Introduction

Sepsis is a systemic inflammatory response (SIRS) with associated organ dysfunction as a result of an infection. It is defined by the presence of two or more SIRS criteria. 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.

SIRS Criteria (≥2 required for sepsis diagnosis)

  • Temperature >38 °C or <36 °C
  • Heart rate of >90 bpm
  • Respiratory rate of >20 breaths/minute or pCO2 of <32 mmHg
  • WBC >12,000 cells/mL or <4,000 cells/mL

Initial Management of Sepsis

  • 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

Pharmacology

Parameter Hydrocortisone Methylprednisolone Fludrocortisone
Dose

IV: 50 mg Q6H or 100 mg Q8H × 5–7 days

IV (succinate): 40–125 mg/day (max 1–2 mg/kg/day)

PO: 0.05 mg/day × 7 days (with a glucocorticoid)
Administration
IV: over ≥30 seconds IV: over several minutes or over 15–60 minutes as an infusion Administer by NG tube
PK/PD
Onset: 1 hr (IV) T½: 2 ± 0.3 hr
Onset: 1 hr (IV) T½: 0.25 ± 0.1 hr
Onset: 1–2 hr (PO) T½: ~3.5 hr
Mechanism of Action
Anti-inflammatory (decreased synthesis/release of inflammatory mediators), immunosuppressive, antiproliferative: vasoconstriction and decreased WBC permeability Same mechanism as hydrocortisone with 4–5× greater potency Mineralocorticoid activity > hydrocortisone or methylprednisolone
Adverse Effects
Increased BP Fluid retention Hyperglycemia Altered behavior
Similar adverse effects as hydrocortisone
Higher fluid retention risk Hypertension ↓ Electrolytes
Warnings & Interactions

Warnings: Adrenal suppression, immunosuppression, psychiatric changes

Interactions: Antacids (separate by 2 hrs), live vaccinations, DDAVP, succinylcholine

Warnings: Adrenal suppression, acute hepatitis (rare)

Interactions: Similar to hydrocortisone

Warnings: Hepatic dysfunction, myasthenia gravis, systemic sclerosis, thyroid disease

Interactions: Similar to hydrocortisone
Compatibility
None tested

Compatible: D5W-½NS, NS

Incompatible: D5W, D5NS, LR

 N/A

Clinical Pearl

Hydrocortisone provides sufficient mineralocorticoid activity as monotherapy. Fludrocortisone should be avoided in specific patient populations including those with congestive heart failure, hepatic, and renal disease.

Overview of Key Evidence

Author / Year Design (n) Intervention Key Findings
Annane D, 2002 (French Trial)1 RCT
n=300 		Hydrocortisone 50 mg IV Q6H + fludrocortisone 50 mcg daily vs placebo × 7 days
↓ Mortality in relative adrenal insufficiency

No increase in adverse events
Yu TJ, 20099 RCT
n=40 		Hydrocortisone 50 mg IV Q6H vs methylprednisolone 20 mg Q12H × 7 days
Higher survival with hydrocortisone
Sprung CL, 2008 (CORTICUS)11 RCT
n=499 		Hydrocortisone 50 mg Q6H vs placebo
No difference in 28-day mortality ↑ Shock reversal rate

Lower rate of progression to MODS
Venkatesh B, 2018 (ADRENAL)8 RCT
n=3,800 Largest 		Hydrocortisone 200 mg IV daily
No difference in 28/90-day mortality ↓ Time to shock resolution

Decreased ICU LOS; fewer blood transfusions; higher AE rate
Annane D, 2018 (APROCCHSS)2 RCT
n=1,280 		Hydrocortisone 50 mg IV Q6H + fludrocortisone 50 mcg PO daily × 7 days; drotrecogin alfa; combination
↓ 90-day mortality ↓ Vasopressor time

Decreased mortality at ICU & hospital discharge; faster SOFA <6

Clinical Conclusions

Bottom Line

Hydrocortisone is the recommended first-line corticosteroid for septic shock refractory to fluid resuscitation. Evidence consistently supports its role in shock reversal, though mortality benefits remain debated.

Per the Surviving Sepsis guidelines, hydrocortisone is recommended first-line for the treatment of septic shock in patients that are refractory to fluid (volume) resuscitation.

Hydrocortisone portrayed greater efficacy in clinical trials than methylprednisolone.

There are no clinical trials comparing hydrocortisone monotherapy vs hydrocortisone + fludrocortisone; however, it is hypothesized that hydrocortisone provides sufficient mineralocorticoid activity as monotherapy without the increased risks of adverse effects.

Avoid fludrocortisone in specific patient populations (i.e., congestive heart failure, hepatic and renal disease, etc.).

Full Reference List

  1. Annane D, Buisson CB, Cariou A, et al. Design and conduct of the APROCCHSS trial. Ann Intensive Care. 2016;6(1):43.
  2. Annane D, Renault A, Brun-Buisson C, et al. Hydrocortisone plus fludrocortisone for adults with septic shock. N Engl J Med. 2018;378(9):809–818.
  3. 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;47(11):1181–1247.
  4. Gibbison B, López-López JA, Higgins JP, et al. Corticosteroids in septic shock: a systematic review and network meta-analysis. Crit Care. 2017;21(1):78.
  5. Hotchkiss RS, Moldawer LL, Opal SM, et al. Sepsis and septic shock. Nat Rev Dis Primers. 2016;2:16045.
  6. Hydrocortisone. UpToDate. 2023.
  7. Hydrocortisone Sodium Succinate. Micromedex. 2023.
  8. Venkatesh B, Finfer S, Cohen J, et al. Adjunctive glucocorticoid therapy in patients with septic shock. N Engl J Med. 2018;378(9):797–808.
  9. Yu TJ, Liu YC, Yu CC, et al. Comparing hydrocortisone and methylprednisolone in patients with septic shock. Adv Ther. 2009;26(7):728–35.
  10. Keh D, Trips E, Marx G, et al. Effect of hydrocortisone on development of shock among patients with severe sepsis: the HYPRESS randomized clinical trial. JAMA. 2016;316(17):1775–1785.
  11. Sprung CL, Annane D, Keh D, et al. Hydrocortisone therapy for patients with septic shock. N Engl J Med. 2008;358(2):111–24.
  12. Gordon AC, Mason AJ, Thirunavukkarasu N, et al. Effect of early vasopressin vs norepinephrine on kidney failure in patients with septic shock: the VANISH randomized clinical trial. JAMA. 2016;316(5):509–18.
Tags: Infectious Disease Corticosteroids Sepsis Septic Shock Steroids

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