Adrenal crisis

At a glance

• Acute adrenal insufficiency is shock with no other obvious cause in someone who can't make cortisol. It kills through hypotension and hypoglycaemia.
• Give hydrocortisone 100 mg IV or IM first. Take cortisol and ACTH if it doesn't delay treatment, but never wait for them.
• Most crises happen in people already known to have adrenal insufficiency or taking long-term glucocorticoids, who are hit by an illness and don't increase their dose.
• Every admission is a chance to prevent the next: sick-day rules, an emergency injection kit and a steroid card.

Causes

Level	Causes
Primary (adrenal)	Autoimmune Addison disease (commonest in Australia), adrenal haemorrhage (anticoagulation, antiphospholipid syndrome, meningococcal sepsis: Waterhouse-Friderichsen), TB, metastases, congenital adrenal hyperplasia, adrenalectomy, drugs (ketoconazole, mitotane, etomidate)
Secondary (pituitary)	Pituitary tumour or surgery, apoplexy, radiotherapy, Sheehan syndrome, hypophysitis from immune checkpoint inhibitors
Tertiary (glucocorticoid-induced)	Long-term oral, inhaled, topical or injected glucocorticoids, stopped suddenly or not increased during illness. By far the commonest overall

• Precipitants: gastroenteritis (vomiting means tablets aren't absorbed), infection, surgery, trauma, missed doses, and starting thyroxine before glucocorticoid replacement.
• Drug interactions: enzyme inducers (rifampicin, phenytoin, carbamazepine) speed cortisol clearance. Ritonavir or cobicistat with inhaled or injected fluticasone or triamcinolone causes iatrogenic Cushing syndrome, then adrenal insufficiency when either drug stops.
• Glucocorticoid-induced risk: the ESE/Endocrine Society 2024 guideline treats anyone on supraphysiological doses (prednisolone above about 4 to 5 mg daily, or hydrocortisone above 15 to 25 mg) for more than 3 to 4 weeks as at risk, whatever the route. The cut-off isn't a safe line: people on long-term doses at or near prednisolone 5 mg can still have a suppressed HPA axis and need sick-day rules.

Pathophysiology worth knowing

• Cortisol maintains vascular tone (it permits catecholamine action), gluconeogenesis and free water excretion. Without it you get vasodilatory shock that responds poorly to fluids and pressors, hypoglycaemia and hyponatraemia.
• Aldosterone is controlled by renin, not ACTH. Only primary disease loses it, giving hyperkalaemia, salt craving and more profound volume depletion.
• Hyperpigmentation (buccal mucosa, palmar creases, scars) comes from high ACTH and its precursor POMC, so it is a sign of primary disease.

Recognition

• Symptoms: profound fatigue, nausea, vomiting, abdominal pain (can mimic an acute abdomen), confusion, collapse.
• Signs: hypotension or postural drop, tachycardia, fever, reduced consciousness.
• Bloods:
  • Hyponatraemia in about 80% (primary and secondary: cortisol deficiency raises ADH)
  • Hyperkalaemia in primary only
  • Hypoglycaemia, more common in children and in hypopituitarism
  • Raised urea, mild hypercalcaemia, eosinophilia, normocytic anaemia
• Suspect it in hypotension that doesn't respond to fluids and vasopressors, recurrent hypoglycaemia in someone with type 1 diabetes (falling insulin needs are an early sign of Addison disease), or anyone wearing a medical alert bracelet.
• Pitfall: a normal potassium doesn't exclude adrenal crisis. Secondary and glucocorticoid-induced disease keep aldosterone.

Investigations

• Before hydrocortisone, if no delay: serum cortisol and plasma ACTH. Add renin and aldosterone when primary disease is possible.
• Prednisolone and hydrocortisone cross-react with cortisol immunoassays, so a random cortisol in someone taking them can't be interpreted. Dexamethasone doesn't cross-react.
• Interpreting a random cortisol in a sick patient: below about 100 nmol/L strongly supports adrenal insufficiency; a value well above 500 nmol/L makes it unlikely. Values between need a short synacthen test once the patient is stable. Assay cut-offs vary, so use the local laboratory's.
• ACTH: high in primary, low or inappropriately normal in secondary.
• Once stable: short synacthen test (250 µg tetracosactide, cortisol at 0 and 30 to 60 minutes). Hold hydrocortisone for 24 hours before testing, or switch to dexamethasone, which doesn't cross-react with the cortisol assay.
• Primary disease: 21-hydroxylase antibodies, then CT adrenals if antibody negative. Secondary: pituitary MRI and the other pituitary axes.
• Pitfall: a synacthen test done within about 4 to 6 weeks of a pituitary insult (surgery, apoplexy) can be falsely normal, because the adrenals haven't yet atrophied.

Management

Immediate

1. Hydrocortisone 100 mg IV or IM as soon as the diagnosis is suspected. This is the step most often delayed in Australian emergency departments.
2. Fluids: 0.9% sodium chloride, 1 L over the first hour, then guided by haemodynamics. Usually 3 to 4 L in the first 24 hours, with care in older people and heart failure.
3. Glucose: check it and treat hypoglycaemia with IV dextrose.
4. Hydrocortisone 200 mg per 24 hours after the bolus, as a continuous infusion or 50 mg every 6 hours IV or IM (NICE NG243, Endocrine Society 2016).
5. Find and treat the trigger: cultures, chest X-ray, urine, lipase, ECG.

• Mineralocorticoid: not needed while hydrocortisone exceeds about 50 mg/day. Restart fludrocortisone (usually 50 to 200 µg daily) in primary disease once the dose is weaned.
• Hyponatraemia: correct no faster than 8 to 10 mmol/L in 24 hours. Hydrocortisone switches off ADH and can cause a brisk water diuresis, so check sodium every 4 to 6 hours.
• Hyperkalaemia usually corrects with fluids and hydrocortisone; treat dangerous levels as in the hyperkalaemia note.

Stepping down

• Taper over 1 to 3 days as the trigger resolves, to oral hydrocortisone at double the usual dose, then back to maintenance (typically 15 to 25 mg daily in 2 or 3 doses, the largest on waking).
• Prednisolone (3 to 5 mg daily) is an alternative for maintenance; dexamethasone is avoided for long-term replacement.

Surgery and procedures

The UK peri-operative guideline (Association of Anaesthetists, RCP and Society for Endocrinology 2020) is widely used in Australia:

• Major surgery or labour: hydrocortisone 100 mg IV at induction, then 200 mg per 24 hours until eating and drinking, then double oral dose for 48 hours or longer.
• Minor procedures: double the usual oral dose on the day, or a single IV dose at the start.

Pregnancy

• Hydrocortisone needs rise in the third trimester (increase by about 20 to 40%). Give 100 mg IV at the onset of active labour or before caesarean section, then stress dosing.
• Prednisolone is acceptable; dexamethasone crosses the placenta and is avoided.

Prevention

• Sick-day rules:
  • Fever above 38°C or illness needing bed rest: double the oral dose until better
  • Vomiting, diarrhoea or unable to take tablets: hydrocortisone 100 mg IM and go to hospital
• Emergency kit: hydrocortisone 100 mg vial (Solu-Cortef), needle and syringe, with the patient and family taught to inject IM. Prescribe the injection so the patient holds their own supply.
• Medical alert ID and a written emergency plan. The Endocrine Society of Australia and the Australian Pituitary Foundation publish patient emergency plans and cards.
• Glucocorticoid-induced disease: anyone stopping long-term glucocorticoids should taper, and needs stress dosing for illness or surgery until HPA axis recovery is shown (ESE/Endocrine Society 2024). Refer to an endocrinologist if the axis hasn't recovered after a year on physiological doses, or after a crisis.
• Immune checkpoint inhibitors: hypophysitis (especially ipilimumab) and primary adrenalitis can present as crisis. Check morning cortisol in anyone on these drugs who becomes fatigued or hypotensive.

Complications

• Death from refractory shock or hypoglycaemia. Annual crisis rates are around 5 to 10 per 100 patient-years in known adrenal insufficiency, with roughly 0.5 deaths per 100 patient-years.
• Osmotic demyelination from over-rapid sodium correction after hydrocortisone.
• Over-replacement long term: weight gain, osteoporosis, hyperglycaemia. Aim for the lowest maintenance dose that controls symptoms.

Pitfalls

• Waiting for a cortisol result or a synacthen test before giving hydrocortisone.
• Assuming the patient on long-term prednisolone 5 mg daily for polymyalgia is safe because the dose is near physiological. The axis can still be suppressed, and illness and vomiting precipitate crisis.
• Using dexamethasone for the acute crisis in primary adrenal insufficiency. It lacks mineralocorticoid activity (though it is reasonable as a one-off to preserve a synacthen test, followed by hydrocortisone).
• Starting thyroxine before hydrocortisone in hypopituitarism.
• Missing adrenal insufficiency as the cause of falling insulin requirements and recurrent hypos in type 1 diabetes, or of unexplained hyponatraemia.
• Forgetting that bilateral adrenal haemorrhage can follow anticoagulation, heparin-induced thrombocytopenia or antiphospholipid syndrome, presenting as abdominal pain and shock.