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

Phase 2

Suspended

• Conditions: Septic Shock
• Interventions: Drug: Placebo; Drug: Fludrocortisone

• Registration Number: NCT05001854
• Lead Sponsor: Rennes University Hospital

Brief 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.

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 Timeline

• Study First Submitted: 2021-07-08
• Study First Submitted QC: 2021-08-03
• Study First Posted: 2021-08-12
• Study Start: 2022-03-31
• Status Verified: 2023-11
• Last Update Submitted: 2023-11-15
• Last Update Posted: 2023-11-18
• Primary Completion: 2024-06
• Study Completion: 2024-12

Recruitment & Eligibility

• Status: SUSPENDED
• Sex: All
• Target Recruitment: 40

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.

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Exclusion Criteria

Not provided

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Control	Placebo	100 μg every 6 hours of placebo per os
Fludrocortisone	Fludrocortisone	100 μg every 6 hours of fludrocortisone per os A pharmacokinetic study is performed in this arm

Primary Outcome Measures

Name	Time	Method
Mean arterial blood pressure (mmHg)	1,5 hours after the second administration of fludrocortisone or placebo (7,5 hours)	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.

Secondary Outcome Measures

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

Trial Locations

Locations (1)

Rennes University Hospital - Intensive Care unit; 🇫🇷 Rennes, Bretagne, France