Fludrocortisone Dose Response Relationship in Septic Shock - FluDReSS

Aim:

• To conduct a multi-centre randomised controlled trial to assess the effect of 3 different dose regimens of fludrocortisone on shock reversal in septic shock patients treated with hydrocortisone.
• To assess the temporal changes in endocrine inflammatory and gene expression markers in septic shock patients.

Hypotheses:

In patients with septic shock treated with hydrocortisone,

• The addition of fludrocortisone to hydrocortisone results in improved vascular responsiveness to vasopressors as compared to hydrocortisone alone
• The improvement of vascular responsiveness with fludrocortisone is in a dose dependent manner
• Enterally administered fludrocortisone results in adequate plasma level
• Patients who have early reversal of shock have higher concentrations of, angiotensin II and angiotensin II-receptor expression and reduced angiotensin converting enzyme 2 (ACE 2) concentrations at baseline and throughout the course of their illness
• Patients who have early reversal of shock have higher concentrations of plasma free cortisol, aldosterone and glucocorticoid and mineralocorticoid receptor expression at baseline and throughout the course of their illness.
• Patients who demonstrate evidence of both greater angiotensin II and glucocorticoid receptor expression will have earlier shock reversal than those who have an increase in expression of either of these receptors.
• There is a different temporal change in the plasma concentrations and receptor expression profiles in early shock reversal patients vs. delayed shock reversal patients.

300 patients will be recruited and randomised to enteral doses of 50mcg fludrocortisone Q24H, Q12H, Q6H or to the control arm of the study. The study will enrol patients admitted to a participating intensive care unit and who meet all the inclusion criteria and no exclusion criteria. Patients in a fludrocortisone arm will receive enteral fludrocortisone for a maximum of 7 days or until sustained shock reversal or until discharge from ICU whichever is earlier.

Blood samples acquired will be analysed for:

• Endocrine - Cortisol, free cortisol, aldosterone and metabolites
• Inflammatory - Cytokine profiles, markers of vasoplegia
• Gene Expression - Whole genome RNA sequencing and single cell sequencing
• To assess the plasma levels following enteral administration of fludrocortisone in all patients enrolled to undertake detailed analysis of fludrocortisone kinetics in a subgroup of 30 patients enrolled (10 patients in each dosing group).

For all patients, data will be collected at baseline and daily whilst in the ICU for up to 8 days. Patients will be followed up to time of discharge from hospital or day 28 if they are still in hospital, whichever occurs first

Inclusion criteria

• Aged 18 years or older
• Documented site, or strong suspicion of infection with 2 of the 4 clinical signs of inflammation:

• Core temperature > 38oC or < 35oC
• Heart rate > 90bpm
• Respiratory rate > 20bpm, or PaCO2 < 32mmHg, or mechanical ventilation
• White cell count > 12 x 109/L or < 4 x 109/L or > 10% immature neutrophils\\
• Being treated with Hydrocortisone at a daily dose of 200mg / day as adjunctive treatment for sepsis
• Being treated with mechanical ventilation at the time of randomisation (includes mask BiPAP/CPAP)
• Being treated with continuous vasopressors or inotropes to maintain a systolic blood pressure > 90mmHg, or mean arterial pressure > 60mmHg or a MAP target set by the treating clinician for maintaining perfusion
• Administration of vasopressors or inotropes for > 4 hours and present at time of randomisation

Exclusion criteria

• Met all inclusion criteria more than 24 hours ago
• Patients taking long term corticosteroids or fludrocortisone
• Patients with systemic fungal infection
• Death is deemed inevitable or imminent during this admission and either the attending physician, patient or surrogate legal decision maker is not committed to active treatment
• Patient unable to receive enteral medication
• Death from underlying disease likely within 90 days
• Patient has been previously enrolled in the study