Fludrocortisone Dose Response Relationship in Septic Shock - FluDReSS

Last updated: January 17, 2024
Sponsor: The George Institute
Overall Status: Completed

Phase

2

Condition

Sepsis And Septicemia

Low Blood Pressure (Hypotension)

Treatment

Standard Therapy

Fludrocortisone Acetate

Clinical Study ID

NCT04494789
GI-CC35837377
  • Ages > 18
  • All Genders

Study Summary

The purpose of this study is to determine the most suitable dose of Fludrocortisone in reversal of sepsis and shock associated with sepsis in patients who are admitted to the ICU.

The investigators will be looking to see whether patients receiving Fludrocortisone at different doses recover quicker and spend less time in hospital and in ICU, and to understand the reasons why this happens at certain doses.

Sepsis is caused by toxic substances (toxins) from bacteria and other organism entering the bloodstream from a site of infection. In some people, the infection can progress to sepsis and septic shock where the functions of organs in the body are affected. Patients suffering from sepsis and septic shock are commonly managed in the intensive care unit (ICU) where they are prescribed antibiotics as standard therapy, as well as other therapies to support the functions of the body.

Fludrocortisone is a steroid that has previously shown to be beneficial to help in shock in patients in ICU, but more information is required about the exact dose that is required to achieve this. This has been shown by previous research.

However, the exact role of Fludrocortisone and the best dose has not been studied adequately to date as well as the ways in how it works within the body. The study aims to look tat the dose and the way it works.

Eligibility Criteria

Inclusion

Inclusion Criteria:

  1. Aged 18 years or older
  2. Documented site, or strong suspicion of infection with 2 of the 4 clinical signs ofinflammation:
  3. Core temperature > 38oC or < 35oC
  4. Heart rate > 90bpm
  5. Respiratory rate > 20bpm, or PaCO2 < 32mmHg, or mechanical ventilation
  6. White cell count > 12 x 109/L or < 4 x 109/L or > 10% immature neutrophils\
  7. Being treated with Hydrocortisone at a daily dose of 200mg / day as adjunctivetreatment for sepsis
  8. Being treated with mechanical ventilation at the time of randomisation (includes maskBiPAP/CPAP)
  9. Being treated with continuous vasopressors or inotropes to maintain a systolic bloodpressure > 90mmHg, or mean arterial pressure > 60mmHg or a MAP target set by thetreating clinician for maintaining perfusion
  10. Administration of vasopressors or inotropes for > 4 hours and present at time ofrandomisation

Exclusion

Exclusion Criteria:

  1. Met all inclusion criteria more than 24 hours ago
  2. Patients taking long term corticosteroids or fludrocortisone
  3. Patients with systemic fungal infection
  4. Death is deemed inevitable or imminent during this admission and either the attendingphysician, patient or surrogate legal decision maker is not committed to activetreatment
  5. Patient unable to receive enteral medication
  6. Death from underlying disease likely within 90 days
  7. Patient has been previously enrolled in the study

Study Design

Total Participants: 155
Treatment Group(s): 2
Primary Treatment: Standard Therapy
Phase: 2
Study Start date:
February 11, 2021
Estimated Completion Date:
June 30, 2023

Study Description

Aim:

  1. 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.

  2. 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,

  1. The addition of fludrocortisone to hydrocortisone results in improved vascular responsiveness to vasopressors as compared to hydrocortisone alone

  2. The improvement of vascular responsiveness with fludrocortisone is in a dose dependent manner

  3. Enterally administered fludrocortisone results in adequate plasma level

  4. 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

    1. concentrations at baseline and throughout the course of their illness

  5. 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.

  6. 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.

  7. 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

Connect with a study center

  • Bankstown Hospital

    Sydney, New South Wales
    Australia

    Site Not Available

  • Blacktown Hospital

    Sydney, New South Wales
    Australia

    Site Not Available

  • Royal North Shore Hospital

    Sydney, New South Wales
    Australia

    Site Not Available

  • Royal Brisbane Women's Hospital

    Brisbane, Queensland
    Australia

    Site Not Available

  • Wesley Hospital

    Brisbane, Queensland
    Australia

    Site Not Available

  • Gold Coast University Hospital

    Gold Coast, Queensland
    Australia

    Site Not Available

  • Mater Misericordiae

    Raymond Terrace, Queensland 4101
    Australia

    Site Not Available

  • Princess Alexandra Hospiital

    Woolloongabba, Queensland 4102
    Australia

    Site Not Available

  • Queen Elizabeth II Hospital

    Adelaide, South Australia
    Australia

    Site Not Available

  • Austin Hospital

    Melbourne, Victoria
    Australia

    Site Not Available

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