Etomidate-Induced Adrenal Suppression

Etomidate induced adrenal suppression is inhibition of cortisol synthesis after etomidate, lasting from hours to days. It follows even a single induction dose and may contribute to refractory shock in sepsis.

Epidemiology. A single dose of 0.3 mg/kg suppresses cortisol response to adrenocorticotropic hormone for 6 to 24 hours in healthy patients, and up to 72 hours in critically ill or older patients. The effect on mortality in sepsis is contested.

Risk factors. Sepsis, septic shock, repeated doses or infusion, critical illness, older age, hepatic impairment and long courses of steroids. Trauma and burns also increase vulnerability.

Pathophysiology.

Etomidate reversibly inhibits adrenal 11-beta-hydroxylase (and to a lesser extent 17-alpha-hydroxylase and cholesterol side chain cleavage), which blocks conversion of 11-deoxycortisol to cortisol and 11-deoxycorticosterone to corticosterone.

Cortisol falls and adrenocorticotropic hormone rises, with a blunted response to stimulation. Cortisol precursors accumulate.

Usually silent. Possible features in a susceptible patient are hypotension that responds poorly to fluid and vasopressors, hyponatraemia, hyperkalaemia, hypoglycaemia, fever and a rising vasopressor need within 24 to 48 hours of the induction dose.

Red flags.

• Refractory shock after etomidate induction.
• Rising vasopressor requirement without other cause.
• Hypoglycaemia with hypotension.
• Chronic steroid therapy or known adrenal disease.

Random cortisol is of limited value in critical illness. A short adrenocorticotropic hormone stimulation test, with 250 microgram tetracosactide IV and cortisol at baseline and 30 to 60 minutes, shows an increment under 250 nmol/L (9 microgram/dL), or a peak under 450 to 500 nmol/L, in suppression. Test during etomidate effect is unreliable, so treat first when the patient is unstable.

Differential diagnosis.

• Sepsis with vasoplegia.
• Haemorrhage.
• Primary or secondary adrenal insufficiency.
• Cardiogenic shock.
• Anaphylaxis.
• Drug related vasodilation.
• Critical illness related corticosteroid insufficiency.

Prevention. Use a single dose only and avoid infusion. Use 0.2 to 0.3 mg/kg IV for induction, 0.15 mg/kg in older adults and unstable patients. Consider ketamine 1 to 2 mg/kg IV (reduced dose in shock) or reduced dose propofol for septic or shocked patients, balancing haemodynamic effects, or administer hydrocortisone when etomidate is chosen in septic shock.

Treatment of suspected suppression with refractory shock.

• Hydrocortisone: 100 mg IV bolus, then 50 mg IV every 6 hours (or 200 mg over 24 hours by infusion); continue until vasopressors are no longer needed, usually 3 to 7 days; maximum 200 mg daily in this indication; monitor glucose, sodium, potassium and blood pressure; caution in uncontrolled infection and in diabetes.
• Add fludrocortisone 50 microgram orally once daily if mineralocorticoid effect is needed (used in some septic shock practice); monitor potassium, sodium and blood pressure; avoid in hypokalaemia and uncontrolled hypertension.

Treat the underlying shock with fluid, vasopressors and source control. Taper steroid after recovery, usually over a few days, if given for longer than 7 days.

Monitoring. Haemodynamics, vasopressor dose, glucose every 2 to 4 hours, sodium, potassium and lactate.

Referral and escalation. Critical care and endocrine review for persistent hypotension or known adrenal disease. Endocrine follow up if adrenal suppression persists beyond 1 week.

Special groups. In septic and older patients prefer alternatives or add steroid cover. In patients on long term steroids give stress dose hydrocortisone.