What are the findings of the CORTICUS (Corticosteroid Therapy of Septic Shock) study, APPROCHS (Activated Protein C and Corticosteroids for Human Septic Shock) study, and ADRENAL (Assessment of Corticosteroid Therapy in Critically Ill Patients) trial regarding the use of corticosteroids in the Intensive Care Unit (ICU) setting?

Landmark Trials on Corticosteroids in ICU: CORTICUS, APPROCHS, and ADRENAL

CORTICUS Study (2008)

CORTICUS (Corticosteroid Therapy of Septic Shock) was a pivotal trial that fundamentally changed how we use ACTH stimulation testing in septic shock, demonstrating that corticosteroid response was similar regardless of adrenal reserve status. 1

Key Findings

• The ACTH stimulation test should NOT be used to identify which patients with septic shock should receive hydrocortisone, as the trial showed similar hemodynamic response to corticosteroids in patients with or without documented critical illness-related corticosteroid insufficiency 2, 1
• Treatment decisions should be based on clinical criteria alone: low blood pressure poorly responsive to vasopressors despite adequate fluid resuscitation 2, 3
• The delta cortisol response (change in baseline cortisol at 60 minutes of <9 μg/dL after cosyntropin 250 μg) or random plasma cortisol <10 μg/dL may be used by clinicians, but should not guide treatment decisions 4

Clinical Impact

• CORTICUS established that the presence or absence of adrenal insufficiency by testing does not predict who will benefit from corticosteroids 1, 3
• This shifted practice away from test-based treatment toward syndrome-based treatment (vasopressor-dependent septic shock) 2, 4

APPROCHS Study

While the provided evidence does not contain specific details about the APPROCHS (Activated Protein C and Corticosteroids for Human Septic Shock) trial, the contemporary guidelines emphasize that corticosteroid therapy in septic shock should focus on vasopressor-dependent patients rather than those with sepsis alone.

Current Guideline Context

• For septic shock not responsive to fluid and moderate to high-dose vasopressor therapy, use IV hydrocortisone <400 mg/day for ≥3 days at full dose (conditional recommendation, low quality evidence) 5, 2, 4
• The recommended dose is specifically 200 mg/day of IV hydrocortisone, administered either as divided doses or continuous infusion 2
• Do NOT use corticosteroids in adult patients with sepsis without shock, as the HYPRESS trial showed no difference in progression to septic shock or mortality 5, 4

ADRENAL Trial Context

The evidence base supporting current septic shock guidelines, which likely incorporates ADRENAL trial findings, recommends hydrocortisone only for vasopressor-dependent septic shock, not for sepsis without shock.

Treatment Protocol Based on Contemporary Evidence

• Initiate hydrocortisone 200 mg/day (50 mg IV every 6 hours or continuous infusion) when septic shock persists despite adequate fluid resuscitation and moderate to high-dose vasopressors 2, 4
• Continue treatment for at least 3-5 days at full dose before considering tapering 2, 1
• Taper gradually over 6-14 days when vasopressors are no longer required, rather than stopping abruptly, to avoid hemodynamic and immunologic rebound 2, 1

Critical Timing and Monitoring

• Never delay treatment for diagnostic procedures in suspected adrenal crisis—mortality is high if untreated 2
• Monitor for hyperglycemia (most common adverse effect), hypernatremia, and secondary infections during treatment 2, 4
• Norepinephrine remains the first-line vasopressor; corticosteroids are added when hypotension persists 2

Common Pitfalls to Avoid

Testing Errors

• Do not wait for ACTH stimulation test results before initiating corticosteroids in vasopressor-dependent septic shock 2, 1, 4
• Do not use plasma free cortisol or salivary cortisol over plasma total cortisol for diagnosis 4

Treatment Errors

• Do not use corticosteroids in sepsis without shock—this provides no benefit and may cause harm 5, 4
• Do not stop corticosteroids abruptly; always taper to prevent inflammatory rebound and hemodynamic deterioration 2, 1
• Avoid using etomidate prior to hydrocortisone initiation, as it may worsen outcomes 2
• Do not use dexamethasone for critical illness-related corticosteroid insufficiency—hydrocortisone is preferred 1

Dosing Errors

• Do not exceed 400 mg/day of hydrocortisone, as higher doses have not shown additional benefit 5, 2, 4
• Do not use high-dose pulse steroids (500-1,000 mg methylprednisolone)—these do not improve survival 6

Evidence Quality and Strength

The recommendations for corticosteroids in septic shock carry conditional strength with low to moderate quality evidence from the Society of Critical Care Medicine and European Society of Intensive Care Medicine 2017 guidelines 5, 4. The evidence consistently shows that clinical criteria (vasopressor-dependent shock) rather than biochemical testing should guide treatment decisions 2, 1, 4.