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Fludrocortisone, in association with hydrocortisone, has demonstrated an improvement in survival in septic shock patients with relative adrenal insufficiency. However, the utility of low doses of steroids and in particular of mineralocorticoids in septic shock is still discussed.
The purpose of the investigators study is to investigate the effects of 3 increasing doses of fludrocortisone (100 μg, 200 μg, 400 μg) in order to determine which dose allows the best pressor response to phenylephrine in healthy volunteers, and simultaneously assess their respective hemodynamic and biological effects.
In a previous study (AFLUCO2) in healthy volunteers with saline-induced hypoaldosteronism, the investigators found that single doses of both hydrocortisone and fludrocortisone induced a significant decrease in the pressor response to phenylephrine, probably due to a rapid non-genomic vasodilatory mechanism, and that these effects were additive.
The investigators also showed that, at the doses used in septic shock, hydrocortisone induced more pronounced mineralocorticoid effects than fludrocortisone and also induced systemic hemodynamic effects whereas fludrocortisone did not.
The investigators now want to perform a dose-response study under normal conditions (ie without saline-induced hypoaldosteronism) and after repeated administrations, to determine the optimal dose of fludrocortisone that allows an increase in the pressor response to phenylephrine and to characterize its concomitant hemodynamic and biological effects.
This placebo-controlled, randomized, double-blind, cross-over, 4-periods (fludrocortisone 100 μg/day, 200 μg/day, 400 μg/day, or placebo) study aims to investigate hemodynamic and biological effects of fludrocortisone administered orally during 5 days, in healthy volunteers.
Each period will be separated from the next one by a washout interval of at least 14 days.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Fludrocortisone 100 μg | Experimental |
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| Fludrocortisone 200 μg | Experimental |
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| Fludrocortisone 400 μg | Experimental |
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| Placebo | Placebo Comparator |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Fludrocortisone 100 μg | Drug | Fludrocortisone 100 μg/day |
| |
| Measure | Description | Time Frame |
|---|---|---|
| Phenylephrine mean blood pressor dose-response relationship. | 1.5 hour after fludrocortisone administration |
| Measure | Description | Time Frame |
|---|---|---|
| Cardiac systolic and diastolic function assessed par transthoracic echocardiography during phenylephrine administration | between 1.5 and 2.5 hours after fludrocortisone administration | |
| Systemic hemodynamic parameters | Systolic, diastolic and mean arterial pressures, heart rate, peripheral pulse pressure, cardiac output, stroke volume, systemic vascular resistances |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Bruno Laviolle, MD | Centre d'Investigation Clinique Inserm 1414, Service de Pharmacologie Clinique, Hôpital de Pontchaillou | Principal Investigator |
| Eric Bellissant, MD, PHD | Centre d'Investigation Clinique Inserm 1414, Service de Pharmacologie Clinique, Hôpital de Pontchaillou | Study Chair |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Rennes University Hospital | Rennes | 35033 | France |
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| ID | Term |
|---|---|
| D005438 | Fludrocortisone |
| ID | Term |
|---|---|
| D006854 | Hydrocortisone |
| D011282 | Pregnenediones |
| D011283 | Pregnenes |
| D011278 | Pregnanes |
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| Fludrocortisone 200 μg |
| Drug |
Fludrocortisone 200 μg/day |
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| Fludrocortisone 400 μg | Drug | Fludrocortisone 400 μg/day |
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| Placebo | Drug |
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| 30min before and 1h, 2h, 3h, 4h, 5h, 6h after fludrocortisone administration |
| Arterial stiffness : carotid-femoral pulse wave velocity | 30min before and 1h, 2h, 3h, 4h, 5h, 6h after fludrocortisone administration |
| Central aortic hemodynamic parameters | Aortic systolic, diastolic and mean arterial pressures, central pulse pressure, central pressure augmentation index (AIx) | 30min before and 1h, 2h, 3h, 4h, 5h, 6h after fludrocortisone administration |
| Plasma parameters | Blood electrolytes, urea, creatinine, glucose, renin, aldosterone | 30min before and 1h, 2h, 3h, 4h, 5h, 6h after fludrocortisone administration |
| Urinary parameters | Diuresis, urinary electrolytes, urea, creatinine, glucose | 30min before and 2h, 4h, 6h after fludrocortisone administration |
| Area under the plasma concentration versus time curve (AUC) | Just before and 5min, 10min, 20min, 30min, 1h, 1h30, 2h, 3h, 4h, 5h, 6h after fludrocortisone administration |
| Plasma half-life of fludrocortisone | Just before and 5min, 10min, 20min, 30min, 1h, 1h30, 2h, 3h, 4h, 5h, 6h after fludrocortisone administration |
| Total Body Clearance | Just before and 5min, 10min, 20min, 30min, 1h, 1h30, 2h, 3h, 4h, 5h, 6h after fludrocortisone administration |
| Apparent volume of distribution | Just before and 5min, 10min, 20min, 30min, 1h, 1h30, 2h, 3h, 4h, 5h, 6h after fludrocortisone administration |
| D013256 |
| Steroids |
| D000072473 | Fused-Ring Compounds |
| D011083 | Polycyclic Compounds |