What is the role of hydrocortisone (hydrocortisone) therapy in a patient with septic shock, particularly in relation to the CORTICUS (Corticosteroid Therapy of Septic Shock) trial and ACTH (Adrenocorticotropic Hormone) stimulation testing?

CORTICUS Trial and Hydrocortisone in Septic Shock

The CORTICUS trial failed to demonstrate mortality benefit from hydrocortisone in septic shock, and the ACTH stimulation test should not be used to guide treatment decisions—instead, reserve hydrocortisone 200 mg/day for patients with refractory shock unresponsive to adequate fluid resuscitation and moderate-to-high dose vasopressors. 1

Key Findings from CORTICUS

The CORTICUS trial fundamentally differed from earlier positive studies in its patient population and yielded negative results 1:

• Enrolled patients with septic shock regardless of vasopressor responsiveness, unlike the French trial which only included patients with blood pressure unresponsive to vasopressors for >60 minutes 1
• Baseline mortality was only 31% in CORTICUS versus 61% in the French trial, indicating a lower-risk population 1
• No mortality benefit was observed with hydrocortisone therapy 1
• ACTH stimulation testing did not predict shock resolution or identify patients who would benefit from steroids 1

Current Evidence-Based Recommendations

When to Use Hydrocortisone

Reserve hydrocortisone for refractory shock only 1, 2:

• Use hydrocortisone 200 mg/day IV only if adequate fluid resuscitation and vasopressor therapy fail to restore hemodynamic stability 1
• Do not use hydrocortisone if blood pressure responds adequately to fluids and vasopressors 1
• Do not use corticosteroids for sepsis without shock—no benefit demonstrated 1, 2

Dosing Protocol

When indicated, administer 1, 2:

• Hydrocortisone 200 mg/day as either divided doses (50 mg IV every 6 hours) or continuous infusion 2
• Continue for at least 3 days at full dose before considering taper 2
• Taper gradually over 6-14 days when vasopressors are discontinued, rather than stopping abruptly 1, 2

Role of ACTH Stimulation Testing

Do not use the ACTH stimulation test to decide who receives hydrocortisone 1:

• The CORTICUS trial showed similar hemodynamic response to steroids in both ACTH responders and non-responders 1
• The interaction between steroid benefit and ACTH test results was not statistically significant 1
• Clinical criteria should guide treatment decisions, not biochemical testing 1, 3

Recent High-Quality Evidence

Patient-Level Meta-Analysis (2023)

The most recent and comprehensive analysis pooled individual patient data from 17 trials (n=7,882) 4:

• No mortality benefit with hydrocortisone alone: RR 0.93 (95% CI 0.82-1.04, P=0.22) 4
• Hydrocortisone with fludrocortisone showed benefit: RR 0.86 (95% CI 0.79-0.92) 4
• Increased vasopressor-free days by 1.24 days (95% CI 0.74-1.73) 4
• Adverse effects: increased risk of hypernatremia (RR 2.01) and muscle weakness (RR 1.73) 4

APROCCHSS Trial (2018)

This high-quality French trial demonstrated mortality benefit with combination therapy 5:

• Hydrocortisone plus fludrocortisone reduced 90-day mortality: 43.0% versus 49.1% (P=0.03) 5
• Relative risk of death 0.88 (95% CI 0.78-0.99) 5
• More vasopressor-free days (17 vs 15 days, P<0.001) 5

Network Meta-Analysis (2024)

The most recent systematic review comparing all regimens 6:

• Fludrocortisone plus hydrocortisone superior to placebo: RR 0.85 (95% CI 0.72-0.99) 6
• Fludrocortisone plus hydrocortisone likely superior to hydrocortisone alone: RR 0.88 (95% CI 0.74-1.03,94.2% probability of superiority) 6
• Hydrocortisone alone showed no significant benefit: RR 0.97 (95% CI 0.87-1.07) 6

Clinical Algorithm

Step 1: Patient has septic shock requiring vasopressors 1

Step 2: Optimize fluid resuscitation and vasopressor therapy first 1

Step 3: If hemodynamic stability achieved → Do not use hydrocortisone 1

Step 4: If shock remains refractory despite adequate fluids and moderate-to-high dose vasopressors → Consider hydrocortisone 200 mg/day 1, 2

Step 5: Add fludrocortisone 50 mcg daily for maximum mortality benefit based on recent evidence 5, 6

Step 6: Continue full dose for at least 3-5 days 2

Step 7: When vasopressors discontinued → Taper over 6-14 days 1, 2

Critical Pitfalls to Avoid

• Do not perform ACTH stimulation testing to guide hydrocortisone decisions—it has no predictive value 1
• Avoid etomidate for intubation if possible—associated with increased mortality when followed by steroids 1
• Never stop steroids abruptly—causes hemodynamic and immunologic rebound 1, 2
• Do not use steroids in sepsis without shock—no benefit and potential harm 1, 2
• Monitor for hyperglycemia and hypernatremia during treatment 4

Reconciling Contradictory Evidence

The divergence between CORTICUS and earlier trials reflects patient selection 1:

• High-risk patients (mortality >60%, vasopressor-unresponsive shock) may benefit from steroids 1
• Lower-risk patients (mortality <50%, responsive to vasopressors) show no benefit 1
• Fludrocortisone addition appears critical for mortality benefit based on most recent evidence 4, 5, 6

The 2012 Surviving Sepsis Campaign guidelines appropriately incorporated CORTICUS findings by recommending steroids only for refractory shock 1, and recent evidence suggests adding fludrocortisone when steroids are indicated 5, 6.