Critical Illness Related Corticosteroids Insufficiency
Conditions
Keywords
critical illness related corticosteroids insufficiency, hydrocortisone, fludrocortisone, ICU, survival
Brief summary
The study aims at assessing the efficacy and the safety of hydrocortisone combined with fludrocortisone compared to placebo in ICU adults with critical illness related corticosteroid insufficiency.
Detailed description
The hypothalamic-pituitary-adrenal axis together with the noradrenergic/vasopressinergic system are the main systems of host response to stress. In 2008 the scientific community described a syndrome called critical illness related corticosteroids insufficiency (CIRCI) in which body homeostasis is lost owing to insufficient cortisol production or bioactivity in tissues. Recent updates of international guidelines have spelled out the pathophysiology, diagnosis and management of CIRCI. The prevalence of CIRCI varies according to case mix and severity of illness. The combination of hydrocortisone and fludrocortisone improved outcomes in septic shock, a condition often complicated with CIRCI. However, there is insufficient evidence on the efficacy of corticosteroids in patients with CIRCI and without septic shock. The hypothesis of the study is that the hydrocortisone-fludrocortisone association will improve ventilation and vasopressor free survival in ICU patients with Critical illness related Corticosteroid Insufficiency. Patients with a SOFA score ≥ 4 will be screened for CIRCI. Patients suffering from CIRCI will be randomized to receive hydrocortisone and fludrocortisone or their placebo. Patients without CIRCI will receive standard of care and will be followed up during 90 days (cohort-observational study).
Interventions
DRUGInvestigational products administration
Investigational products include: * Hydrocortisone hemisuccinate 50 mg: one intravenous injection every 6 hours, and * 9 alpha fludrocortisone 50 μg: one tablet per day via a nasogastric tube. All treatments will be stopped after 7 days or until the patient has left the intensive care unit (whichever occurs first) without tapering off.
DRUGPlacebo administration
Placebos for hydrocortisone and for fludrocortisone, administered in same manner as the active drugs in the interventional arm, for 7 days.
Sponsors
Assistance Publique - Hôpitaux de Paris
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
* Adult (≥ 18 years); * Hospitalized in an intensive care unit; * SOFA score ≥ 4, for at least 6 consecutive hours; * Informed written consent from patient or from legally authorized next of kin, or emergency deferred consent; * Affiliation to a social security system or to a universal health coverage (Couverture Maladie Universelle, CMU).
Exclusion criteria
* Any suspected or proven acute adrenal insufficiency (As defined in international guidelines; basal cortisol \< 5 μg/dL or peak (60) cortisol \<18 μg/dL) * Expected death or withdrawal of life-sustaining treatments within 48 hours * Known chronic adrenal insufficiency * Concomitant treatment that inhibits cortisol production * Septic shock (Singer Jama 2016) * Active tuberculosis or fungal infection * Active viral hepatitis or active infection with herpes viruses * Hypersensitivity or contraindication to hydrocortisone, fludrocortisone or Synacthène® or any of their excipients ( SmPC) * Patient needing either anti-inflammatory corticosteroids or substitutive hydrocortisone for any reason (Such as those suffering from COVID-19 pneumonia requiring oxygen therapy). * Current treatment by more than 15 mg/d of prednisone (or equivalent) for more than 30 days * Diabetic ketoacidosis or hyperglycemic hyperosmolar syndrome * Pregnant or breastfeeding woman * Moribund patient * Previously enrolled in this study * Participation to another interventional study that focuses on CIRCI and/or corticoid drugs and/or that addresses a similar primary endpoint as Hornbill ( ventilator- and vasopressor-free survival ) * Patient under guardianship or tutorship Note: Included patients for whom acute adrenal insufficiency would be detected in the Synacthen ® test performed as part of the research for the diagnosis of CIRCI will not be randomized since they should be treated by corticosteroids.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| number of ventilator- and vasopressor-free days | at day 30 | number of ventilator- and vasopressor-free days within 30 days (deaths assigned zero days) after randomisation. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of days alive without vasopressors | at day 30 | Number of days alive without vasopressors on day 30 after randomization. |
| Number of days alive free of mechanical ventilation | at day 30 | Number of days alive free of mechanical ventilation on day 30 after randomization. |
| Number of days alive with SOFA < 4 | daily un to 30 days | Number of days alive with SOFA \< 4 in the 30 days after randomization |
| Withhold and/or withdraw proportion | up to 3 months | Proportion of patients with a decision to withhold and/or withdraw active treatments. |
| ICU duration | up to 3 months | Duration of stay (unit: day and minutes) at ICU. |
| duration of hospitalization of stay | daily up to 30 days | Duration of hospitalization of stay. |
| Rate of re-admission to the ICU | daily up to 30 days | Rate of re-admission to the ICU during the 30 days after randomization. |
| Safety endpoints - serious adverse events associated with corticosteroids | daily up to 30 days | \- Proportion of patients affected by any serious adverse events associated with corticosteroids, among the following: hospital-acquired infections, hyperglycemia, hypernatremia, neurological disorders (coma, stroke or muscle weakness) during the 30 days after randomization. |
| Safety endpoints - hospital-acquired infections proportion | daily up to 30 days | \- Proportion of patients affected by hospital-acquired infections; |
| Mortality rates | at day 30, 90 and 180 | Mortality rates at ICU and hospital discharge and at day 30, 90 and 180 after randomization |
| Safety endpoints - hypernatremia | daily up to 30 days | \- Number of episodes of hypernatremia during ICU stay or up to day 30, whichever occurs first; |
| Safety endpoints - Gastroduodenal bleeding | daily up to 30 days | \- Gastroduodenal bleeding requiring transfusion or hemostatic treatment during ICU stay or up to day 30, whichever occurs first; |
| Safety endpoints - corticosteroids administration requiring | daily up to 30 days | \- Number of patients requiring the administration corticosteroids following the end of the administration of the experimental treatment. |
| Rate of ventilation and vasopressors free survival at day 90 | at day 90 | Secondary endpoint concerning screened but non-randomised patients: Rate of ventilation and vasopressors free survival at day 90 in subjects devoid of CIRCI |
| Renal replacement therapy (RRT)-free days | up to day 30 | Renal replacement therapy (RRT)-free days up to Day 30 after randomisation (excluding patients on RRT for chronic renal failure at time of randomisation) |
| response to glucocorticoids | up to 3 months | Score of cutaneous vasoconstrictor response to glucocorticoids |
| Change in quality of life | up to Day 30 and 90 | Change in utility, based on the EuroQol group's 5-dimension 5-level (EQ-5D-5L) questionnaire, up to Day 30 and 90 after randomisation |
| Rate of ventilation | at day 30 | Endpoint concerning non-randomised patients: Rate of ventilation at day 30 post SYNACTHENE® test |
| Vasopressors free days | at day 30 | Endpoint concerning non-randomised patients: Vasopressors free days at day 30 post SYNACTHENE® test |
| Safety endpoints - hyperglycemia | daily up to 30 days | \- Number of episodes of hyperglycemia during ICU stay or up to day 30, whichever occurs first; |
Countries
France
Contacts
Primary ContactNicholas HEMING, MD, PhD
Backup ContactDjillali ANNANE, MD, PhD
Outcome results
None listed