Clinical Trial

. 2024 Dec;50(12):2050-2060.

doi: 10.1007/s00134-024-07616-z. Epub 2024 Sep 5.

Fludrocortisone dose-response relationship in septic shock: a randomised phase II trial

James Walsham^{1

2}, Naomi Hammond^{3

4

5}, Antje Blumenthal², Jeremy Cohen^{2

6

7}, John Myburgh^{3

5

8}, Simon Finfer^{3

5

9}, David Evans², Sandra Peake^{10

11}, Peter Kruger^{1

2}, James McCullough¹², Loki Johnk¹³, Dhaval Ghelani^{14

15

16}, Laurent Billot^{3

5}, Sana Shan³, Jason Meyer¹, Dorrilyn Rajbhandari³, Carolyn Koch³, Rinaldo Bellomo^{17

18

19}, Louise M Burrell^{17

19}, Morag Young^{19

20}, Michael Roberts²¹, Lorraine Mackenzie^{21

22}, Gregory Medley², Joshua Dalton^{21

22}, Balasubramanian Venkatesh^{23

24

25}

Affiliations

¹ Princess Alexandra Hospital, Brisbane, Australia.
² University of Queensland, Brisbane, Australia.
³ The George Institute for Global Health, Sydney, Australia.
⁴ Royal North Shore Hospital, Sydney, Australia.
⁵ University of New South Wales, Sydney, Australia.
⁶ The Wesley Hospital, Brisbane, Australia.
⁷ Royal Brisbane Hospital, Brisbane, Australia.
⁸ St. George Hospital, Sydney, Australia.
⁹ School of Public Health, Faculty of Medicine, Imperial College London, London, UK.
¹⁰ The Queen Elizabeth Hospital, Adelaide, SA, Australia.
¹¹ University of Adelaide, Adelaide, Australia.
¹² Gold Coast University Hospital, Gold Coast, QLD, Australia.
¹³ Mater Hospital, Brisbane, Australia.
¹⁴ Blacktown Hospital, Sydney, Australia.
¹⁵ University of Sydney, Sydney, Australia.
¹⁶ Western Sydney University, Sydney, Australia.
¹⁷ Austin Hospital, Melbourne, Australia.
¹⁸ Australia and New Zealand Research Centre, Melbourne, Australia.
¹⁹ Department of Medicine, University of Melbourne, Austin Health, Australia.
²⁰ Baker Heart and Diabetes Institute, Melbourne, Australia.
²¹ Therapeutics Research Centre, Basil Hetzel Institute for Translational Health Research, The Queen Elizabeth Hospital, Adelaide, Australia.
²² University of South Australia, Adelaide, Australia.
²³ The George Institute for Global Health, Sydney, Australia. bvenkatesh@georgeinstitute.org.au.
²⁴ University of New South Wales, Sydney, Australia. bvenkatesh@georgeinstitute.org.au.
²⁵ Gold Coast University Hospital, Gold Coast, QLD, Australia. bvenkatesh@georgeinstitute.org.au.

PMID: 39235623
PMCID: PMC11588801
DOI: 10.1007/s00134-024-07616-z

Clinical Trial

Fludrocortisone dose-response relationship in septic shock: a randomised phase II trial

James Walsham et al. Intensive Care Med. 2024 Dec.

. 2024 Dec;50(12):2050-2060.

doi: 10.1007/s00134-024-07616-z. Epub 2024 Sep 5.

Authors

Affiliations

¹ Princess Alexandra Hospital, Brisbane, Australia.
² University of Queensland, Brisbane, Australia.
³ The George Institute for Global Health, Sydney, Australia.
⁴ Royal North Shore Hospital, Sydney, Australia.
⁵ University of New South Wales, Sydney, Australia.
⁶ The Wesley Hospital, Brisbane, Australia.
⁷ Royal Brisbane Hospital, Brisbane, Australia.
⁸ St. George Hospital, Sydney, Australia.
⁹ School of Public Health, Faculty of Medicine, Imperial College London, London, UK.
¹⁰ The Queen Elizabeth Hospital, Adelaide, SA, Australia.
¹¹ University of Adelaide, Adelaide, Australia.
¹² Gold Coast University Hospital, Gold Coast, QLD, Australia.
¹³ Mater Hospital, Brisbane, Australia.
¹⁴ Blacktown Hospital, Sydney, Australia.
¹⁵ University of Sydney, Sydney, Australia.
¹⁶ Western Sydney University, Sydney, Australia.
¹⁷ Austin Hospital, Melbourne, Australia.
¹⁸ Australia and New Zealand Research Centre, Melbourne, Australia.
¹⁹ Department of Medicine, University of Melbourne, Austin Health, Australia.
²⁰ Baker Heart and Diabetes Institute, Melbourne, Australia.
²¹ Therapeutics Research Centre, Basil Hetzel Institute for Translational Health Research, The Queen Elizabeth Hospital, Adelaide, Australia.
²² University of South Australia, Adelaide, Australia.
²³ The George Institute for Global Health, Sydney, Australia. bvenkatesh@georgeinstitute.org.au.
²⁴ University of New South Wales, Sydney, Australia. bvenkatesh@georgeinstitute.org.au.
²⁵ Gold Coast University Hospital, Gold Coast, QLD, Australia. bvenkatesh@georgeinstitute.org.au.

PMID: 39235623
PMCID: PMC11588801
DOI: 10.1007/s00134-024-07616-z

Abstract

Background: The combination of intravenous hydrocortisone and enteral fludrocortisone may reduce mortality in patients with septic shock. The optimal dose and reliability of absorption of fludrocortisone in critically ill patients are unclear.

Methods: In a multi-centre, open label, phase II randomized clinical trial, intravenous hydrocortisone alone or in combination with one of three doses of enteral fludrocortisone (50 µg, 100 µg or 200 µg daily) for 7 days was compared in patients with septic shock. The primary outcome was time to shock resolution. We conducted pharmacokinetic studies to assess absorption.

Results: Out of 153 enrolled patients, 38 (25%) received hydrocortisone alone, 42 (27%) received additional 50 µg, 36 (24%) received 100 µg and 37 (24%) received 200 µg fludrocortisone. Plasma concentrations of fludrocortisone were detected in 97% of patients at 3 h-median (interquartile range [IQR]) 261 (156-334) ng/L. There was no significant difference in the time to shock resolution between groups with median (IQR) of 3 (2.5-4.5), 3 (2-4), 3 (2-6) and 3 (2-5.5) days in the hydrocortisone alone, 50 µg, 100 µg and 200 µg fludrocortisone groups, respectively. The corresponding 28-day mortality rates were 9/38 (24%), 7/42 (17%), 4/36 (11%) and 4/37 (11%), respectively. There were no significant differences between groups with respect to, recurrence of shock, indices of organ failure or other secondary outcomes.

Conclusions: Enteral fludrocortisone resulted in detectable plasma fludrocortisone concentrations in the majority of critically ill patients with septic shock, although they varied widely indicating differing absorption and bioavailability. Its addition to hydrocortisone was not associated with shorter time to shock resolution.

Keywords: Fludrocortisone; Hydrocortisone; Pharmacokinetics; Septic shock.

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Conflict of interest statement

Declarations. Conflicts of interest: BV, JM, NH and SF are supported by a Leadership Fellowship and AB from an Ideas Grant from the National Health and Medical Research Council of Australia. BV and NH receive institutional research support from Baxter for the conduct of a clinical trial in patients with diabetic ketoacidosis. AB is supported by an Australian Research Council Future Fellowship and grants from the Translational Research Institute, Australian Infectious diseases Research Centre and Metro South health. JD, MR and LM are supported by a grant from the Hospital Research Foundation. MY is supported by a grant from the Baker Foundation and the Australian Research Council. SF has received consulting fees from RevImmune Inc and is Director of Sepsis Australia (honorary) and Asia Pacific Sepsis Alliance (honorary). All other others do not report any conflict of interest.

Figures

**Fig. 1**
Cumulative incidence plot of shock resolution for groups according to dose of fludrocortisone received. The dotted line represents no fludrocortisone group, the dotted and interrupted lines—50 mcg group, the interrupted lines 100 mcg group and the continuous line 200 mcg group

**Fig. 2**
Visual depiction of FC plasma levels at pre-dosing (0 h) (closed symbol) and 3 h (open symbol) after FC dosing for the FC dosing regimens populations for 50 (), 100 () and 200 () mcg. Also shown are the 3 h values for each dosing regimen after adjusting for elimination of their pre-dose over the 3 h dosing interval (), along with the median ± IQR for each group. No significant difference between the adjusted values was found with a Kruskal–Wallis test (p > 0.05)

formula image — **Fig. 2**
Visual depiction of FC plasma levels at pre-dosing (0 h) (closed symbol) and 3 h (open symbol) after FC dosing for the FC dosing regimens populations for 50 (), 100 () and 200 () mcg. Also shown are the 3 h values for each dosing regimen after adjusting for elimination of their pre-dose over the 3 h dosing interval (), along with the median ± IQR for each group. No significant difference between the adjusted values was found with a Kruskal–Wallis test (p > 0.05)

See this image and copyright information in PMC

References

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Fludrocortisone dose-response relationship in septic shock: a randomised phase II trial

Affiliations

Fludrocortisone dose-response relationship in septic shock: a randomised phase II trial

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Research Materials

Miscellaneous