Septic Shock
Conditions
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
Interventions
DRUGFludrocortisone
100 μg every 6 hours of fludrocortisone per os
DRUGPlacebo
100 μg every 6 hours of placebo per os
Sponsors
H.A.C. PHARMA
Rennes University Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| Heart rate | Baseline, before the first administration of the drug (fludrocortisone/placebo) | Heart rate |
| arterial pressure | Baseline, before the first administration of the experimental drug (fludrocortisone/placebo) | Mean arterial pressure, systolic arterial pressure, diasystolic arterial pressure |
| Cardiac output | Baseline, before the first administration of the experimental drug (fludrocortisone/placebo) | Cardiac output |
| Cardiac index | Baseline, before the first administration of the experimental drug (fludrocortisone/placebo) | Cardiac index |
| Indexed Systemic Vascular Resistances (ISVR) | Baseline, before the first administration of the experimental drug (fludrocortisone/placebo) | Indexed Systemic Vascular Resistances (ISVR) |
| Indexed Global Telediastolic Volume (IGVT) | Baseline, before the first administration of the experimental drug (fludrocortisone/placebo) | Indexed Global Telediastolic Volume (IGVT) |
| Ejection Volume Variability (EVV) | Baseline, before the first administration of the experimental drug (fludrocortisone/placebo) | Ejection Volume Variability (EVV) |
| Extravascular Pulmonary Water (EVW) | Baseline, before the first administration of the experimental drug (fludrocortisone/placebo) | Extravascular Pulmonary Water (EVW) |
| Mortality | Day 28 | Percentage of deceased patients |
| 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) |
| Inflammation markers | Baseline, before the first administration of the experimental drug (fludrocortisone/placebo) | IFNγ, TNF α, IL1β, IL6, IL10 dosage |
| natremia dosage | Baseline, before the first administration of the experimental drug (fludrocortisone/placebo) | blood sodium |
| urinary sodium dosage | Baseline, before the first administration of the experimental drug (fludrocortisone/placebo) | urinary sodium |
| kalemia dosage | Baseline, before the first administration of the experimental drug (fludrocortisone/placebo) | blood potassium |
| urinary potassium dosage | Baseline, before the first administration of the experimental drug (fludrocortisone/placebo) | urinary potassium |
| 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 |
Other
| Measure | Time frame | Description |
|---|---|---|
| Dose-response relationship | 1,5 hours after the second administration of fludrocortisone or placebo (7,5 hours) | 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. |
Countries
France
Outcome results
None listed