Hydrocortisone

Contents

Pharmacology

Hydrocortisone is the synthetic form of cortisol — the endogenous glucocorticoid produced by the adrenal cortex (zona fasciculata).

Steroid Potency Comparison

Agent Glucocorticoid potency Mineralocorticoid potency Equivalent dose
Hydrocortisone 1 1 20 mg
Prednisolone 4 0.8 5 mg
Methylprednisolone 5 0.5 4 mg
Dexamethasone 25 ~0 0.75 mg

In critical care, hydrocortisone is preferred over dexamethasone when mineralocorticoid activity (sodium retention, volume support) is desired — particularly in septic shock where hyponatraemia and intravascular depletion coexist.

Pharmacokinetics

  • Biological effect duration: 8–12 hours; plasma half-life ~1.5–2 hours
  • Hepatic metabolism (11β-hydroxysteroid dehydrogenase)
  • IV formulation: sodium succinate salt; rapid non-genomic effects (minutes) + slower genomic effects (hours)

Mechanism of Action in Shock

Genomic Effects (hours)

Glucocorticoid diffuses into cells → binds cytoplasmic glucocorticoid receptor (GR) → GR–steroid complex translocates to nucleus → modulates transcription:

  • Anti-inflammatory: ↓ TNF-α, IL-1, IL-6, COX-2, iNOS, phospholipase A₂
  • Upregulates: gluconeogenesis, cortisol-binding proteins, adrenergic receptor expression

Non-Genomic Effects (minutes)

  • Direct membrane effects
  • Rapid ↑ responsiveness of adrenergic receptors — this is the primary mechanism of vasopressor-sparing in septic shock

Vasopressor-Sparing Mechanism

In septic shock, catecholamine receptor downregulation causes vasopressor resistance. Hydrocortisone upregulates α₁ and β₁ adrenergic receptor expression → restores catecholamine sensitivity. The vasopressor-sparing effect (faster noradrenaline weaning) is consistent across all trials, regardless of mortality benefit.

Critical Illness–Related Corticosteroid Insufficiency (CIRCI)

A subset of critically ill patients cannot mount adequate cortisol response to stress:

  • Traditional definition: random cortisol <276 nmol/L OR delta cortisol <250 nmol/L after 250 mcg ACTH (short synacthen)
  • However, ACTH stimulation test is unreliable in critical illness — cortisol-binding globulin (CBG) and albumin fall in critical illness, lowering total cortisol while free (active) cortisol may be normal
  • Current guidance: do NOT use ACTH test to guide steroid therapy in septic shock; clinical indication (vasopressor-dependent shock) is the trigger

Clinical Indications in Critical Care

1. Septic Shock (Vasopressor-Dependent)

  • Surviving Sepsis Campaign (2021): hydrocortisone 200 mg/day if haemodynamically unstable despite adequate resuscitation and vasopressors — weak recommendation
  • Effect: accelerates shock reversal and vasopressor weaning (all trials); mortality benefit uncertain

2. Adrenal Crisis

  • Hydrocortisone 100 mg IV stat → 50–100 mg IV 6-hourly
  • Do not delay for ACTH test; treat empirically if clinical suspicion
  • Causes: known Addison's disease, prolonged steroid therapy, meningococcal septicaemia with adrenal haemorrhage (Waterhouse-Friderichsen syndrome)
  • Long-term steroid patients: sick day rules — double/triple oral dose; if unable to take oral or shocked: IV hydrocortisone

3. ARDS and COVID-19

  • Dexamethasone 6 mg/day (RECOVERY trial) reduces mortality in COVID-19 requiring supplemental oxygen or ventilation — note dexamethasone, not hydrocortisone
  • In non-COVID ARDS with concomitant refractory shock: hydrocortisone commonly used; evidence for ARDS alone weaker

4. Bacterial Meningitis (adjunctive)

  • Dexamethasone 0.15 mg/kg IV 6-hourly × 4 days (given before or with antibiotics) reduces neurological sequelae — H. influenzae type b and pneumococcal meningitis

Trial Evidence

CORTICUS (Sprung, NEJM 2008)

  • n=499; septic shock; hydrocortisone 50 mg IV 6-hourly × 5 days
  • Result: no improvement in 28-day mortality; faster shock reversal; higher superinfection rate
  • Enrolled heterogeneous patients including less severe shock; used ACTH stratification

ADRENAL (Venkatesh, NEJM 2018)

  • n=3,658; mechanically ventilated septic shock; hydrocortisone 200 mg/day continuous infusion × 7 days
  • Result: no significant difference in 90-day mortality (27.9% vs 28.8%); significantly shorter vasopressor duration (3 vs 4 days), faster ICU discharge; no increase in superinfection or GI bleeding

APROCCHSS (Annane, NEJM 2018)

  • n=1,241; 2×2 factorial; septic shock + relative adrenal insufficiency; hydrocortisone 50 mg 6-hourly + fludrocortisone 50 mcg/day × 7 days
  • Result: 90-day mortality significantly reduced (43.0% vs 49.1%); shorter vasopressor duration
  • More severely ill cohort than ADRENAL; enrolled only cortisol non-responders + ACTH non-responders

Synthesis

Vasopressor-sparing: consistent across all trials. Mortality benefit: suggested by APROCCHSS in the sickest patients; not confirmed by ADRENAL in a broader population. Current guidance: hydrocortisone in refractory vasopressor-dependent shock.

Dosing

Septic Shock

  • 200 mg/day IV — either continuous infusion or 50 mg 6-hourly
  • Duration: minimum 5–7 days; wean when vasopressors discontinued; taper over 2–3 days to avoid rebound

Adrenal Crisis

  • 100 mg IV stat → 50–100 mg IV 6-hourly; convert to oral when clinically stable

Side Effects in ICU

Effect Clinical Significance
Hyperglycaemia Very common; ↑ insulin requirements; target glucose 6–10 mmol/L
Hypokalaemia Mineralocorticoid effect; check daily electrolytes
Muscle weakness Worsens ICU-acquired weakness; minimise duration
GI bleeding Controversial; not increased in ADRENAL; combine with PPI if other risk factors
Superinfection Increased in CORTICUS (not ADRENAL); monitor for fungal and bacterial infections
Psychiatric Delirium, agitation — especially at higher doses

Viva Questions

1. What is the mechanism by which hydrocortisone reduces vasopressor requirements in septic shock?

Two principal mechanisms operate. First, hydrocortisone upregulates the expression of adrenergic receptors (α₁ and β₁) — catecholamine receptor downregulation is a major contributor to vasopressor resistance in septic shock, and restoring receptor density enhances sensitivity to noradrenaline and adrenaline. This effect begins within minutes via non-genomic membrane mechanisms. Second, hydrocortisone suppresses iNOS (inducible nitric oxide synthase) transcription — a genomic effect taking several hours. Reduced iNOS activity → less nitric oxide → reduced vasodilation. Additionally, inhibition of phospholipase A₂ and COX-2 reduces prostaglandin-mediated vasodilation. These mechanisms explain the consistent finding across CORTICUS, ADRENAL, and APROCCHSS that hydrocortisone accelerates vasopressor weaning regardless of whether there is a mortality benefit.

2. Compare the ADRENAL and APROCCHSS trials. Why do they have different mortality results?

Both enrolled vasopressor-dependent septic shock patients on mechanical ventilation and used similar hydrocortisone doses (~200 mg/day for 7 days). ADRENAL (n=3,658) found no mortality difference at 90 days; APROCCHSS (n=1,241) found a significant reduction (43% vs 49%). The key difference is patient selection and co-intervention. APROCCHSS enrolled only patients with relative adrenal insufficiency (cortisol non-responders to ACTH stimulation) and added fludrocortisone — a selective mineralocorticoid. This selected a more severely ill, adrenal-compromised cohort. ADRENAL enrolled all mechanically ventilated septic shock patients regardless of cortisol, diluting the signal from those who might truly benefit. See the CORTICUS journal club for earlier data showing similar patterns. The practical synthesis: hydrocortisone consistently reduces vasopressor duration; mortality benefit is most plausible in the most severely ill patients with genuine relative adrenal insufficiency and high vasopressor requirements.

3. A patient on long-term oral prednisolone 10 mg/day is admitted with pneumonia and hypotension. How do you manage potential adrenal insufficiency?

This patient is at risk of adrenal crisis — prolonged exogenous steroid use suppresses the hypothalamic-pituitary-adrenal (HPA) axis, impairing endogenous cortisol response to acute physiological stress. The risk is significant with doses ≥7.5 mg prednisolone/day for ≥3 weeks (equivalent to ≥10 mg hydrocortisone/day). Management: do not wait for investigations — if the patient is haemodynamically compromised and on long-term steroids, treat empirically. Give hydrocortisone 100 mg IV stat, followed by 50–100 mg IV 6-hourly. This provides physiological plus stress-level cortisol replacement. Simultaneously treat the underlying cause (antibiotics, fluid resuscitation for septic physiology). A random cortisol can be drawn before the first hydrocortisone dose but should not delay treatment. Once stable, taper hydrocortisone back towards their usual prednisolone dose as the acute illness resolves. Their usual oral prednisolone should be restarted as soon as oral intake is reliable.