What is the mechanism of action of corticosteroids (CS), such as hydrocortisone, in the management of sepsis?

Mechanism of Action of Corticosteroids in Sepsis Management

Corticosteroids in sepsis work primarily by suppressing systemic inflammation, restoring cardiovascular homeostasis, and modulating the dysregulated host immune response through both genomic and non-genomic pathways. 1

Anti-inflammatory Effects

• Genomic mechanisms:

  • Bind to intracellular glucocorticoid receptors
  • Translocate to the nucleus and regulate gene expression
  • Inhibit production of pro-inflammatory cytokines (IL-1β, IFN-γ, TNF-α, IL-6) 2
  • Suppress expression of inflammatory mediators
  • Reduce production of prostaglandins and free radicals 3

• Non-genomic mechanisms:

  • Rapid effects occurring within minutes (vs. hours for genomic effects)
  • Direct interaction with cell membranes
  • Inhibition of chemotaxis and adhesion molecule expression 3
  • Immediate modulation of inflammatory cascades

Cardiovascular Effects

• Restoration of vascular tone:

  • Increase mean arterial blood pressure
  • Enhance sensitivity to vasopressors (catecholamines)
  • Improve microcirculation 3
  • Reduce vasodilatory shock

• Endothelial stabilization:

  • Decrease capillary permeability
  • Reduce tissue edema
  • Improve tissue perfusion

Adrenal Insufficiency Correction

• Approximately 25% of patients with septic shock develop relative adrenal insufficiency 4
• Characterized by inadequate cortisol production relative to physiological stress
• Corticosteroids supplement this deficiency, especially in vasopressor-dependent shock 4

Hemodynamic Stabilization

• Improve hemodynamic variables in severe sepsis 2
• Reduce duration of vasopressor therapy 5
• Faster resolution of shock 4

Organ Function Restoration

• Terminate systemic and tissue inflammation
• Restore organ function through reduced inflammation
• Prevent progression of organ failure 1

Clinical Application Based on Mechanism

1. Patient selection:

   • Recommended for septic shock unresponsive to fluid resuscitation and vasopressors 6, 4
   • Not recommended for sepsis without shock 6, 4

2. Dosing based on mechanism:

   • Low-dose hydrocortisone (200-300 mg/day) preferred 4
   • High-dose corticosteroids increase mortality and secondary infections 6
   • Continuous infusion preferred over bolus to avoid glucose peaks 4

3. Duration considerations:

   • Continue until shock resolution and vasopressors no longer required 4
   • Gradual tapering recommended to avoid hemodynamic and immunologic rebound effects 4

Potential Adverse Effects Related to Mechanism

• Hyperglycemia due to gluconeogenic effects
• Hypernatremia from mineralocorticoid activity
• Increased risk of secondary infections with prolonged use
• Rebound inflammation if discontinued abruptly 4

Understanding the complex mechanisms of corticosteroids in sepsis helps explain why they are beneficial in septic shock but not recommended in sepsis without shock, and why proper patient selection, dosing, and duration are critical for optimal outcomes.