Epinephrine

Epinephrine, a catecholamine secreted by the adrenal gland, is an important central nervous system (CNS) neurotransmitter and has a central role in autonomic regulation including intestinal and bronchial smooth muscle tone, vascular tone, glucose metabolism, and cardiac rate and contractility. Endogenous plasma concentrations in resting adults are normally small, less than 30 pg/mL, but may increase by markedly during stress. Traditionally urinary catecholamines, including epinephrine, are usually measured to diagnose disease states and not serum levels. However, some authors advocate for serum measurements.

The reference range of urinary epinephrine excretion varies by age, as follows.

Adult/elderly: < 20 mcg/24 hr or < 109 nmol/day (SI units) ^[1]

Child ^[1] :

• 0-1 year: 0-2.5 mcg/24 hr
• 1-2 years: 0-3.5 mcg/24 hr
• 2-4 years: 0-6 mcg/24 hr
• 4-7 years: 0.2-10 mcg/24 hr
• 7-10 years: 0.5-14 mcg/24 hr

The following conditions are associated with elevated levels of urine catecholamines:

• Pheochromocytoma ^{[2, 3, 4, 5, 6, 7, 8, 9]} : Norepinephrine (>170 µg/24 h); epinephrine (>35 µg/24 h)

• Neuroblastoma ^[10]

• Ganglioneuroma

• Acute myocardial infarction

• Hypothyroidism

• Diabetic ketoacidosis

• Chronic manic-depressive states

The following conditions are associated with decreased levels of urine catecholamines:

• Diabetic neuropathy

• Parkinson disease

Pheochromocytoma

The classic triad of symptoms in patients with a pheochromocytoma consists of episodic headache, sweating, and tachycardia. It is unusual for all 3 to be present. When pheochromocytoma is suspected measurement of plasma fractionated metanephrines, 24-hour urinary fractionated metanephrines and 24-hour urinary catecholamine measurements are all in use. In one large study, sensitivity was high for both plasma fractionated metanephrines and urinary total metanephrines (95.8% and 94%, respectively) and lower for urinary epinephrine (72.1%). Despite relatively low sensitivity, specificity was highest for urinary epinephrine (99.9%). ^[11] Epinephrine evaluation should therefore not be used as first-line testing for pheochromocytoma, although it can be useful when the diagnosis not completely ruled out by results of urine or plasma metanephrine testing.

Neuroblastoma

The biochemical diagnosis and follow-up of neuroblastoma may benefit from urinary catecholamine measurements with spot or 24-hour urine testing. Results of one or more of these tests may be increased.

Pretest instructions and considerations

Epinephrine testing should not be performed in patients in withdrawal from any drugs (legal or illegal) associated with known rebound plasma catecholamine release during the withdrawal period.

Drugs that release or hinder metabolism of epinephrine, norepinephrine, or dopamine should be discontinued for at least one week prior to specimen collection. However, if discontinuation of such drugs is not possible for medical reasons, the laboratory should be contacted to decide if a shorter drug-discontinuation period would be acceptable.

The following drugs can increase catecholamine measurements:

• Alcohol

• Aminophylline

• Amphetamines

• Buspirone

• Caffeine

• Cocaine

• Decongestants such as phenylephrine or pseudoephedrine

• Withdrawal from recreational or medical sedatives, especially alcohol, benzodiazepines (eg, diazepam), opioids, and certain central-acting antihypertensives (especially clonidine)

• Levodopa

• Methyldopa

• Phenothiazines

• Reserpine

• Tricyclic antidepressants

Drugs that can decrease catecholamine measurements include the following:

• Clonidine

• Disulfiram

• Guanethidine

• MAOIs

• Salicylates

Epinephrine, norepinephrine, or dopamine injections or infusions should be discontinued at least 12 hours before the urine specimen is collected, except when the test is being used for drug monitoring.

For optimal results, the specimen should be collected during a hypertensive episode.

Collection instructions

Beginning after voiding, urine is collected for 24 hours.

As a preservative, 25 mL of 50% acetic acid is added when the collection begins; in children younger than 5 years, 15 mL of 50% acetic acid is used. Acetic acid is used to keep the pH between approximately 2 and 4.

Description

Epinephrine, dopamine, and norepinephrine (catecholamines) are important CNS neurotransmitters and have vital roles in the autonomic regulation of many functions of homeostasis, including intestinal and bronchial smooth muscle tone, vascular tone, glucose metabolism, and cardiac rate and contractility. The catecholamines are derived from tyrosine via a series of enzymatic conversions. Their actions are mediated by alpha-adrenergic and beta-adrenergic receptors and dopamine receptors and exist in multiple subforms. Epinephrine, dopamine, and norepinephrine overlap but differ in their receptor activation profile and resulting biological actions.

The structure of epinephrine is depicted in the image below.

The fraction of the catecholamines that circulates systemically is derived almost exclusively from the adrenal medulla, while sympathetic ganglia make small contributions. The plasma contains small amounts of catecholamines, but these levels can rise rapidly and dramatically following changes in environmental temperature, posture, physical and emotional stress, blood loss, hypovolemia, hypoglycemia, hypotension, and exercise.

Indications/Applications

Levels of urinary catecholamines may be elevated in association with pheochromocytoma, a tumor of catecholamine-producing cells of the adrenal medulla, or, less commonly, the sympathetic ganglia (paraganglioma). It is characterized by episodic or sustained hypertension and often causes intermittent palpitations, cardiac arrhythmias, headache, sweating, pallor, anxiety, tremors, and nausea.

Neuroblastoma and related tumors (ganglioneuromas and ganglioneuroblastomas), as well as other neuroectodermal tumors (in rarer cases), may be associated with increased levels of one or more catecholamines.

Conversely, primary and secondary syndromes of autonomic dysfunction or failure and autonomic neuropathies are associated with either inadequate production of one or more catecholamines or with an insufficient release of catecholamines in response to appropriate physiological stimuli (eg, change in posture from the supine position to the standing position, exposure to cold, exercise, stress). ^[12]

Because of the lability of serum catecholamine concentrations, "spot" testing is not useful.

Considerations

Concentrations of catecholamines can be significantly affected by many alterations in pathologic and physiologic states.

Patients who are to undergo catecholamine testing should avoid any environmental factors associated with an increase in endogenous catecholamine production, including the following:

• Loud noise

• Stress/Anxiety

• Discomfort/Pain

• Certain body positions/posture changes

• Consumption of food, caffeinated beverages, and nicotine (nicotine and caffeine result in short-term fluctuations—a few minutes to hours)