Clinical trial NCT05001854: Hemodynamics Effects of Fludrocortisone on the Pressor Response to Noradrenaline Septic Shock Patients
Official title: Evaluation of the Hemodynamics Effects of Fludrocortisone on the Pressor Response to Noradrenaline in Septic Shock Patients
Study type: INTERVENTIONAL
Overall status: SUSPENDED
Phase: PHASE2
PHASE3
Conditions: Septic Shock
Lead sponsor: Rennes University Hospital
Sponsor class: OTHER
Collaborators: name: H.A.C. PHARMA
First posted: 2021-08-12
Enrollment: 40
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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

Eligibility criteria: 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.

Primary outcomes:
measure: Mean arterial blood pressure (mmHg)
timeFrame: 1,5 hours after the second administration of fludrocortisone or placebo (7,5 hours)
Secondary outcomes:
measure: Heart rate
timeFrame: Baseline, before the first administration of the drug (fludrocortisone/placebo)
measure: Heart rate
timeFrame: 1,5 hours after the second administration of fludrocortisone or placebo (7,5 hours)
measure: Heart rate
timeFrame: After the 3rd administration of fludrocortisone or placebo (12 hours)
measure: Heart rate
timeFrame: After the 4th administration of fludrocortisone or placebo (18 hours)
measure: arterial pressure
timeFrame: Baseline, before the first administration of the experimental drug (fludrocortisone/placebo)
measure: arterial pressure
timeFrame: 1,5 hours after the second administration of fludrocortisone or placebo (7,5 hours)
measure: arterial pressure
timeFrame: After the 3rd administration of fludrocortisone or placebo (12 hours)
measure: arterial pressure
timeFrame: After the 4th administration of fludrocortisone or placebo (18 hours)
measure: Cardiac output
timeFrame: Baseline, before the first administration of the experimental drug (fludrocortisone/placebo)
measure: Cardiac output
timeFrame: 1,5 hours after the second administration of fludrocortisone or placebo (7,5 hours)
measure: Cardiac output
timeFrame: After the 3rd administration of fludrocortisone or placebo (12 hours)
measure: Cardiac output
timeFrame: After the 4th administration of fludrocortisone or placebo (18 hours)
measure: Cardiac index
timeFrame: Baseline, before the first administration of the experimental drug (fludrocortisone/placebo)
measure: Cardiac index
timeFrame: 1,5 hours after the second administration of fludrocortisone or placebo (7,5 hours)
measure: Cardiac index
timeFrame: After the 3rd administration of fludrocortisone or placebo (12 hours)
measure: Cardiac index
timeFrame: After the 4th administration of fludrocortisone or placebo (18 hours)
measure: Indexed Systemic Vascular Resistances (ISVR)
timeFrame: Baseline, before the first administration of the experimental drug (fludrocortisone/placebo)
measure: Indexed Systemic Vascular Resistances (ISVR)
timeFrame: 1,5 hours after the second administration of fludrocortisone or placebo (7,5 hours)
measure: Indexed Systemic Vascular Resistances (ISVR)
timeFrame: After the 3rd administration of fludrocortisone or placebo (12 hours)
measure: Indexed Systemic Vascular Resistances (ISVR)
timeFrame: After the 4th administration of fludrocortisone or placebo (18 hours)
measure: Indexed Global Telediastolic Volume (IGVT)
timeFrame: Baseline, before the first administration of the experimental drug (fludrocortisone/placebo)
measure: Indexed Global Telediastolic Volume (IGVT)
timeFrame: 1,5 hours after the second administration of fludrocortisone or placebo (7,5 hours)
measure: Indexed Global Telediastolic Volume (IGVT)
timeFrame: After the 3rd administration of fludrocortisone or placebo (12 hours)
measure: Indexed Global Telediastolic Volume (IGVT)
timeFrame: After the 4th administration of fludrocortisone or placebo (18 hours)
measure: Ejection Volume Variability (EVV)
timeFrame: Baseline, before the first administration of the experimental drug (fludrocortisone/placebo)
measure: Ejection Volume Variability (EVV)
timeFrame: 1,5 hours after the second administration of fludrocortisone or placebo (7,5 hours)
measure: Ejection Volume Variability (EVV)
timeFrame: After the 3rd administration of fludrocortisone or placebo (12 hours)
measure: Ejection Volume Variability (EVV)
timeFrame: After the 4th administration of fludrocortisone or placebo (18 hours)
measure: Extravascular Pulmonary Water (EVW)
timeFrame: Baseline, before the first administration of the experimental drug (fludrocortisone/placebo)
measure: Extravascular Pulmonary Water (EVW)
timeFrame: 1,5 hours after the second administration of fludrocortisone or placebo (7,5 hours)
measure: Extravascular Pulmonary Water (EVW)
timeFrame: After the 3rd administration of fludrocortisone or placebo (12 hours)
measure: Extravascular Pulmonary Water (EVW)
timeFrame: After the 4th administration of fludrocortisone or placebo (18 hours)
measure: Mortality
timeFrame: Day 28
measure: Mortality
timeFrame: Day 90
measure: Length of stay in intensive care unit
timeFrame: Day 90
measure: Length of stay in care unit
timeFrame: Day 90
measure: Time to wean from catecholamines
timeFrame: Day 90
measure: Duration of mechanical ventilation (MV)
timeFrame: Day 90
measure: Inflammation markers
timeFrame: Baseline, before the first administration of the experimental drug (fludrocortisone/placebo)
measure: Inflammation markers
timeFrame: 1,5 hours after the second administration of fludrocortisone or placebo (7,5 hours)
measure: natremia dosage
timeFrame: Baseline, before the first administration of the experimental drug (fludrocortisone/placebo)
measure: natremia dosage
timeFrame: 1,5 hours after the second administration of fludrocortisone or placebo (7,5 hours)
measure: urinary sodium dosage
timeFrame: Baseline, before the first administration of the experimental drug (fludrocortisone/placebo)
measure: urinary sodium dosage
timeFrame: 1,5 hours after the second administration of fludrocortisone or placebo (7,5 hours)
measure: kalemia dosage
timeFrame: Baseline, before the first administration of the experimental drug (fludrocortisone/placebo)
measure: kalemia dosage
timeFrame: 1,5 hours after the second administration of fludrocortisone or placebo (7,5 hours)
measure: urinary potassium dosage
timeFrame: Baseline, before the first administration of the experimental drug (fludrocortisone/placebo)
measure: urinary potassium dosage
timeFrame: 1,5 hours after the second administration of fludrocortisone or placebo (7,5 hours)
measure: pharmacokinetics of fludrocortisone : Area under the plasma concentration-time curve (plasma concentrations of fludrocortisone at 5 times)
timeFrame: After 4th dose of fludrocortisone (18 hours)
Other outcomes:
measure: Dose-response relationship
timeFrame: 1,5 hours after the second administration of fludrocortisone or placebo (7,5 hours)
Locations:
city: Rennes
country: France
facility: Rennes University Hospital - Intensive Care unit
state: Bretagne
Study officials:
affiliation: Rennes University Hospital
name: Bruno Laviolle, MD, PhD
role: STUDY_CHAIR
affiliation: Rennes University Hospital
name: Harmonie Perrichet, MD
role: PRINCIPAL_INVESTIGATOR
References: