Introduction

  1. Sepsis is a systemic inflammatory response (SIRS) with associated organ dysfunction as a result of an infection.
  2. Sepsis is defined as ≥2 of the criteria:
    • Temperature >38 ºC or <36 ºC
    • Heart rate of >90 bpm
    • Respiratory rate of >20 breaths/minute or pCO2 of <32 mmHg
    • WBC >12,000 cells/mL or <4000 cells/mL

Clinical Detail

  • Initial management of sepsis includes:
    • Intravenous fluids (LR/NS) 30 mL/kg (based on total body weight) administered within the first 3 hours.
    • Empiric antibiotic therapy based on the common bacteria and site of infection initiated within the first hour.
  • Per the Surviving Sepsis guidelines, IV hydrocortisone is recommended for patients at least 4 hours after initiation of norepinephrine/epinephrine ≥0.25 mcg/kg/min to maintain a MAP of ≥65 mmHg.

Pharmacology

 HydrocortisoneMethylprednisoloneFludrocortisone
DoseIV: 50 mg Q6H or 100 mg Q8H x 5-7 daysIV (succinate): 40 to 125 mg/day (maximum of 1 to 2 mg/kg/day)PO (in addition to another glucocorticoid): 0.05 mg/day x 7 days
AdministrationIV: over ≥30 secondsIV: over several minutes or over 15 to 60 minutes as an infusionAdminister by NG tube
PK/PD-Onset of action (IV): 1 hour
-T ½ elimination (IV): 2 +/- 0.3 hours		-Onset of action (IV): 1 hour
-T ½ elimination (IV): 0.25 +/- 0.1 hour		-Onset of action (PO): 1-2 hours
-T ½ elimination (PO): ~3.5 hours
Mechanism of Action-Anti-inflammatory (decreased synthesis and release of inflammatory mediators)
-Immunosuppressive (decreased response to hypersensitivity reactions)
-Antiproliferative: vasoconstriction and decreased permeability of WBC to the injury		-Same mechanism of action as hydrocortisone with a 4-5x greater potency-Mineralocorticoid activity > hydrocortisone or methylprednisolone
Adverse Effects-Cardiovascular: increased blood pressure
-Endocrine: fluid retention, hyperglycemia, weight gain
-Gastrointestinal: increased appetite
-Psychiatric: altered behavior		-Similar adverse effects as hydrocortisone-Higher risk of fluid retention, hypertension, and decreased electrolyte concentrations
Drug Interactions & WarningsWarnings: adrenal suppression, immunosuppression (higher doses for increased duration of therapy), psychiatric changes
Drug Interactions: antacids (separate by 2 hours), live vaccinations, DDAVP (risk of hyponatremia), succinylcholine		Warnings: adrenal suppression, acute hepatitis (rare)
Drug Interactions: similar to hydrocortisone and fludrocortisone		Warnings: patients with underlying hepatic dysfunction, myasthenia gravis, systemic sclerosis, or thyroid disease
Drug Interactions: similar to hydrocortisone and methylprednisolone
CompatibilityDrug in Solution: None testedDrug in Solution:
-Compatible: D5W-½ NS, NS
-Incompatible: D5W, D5NS, LR		N/A

Dosing and properties per product labeling / tertiary references (UpToDate, Micromedex).

A note on dexamethasone: Dexamethasone is a potent, long-acting glucocorticoid that is sometimes used (e.g., when hydrocortisone is unavailable), but it is not the guideline-preferred agent for septic shock. Unlike hydrocortisone, it has essentially no mineralocorticoid activity. Network meta-analysis has not shown any single corticosteroid to be clearly superior on mortality (Gibbison 2017), but the major modern trials (ADRENAL, APROCCHSS) and current guidelines (Surviving Sepsis; 2024 SCCM update) center on hydrocortisone, with or without fludrocortisone.

Evidence

Author, YearDesign (Sample Size)Intervention & ComparisonOutcome
Annane et al., 2002
(French Trial)		RCT (n=300)HC 50 mg IV Q6H + fludrocortisone 50 mcg PO daily x 7 days vs placeboReduced risk of death in septic shock with relative adrenal insufficiency (non-responders) without increasing adverse events; faster vasopressor withdrawal
Sprung et al., 2008
(CORTICUS)		RCT (n=499)HC 50 mg IV Q6H vs placeboNo significant difference in 28-day mortality; faster shock reversal but higher rate of superinfection
Yu et al., 2009RCT (n=40)HC 50 mg IV Q6H vs methylprednisolone 20 mg Q12H x 7 daysHigher survival with hydrocortisone vs methylprednisolone
Annane et al., 2010
(COIITSS)		2x2 factorial RCT (n=509)In HC-treated septic shock: + fludrocortisone vs placebo (and intensive vs conventional insulin)Adding fludrocortisone did not significantly lower in-hospital mortality (42.9% vs 45.8%); intensive insulin gave no mortality benefit and more hypoglycemia
Gordon et al., 2016
(VANISH)		2x2 factorial RCT (n=421)Vasopressin vs norepinephrine, each ± hydrocortisoneNo significant difference in kidney failure–free days or 28-day mortality; no significant effect from the hydrocortisone comparison
Keh et al., 2016
(HYPRESS)		RCT (n=380)HC 200 mg/day infusion x 5 days then taper vs placebo, in severe sepsis (pre-shock)No reduction in progression to septic shock (21.2% vs 22.9%) or in 28-/90-day mortality
Gibbison et al., 2017Systematic review + network meta-analysis (22 RCTs)Systemic corticosteroids (molecule-level comparison)Long-course low-dose steroids increased shock reversal; hydrocortisone favored over methylprednisolone for shock reversal
Venkatesh et al., 2018
(ADRENAL)		RCT (n=3,800)HC 200 mg/day continuous IV infusion vs placeboNo difference in 90-day mortality; faster resolution of shock, faster ICU discharge, and less blood transfusion
Annane et al., 2018
(APROCCHSS)		RCT (n=1,241)HC 50 mg IV Q6H + fludrocortisone 50 mcg PO daily x 7 days vs placeboReduced 90-day mortality (43.0% vs 49.1%); more vasopressor-free and ventilator-free days
Recent Evidence & Guidance (2024-2025)
SCCM Focused-Update Guideline (Chaudhuri et al.), 2024Clinical practice guideline (GRADE)Corticosteroids in septic shock / ARDS / severe CAP
  • Conditional recommendation FOR corticosteroids in septic shock
  • Strong recommendation AGAINST high-dose/short-duration steroids in septic shock
Teja et al., 2024Bayesian network meta-analysis (17 RCTs, n=7,688)HC + fludrocortisone vs HC alone vs placeboHC + fludrocortisone had the lowest all-cause mortality (RR 0.85, 98.3% probability of being the best treatment); HC alone not significantly better than placebo
Lai et al., 2024Bayesian NMA + target-trial emulation (n=95,841)HC + fludrocortisone vs HC alone vs placeboHC + fludrocortisone had the lowest short-term mortality vs placebo (OR 0.79; NNT 21), ranked above HC alone
Lv et al., 2025Meta-analysis (18 RCTs, n=7,982), dose-stratifiedCorticosteroids vs placeboReduced 28-day mortality (RR 0.88, 95% CI 0.79-0.98); benefit concentrated at 201-300 mg/day HC-equivalent and with HC + fludrocortisone

HC = hydrocortisone; FC = fludrocortisone; NMA = network meta-analysis. Trial years and sample sizes verified against primary sources (PubMed).

Conclusions

  • Per the Surviving Sepsis guidelines, hydrocortisone is recommended for septic shock that remains refractory to fluid resuscitation and vasopressors; the 2024 SCCM focused-update guideline conditionally recommends corticosteroids in septic shock and recommends against high-dose/short-duration regimens.
  • Hydrocortisone is generally preferred over methylprednisolone (favored for shock reversal in network meta-analysis; Yu 2009 showed numerically higher survival, though not statistically significant).
  • Direct head-to-head RCT evidence comparing hydrocortisone alone with hydrocortisone + fludrocortisone is limited (COIITSS 2010 found no significant mortality benefit from adding fludrocortisone); however, recent network meta-analyses (Teja 2024, Lai 2024) suggest the combination may achieve lower mortality than hydrocortisone alone.
    • Fludrocortisone should be used cautiously or avoided in specific patient populations (e.g., congestive heart failure, hepatic or renal disease).

References

  • Annane D, Buisson CB, Cariou A, Martin C, Misset B, Renault A, Lehmann B, Millul V, Maxime V, Bellissant E; APROCCHSS Investigators for the TRIGGERSEP Network. Design and conduct of the activated protein C and corticosteroids for human septic shock (APROCCHSS) trial. Ann Intensive Care. 2016 Dec;6(1):43.
  • Annane D, Renault A, Brun-Buisson C, Megarbane B, Quenot JP, Siami S, Cariou A, Forceville X, Schwebel C, Martin C, Timsit JF, Misset B, Ali Benali M, Colin G, Souweine B, Asehnoune K, Mercier E, Chimot L, Charpentier C, François B, Boulain T, Petitpas F, Constantin JM, Dhonneur G, Baudin F, Combes A, Bohé J, Loriferne JF, Amathieu R, Cook F, Slama M, Leroy O, Capellier G, Dargent A, Hissem T, Maxime V, Bellissant E; CRICS-TRIGGERSEP Network. Hydrocortisone plus Fludrocortisone for Adults with Septic Shock. N Engl J Med. 2018 Mar 1;378(9):809-818.
  • Evans L, Rhodes A, Alhazzani W, et al. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021. Intensive Care Med. 2021 Nov;47(11):1181-1247.
  • Gibbison B, López-López JA, Higgins JP, Miller T, Angelini GD, Lightman SL, Annane D. Corticosteroids in septic shock: a systematic review and network meta-analysis. Crit Care. 2017 Mar 28;21(1):78.
  • Hotchkiss RS, Moldawer LL, Opal SM, Reinhart K, Turnbull IR, Vincent JL. Sepsis and septic shock. Nat Rev Dis Primers. 2016 Jun 30;2:16045.
  • Hydrocortisone (2023) UpToDate. Available at: https://www.uptodate.com (Accessed: 13 August 2023).
  • Hydrocortisone Sodium Succinate (2023) Micromedex. Available at: https://www.micromedexsolutions.com (Accessed: 13 August 2023).
  • Venkatesh B, Finfer S, Cohen J, Rajbhandari D, Arabi Y, Bellomo R, Billot L, Correa M, Glass P, Harward M, Joyce C, Li Q, McArthur C, Perner A, Rhodes A, Thompson K, Webb S, Myburgh J; ADRENAL Trial Investigators and the Australian-New Zealand Intensive Care Society Clinical Trials Group. Adjunctive Glucocorticoid Therapy in Patients with Septic Shock. N Engl J Med. 2018 Mar 1;378(9):797-808.
  • Yu TJ, Liu YC, Yu CC, Tseng JC, Hua CC, Wu HP. Comparing hydrocortisone and methylprednisolone in patients with septic shock. Adv Ther. 2009 Jul;26(7):728-35.
  • Keh D, Trips E, Marx G, Wirtz SP, Abduljawwad E, Bercker S, Bogatsch H, Briegel J, Engel C, Gerlach H, Goldmann A, Kuhn SO, Hüter L, Meier-Hellmann A, Nierhaus A, Kluge S, Lehmke J, Loeffler M, Oppert M, Resener K, Schädler D, Schuerholz T, Simon P, Weiler N, Weyland A, Reinhart K, Brunkhorst FM; SepNet-Critical Care Trials Group. Effect of Hydrocortisone on Development of Shock Among Patients With Severe Sepsis: The HYPRESS Randomized Clinical Trial. JAMA. 2016 Nov 1;316(17):1775-1785. doi: 10.1001/jama.2016.14799. PMID: 27695824.
  • Sprung CL, Annane D, Keh D, Moreno R, Singer M, Freivogel K, Weiss YG, Benbenishty J, Kalenka A, Forst H, Laterre PF, Reinhart K, Cuthbertson BH, Payen D, Briegel J; CORTICUS Study Group. Hydrocortisone therapy for patients with septic shock. N Engl J Med. 2008 Jan 10;358(2):111-24. doi: 10.1056/NEJMoa071366. PMID: 18184957.
  • Gordon AC, Mason AJ, Thirunavukkarasu N, Perkins GD, Cecconi M, Cepkova M, Pogson DG, Aya HD, Anjum A, Frazier GJ, Santhakumaran S, Ashby D, Brett SJ; VANISH Investigators. Effect of Early Vasopressin vs Norepinephrine on Kidney Failure in Patients With Septic Shock: The VANISH Randomized Clinical Trial. JAMA. 2016 Aug 2;316(5):509-18. doi: 10.1001/jama.2016.10485. PMID: 27483065.
  • Annane D, Cariou A, Maxime V, et al; COIITSS Study Investigators. Corticosteroid treatment and intensive insulin therapy for septic shock in adults: a randomized controlled trial. JAMA. 2010;303(4):341-348. doi:10.1001/jama.2010.2
  • Chaudhuri D, Nei AM, Rochwerg B, et al. 2024 Focused Update: Guidelines on Use of Corticosteroids in Sepsis, Acute Respiratory Distress Syndrome, and Community-Acquired Pneumonia. Crit Care Med. 2024;52(5):e219-e233. doi:10.1097/CCM.0000000000006172
  • Teja B, et al. Effectiveness of Fludrocortisone Plus Hydrocortisone versus Hydrocortisone Alone in Septic Shock: A Bayesian Network Meta-Analysis. Am J Respir Crit Care Med. 2024;209(10):1219-1228. doi:10.1164/rccm.202310-1785OC
  • Lai PC, et al. Do We Need to Administer Fludrocortisone in Addition to Hydrocortisone in Adult Patients With Septic Shock? A Bayesian Network Meta-Analysis. Crit Care Med. 2024;52(4):e193-e202. doi:10.1097/CCM.0000000000006161
  • Lv R, et al. Corticosteroids for sepsis and septic shock: a meta-analysis of 18 RCTs. BMC Anesthesiol. 2025;25(1):511. doi:10.1186/s12871-025-03388-1
Tags: corticosteroids sepsis hydrocortisone shock

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