What is the pathophysiology of sepsis and how does low‑dose hydrocortisone improve outcomes according to current guidelines?

Pathophysiology of Sepsis and Mechanism of Hydrocortisone Benefit

How Sepsis Causes Hemodynamic Collapse

Sepsis triggers a dysregulated host inflammatory response to infection that leads to vasodilatory shock through multiple mechanisms: massive release of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α, IFN-γ), endothelial dysfunction with capillary leak, and relative adrenal insufficiency (critical illness-related corticosteroid insufficiency, or CIRCI). 1, 2

• The systemic inflammatory cascade causes widespread vasodilation and loss of vascular tone, resulting in distributive shock that manifests as hypotension refractory to fluid resuscitation. 1
• Endothelial injury leads to increased capillary permeability, causing intravascular volume depletion despite adequate fluid administration. 1
• Critical illness impairs the hypothalamic-pituitary-adrenal axis, creating a state of relative adrenal insufficiency where cortisol production cannot meet the increased metabolic demands of severe sepsis. 3, 4
• The combination of these mechanisms results in vasopressor-dependent shock, where norepinephrine and other catecholamines are required to maintain mean arterial pressure ≥65 mmHg. 1

Mechanisms by Which Hydrocortisone Improves Outcomes

Hydrocortisone at 200 mg/day restores hemodynamic stability through three synergistic mechanisms: potent anti-inflammatory effects that suppress cytokine storm, restoration of vascular responsiveness to catecholamines, and correction of relative adrenal insufficiency. 3, 2

Anti-Inflammatory Effects

• Hydrocortisone dramatically reduces serum levels of pro-inflammatory cytokines including IL-1β, IL-6, TNF-α, and IFN-γ, thereby dampening the excessive inflammatory response that drives vasodilation and organ injury. 2
• This cytokine suppression occurs within hours of hydrocortisone administration and correlates with improved hemodynamic parameters. 2
• The anti-inflammatory effect is dose-dependent; low-dose regimens (<400 mg/day) provide benefit without the immunosuppressive harm seen with high-dose protocols. 3, 5

Restoration of Vascular Tone and Catecholamine Responsiveness

• Hydrocortisone restores vascular smooth muscle responsiveness to endogenous and exogenous catecholamines, allowing lower vasopressor doses to achieve target blood pressure. 3, 2
• This mechanism explains why hydrocortisone accelerates shock reversal (hazard ratio ≈1.9 for earlier vasopressor discontinuation) and reduces total vasopressor requirements. 3
• The hemodynamic benefit is most pronounced in patients with vasopressor-refractory shock requiring norepinephrine >0.1–0.2 µg/kg/min for more than 60 minutes. 3

Correction of Relative Adrenal Insufficiency

• In critical illness, cortisol production often cannot meet the 10-fold increase in metabolic demand, creating functional adrenal insufficiency even when baseline cortisol levels appear normal. 4
• Hydrocortisone 200 mg/day provides supraphysiologic glucocorticoid replacement that compensates for this relative insufficiency. 3, 4
• This mechanism is independent of ACTH stimulation test results, which is why the test is not recommended for guiding therapy. 3, 5

Evidence for Clinical Benefit

The mortality benefit of hydrocortisone is confined to patients with vasopressor-refractory septic shock; the French Annane trial demonstrated 53% mortality with hydrocortisone versus 63% with placebo (hazard ratio 0.67, p=0.02) in this high-risk population. 3

• The subsequent CORTICUS trial showed no mortality benefit when hydrocortisone was given to all septic shock patients regardless of vasopressor responsiveness, confirming that benefit requires true refractory shock. 3
• The HYPRESS trial definitively established that hydrocortisone provides no benefit in severe sepsis without shock (21.2% vs 22.9% progression to shock, p=0.70), and should never be used in this population. 6
• Across all major trials, hydrocortisone consistently accelerates shock reversal and reduces vasopressor duration, even when mortality benefit is not demonstrated. 3, 7

Critical Guideline-Based Indications

Hydrocortisone 200 mg/day IV is indicated only when MAP remains <65 mmHg despite ≥30 mL/kg crystalloid resuscitation AND norepinephrine >0.1–0.2 µg/kg/min for more than 60 minutes. 3, 5

• This narrow indication reflects the Surviving Sepsis Campaign's conditional recommendation (Grade 2C) based on the evidence that benefit is limited to vasopressor-unresponsive shock. 1, 3
• Hydrocortisone should never be used in sepsis without shock, as it provides no benefit and increases hyperglycemia risk. 5, 6
• The dose must be ≤400 mg/day (typically 200 mg/day) given as continuous infusion or divided doses every 6 hours, maintained for at least 3 days before considering taper. 3, 5

Common Pitfalls to Avoid

• Do not use ACTH stimulation testing to decide who receives hydrocortisone; the test does not predict shock reversal or mortality benefit and delays treatment. 3, 5
• Never discontinue hydrocortisone abruptly; taper gradually over 6–14 days after vasopressors are stopped to avoid rebound inflammation and hemodynamic deterioration. 3, 4
• Avoid fludrocortisone combination therapy; 2024 evidence shows no improvement in shock-free days or mortality when added to hydrocortisone. 3
• Do not use etomidate for intubation in patients who may require hydrocortisone, as it suppresses the HPA axis and may worsen outcomes. 1
• Monitor blood glucose closely; hyperglycemia is the most common adverse effect and requires insulin therapy targeting glucose <180 mg/dL. 5, 4