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

Rennes University Hospital40 enrolled

Overview

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.

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

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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.

Outcomes

Primary Outcomes

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.

Time frame: 1,5 hours after the second administration of fludrocortisone or placebo (7,5 hours)

Secondary Outcomes

Heart rate

Time frame: Baseline, before the first administration of the drug (fludrocortisone/placebo)

Heart rate

Time frame: 1,5 hours after the second administration of fludrocortisone or placebo (7,5 hours)

Heart rate

Time frame: After the 3rd administration of fludrocortisone or placebo (12 hours)

Heart rate

Time frame: After the 4th administration of fludrocortisone or placebo (18 hours)

arterial pressure

Mean arterial pressure, systolic arterial pressure, diasystolic arterial pressure

Time frame: Baseline, before the first administration of the experimental drug (fludrocortisone/placebo)

arterial pressure

Mean arterial pressure, systolic arterial pressure, diasystolic arterial pressure

Time frame: 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

Time frame: After the 3rd administration of fludrocortisone or placebo (12 hours)

arterial pressure

Mean arterial pressure, systolic arterial pressure, diasystolic arterial pressure

Time frame: After the 4th administration of fludrocortisone or placebo (18 hours)

Cardiac output

Time frame: Baseline, before the first administration of the experimental drug (fludrocortisone/placebo)

Cardiac output

Time frame: 1,5 hours after the second administration of fludrocortisone or placebo (7,5 hours)

Cardiac output

Time frame: After the 3rd administration of fludrocortisone or placebo (12 hours)

Cardiac output

Time frame: After the 4th administration of fludrocortisone or placebo (18 hours)

Cardiac index

Time frame: Baseline, before the first administration of the experimental drug (fludrocortisone/placebo)

Cardiac index

Time frame: 1,5 hours after the second administration of fludrocortisone or placebo (7,5 hours)

Cardiac index

Time frame: After the 3rd administration of fludrocortisone or placebo (12 hours)

Cardiac index

Time frame: After the 4th administration of fludrocortisone or placebo (18 hours)

Indexed Systemic Vascular Resistances (ISVR)

Time frame: Baseline, before the first administration of the experimental drug (fludrocortisone/placebo)

Indexed Systemic Vascular Resistances (ISVR)

Time frame: 1,5 hours after the second administration of fludrocortisone or placebo (7,5 hours)

Indexed Systemic Vascular Resistances (ISVR)

Time frame: After the 3rd administration of fludrocortisone or placebo (12 hours)

Indexed Systemic Vascular Resistances (ISVR)

Time frame: After the 4th administration of fludrocortisone or placebo (18 hours)

Indexed Global Telediastolic Volume (IGVT)

Time frame: Baseline, before the first administration of the experimental drug (fludrocortisone/placebo)

Indexed Global Telediastolic Volume (IGVT)

Time frame: 1,5 hours after the second administration of fludrocortisone or placebo (7,5 hours)

Indexed Global Telediastolic Volume (IGVT)

Time frame: After the 3rd administration of fludrocortisone or placebo (12 hours)

Indexed Global Telediastolic Volume (IGVT)

Time frame: After the 4th administration of fludrocortisone or placebo (18 hours)

Ejection Volume Variability (EVV)

Time frame: Baseline, before the first administration of the experimental drug (fludrocortisone/placebo)

Ejection Volume Variability (EVV)

Time frame: 1,5 hours after the second administration of fludrocortisone or placebo (7,5 hours)

Ejection Volume Variability (EVV)

Time frame: After the 3rd administration of fludrocortisone or placebo (12 hours)

Ejection Volume Variability (EVV)

Time frame: After the 4th administration of fludrocortisone or placebo (18 hours)

Extravascular Pulmonary Water (EVW)

Time frame: Baseline, before the first administration of the experimental drug (fludrocortisone/placebo)

Extravascular Pulmonary Water (EVW)

Time frame: 1,5 hours after the second administration of fludrocortisone or placebo (7,5 hours)

Extravascular Pulmonary Water (EVW)

Time frame: After the 3rd administration of fludrocortisone or placebo (12 hours)

Extravascular Pulmonary Water (EVW)

Time frame: After the 4th administration of fludrocortisone or placebo (18 hours)

Mortality

Percentage of deceased patients

Time frame: Day 28

Mortality

Percentage of deceased patients

Time frame: Day 90

Length of stay in intensive care unit

Time frame: Day 90

Length of stay in care unit

Time frame: Day 90

Time to wean from catecholamines

Time frame: Day 90

Duration of mechanical ventilation (MV)

Time frame: Day 90

Inflammation markers

IFNγ, TNF α, IL1β, IL6, IL10 dosage

Time frame: Baseline, before the first administration of the experimental drug (fludrocortisone/placebo)

Inflammation markers

IFNγ, TNF α, IL1β, IL6, IL10 dosage

Time frame: 1,5 hours after the second administration of fludrocortisone or placebo (7,5 hours)

natremia dosage

blood sodium

Time frame: Baseline, before the first administration of the experimental drug (fludrocortisone/placebo)

natremia dosage

blood sodium

Time frame: 1,5 hours after the second administration of fludrocortisone or placebo (7,5 hours)

urinary sodium dosage

urinary sodium

Time frame: Baseline, before the first administration of the experimental drug (fludrocortisone/placebo)

urinary sodium dosage

urinary sodium

Time frame: 1,5 hours after the second administration of fludrocortisone or placebo (7,5 hours)

kalemia dosage

blood potassium

Time frame: Baseline, before the first administration of the experimental drug (fludrocortisone/placebo)

kalemia dosage

blood potassium

Time frame: 1,5 hours after the second administration of fludrocortisone or placebo (7,5 hours)

urinary potassium dosage

urinary potassium

Time frame: Baseline, before the first administration of the experimental drug (fludrocortisone/placebo)

urinary potassium dosage

urinary potassium

Time frame: 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.

Time frame: After 4th dose of fludrocortisone (18 hours)

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

Overview

Conditions

Interventions

Eligibility

Locations (1)

Outcomes

Primary Outcomes

Secondary Outcomes