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

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

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.

Study Overview

• Status: Suspended
• Conditions: Septic Shock
• Intervention / Treatment: Drug: Fludrocortisone; Drug: Placebo

Detailed 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

• Study Type: Interventional
• Enrollment (Estimated): 40
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• France
  • Bretagne
    • Rennes, Bretagne, France, 35033
      • Rennes University Hospital - Intensive Care unit

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Fludrocortisone; 100 μg every 6 hours of fludrocortisone per os A pharmacokinetic study is performed in this arm	Drug: Fludrocortisone; 100 μg every 6 hours of fludrocortisone per os; Other Names: Flucortac
Placebo Comparator: Control; 100 μg every 6 hours of placebo per os	Drug: Placebo; 100 μg every 6 hours of placebo per os

What is the study measuring?

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)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 γ reflecting the sigmoidality of the curve.	1,5 hours after the second administration of fludrocortisone or placebo (7,5 hours)

Collaborators and Investigators

• Sponsor: Rennes University Hospital
• Collaborators: H.A.C. PHARMA
• Investigators: Principal Investigator: Harmonie Perrichet, MD, Rennes University Hospital; Study Chair: Bruno Laviolle, MD, PhD, Rennes University Hospital

Study record dates

Study Major Dates

• Study Start (Actual): March 31, 2022
• Primary Completion (Estimated): June 1, 2024
• Study Completion (Estimated): December 1, 2024

Study Registration Dates

• First Submitted: July 8, 2021
• First Submitted That Met QC Criteria: August 3, 2021
• First Posted (Actual): August 12, 2021

Study Record Updates

• Last Update Posted (Estimated): November 17, 2023
• Last Update Submitted That Met QC Criteria: November 15, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Sepsis; Shock, Septic; Shock; Anti-Inflammatory Agents; Fludrocortisone
• Other Study ID Numbers: 35RC19_8860; 2020-001430-35 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No