Anti-Inflammatory Mechanisms
- Annexin-A1 induction → inhibits cytosolic phospholipase A2 → reduces arachidonic acid availability for all eicosanoid pathways (prostaglandins, thromboxanes, leukotrienes)
- Transcriptional repression of cyclooxygenase-2 via nuclear factor kappa-B inhibition
- Broader spectrum than nonsteroidal anti-inflammatory drugs (cyclooxygenase only)
- GR monomer tethers to p65 subunit → blocks coactivator binding
- Induces I-kappa-B-alpha transcription → sequesters NF-kB in cytoplasm
- Recruits HDAC2 to promoters → closes chromatin (impaired in COPD/smokers)
- Cytokines suppressed: IL-1β, IL-2, IL-6, IL-8, TNF-α, IFN-γ, iNOS, ICAM-1
Immune Cell Effects
| Cell Type | Effect on Count | Mechanism and Clinical Note |
|---|
| Neutrophils |
↑ 2–3x (neutrophilia) |
Reduced adhesion molecule expression (demargination) + marrow release. Does NOT indicate infection in steroid-treated patients |
| T lymphocytes |
↓ 70–90% (lymphopenia) |
Redistribution to lymphoid tissue; IL-2 suppression blocks clonal expansion. Reverses within 24 h of single dose |
| Eosinophils |
↓ (eosinopenia) |
Apoptosis promotion. Eosinopenia confirms glucocorticoid receptor engagement; rising count suggests non-compliance |
| Macrophages |
Function impaired |
Reduced MHC class II, respiratory burst, IL-1β/TNF-α output → risk of intracellular pathogens |
Critical Illness and Organ-Specific Applications
- Septic shock: Hydrocortisone 200 mg/day only if refractory to fluids + vasopressors (norepinephrine >0.25 mcg/kg/min). ADRENAL: no mortality benefit but faster shock reversal. APROCCHSS: mortality benefit with hydrocortisone + fludrocortisone in severe shock
- COVID-19 ARDS (RECOVERY trial): Dexamethasone 6 mg daily ×10 days for patients requiring oxygen or ventilation. NNT ~8 for ventilated patients. No benefit (trend toward harm) if no oxygen required
- Cerebral edema: Dexamethasone 4–16 mg/day for peritumoral edema
- Bacterial meningitis: Dexamethasone 0.15 mg/kg every 6 h ×4 days with first antibiotic dose → reduces sensorineural hearing loss
- RA bridge: Prednisone 5–10 mg/day while awaiting disease-modifying antirheumatic drug onset; intra-articular methylprednisolone/triamcinolone for mono/oligoarticular flares
- Giant cell arteritis: Prednisone 40–60 mg/day; IV methylprednisolone pulse immediately if visual symptoms present — delay risks permanent blindness. Tocilizumab enables faster taper
- Severe SLE: IV methylprednisolone 500–1000 mg ×3 days, then prednisone 1 mg/kg/day + mycophenolate mofetil or cyclophosphamide
- Inhaled corticosteroids: High first-pass metabolism limits systemic bioavailability. High-dose fluticasone (>500 mcg/day) can suppress hypothalamic-pituitary-adrenal axis
Perioperative Stress-Dose Protocol
| Surgical Category | Stress-Dose Regimen | Notes |
|---|
| Minor (local/regional, same-day) |
No supplementation — continue usual oral dose |
If NPO, give usual dose as IV hydrocortisone equivalent |
| Moderate (general anesthesia, 1–2 day stay) |
Hydrocortisone 50 mg IV at induction, then 25 mg IV every 8 h ×24 h |
Resume usual oral dose when tolerating diet |
| Major (prolonged, ICU anticipated) |
Hydrocortisone 100 mg IV at induction, then 50 mg IV every 8 h ×24–48 h, taper over 48–72 h |
Extend if fever, hypotension, or active infection prolongs stress state |
| Emergency (unknown status) |
Hydrocortisone 100 mg IV empirically — do not delay |
Draw cortisol + ACTH before dose if timing allows; hemodynamic response within 30–60 min confirms diagnosis |
Who Needs Stress Dosing?
No supplementation needed: prednisone equivalent <5 mg/day (any duration); any steroid <3 weeks; off glucocorticoids >3 months.
Full supplementation required: prednisone >20 mg/day for >3 weeks; any patient with Cushingoid features. Moderate-dose patients (5–20 mg/day, ≥3 weeks): supplement proportional to surgical stress.