Pheochromocytoma, Emergency Medicine

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Pheochromocytoma, Emergency Medicine

Basics

Description

Stable patient with mild hypertension.

Pheochromocytoma (pheo) is a catecholamine-producing tumor arising from the chromaffin tissues of the sympathetic nervous system.
Origin from the adrenal medulla or sympathetic ganglia:80% solitary adrenal (usually the right side)10% bilateral (usually inherited form)10% extra-adrenal in location:Abdominal, within mesenteric ganglia (86%)Thorax (10%), neck (3%), bladder (1%)10% malignant (usually inherited form)
Incidence:0.2 " 0.4% of hypertensive patients, but higher proportion of patients with severe hypertension2 " 8/million population per yearPeaks in decades 3 " 5, 10% in childrenMale = femaleIn about 1/2 of the cases, the diagnosis is made postmortem.10% asymptomatic, incidental on CT
Genetics:Inherited form 25%, autosomal dominantUsually associated with multiple endocrine neoplasia (MEN) 2A, less so with MEN 2B or von Hippel " Lindau (VHL) disease:MEN 2A (medullary thyroid carcinoma [CA], pheo, and hyperparathyroidism)MEN 2B (medullary thyroid CA, pheo, oral mucosal neuromas, skeletal and bony abnormalities)VHL (hemangioblastomas of retina and CNS, pancreas and renal cysts, and pheoOther associated diseases: Neurofibromatosis, tuberous sclerosis, Sturge " Weber syndrome, paragangliomas of the neck

80% solitary adrenal (usually the right side)
10% bilateral (usually inherited form)
10% extra-adrenal in location:Abdominal, within mesenteric ganglia (86%)Thorax (10%), neck (3%), bladder (1%)
10% malignant (usually inherited form)

Abdominal, within mesenteric ganglia (86%)
Thorax (10%), neck (3%), bladder (1%)

0.2 " 0.4% of hypertensive patients, but higher proportion of patients with severe hypertension
2 " 8/million population per year
Peaks in decades 3 " 5, 10% in children
Male = female
In about 1/2 of the cases, the diagnosis is made postmortem.
10% asymptomatic, incidental on CT

Inherited form 25%, autosomal dominant
Usually associated with multiple endocrine neoplasia (MEN) 2A, less so with MEN 2B or von Hippel " Lindau (VHL) disease:MEN 2A (medullary thyroid carcinoma [CA], pheo, and hyperparathyroidism)MEN 2B (medullary thyroid CA, pheo, oral mucosal neuromas, skeletal and bony abnormalities)VHL (hemangioblastomas of retina and CNS, pancreas and renal cysts, and pheo
Other associated diseases: Neurofibromatosis, tuberous sclerosis, Sturge " Weber syndrome, paragangliomas of the neck

MEN 2A (medullary thyroid carcinoma [CA], pheo, and hyperparathyroidism)
MEN 2B (medullary thyroid CA, pheo, oral mucosal neuromas, skeletal and bony abnormalities)
VHL (hemangioblastomas of retina and CNS, pancreas and renal cysts, and pheo

Etiology

The tumor synthesizes and stores catecholamines in the same manner as the normal adrenal medulla.
Tumors predominantly secrete norepinephrine, and to a lesser extent epinephrine (some tumors are epinephrine predominant, in which hypotensive episodes are characteristic)
Paroxysmal release of catecholamines:Spontaneously due to changes in blood flow or tumor necrosisDirect pressure on the gland from external forces (trauma, exercise)Precipitation of release (opiates, glucagon, metoclopramide, steroids, foods with tyramine, iodinated contrast media)Augmentation of catecholamine effect (tricyclic antidepressants [TCAs], ²-blockers, sympathomimetics)

Spontaneously due to changes in blood flow or tumor necrosis
Direct pressure on the gland from external forces (trauma, exercise)
Precipitation of release (opiates, glucagon, metoclopramide, steroids, foods with tyramine, iodinated contrast media)
Augmentation of catecholamine effect (tricyclic antidepressants [TCAs], ²-blockers, sympathomimetics)

Diagnosis

Signs and Symptoms

Hypertension, moderate to severe, refractory to treatment:40%: Paroxysms with normal BP between episodes30%: Sustained hypertension with paroxysms30%: Sustained hypertension without paroxysmsSometimes normotensive in familial forms and small tumors: <5%
Paroxysmal symptomsSudden onset, gradual resolutionDuration: Minutes to hours (average 20 min)Intervals: Hours to months (average weekly)Increasing frequency, duration, and severity with time
Clinical characteristics of paroxysmsHypertensive crisis or urgencyHeadache " abrupt, throbbing, bilateralTachycardia/palpitationsProfuse diaphoresis/pallorApprehension/anxiety/tremulousShock associated with trauma, surgery, parturition, anesthesia
Acute crisisProlonged (>24hr) severe paroxysmSevere HTN or shock, hyperpyrexiaMultiorgan failure/lactic acidosisPulmonary edema due to cardiomyopathy (dilated, hypertrophic or Takotsubo)Stroke (SAH, PRES, RCVS, embolic)Severe headache/encephalopathyChest pain (MI/dissection)Acute abdomenHemorrhagic tumor necrosisMesenteric infarction
Chronic symptomsChest pains/palpitationsOrthostasis (decreased plasma volume and blunted sympathetic reflexes)Constipation can be severe, leading to ileus or pseudo-obstruction (catecholamines inhibit peristalsis)Weight loss/fevers (increased metabolism)Lethargy, fatigue (catecholamine withdrawal))Polydipsia, polyuria (glucose intolerance)Anxiety, tremors, heat intolerance

40%: Paroxysms with normal BP between episodes
30%: Sustained hypertension with paroxysms
30%: Sustained hypertension without paroxysms
Sometimes normotensive in familial forms and small tumors: <5%

Sudden onset, gradual resolution
Duration: Minutes to hours (average 20 min)
Intervals: Hours to months (average weekly)
Increasing frequency, duration, and severity with time

Hypertensive crisis or urgency
Headache " abrupt, throbbing, bilateral
Tachycardia/palpitations
Profuse diaphoresis/pallor
Apprehension/anxiety/tremulous
Shock associated with trauma, surgery, parturition, anesthesia

Prolonged (>24hr) severe paroxysm
Severe HTN or shock, hyperpyrexia
Multiorgan failure/lactic acidosis
Pulmonary edema due to cardiomyopathy (dilated, hypertrophic or Takotsubo)
Stroke (SAH, PRES, RCVS, embolic)
Severe headache/encephalopathy
Chest pain (MI/dissection)
Acute abdomenHemorrhagic tumor necrosisMesenteric infarction

Hemorrhagic tumor necrosis
Mesenteric infarction

Chest pains/palpitations
Orthostasis (decreased plasma volume and blunted sympathetic reflexes)
Constipation can be severe, leading to ileus or pseudo-obstruction (catecholamines inhibit peristalsis)
Weight loss/fevers (increased metabolism)
Lethargy, fatigue (catecholamine withdrawal))
Polydipsia, polyuria (glucose intolerance)
Anxiety, tremors, heat intolerance

Moderate to severe hypertension, often with orthostatic changes
Tachycardic, diaphoretic, evidence of weight loss, low-grade fever
Pallor, cold hands and feet (flushing not seen, except rarely after a paroxysm)
Tremor, anxiety
Mydriasis, hypertensive retinopathy
Cafe au lait spots, neurofibromas, thyroid nodule
No palpable masses (tumors tend to be small)

Essential Workup

Accurate BP determination with orthostatic BPs
ECG to exclude ischemia or dysrhythmias

Diagnosis Tests & Interpretation

Overdiagnosis in >20% from misinterpretation of borderline biochemical tests and overzealous imaging
Underdiagnosis is common from failure to consider the diagnosis or ignoring adrenal masses on CT.

CBC:Elevated hemoglobin due to diminished plasma volumeElevated WBC from demargination
Electrolytes, BUN, creatinine, glucose:Lactic acidosisRenal failure secondary to hypertensive nephropathyHyperglycemia due to impaired response to insulin and effect of catecholaminesHypercalcemia due to excess parathyroid hormone
Urinalysis: Proteinuria and hematuria
Plasma-free metanephrine (fractionated):96% sensitive, 85% specific " best screening test. Normal level excludes diagnosis, but many false positivesLeast likely to be interfered by medications or stress and no special prep for venipuncture
24 hr urine collection for free catecholamines and metanephrine (total and fractionated):99.7% combined specificity and 87.5% sensitivity (best test for confirmation)Must include creatinine to verify adequate collectionMedications that interfere: Levodopa, methyldopa, monoamine oxidase inhibitors (MAOIs), labetalol, propranolol, radiographic contrast media, sympathomimetics, benzodiazepines, TCAs, caffeine, nicotine

Elevated hemoglobin due to diminished plasma volume
Elevated WBC from demargination

Lactic acidosis
Renal failure secondary to hypertensive nephropathy
Hyperglycemia due to impaired response to insulin and effect of catecholamines
Hypercalcemia due to excess parathyroid hormone

96% sensitive, 85% specific " best screening test. Normal level excludes diagnosis, but many false positives
Least likely to be interfered by medications or stress and no special prep for venipuncture

99.7% combined specificity and 87.5% sensitivity (best test for confirmation)
Must include creatinine to verify adequate collection
Medications that interfere: Levodopa, methyldopa, monoamine oxidase inhibitors (MAOIs), labetalol, propranolol, radiographic contrast media, sympathomimetics, benzodiazepines, TCAs, caffeine, nicotine

CT sensitive for adrenal masses >1 cm (IV contrast may pose a slight risk):5% of incidental adrenal tumors seen on CT are pheos.
MRI or positron emission tomography more sensitive in identifying adrenal pheos as well as identifying extra-adrenal tumors
Metaiodobenzylguanidine (radionuclear scintiscan: High specificity for localization, but not sensitive enough to exclude pheo)
Chest radiograph for pulmonary edema
CT head for CVA/intracranial bleed

5% of incidental adrenal tumors seen on CT are pheos.

Clonidine suppression test if diagnosis uncertain (levels not suppressed if pheo)
Provocative testing with glucagon is not recommended.
Fine-needle aspiration is contraindicated.
Laparoscopic resection is feasible in many cases.

Differential Diagnosis

Alcohol withdrawal syndrome
Autonomic hyperreflexia
Cerebral vascular accident
Cocaine or amphetamine intoxication
Hypertensive crisis
Migraines/subarachnoid hemorrhage
Panic attack
Postural tachycardia syndrome
Paroxysmal supraventricular tachycardia
Posterior reversible encephalopathy syndrome
Serotonin syndrome
Thyrotoxicosis
Toxemia

Treatment

Pre-Hospital

IV access, oxygen
Continuous cardiac/BP monitoring
Nitroglycerin 0.4 mg SL for chest pain and HTN

Ed Treatment/Procedures

Phentolamine:α-blockade:1 mg IV test dose2.5 " 5 mg IV bolus given at 1 mg/min repeat bolus every 5 " 15 min to BP control. Follow by infusionInfusion starting at 0.1 mg/min titrated up to 1 mg/minVigorous fluid resuscitation required as vasoconstriction is relievedTraditional approach, but Nicardipine or Nitroprusside drip may be more practical
²-blockade:Add toα-blockade for further BP controlIf tachycardia develops during induction ofα-blockadeNEVER USE ALONE: Institution of ²-blockade without priorα-adrenergic blockade may exacerbate hypertension by antagonizing ²-mediated vasodilation in smooth muscle.Esmolol: Load 500 Όg/kg over 1 min, followed by 50 Όg/kg/min for 4 min; if adequate therapeutic effect not achieved within 5 min, repeat loading dose and increase infusion to 100 Όg/kg/min; repeat loading dose and titrate infusion rate upward at 50 Όg/kg/min q4 " q5min as needed; omit further loading doses once nearing therapeutic target.Labetalol: Begin with 10 " 20 mg IV; BP falls within 5 min, maximum effect at 10 min; can double IV dose q15 " q30min until target reached (α-blockade inadequate to be relied on as a single agent).Metoprolol: 5 mg IV q15min until response
Resistance toα- and ²-blockade or 1st-line option if unfamiliar with Phentolamine:Nitroprusside:Start at 0.5 Όg/kg/minTitrate by 0.5 Όg/kg/min incrementsMaximum dose 10, average needed 3 " 4Nicardipine:Start infusion at 5 mg/hrTitrate up by 2.5 mg/hr every 15 min15 mg/hr maximum doseAdd ²-blockade to vasodilator if needed
Ventricular tachydysrhythmias:Lidocaine:50 " 100 mg bolusRepeat bolus q5min (5 mg/kg max.)Esmolol 50 " 200 Όg/kg/min infusion

1 mg IV test dose
2.5 " 5 mg IV bolus given at 1 mg/min repeat bolus every 5 " 15 min to BP control. Follow by infusion
Infusion starting at 0.1 mg/min titrated up to 1 mg/min
Vigorous fluid resuscitation required as vasoconstriction is relieved
Traditional approach, but Nicardipine or Nitroprusside drip may be more practical

Add toα-blockade for further BP control
If tachycardia develops during induction ofα-blockade
NEVER USE ALONE: Institution of ²-blockade without priorα-adrenergic blockade may exacerbate hypertension by antagonizing ²-mediated vasodilation in smooth muscle.
Esmolol: Load 500 Όg/kg over 1 min, followed by 50 Όg/kg/min for 4 min; if adequate therapeutic effect not achieved within 5 min, repeat loading dose and increase infusion to 100 Όg/kg/min; repeat loading dose and titrate infusion rate upward at 50 Όg/kg/min q4 " q5min as needed; omit further loading doses once nearing therapeutic target.
Labetalol: Begin with 10 " 20 mg IV; BP falls within 5 min, maximum effect at 10 min; can double IV dose q15 " q30min until target reached (α-blockade inadequate to be relied on as a single agent).
Metoprolol: 5 mg IV q15min until response

Nitroprusside:Start at 0.5 Όg/kg/minTitrate by 0.5 Όg/kg/min incrementsMaximum dose 10, average needed 3 " 4
Nicardipine:Start infusion at 5 mg/hrTitrate up by 2.5 mg/hr every 15 min15 mg/hr maximum dose
Add ²-blockade to vasodilator if needed

Start at 0.5 Όg/kg/min
Titrate by 0.5 Όg/kg/min increments
Maximum dose 10, average needed 3 " 4

Start infusion at 5 mg/hr
Titrate up by 2.5 mg/hr every 15 min
15 mg/hr maximum dose

Lidocaine:50 " 100 mg bolusRepeat bolus q5min (5 mg/kg max.)
Esmolol 50 " 200 Όg/kg/min infusion

50 " 100 mg bolus
Repeat bolus q5min (5 mg/kg max.)

Medication

Phenoxybenzamine: Start at 10 mg BID orally, titrate up 10 mg every other day until desired effect (start at least 7 days preop).
Otherα-blockers (1st dose effect):Doxazosin: 1 " 8 mg/d (start at 1 mg)Terazosin: 1 " 10 mg/d (start at 1 mg)
²-blocker added to control reflex tachycardia:Metoprolol or atenolol: 25 " 100 mg/d

Doxazosin: 1 " 8 mg/d (start at 1 mg)
Terazosin: 1 " 10 mg/d (start at 1 mg)

Metoprolol or atenolol: 25 " 100 mg/d

Calcium-channel blockers:Amlodipine, nicardipine, or nifedipine
Inhibition of catecholamine synthesis:Metyrosine: 250 " 500 mg q6h

Amlodipine, nicardipine, or nifedipine

Metyrosine: 250 " 500 mg q6h

²-blockers (if not pretreated withα-blocker)
Glucagon
Glucocorticoids
Iodinated contrast media (ionic)
Ketamine
Metoclopramide
Opiates
Sympathomimetics, including over-the-counter decongestants

May be confused with toxemia, but proteinuria is usually absent
MRI is the preferred imaging modality.
Nitroprusside should not be used for hypertensive crisis, but all other BP medications are acceptable.
Spontaneous vaginal delivery will likely precipitate hypertensive crisis, such that C-section should be planned.

Follow-Up

Disposition

Suspicion of pheo in an ill or toxic patient with labile swings in BP
Hypertensive urgency or crisis
Cardiac arrhythmias
End organ compromise: Congestive heart failure, myocardial infarction, renal insufficiency, CVA, abdominal pain

Follow-Up Recommendations

Obtain plasma-free metanephrine during a hypertensive episode.
Consider initiating doxazosin or terazosin or a calcium-channel blocker for BP control.
Arrange close follow-up

Pearls and Pitfalls

Paroxysms of severe hypertension, headache, intense diaphoresis, and palpitations comprise a tetrad very suggestive of pheo.
Pallor and sweating, not flushing, is typical of pheo crisis.
Orthostasis is common in pheo and it is further aggravated byα-blockade, unless volume repletion is not done concomitantly.
Consider pheo in unexplained shock, multisystem organ failure, cardiomyopathy, new glucose intolerance with weight loss.
Never administer ²-blockers (even labetalol) beforeα-blockade in patients with pheo
Plasma-free metanephrine during an attack is very sensitive but not specific in the diagnosis

Additional Reading

Anderson NE, Chung K, Willoughby E, et al. Neurologic manifestations of phaeochromocytomas and secretory paragangliomas: A reappraisal. J Neurol Neurosurg Psychiatry. 2013;84:452 " 457.
Donckier JE, Michel L. Pheochromocytoma: State-of-the-art. Acta Chir Belg. 2010;110(2):140 " 148.
Mannelli M, Lenders JW, Pacak K, et al. Subclinical pheochromocytoma. Best Pract Res Clin Endocrinol Metab. 2012;26:507 " 515.
Prejbisz A, Lenders JW, Eisenhofer G, et al. Cardiovascular manifestations of pheochromocytoma. J Hypertens. 2011;29:2049 " 2060.
Scholten A, Cisco RM, Vriens MR, et al. Pheochromocytoma is not a surgical emergency. J Clin Endocrinol Metab. 2013;98(2):581 " 591.
Yu R, Nissen NN, Chopra P, et al. Diagnosis and treatment of pheochromocytoma in an academic hospital from 1997 to 2007. Am J Med. 2009;122:85 " 95.

Codes

ICD9

194.0 Malignant neoplasm of adrenal gland
227.0 Benign neoplasm of adrenal gland

ICD10

C74.10 Malignant neoplasm of medulla of unspecified adrenal gland
C74.12 Malignant neoplasm of medulla of left adrenal gland
D35.00 Benign neoplasm of unspecified adrenal gland
C74.11 Malignant neoplasm of medulla of right adrenal gland
C74.1 Malignant neoplasm of medulla of adrenal gland
D35.01 Benign neoplasm of right adrenal gland
D35.02 Benign neoplasm of left adrenal gland
D35.0 Benign neoplasm of adrenal gland

SNOMED

302835009 Pheochromocytoma (disorder)
91967007 Benign neoplasm of adrenal gland (disorder)
363355002 Malignant tumor of adrenal gland (disorder)