Steroids in Sepsis: Savior or Villain?
When to Use Hydrocortisone: The Critical Threshold
Hydrocortisone 200 mg/day is indicated only when septic shock remains refractory to adequate fluid resuscitation (≥30 mL/kg crystalloid) and moderate-to-high dose vasopressors (norepinephrine >0.1–0.2 µg/kg/min) for more than 60 minutes. 1 This narrow indication represents the consensus position where steroids shift from potential villain to potential savior.
The 2012 Surviving Sepsis Campaign guidelines frame this as a conditional recommendation: do not use hydrocortisone if adequate fluid resuscitation and vasopressor therapy restore hemodynamic stability; only when this fails should you consider intravenous hydrocortisone at 200 mg per day. 2 This recommendation carries a Grade 2C rating, reflecting moderate-quality evidence with important caveats.
The Evidence: Why the Narrow Window Matters
The mortality benefit of steroids is confined to the sickest patients. The landmark French trial by Annane (2002) demonstrated a 10% absolute mortality reduction (53% vs 63%, hazard ratio 0.67) in patients with vasopressor-unresponsive shock and relative adrenal insufficiency. 1 However, the subsequent CORTICUS trial showed no mortality benefit when steroids were given to all septic shock patients regardless of vasopressor responsiveness, underscoring that benefit exists only in refractory shock. 1
The baseline mortality difference between these trials is striking: 61% in the French study versus 31% in CORTICUS. 1 This disparity confirms that steroids help only when shock severity crosses a critical threshold—specifically, when patients require escalating vasopressors despite optimal resuscitation.
Recent evidence from the ADRENAL and APROCCHSS trials provides conflicting signals on mortality, likely due to differences in patient selection and corticosteroid regimens. 3 However, both trials consistently show that hydrocortisone accelerates shock reversal (hazard ratio ≈1.9 for earlier vasopressor discontinuation) and reduces total vasopressor requirements. 1 A 2023 prospective study found that early initiation (≤3 hours) reduced time to vasopressor discontinuation by 12 hours compared to late initiation (25 vs 37 hours, p=0.009). 4
Practical Dosing and Administration
Standard regimen: Hydrocortisone 200 mg/day as a continuous IV infusion (preferred) or 50 mg IV every 6 hours. 1, 5 Continuous infusion is favored for steady plasma levels, though clinical outcomes are similar. 2
Do not add fludrocortisone. A 2024 network meta-analysis found no improvement in shock-free days, shock duration, or mortality when fludrocortisone was combined with hydrocortisone. 1 While one 2024 systematic review suggested fludrocortisone plus hydrocortisone might reduce mortality (RR 0.88,94.2% probability of superiority), this relied primarily on indirect evidence with only two head-to-head trials, and the finding conflicts with propensity-weighted analyses showing no benefit. 6, 1
Duration and tapering: Maintain full-dose hydrocortisone for at least 3 days before considering dose reduction. 1, 5 Begin tapering only after vasopressors are discontinued, tapering gradually over 6–14 days to avoid rebound inflammation and hemodynamic deterioration. 1, 5 Abrupt discontinuation is contraindicated. 1
Critical Pitfalls: When Steroids Become the Villain
Do not use the ACTH stimulation test to select patients for hydrocortisone. The CORTICUS trial proved that test results do not predict faster shock resolution or mortality benefit (Grade 2B recommendation against). 2, 1
Steroids are contraindicated in sepsis without shock. The benefit is limited to patients requiring vasopressor support (Grade 1D recommendation). 2, 1
Avoid high-dose regimens (>400 mg/day). These provide no additional benefit and increase adverse events. 1, 3 Meta-analyses confirm that low-dose regimens (200 mg/day) do not significantly increase superinfection rates, whereas high-dose regimens are associated with excess harm. 1
Do not delay appropriate vasopressor escalation. If hydrocortisone is indicated, it should complement—not replace—optimal vasopressor therapy. Norepinephrine remains the first-line vasopressor, with vasopressin 0.03 units/minute added for refractory hypotension. 2
The Verdict: Conditional Savior in Refractory Shock
Hydrocortisone is neither universal savior nor villain—it is a conditional therapy for a specific subset of critically ill patients. The mortality benefit appears greatest in septic shock patients with high vasopressor requirements, evidence of multiorgan failure, and primary lung infections. 3 Steroids consistently accelerate shock reversal and may shorten mechanical ventilation duration, but do not improve mortality in unselected septic shock populations. 3, 7
The practical algorithm: After administering ≥30 mL/kg crystalloid and initiating norepinephrine targeting MAP ≥65 mmHg, if the patient requires norepinephrine >0.1–0.2 µg/kg/min for more than 60 minutes, start hydrocortisone 200 mg/day as a continuous infusion. 1, 5 Continue full-dose therapy for at least 3 days, then taper gradually over 6–14 days after vasopressors are discontinued. 1, 5 Monitor for hyperglycemia (the most common adverse effect) but recognize that superinfection risk is not significantly increased at low doses. 1, 3