Combination of Hydrocortisone and Fludrocortisone in the Treatment of Septic Shock


Septic shock is a severe form of sepsis, where the body’s response to infection results in systemic inflammation, hypotension, and organ dysfunction.

Despite advances in critical care, septic shock remains a major cause of morbidity and mortality worldwide. Current treatment guidelines emphasize early identification, infection source control, and appropriate antibiotic therapy. However, the role of corticosteroids in septic shock management remains controversial.

Mechanism of Action: Hydrocortisone and fludrocortisone are synthetic corticosteroids that mimic the effects of endogenous cortisol and aldosterone, respectively. Hydroortisone exerts its effects by reducing inflammation stabilizing cell membranes, and modulating the immune response.

Fludrocortisone, a mineralocorticoid, promotes sodium retention and increases blood pressure by enhancing the effects of angiotensin II on blood vessels. combination of these two drugs may provide a synergistic effect, targeting both inflammation and hemodynamic instability in septic shock patients.

Clinical Trials: The HYPRESS trial (2016) investigated the use of hydrocortisone alone in septic shock patients, showing no significant difference in mortality rates compared to placebo. However, the ADRENAL trial (2018) and the APROCCHSS trial (2018) evaluated the combination of hydrocortisone and fludrocortisone.

The ADRENAL trial did not show a significant reduction in 90-day mortality but reported a faster resolution of shock and reduced need for blood pressure support. The APROCCHSS trial demonstrated a significant reduction in mortality rates and faster shock reversal using the combination therapy.

Benefits and Drawbacks: The combination of hydrocortisone and fludrocortisone may provide benefits in septic shock treatment by reducing inflammation, improving hemodynamics, and hastening shock reversal. However, potential drawbacks include increased risk of hyperglycemia, secondary infections, and gastrointestinal bleeding. The optimal dosing, duration, and patient selection for this therapy remain areas of ongoing research.

A new research put in evidence that in multicenter cohort study among 88 275 patients with septic shock receiving norepinephrine who initiated hydrocortisone treatment, the addition of fludrocortisone to hydrocortisone was associated with a 3.7% lower adjusted absolute risk difference in the primary composite outcome of mortality or discharge to hospice compared with initiation of hydrocortisone alone.

Results  Analyses included 88 275 patients, 2280 who began treatment with hydrocortisone-fludrocortisone (median [IQR] age, 64 [54-73] years; 1041 female; 1239 male) and 85 995 (median [IQR] age, 67 [57-76] years; 42 136 female; 43 859 male) who began treatment with hydrocortisone alone. The primary composite outcome of death in hospital or discharge to hospice occurred among 1076 (47.2%) patients treated with hydrocortisone-fludrocortisone vs 43 669 (50.8%) treated with hydrocortisone alone (adjusted absolute risk difference, −3.7%; 95% CI, −4.2% to −3.1%; P < .001).

Meaning  Among patients with septic shock receiving norepinephrine who initiated hydrocortisone treatment, the addition of fludrocortisone was associated with lower rates of the composite of death or discharge to hospice compared with hydrocortisone alone.


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