortisone or placebo (7,5 hours) | 
| urinary potassium dosage | urinary potassium | Baseline, before the first administration of the experimental drug (fludrocortisone/placebo) | 
| urinary potassium dosage | urinary potassium | 1,5 hours after the second administration of fludrocortisone or placebo (7,5 hours) | 
| pharmacokinetics of fludrocortisone : Area under the plasma concentration-time curve (plasma concentrations of fludrocortisone at 5 times) | in the experimental group only. | After 4th dose of fludrocortisone (18 hours) |