• Gladness D Nethathe, Jeffrey Lipman, Ronald Anderson, Peter J Fuller, and Charles Feldman.
• School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa; Department of Anaesthesia and Perioperative Medicine, Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia; Academy of Critical Care, Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia. Electronic address: gladness.nethathe@wits.ac.za.
• Br J Anaesth. 2024 Jan 1; 132 (1): 536553-65.

AbstractTwo randomised controlled trials have reported a reduction in mortality when adjunctive hydrocortisone is administered in combination with fludrocortisone compared with placebo in septic shock. A third trial did not support this finding when hydrocortisone administered in combination with fludrocortisone was compared with hydrocortisone alone. The underlying mechanisms for this mortality benefit remain poorly understood. We review the clinical implications and potential mechanisms derived from laboratory and clinical data underlying the beneficial role of adjunctive fludrocortisone with hydrocortisone supplementation in septic shock. Factors including distinct biological effects of glucocorticoids and mineralocorticoids, tissue-specific and mineralocorticoid receptor-independent effects of mineralocorticoids, and differences in downstream signalling pathways between mineralocorticoid and glucocorticoid binding at the mineralocorticoid receptor could contribute to this interaction. Furthermore, pharmacokinetic and pharmacodynamic disparities exist between aldosterone and its synthetic counterpart fludrocortisone, potentially influencing their effects. Pending publication of well-designed, randomised controlled trials, a molecular perspective offers valuable insights and guidance to help inform clinical strategies.Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.

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