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

Septic Shock Clinical Trial

— FLUDROSEPSIS  

Official title:

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

Clinical Trial Details — Status: Suspended

Administrative data

• NCT number: NCT05001854
• Other study ID #: 35RC19_8860
• Secondary ID: 2020-001430-35
• Status: Suspended
• Phase: Phase 2/Phase 3
• Start date: March 31, 2022
• Est. completion date: December 2024

Study information

• Verified date: November 2023
• Source: Rennes University Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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

Recruitment information / eligibility

• Status: Suspended
• Enrollment: 40
• Est. completion date: December 2024
• Est. primary completion date: June 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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 ß-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.

Related Conditions & MeSH terms

• Septic Shock
• Shock
• Shock, Septic

Intervention

Drug:
• Fludrocortisone
100 µg every 6 hours of fludrocortisone per os
• Placebo
100 µg every 6 hours of placebo per os

Locations

Country	Name	City	State
France	Rennes University Hospital - Intensive Care unit	Rennes	Bretagne

Sponsors (2)

Lead Sponsor	Collaborator
Rennes University Hospital	H.A.C. PHARMA

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Dose-response relationship	The dose-response relationship (mean arterial blood pressure to doses of norepinephrine) will be modeled according to a sigmoid Emax model with determination of the maximum effect (Emax) obtained on blood pressure, estimation of the dose of norepinephrine inducing half of the Emax (ED50), and the Hill coefficient ? reflecting the sigmoidality of the curve.	1,5 hours after the second administration of fludrocortisone or placebo (7,5 hours)
Primary	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	Heart rate	Heart rate	Baseline, before the first administration of the drug (fludrocortisone/placebo)
Secondary	Heart rate	Heart rate	1,5 hours after the second administration of fludrocortisone or placebo (7,5 hours)
Secondary	Heart rate	Heart rate	After the 3rd administration of fludrocortisone or placebo (12 hours)
Secondary	Heart rate	Heart rate	After the 4th administration of fludrocortisone or placebo (18 hours)
Secondary	arterial pressure	Mean arterial pressure, systolic arterial pressure, diasystolic arterial pressure	Baseline, before the first administration of the experimental drug (fludrocortisone/placebo)
Secondary	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)
Secondary	arterial pressure	Mean arterial pressure, systolic arterial pressure, diasystolic arterial pressure	After the 3rd administration of fludrocortisone or placebo (12 hours)
Secondary	arterial pressure	Mean arterial pressure, systolic arterial pressure, diasystolic arterial pressure	After the 4th administration of fludrocortisone or placebo (18 hours)
Secondary	Cardiac output	Cardiac output	Baseline, before the first administration of the experimental drug (fludrocortisone/placebo)
Secondary	Cardiac output	Cardiac output	1,5 hours after the second administration of fludrocortisone or placebo (7,5 hours)
Secondary	Cardiac output	Cardiac output	After the 3rd administration of fludrocortisone or placebo (12 hours)
Secondary	Cardiac output	Cardiac output	After the 4th administration of fludrocortisone or placebo (18 hours)
Secondary	Cardiac index	Cardiac index	Baseline, before the first administration of the experimental drug (fludrocortisone/placebo)
Secondary	Cardiac index	Cardiac index	1,5 hours after the second administration of fludrocortisone or placebo (7,5 hours)
Secondary	Cardiac index	Cardiac index	After the 3rd administration of fludrocortisone or placebo (12 hours)
Secondary	Cardiac index	Cardiac index	After the 4th administration of fludrocortisone or placebo (18 hours)
Secondary	Indexed Systemic Vascular Resistances (ISVR)	Indexed Systemic Vascular Resistances (ISVR)	Baseline, before the first administration of the experimental drug (fludrocortisone/placebo)
Secondary	Indexed Systemic Vascular Resistances (ISVR)	Indexed Systemic Vascular Resistances (ISVR)	1,5 hours after the second administration of fludrocortisone or placebo (7,5 hours)
Secondary	Indexed Systemic Vascular Resistances (ISVR)	Indexed Systemic Vascular Resistances (ISVR)	After the 3rd administration of fludrocortisone or placebo (12 hours)
Secondary	Indexed Systemic Vascular Resistances (ISVR)	Indexed Systemic Vascular Resistances (ISVR)	After the 4th administration of fludrocortisone or placebo (18 hours)
Secondary	Indexed Global Telediastolic Volume (IGVT)	Indexed Global Telediastolic Volume (IGVT)	Baseline, before the first administration of the experimental drug (fludrocortisone/placebo)
Secondary	Indexed Global Telediastolic Volume (IGVT)	Indexed Global Telediastolic Volume (IGVT)	1,5 hours after the second administration of fludrocortisone or placebo (7,5 hours)
Secondary	Indexed Global Telediastolic Volume (IGVT)	Indexed Global Telediastolic Volume (IGVT)	After the 3rd administration of fludrocortisone or placebo (12 hours)
Secondary	Indexed Global Telediastolic Volume (IGVT)	Indexed Global Telediastolic Volume (IGVT)	After the 4th administration of fludrocortisone or placebo (18 hours)
Secondary	Ejection Volume Variability (EVV)	Ejection Volume Variability (EVV)	Baseline, before the first administration of the experimental drug (fludrocortisone/placebo)
Secondary	Ejection Volume Variability (EVV)	Ejection Volume Variability (EVV)	1,5 hours after the second administration of fludrocortisone or placebo (7,5 hours)
Secondary	Ejection Volume Variability (EVV)	Ejection Volume Variability (EVV)	After the 3rd administration of fludrocortisone or placebo (12 hours)
Secondary	Ejection Volume Variability (EVV)	v	After the 4th administration of fludrocortisone or placebo (18 hours)
Secondary	Extravascular Pulmonary Water (EVW)	Extravascular Pulmonary Water (EVW)	Baseline, before the first administration of the experimental drug (fludrocortisone/placebo)
Secondary	Extravascular Pulmonary Water (EVW)	Extravascular Pulmonary Water (EVW)	1,5 hours after the second administration of fludrocortisone or placebo (7,5 hours)
Secondary	Extravascular Pulmonary Water (EVW)	Extravascular Pulmonary Water (EVW)	After the 3rd administration of fludrocortisone or placebo (12 hours)
Secondary	Extravascular Pulmonary Water (EVW)	Extravascular Pulmonary Water (EVW)	After the 4th administration of fludrocortisone or placebo (18 hours)
Secondary	Mortality	Percentage of deceased patients	Day 28
Secondary	Mortality	Percentage of deceased patients	Day 90
Secondary	Length of stay in intensive care unit	Length of stay in intensive care unit	Day 90
Secondary	Length of stay in care unit	Length of stay in care unit	Day 90
Secondary	Time to wean from catecholamines	Time to wean from catecholamines	Day 90
Secondary	Duration of mechanical ventilation (MV)	Duration of mechanical ventilation (MV)	Day 90
Secondary	Inflammation markers	IFN?, TNF a, IL1ß, IL6, IL10 dosage	Baseline, before the first administration of the experimental drug (fludrocortisone/placebo)
Secondary	Inflammation markers	IFN?, TNF a, IL1ß, IL6, IL10 dosage	1,5 hours after the second administration of fludrocortisone or placebo (7,5 hours)
Secondary	natremia dosage	blood sodium	Baseline, before the first administration of the experimental drug (fludrocortisone/placebo)
Secondary	natremia dosage	blood sodium	1,5 hours after the second administration of fludrocortisone or placebo (7,5 hours)
Secondary	urinary sodium dosage	urinary sodium	Baseline, before the first administration of the experimental drug (fludrocortisone/placebo)
Secondary	urinary sodium dosage	urinary sodium	1,5 hours after the second administration of fludrocortisone or placebo (7,5 hours)
Secondary	kalemia dosage	blood potassium	Baseline, before the first administration of the experimental drug (fludrocortisone/placebo)
Secondary	kalemia dosage	blood potassium	1,5 hours after the second administration of fludrocortisone or placebo (7,5 hours)
Secondary	urinary potassium dosage	urinary potassium	Baseline, before the first administration of the experimental drug (fludrocortisone/placebo)
Secondary	urinary potassium dosage	urinary potassium	1,5 hours after the second administration of fludrocortisone or placebo (7,5 hours)
Secondary	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)