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Level 2 of 6Must-remember

Adrenal crisis: recognition and emergency glucocorticoid

Assess, manage and stay safe — enough on its own

The card — assess, manage, caution

Assessment— look, ask, measure

  • Know what you are looking for: adrenal crisis is circulatory collapse caused by the sudden inadequacy of circulating cortisol — an acute deterioration in health status with absolute hypotension (systolic below 100 mmHg) or relative hypotension (systolic at least 20 mmHg below the patient's usual value), whose features resolve within one to two hours of parenteral glucocorticoid.
  • Ask the question that actually finds the disease: not "does this look like Addison's?" but "has this patient had steroids — inhaled or topical included, stopped within the past year included?" — HPA suppression by exogenous glucocorticoid affects 0.5–2% of the population of developed countries, whereas Addison's disease has an incidence of only 3–4 per million per year and a prevalence of 40–60 per million.
  • Take the steroid history in detail: glucocorticoids given orally or systemically for longer than four weeks, repeated courses within the previous year, or a dose exceeding the equivalent of 5 mg prednisolone daily all suppress the axis — and all glucocorticoid therapy, including inhaled and topical preparations, can do so.
  • Look for the chronic prodrome: weight loss (a uniform presenting feature in primary disease), anorexia, profound fatigue, weakness, nausea, vomiting, abdominal pain, myalgia, postural dizziness, salt craving, and pigmentation of sun-exposed and pressure areas, palmar creases, knuckles, buccal mucosa, conjunctivae and recent scars.
  • Two signs carry disproportionate discriminant value: buccal and palmar-crease pigmentation (present in over 90% of Addison's disease) and postural hypotension (80–90%, often when the supine pressure is still normal).
  • The crisis itself: circulatory shock with severe hypotension, hyponatraemia and hyperkalaemia, with hypoglycaemia and hypercalcaemia in some instances, accompanied by muscle cramps, nausea, vomiting, diarrhoea, abdominal pain and unexplained fever; abdominal pain may mimic peritonitis, confusion and reduced consciousness are common, and seizures usually reflect hypoglycaemia or profound hyponatraemia.
  • Measure and interpret the bedside numbers: blood pressure lying and standing, capillary glucose (hypoglycaemia in a non-diabetic adult is a danger sign), sodium, potassium, urea (disproportionately raised), a blood gas with lactate, and a 12-lead ECG for hyperkalaemic change and ischaemia.Not available at your setup — Serum electrolytes, Arterial blood gas.
  • The near-diagnostic combination in primary disease: hypotension with hyponatraemia, hyperkalaemia and a urine sodium inappropriately high — much greater than 20 mmol/L — in a hypovolaemic patient.
  • But know what secondary disease removes: in secondary (central) insufficiency aldosterone secretion is preserved, so there is no pigmentation, no hyperkalaemia and less volume depletion, with more prominent hypoglycaemia and often other pituitary deficits — their absence excludes nothing.
  • Danger signs demanding immediate treatment: shock unresponsive to adequate fluid, or to fluid plus vasopressor; hypotension with hyponatraemia, hyperkalaemia and a high urine sodium; any hypotensive patient who takes steroids, has taken them within the past year, or carries a steroid card, alert bracelet or hydrocortisone ampoule; hypoglycaemia in a non-diabetic adult; reduced consciousness or seizure with hyponatraemia; hyperkalaemic ECG change; purpuric rash with shock (Waterhouse–Friderichsen); sudden headache with visual loss (pituitary apoplexy); a steroid-dependent patient who is vomiting; and any shocked neonate.
  • Grade the severity physiologically: systolic below 90 mmHg or at least 20 mmHg below usual and unresponsive to the first litre of fluid; shock index (heart rate ÷ systolic) above 1.0; lactate above 2 mmol/L, and above 4 mmol/L marking profound hypoperfusion; urine output below 0.5 mL/kg/h; any reduction in Glasgow Coma Scale, delirium or seizure; sodium below 125 mmol/L; potassium 6.0 mmol/L or more or any hyperkalaemic ECG change; glucose below 4.0 mmol/L or refractory; and failure of blood pressure to improve within one hour of 100 mg hydrocortisone plus 2 L crystalloid.Not available at your setup — Serum electrolytes.
  • Hunt the precipitant, because finding it is part of the treatment: infection (much the commonest, and often occult); gastrointestinal illness (a vomited tablet is a dose never given); surgery, trauma, burns and childbirth without increased steroid cover; missed, stopped or wrongly tapered doses; myocardial infarction; levothyroxine started before glucocorticoid; and enzyme-inducing drugs (rifampicin, phenytoin, carbamazepine).
  • Send one clotted sample for serum cortisol, with plasma ACTH if the laboratory can process it, drawn in the same venepuncture as the cannula — and if that would cost any time in a shocked patient, give the hydrocortisone first and record that the sample was post-treatment.
  • Expect the blood count to point away from an acute abdomen: adrenal insufficiency produces lymphocytosis and eosinophilia, whereas in an acute abdomen neutrophilia is the rule; anaemia is masked by haemoconcentration and emerges only after rehydration.
  • Think of the crisis in the shocked child or neonate: the commonest cause of primary insufficiency in childhood is congenital adrenal hyperplasia, of which 21-hydroxylase deficiency is the commonest form, occurring in about 1 in 15 000 births — the five- to fourteen-day-old baby who is vomiting, feeding poorly, failing to regain birth weight, floppy and shocked, regularly mistaken for reflux, sepsis or pyloric stenosis.
  • The most important red flag is conceptual: the shock that does not add up — hypotension out of proportion to the apparent illness, or unexplained after an hour of competent resuscitation.

Management— do this, in order

  • Treat on suspicion and confirm retrospectively: take the pre-treatment sample if it costs no time, then give hydrocortisone. A dose given to a patient who did not need it does no harm; a dose withheld from one who did may be fatal. Treatment must never be delayed for the results of investigations.
  • First line, adults: hydrocortisone sodium succinate 100 mg by intravenous bolus. If a vein cannot be obtained quickly, give it intramuscularly into the anterolateral thigh and keep trying for the vein.Doctor / Nurse
  • Continuation, adults: 200 mg of hydrocortisone in the first 24 hours, given as 50 mg intravenously or intramuscularly every 6 hours or as a continuous infusion; no dose may be omitted — a patient stabilised at midnight who deteriorates at dawn has usually simply missed a dose. Reduce the dose as the clinical situation improves, guided by blood pressure, mental state, appetite and electrolytes.Doctor / NurseNot available at your setup — Infusion pump.
  • Fludrocortisone is not required acutely — at these doses hydrocortisone provides ample mineralocorticoid effect.
  • If hydrocortisone is unavailable: dexamethasone 4 mg IV (≈ 160 mg hydrocortisone; loses essentially all mineralocorticoid activity, so give saline generously, but does not cross-react in the cortisol assay), prednisolone 25 mg IV or orally (≈ 100 mg), methylprednisolone 20 mg IV (≈ 100 mg), or cortisone acetate 125 mg orally (≈ 100 mg; needs hepatic conversion and an intact gut — a last resort).Doctor / Nurse
  • Children — immediate glucocorticoid, hydrocortisone sodium succinate IV or IM as a single stat bolus: under 1 year 25 mg, 1–5 years 50 mg, over 5 years 100 mg (equivalently 100 mg/m²). Never delay the first dose to calculate a body surface area.Doctor / Nurse
  • Children — continuation: approximately 100 mg/m² per 24 hours divided 6-hourly, in practice the same age-banded dose repeated six-hourly, reduced as the child improves.Doctor / Nurse
  • Fluid, adults: 1 L of 0.9% sodium chloride over 30–60 minutes with the hydrocortisone bolus; several litres are usually needed over 24 hours. Initial rates of up to 1 L per hour are permitted with continuous cardiac monitoring in a profoundly shocked adult; in cardiac or renal disease and in the elderly, slow down and reassess after each litre using jugular venous pressure, lung bases, urine output and the pressure response.
  • Fluid, children: 0.9% sodium chloride 10–20 mL/kg over 10–20 minutes, reassess, repeat as required.
  • Cardiac monitoring is mandatory from the outset, because the potassium may be high and large volumes are being infused rapidly.
  • Glucose: check capillary glucose immediately and hourly, and treat a value below 4.0 mmol/L with intravenous 10% glucose — adult 100–200 mL, child 2 mL/kg by slow intravenous injection — followed by an infusion titrated to hourly glucose if recurrent.
  • Potassium: hyperkalaemia in adrenal crisis usually responds to volume replacement and glucocorticoid alone and only occasionally requires specific therapy; if the potassium is 6.5 mmol/L or more or there are hyperkalaemic ECG changes, treat it in its own right with intravenous calcium, insulin with glucose and nebulised salbutamol.Not available at your setup — Serum electrolytes.
  • Sodium — the danger is the correction, not the value: where the sodium is below 125 mmol/L, do not allow it to rise by more than 10 mmol/L in 24 hours; recheck electrolytes every 4–6 hours for the first day and slow the infusion, or substitute hypotonic fluid if over-correction has occurred, when the sodium climbs faster than about 0.4 mmol/L per hour.Not available at your setup — Serum electrolytes.
  • Treat the precipitant: because bacterial infection frequently precipitates adrenal crisis, give broad-spectrum antibiotics empirically after cultures while awaiting results.Doctor / NurseNot available at your setup — Blood culture.
  • If the pressure has not improved after 2 L of crystalloid and 100 mg of hydrocortisone within an hour, work through five questions in order: has enough steroid been given (repeat hydrocortisone 100 mg intravenously, since an intramuscular dose may not have absorbed in a shocked vasoconstricted patient); has enough volume been given; is there a second shock state (occult haemorrhage, myocardial infarction, pulmonary embolism, tension pneumothorax, tamponade, anaphylaxis, above all uncontrolled sepsis with an undrained source); start a vasopressor; and reconsider the anatomy.Doctor / Nurse
  • Noradrenaline is the vasopressor of choice for vasoplegic shock, titrated to a mean arterial pressure of around 65 mmHg with invasive monitoring — but cortisol is what restores vascular responsiveness to catecholamines, so the steroid must precede the pressor; escalating noradrenaline in an untreated crisis achieves nothing.Doctor / NurseNot available at your setup — Infusion pump, ICU / HDU bed.
  • Convert to oral therapy only when the patient is genuinely well and reliably absorbing: oral hydrocortisone 20 mg 8-hourly, reduced over a few days to a maintenance of 15–25 mg daily in two or three divided doses weighted to the morning — for example 10 mg on waking and 5 mg at about 15:00, or 10 mg at 07:00, 10 mg at 13:00 and 5 mg at 19:00, the total preferably not exceeding 20–25 mg daily.
  • Before discharge, prevent the next crisis: written sick-day rules, a steroid emergency card, an alert bracelet, and a hydrocortisone 100 mg ampoule and syringe for intramuscular self-injection with patient and relative trained in its use — double the oral hydrocortisone for any febrile illness needing bed rest, and use the 100 mg intramuscular ampoule and seek care the same day if vomiting, diarrhoea or unable to swallow.

Caution— what harms

  • Never delay treatment for the results of investigations — the third diagnostic criterion (resolution within one to two hours of parenteral glucocorticoid) is retrospective, so adrenal crisis is confirmed by its response to treatment, not by any test available at the moment of decision.
  • Never perform an ACTH (Synacthen) stimulation test on a shocked patient; investigation should precede treatment only in patients with features of chronic insufficiency and no haemodynamic compromise.
  • Never give levothyroxine before glucocorticoid in suspected adrenal or pituitary disease, including suspected myxoedema coma — it precipitates crisis.
  • Do not let the sodium rise too fast: below 125 mmol/L allow no more than a 10 mmol/L rise in 24 hours, because hyponatraemia here is both depletional and dilutional and both mechanisms reverse quickly once saline and hydrocortisone are given — osmotic demyelination (central pontine myelinolysis) is a disease inflicted rather than presented with.
  • Do not rely on a random cortisol to exclude the diagnosis: it may fall within the population reference range while being grossly inappropriate for a critically ill patient, thresholds are assay-dependent, and in a critically ill patient do not consider the diagnosis excluded below about 550 nmol/L.
  • Remember what distorts the cortisol: total cortisol tracks cortisol-binding globulin, so oestrogen therapy and pregnancy raise it (falsely reassuring) and hypoalbuminaemia and critical illness lower it (falsely alarming); hydrocortisone and prednisolone cross-react in most cortisol immunoassays whereas dexamethasone does not, and hydrocortisone must not be given for at least 8 hours before a cortisol measurement or stimulation test.
  • A normal stimulation test does not exclude acute ACTH deficiency: the test depends on ACTH-dependent adrenal atrophy, which takes roughly two weeks to develop after pituitary damage, so it may be normal in pituitary apoplexy — falsely reassuring in exactly the situation that kills fastest.
  • Normal electrolytes do not exclude the diagnosis, and hyperkalaemia and pigmentation are absent in secondary insufficiency, so their absence excludes nothing; pigmentation takes months to develop and is therefore absent in a crisis of sudden onset.Not available at your setup — Serum electrolytes.
  • Adrenal crisis and sepsis look identical and frequently coexist — sepsis is the commonest precipitant, so refractory vasoplegia despite adequate fluid and vasopressor should prompt glucocorticoid rather than a further escalation of the pressor.
  • In a steroid-treated patient the anti-inflammatory action of glucocorticoid masks the signs of disease: perforation of a viscus may be silent, there may be no febrile response, and the white cell count is raised by glucocorticoid itself (predominantly neutrophils) — so neither a benign abdomen nor a reassuring count means what it usually means, and anaesthesia in an untreated crisis may be fatal.
  • A vomiting steroid-dependent patient has had no steroid, whatever the tablet box says — a vomited tablet is a dose never given, and the patient must return to the parenteral route.
  • Do not omit a dose: the commonest reason a stabilised patient deteriorates hours later is simply a missed dose of hydrocortisone.
  • Do not give fludrocortisone acutely, and do not add it later until hydrocortisone falls below 50 mg daily, because above that hydrocortisone itself provides sufficient mineralocorticoid receptor stimulation (40 mg hydrocortisone ≈ 100 micrograms fludrocortisone).
  • Beware rapid large-volume saline in cardiac or renal disease and in the elderly — it may precipitate pulmonary oedema; and long-term over-replacement causes weight gain, glucose intolerance, hypertension and bone loss, with doses equivalent to 30 mg hydrocortisone or more affecting bone metabolism.
  • Do not make any statement about the sex of an infant with ambiguous genitalia to the family before urgent specialist endocrine assessment.
  • Do not measure cortisol to judge the adequacy of long-term replacement — it is not recommended; judge by wellbeing and weight, since excess weight gain indicates over-replacement while persistent lethargy or hyperpigmentation suggests an inadequate dose or poor absorption.

Refer / escalate

Escalate or transfer urgently if the blood pressure fails to improve within one hour of 100 mg hydrocortisone plus 2 L crystalloid, if there is refractory shock needing a vasopressor, sodium below 125 mmol/L, potassium 6.5 mmol/L or more or hyperkalaemic ECG change, reduced consciousness or seizure, purpuric rash with shock, sudden headache with visual loss, or any shocked neonate or child with suspected congenital adrenal hyperplasia.

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