Corticosteroids in Septic Shock: Current Evidence, Controversies, and Clinical Implications

Background: Septic shock is the most severe cardiovascular manifestation of sepsis and remains associated with substantial morbidity and mortality despite advances in antimicrobial therapy, hemodynamic resuscitation, organ support, and critical care. Corticosteroids have been investigated for decades as adjunctive therapy because of their potential to modulate the dysregulated inflammatory response, restore vascular responsiveness to catecholamines, and compensate for abnormalities of the hypothalamic-pituitary-adrenal axis occurring during critical illness. Nevertheless, uncertainty remains regarding their effect on mortality, the optimal corticosteroid regimen, the role of mineralocorticoid supplementation, and the ideal timing of treatment. Objective: To critically review the current evidence regarding the use of corticosteroids in adult patients with septic shock, with particular emphasis on physiological mechanisms, clinical outcomes, corticosteroid selection and dosing, the role of fludrocortisone, adverse effects, timing of initiation, and current guideline recommendations. Methods: An updated structured literature review was performed based on the original review and supplemented with contemporary evidence through 2026. PubMed/MEDLINE-indexed randomized controlled trials, systematic reviews, meta analyses, clinical practice guidelines, and major contemporary reviews were considered. Particular emphasis was placed on Sepsis-3 definitions, the ADRENAL and APROCCHSS randomized trials, patient level meta analyses, dose-response analyses, and the 2024 Society of Critical Care Medicine focused guideline update. Results: Current evidence supports the use of intravenous corticosteroids in adults with septic shock who continue to require vasopressor therapy despite adequate initial resuscitation. Hydrocortisone at approximately 200 mg/day remains the most widely supported regimen. Corticosteroids consistently accelerate shock reversal and reduce vasopressor exposure, whereas their effect on mortality is less consistent. ADRENAL demonstrated no significant reduction in 90 day mortality with hydrocortisone alone, whereas APROCCHSS demonstrated lower 90 day mortality with hydrocortisone plus fludrocortisone. Subsequent patient-level and network meta analyses suggest that any mortality benefit may be more evident when hydrocortisone is combined with fludrocortisone, although direct evidence comparing combination therapy with hydrocortisone alone remains limited. Hyperglycemia, hypernatremia, and neuromuscular weakness are clinically relevant adverse effects. High dose, short duration corticosteroid regimens are not recommended. Conclusions: Corticosteroids should not be considered routine therapy for all patients with sepsis. Their principal contemporary indication is persistent vasopressor dependent septic shock despite adequate resuscitation. Hydrocortisone 200 mg/day, administered intravenously as either intermittent doses or continuous infusion, represents the most established approach. The principal demonstrated benefit is more rapid shock reversal rather than a consistently proven mortality reduction. The additional use of fludrocortisone remains biologically plausible and supported by important trial and meta-analytic evidence, but uncertainty persists regarding its incremental benefit. Treatment should therefore be individualized according to the severity and trajectory of shock, competing indications, and potential adverse effects.