Critical Illness-Related Corticosteroid Insufficiency

Critical illness related corticosteroid insufficiency is inadequate cellular glucocorticoid activity for the severity of illness, resulting from reduced cortisol production, altered cortisol metabolism, or tissue resistance to cortisol. It is linked to refractory hypotension, prolonged vasopressor dependence and worse outcome in sepsis, ARDS and other critical illness.

Epidemiology. It is reported in up to 10 to 20% of patients in intensive care and in up to 60% of those with septic shock, depending on the definition and test used.

Causes and associations. Sepsis and septic shock, ARDS, severe community acquired pneumonia, trauma, burns, pancreatitis, cardiac surgery, adrenal haemorrhage, etomidate use, ketoconazole, azole antifungals and drugs that induce cortisol metabolism (rifampicin, phenytoin), prior glucocorticoid therapy, HIV and low cholesterol states.

Pathophysiology. Inflammatory mediators suppress hypothalamic and pituitary function and adrenal synthesis. Cortisol binding globulin and albumin fall in critical illness, which lowers total cortisol (free cortisol may be normal). Receptor resistance from glucocorticoid receptor changes reduces cortisol effects.

Presentation is hypotension that depends on increasing doses of vasopressor, delayed shock reversal, hypoglycaemia, hyponatraemia, hyperkalaemia, eosinophilia, fever and altered mental state, in a critically ill patient. There are no specific features, so diagnosis relies on context and testing.

Red flags.

• Shock needing noradrenaline over 0.25 microgram/kg/min for 4 hours or more.
• Hypoglycaemia, hyponatraemia or hyperkalaemia in septic shock.
• Recent etomidate induction or long term glucocorticoid use.

Random total cortisol under 276 nmol/L (10 microgram/dL) in severe illness, or an increase of under 250 nmol/L (9 microgram/dL) after cosyntropin 250 microgram IV (peak at 30 or 60 minutes), supports the diagnosis. Both tests have limits, especially with low albumin (interpret with free cortisol if available). Treatment decisions are based on the clinical picture and not on testing alone. Also check sodium, potassium, glucose, ACTH and exclude adrenal haemorrhage by CT when suspected.

Differential diagnosis. Primary adrenal insufficiency, secondary adrenal insufficiency from pituitary disease or glucocorticoid withdrawal, adrenal haemorrhage, hypothyroidism, vasoplegia and refractory septic shock of other cause.

Septic shock. Hydrocortisone 50 mg IV every 6 hours (or 200 mg daily by continuous infusion) for patients on noradrenaline 0.25 microgram/kg/min or more for at least 4 hours. Continue until vasopressors are stopped, usually 3 to 7 days, then stop or taper over 3 to 5 days. Fludrocortisone 50 microgram daily by tube may be added (benefit is uncertain).

Severe community acquired pneumonia. Hydrocortisone 200 mg IV daily for 4 to 7 days, or 50 mg every 6 hours, in patients with severe disease (respiratory failure), not in influenza.

ARDS. Dexamethasone 20 mg IV daily for 5 days then 10 mg daily for 5 days in moderate to severe disease, or methylprednisolone 1 mg/kg daily with a taper, started early.

Known adrenal insufficiency or recent steroid therapy. Stress dosing: hydrocortisone 100 mg IV then 200 mg daily (50 mg every 6 hours), continuing until stable.

Avoid etomidate for induction in septic shock, and avoid high dose methylprednisolone for sepsis without another indication.

Adverse effects and monitoring. Hyperglycaemia (aim glucose 7.8 to 10 mmol/L with insulin), hypernatraemia, hypokalaemia, myopathy, delirium, infection and gastrointestinal bleeding (proton pump inhibitor in ventilated patients). Monitor glucose every 4 to 6 hours, electrolytes daily, vasopressor dose and lactate.

Withdrawal. Taper after prolonged therapy to avoid rebound hypotension and test adrenal reserve if therapy lasted over 3 weeks.

Referral and escalation. Endocrinology for persistent insufficiency, and intensive care. Search for adrenal haemorrhage or pituitary disease when the course is unexpected.

Special groups. In pregnancy, hydrocortisone is preferred (crosses placenta little). In children, hydrocortisone 2 mg/kg IV bolus (maximum 100 mg), then 50 to 100 mg/m2 daily in divided doses.