Phaeochromocytoma Crisis

Phaeochromocytoma crisis is acute haemodynamic instability with end organ dysfunction caused by massive catecholamine release from a phaeochromocytoma or paraganglioma. It may present as hypertensive crisis, shock or multisystem failure, and may be the first presentation of the tumour.

Epidemiology. Phaeochromocytoma and paraganglioma occur in about 2 to 8 people in a million each year. Crisis is uncommon but carries high mortality when unrecognised, and many cases are first diagnosed during crisis. About 30 to 40% of tumours carry a germline variant (for example SDHx, VHL, RET, NF1).

Triggers.

• Glucocorticoids, including dexamethasone.
• Beta blockers given without prior alpha blockade.
• Metoclopramide, droperidol and some antipsychotics.
• Opioids, ketamine, and anaesthetic induction or intubation.
• Monoamine oxidase inhibitors, tricyclic antidepressants, serotonin and noradrenaline reuptake inhibitors, and sympathomimetics.
• Glucagon, tumour palpation or biopsy, surgery, trauma, pregnancy and delivery, chemotherapy, and spontaneous tumour haemorrhage or necrosis.

Severity. Hypertensive crisis with end organ injury, shock with catecholamine cardiomyopathy, and multisystem crisis with temperature over 40 °C, encephalopathy and failure of two or more organs.

Pathophysiology. Excess adrenaline and noradrenaline cause intense vasoconstriction and tachycardia, then myocardial injury (a stress cardiomyopathy pattern), coronary spasm, arrhythmia, pulmonary oedema and mesenteric ischaemia. Catecholamine depletion or unopposed beta stimulation produces cardiogenic shock and hypotension. Hyperglycaemia, lactic acidosis and rhabdomyolysis follow.

Presentation includes severe headache, sweating, palpitations, pallor, chest pain, dyspnoea, nausea, abdominal pain, anxiety and confusion. Blood pressure may be severely raised, labile, or low with shock. Fever, seizures, stroke, acute pulmonary oedema, arrhythmia, ARDS, ischaemic bowel, hyperglycaemia and acute kidney injury can occur.

Red flags.

• Hypertension with sweating, pallor and tachycardia and no clear cause.
• Crisis after a glucocorticoid, beta blocker, metoclopramide or anaesthetic induction.
• Cardiogenic shock with a normal coronary angiogram.
• Known adrenal mass, family history or genetic syndrome.

Treatment is not delayed for confirmation. Measure plasma free metanephrines (ideally supine, and a level over three times the upper reference limit is strongly suggestive) or 24-hour urinary fractionated metanephrines. Drug interference matters, since tricyclics and serotonin and noradrenaline reuptake inhibitors raise values.

Other tests: ECG, troponin, natriuretic peptide, echocardiogram (global or apical hypokinesia), glucose, lactate, electrolytes, creatinine, creatine kinase, liver tests and blood gas. Adrenal CT or MRI once stable. Non-ionic contrast is acceptable with alpha blockade.

Differential diagnosis.

• Sympathomimetic toxicity (cocaine, amphetamines).
• Thyroid storm, serotonin syndrome and neuroleptic malignant syndrome.
• Malignant hypertension, eclampsia, autonomic dysreflexia and drug or alcohol withdrawal.
• Acute coronary syndrome, sepsis and monoamine oxidase inhibitor interaction.

Admit to intensive care with continuous arterial pressure and ECG monitoring. Stop the trigger. Avoid glucocorticoids and unopposed beta blockade.

Hypertensive crisis.

• Phentolamine 1 to 5 mg IV bolus, repeated every 5 minutes as needed, then an infusion of 0.2 to 2 mg/min titrated to pressure. There is no firm maximum, so titrate to effect and monitor for tachycardia, hypotension and arrhythmia.
• Nicardipine 5 mg/h IV, increased by 2.5 mg/h every 5 to 15 minutes to a maximum of 15 mg/h. Monitor heart rate and blood pressure, and reduce in liver impairment.
• Sodium nitroprusside 0.3 to 0.5 microgram/kg/min IV, titrated to a maximum of 10 microgram/kg/min, for the shortest possible time. Monitor thiocyanate and cyanide (acidosis, rising lactate), and avoid prolonged use in renal or liver impairment.
• Clevidipine 1 to 2 mg/h IV, doubling every 90 seconds at first and then more slowly, to a usual maximum of 21 mg/h (up to 32 mg/h short term), is an alternative where available.

Tachyarrhythmia, only after alpha blockade. Esmolol 500 microgram/kg IV over 1 minute, then 50 to 300 microgram/kg/min. Labetalol is a weak alpha blocker and is not first choice.

Shock and catecholamine cardiomyopathy. Give cautious volume and avoid catecholamines where possible. If a vasopressor is unavoidable, use the lowest noradrenaline dose or vasopressin 0.01 to 0.04 units/min. Consider early venoarterial ECMO for refractory cardiogenic shock. Treat pulmonary oedema with vasodilation, and not with a diuretic alone.

Supportive care. Control temperature, treat seizures with a benzodiazepine, correct acidosis and glucose, manage acute kidney injury and avoid triggering drugs.

Definitive treatment. Once stable, start alpha blockade for 10 to 14 days before surgery: phenoxybenzamine 10 mg every 12 hours, increased by 10 to 20 mg every 2 to 3 days (maximum about 1 mg/kg daily), or doxazosin 2 mg daily increasing to 32 mg daily. Add a beta blocker only after adequate alpha blockade, with a high sodium diet and fluid loading. Operate in a unit with phaeochromocytoma experience. Urgent resection during crisis is reserved for failure of medical control.

Monitoring. Continuous arterial pressure, ECG, heart rate, lactate, troponin, echocardiography, glucose, creatinine and temperature.

Referral and escalation. Early endocrinology, endocrine surgery, cardiology and intensive care. Genetic counselling and testing after recovery.

Special groups. In pregnancy, give phentolamine for crisis, use alpha blockade and deliver in a specialist centre, and avoid beta blockade without alpha blockade. In children, phentolamine is 0.05 to 0.1 mg/kg IV. In renal or liver impairment, limit nitroprusside and reduce nicardipine.