What is the role of hydrocortisone (cortisol) in the management of septic shock?

Hydrocortisone for Septic Shock

Primary Recommendation

Administer hydrocortisone 200 mg/day intravenously (as continuous infusion or divided doses) only in patients with septic shock who remain hypotensive despite adequate fluid resuscitation and vasopressor therapy; do not use hydrocortisone in sepsis without shock. 1, 2, 3

When to Initiate Hydrocortisone

Specific Criteria for Adults

• Reserve hydrocortisone exclusively for vasopressor-unresponsive septic shock after adequate fluid resuscitation has been completed 1, 2
• Initiate when patients require moderate-to-high dose vasopressors (>0.1 μg/kg/min norepinephrine equivalent) 2
• Do not administer in sepsis without shock—this provides no benefit and may cause harm 2, 3

Absolute Indications (Immediate Treatment Required)

• Absolute adrenal insufficiency (peak cortisol after ACTH stimulation <18 μg/dL) with catecholamine-resistant shock 4
• Patients with purpura fulminans, Waterhouse-Friderichsen syndrome, prior chronic steroid therapy, or pituitary/adrenal abnormalities 4
• Death from absolute adrenal insufficiency occurs within 8 hours of presentation—obtain cortisol level when empiric hydrocortisone is administered but do not delay treatment 4

Dosing Protocol

Standard Adult Dosing

• 200 mg/day hydrocortisone for at least 3 days at full dose 1, 2, 3
• Administer as continuous infusion (preferred) or divided doses every 6 hours 2, 3
• Use low-dose, long-duration therapy (<400 mg/day); avoid high-dose short courses as they are ineffective or harmful 2
• Taper gradually when vasopressors are no longer required—do not stop abruptly 1

Pediatric Dosing

• Initial stress dose: 50 mg/m²/24 hours 4
• May titrate between 2-50 mg/kg/day as continuous infusion or intermittent dosing to reverse shock 4
• For newborns: approximately 5-6 mg/kg/day initially, can increase to 50 mg/kg/day if needed 3
• Approximately 25% of children with septic shock have absolute adrenal insufficiency 4, 3

Diagnostic Testing Approach

What NOT to Do

• Do not use ACTH stimulation testing to guide hydrocortisone therapy decisions—it does not predict shock reversal or mortality benefit 1, 2
• Do not delay treatment while awaiting cortisol results in suspected absolute adrenal insufficiency 3

When Testing May Be Useful

• Random cortisol levels can diagnose absolute adrenal insufficiency (inappropriately low cortisol in shock warrants treatment per traditional adrenal insufficiency guidelines) 1
• Consider obtaining baseline cortisol before starting treatment, though treatment should not be delayed 3
• Delta cortisol <9 μg/dL after cosyntropin (250 μg) or random cortisol <10 μg/dL may help identify adrenal insufficiency 3

Expected Benefits and Timeline

Hemodynamic Effects

• Faster shock reversal compared to placebo (median 3 days vs 4 days) 5
• More rapid vasopressor withdrawal 6, 5
• Shorter duration of initial mechanical ventilation episode 5

Mortality Outcomes

• No mortality benefit demonstrated in recent high-quality trials (ADRENAL 2018, CORTICUS 2008) 6, 5
• The ADRENAL trial (2018, n=3800) showed 27.9% mortality with hydrocortisone vs 28.8% with placebo at 90 days (P=0.50) 5
• CORTICUS trial (2008, n=499) showed no mortality difference regardless of ACTH response 6
• Improved shock reversal is the primary benefit, not survival 1, 7

Adverse Effects and Monitoring

Common Risks

• Hyperglycemia—most common adverse effect requiring monitoring 2
• Increased risk of superinfection, including new sepsis and septic shock 1, 6
• Hypernatremia 2
• More frequent blood transfusions in some studies (though ADRENAL showed fewer transfusions) 5

Monitoring Requirements

• Blood glucose levels closely
• Signs of new infection
• Serum sodium
• Hemodynamic parameters for shock reversal

Critical Pitfalls to Avoid

Drug Interactions

• Avoid etomidate for intubation in septic shock patients—it suppresses the hypothalamic-pituitary-adrenal axis and may increase mortality when used before steroid administration 1

Inappropriate Use

• Do not use in sepsis without shock 2
• Do not use high-dose short-course steroids (>400 mg/day for 1-2 days) 2, 7
• Do not rely on ACTH stimulation testing to determine treatment eligibility 1, 2
• Do not stop abruptly—taper when vasopressors are discontinued 1

Pediatric-Specific Considerations

• Maintain equipoise regarding adjunctive steroid therapy in pediatric sepsis outside of absolute adrenal insufficiency—prospective trials are still needed 4
• Unlike dexamethasone (which causes neurologic complications in premature infants), hydrocortisone does not cause similar complications 4
• Wean treatment as tolerated to minimize long-term toxicities 4

Role of Fludrocortisone

• The role of adjunctive fludrocortisone remains uncertain 7, 8
• Can be added on a case-by-case basis in refractory shock 8
• Earlier adult guidelines recommended fludrocortisone with hydrocortisone for dopamine-resistant shock, but current evidence does not strongly support routine use 4