Why give alpha blocker before beta blocker in pheochromocytoma

Pheochromocytomas are catecholamine-secreting neuroendocrine tumors. They most frequently arise from chromaffin cells within the adrenal gland; less commonly they originate outside the adrenal gland, known as extra-adrenal paraganglioma (usually in the abdomen). Patients classically present with symptoms and signs of excess catecholamines, including headache, palpitations, diaphoresis, and paroxysmal or sustained hypertension. Pheochromocytomas can occur sporadically or as a part of certain well-known genetic syndromes. These tumors may be discovered incidentally (so-called adrenal incidentalomas or, more commonly, as the result of a diagnostic work-up in the setting of overt clinical symptoms.


II. Diagnostic Confirmation: Are you sure your patient has pheochromocytoma?

Although most symptoms and signs of this disorder can be traced to excess catecholamines, the clinical presentation is actually quite variable. Diagnosis can be confirmed by appropriate serological or urinary testing suggesting elevated catecholamine levels, and imaging findings supporting the diagnosis of an adrenal or extra-adrenal tumor.

A. History Part I: Pattern recognition:

1. Paroxysmal character: Due to the episodic nature of catecholamine release, signs and symptoms classically are paroxysmal, lasting minutes to an hour.

2. Patient-reported symptoms: Most commonly, headaches, palpitations, and sweats (comprising the “classic triad”), as well as nausea and anxiety (can mimic panic attacks).

3. Hypertension: Occurs in most patients but maybe continuous or paroxysmal. Examination for stigmata of hypertension (such as left ventricular hypertrophy on the ECG) may be useful if BP readings are initially normal.

4. Family history: Approximately 25% of pheochromocytomas are genetic. As such, patients may have a family history of the tumor or other evidence of a genetic syndrome. Pheochromocytomas commonly occur in multiple endocrine neoplasia type 2, von Hippel-Lindau, neurofibromatosis type 1 and the familial paraganglioma syndromes.

B. History Part 2: Prevalence

Pheochromocytomas occur in <0.6% of patients with hypertension; annual incidence in the U.S. is 500-1600 cases per year. They represent an estimated 5% of adrenal incidentalomas.

C. History Part 3: Competing diagnoses that can mimic pheochromocytoma.

Because the presentation of a pheochromocytoma is so widely variable, one must carefully consider alternative etiologies.

1. Ingestions

Stimulants such as amphetamines, cocaine, decongestants also cause hyperadrenergic signs or symptoms.

2. Endocrine disorders

Hyperthyroidism can cause palpitations, anxiety, diaphoresis as well as hypertension.

3. Infection, malignancy, and miscellaneous conditions

Patients with significant night sweats as a predominant symptom should be evaluated for malignancy and occult infection including Mycobacterium. Paroxysmal symptoms may be a feature of mastocytosis, carcinoid syndrome, panic attack, and primary dysrhythmias among many others.

4. Other causes of secondary hypertension Additional causes of secondary hypertension include renal artery stenosis, mineralcorticoid excess, coarctation of the aorta, and obstructive sleep apnea.

5. Other causes of adrenal masses Identification of an adrenal nodule or mass on imaging studies should prompt further evaluation under most circumstances. Pheochromocytomas are frequently identified in this fashion, and need to be distinguished from adrenal hyperplasia, adrenal adenomas, adrenal carcinoma, and metastatic adrenal disease. See the section on evaluation of adrenal mass for details.

D. Physical Examination Findings.

Hypertension and/or tachycardia (may be paroxysmal).

Orthostatic hypotension (reflecting intravascular volume depletion and desensitization of catecholamine receptors).

Pallor (due to vasoconstriction).

Episodic flushing of the face.

E. What diagnostic tests should be performed?

Confirming the diagnosis of pheochromocytoma requires biochemical testing. If clinical evidence is compelling (taking into account symptomatology, physical examination, biochemical results, and family history), imaging should be performed to localize it.

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?


Catecholamines were historically measured, but their episodic release makes them not sufficiently sensitive and they have been abandoned in favor of metanephrines. Metanephrine and normetanephrine are metabolites of epinephrine and norepinephrine, respectively, that are produced at a more stable level from within chromaffin cells.

There is not a clear consensus on the preferred initial metanephrine test. Both plasma free metanephrines and 24-hour urinary fractionated metanephrines can be performed. Note that the very low population incidence rate of pheochromocytoma and the high degree of sensitivity of these tests means that there is considerable risk of false positives. Patients should be counseled to avoid the sources of falsely elevated levels of catecholamines for 8-12 hours prior to testing (outlined below).

Given the potential for elevations associated with behavior/ingestions, values more than 2-fold above normal are generally considered to be more suggestive of pheochromocytoma. Values more than 4-fold above normal are particularly compelling.

If ambiguity of diagnosis exists, one can perform the alternate biochemical test (i.e., if plasma was borderline elevated, perform the 24-hour urine). One also can repeat the test under more optimal conditions: have the patient fast overnight and rest supine for 30 minutes prior to taking sample while still in the supine position. Historically, the clonidine suppression test was used for confirmation (central alpha-2 receptor agonist that reduces catecholamine production by the sympathetic nervous system but has no effect on autologous production by pheochromocytomas), but is not common practice today.

Causes of falsely elevated levels of metanephrines and catecholamines:

1. Physical stress or illness or rigorous exercise can all lead to physiologically elevated levels of catecholamines.

2. Medications and ingestions: Tricyclic antidepressants, cyclobenzaprine, acetaminophen, MAO inhibitors, phenoxybenzaprine, levodopa, ephedrine/pseudoephedrine/phenylephrine, amphetamines and cocaine, prochlorperazine, buspirone, sulphasalazine, and to a less extent beta blockers, alpha-1 blockers, caffeine, nicotine, ethanol, and certain foods (e.g., fruit juice, nuts, legumes, tomatoes, potatoes, bananas) are all known to interact with serum and/or urine catecholamine levels.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Note: Because of the low prevalence of these tumors, there should be ample clinical or laboratory evidence for a possible pheochromocytoma or paraganglioma before an attempt to localize the tumor by imaging is undertaken.

CT or MRI Scan of the Abdomen and Pelvis:

CT with contrast is the first-line modality, but MRI may be preferred for certain patients (e.g., pregnancy, contrast allergy) and for metastatic disease. The specificity of computed tomography (CT) and magnetic resonance imaging (MRI) scan is limited by the potential for adrenal incidentalomas, but both are highly sensitive. Note that with older iodinated contrast agents there was concern for precipitation of catecholamine storm but recent studies have suggested this is no longer a risk and patients do not need to be premedicated. Figure 1 is a CT of a right-sided adrenal pheochromocytoma.

MIBG Scintigraphy. This patient had a 9cm adrenal pheochromocytoma and a small peri-aortic paraganglioma.
Why give alpha blocker before beta blocker in pheochromocytoma

Functional Imaging:

Functional imaging can be useful if the mass identified on conventional imaging is not clearly a pheochromocytoma, if there is concern for metastatic disease, or if a paraganglioma is suspected. A 123I-metaiodobenzylguanidine scan (MIBG) involves the administration of radioactive tracer resembling norepinephrine in structure. Of note, certain medications such as labetalol may interfere with uptake and need to be discontinued at least 14 days before the scan. 18F-fluorodeoxyglucose positron emission tomography (PET)/CT scans is also recommended for metastatic disease.

Figure 2 is MIBG scan of the same tumor depicted in Figure 1.

CT cross section of the same tumor as in Figure 1.
Why give alpha blocker before beta blocker in pheochromocytoma

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis

Plasma catecholamine levels: As discussed above, plasma catecholamine levels are too volatile to be sufficiently sensitive.

Plasma Vanillyl Mandelic Acid (VMA): VMA is the next step in the breakdown of normetanephrine and epinephrine. Not recommended.

Plasma Chromogrannin A: Contained in secretory granules and released from neuroendocrine cells, it is not sufficiently specific (increased by medications like proton pump inhibitors).

III. Default Management

Management is a multidisciplinary endeavour, involving internal medicine, endocrinology, and surgery. Immediate management should focus on control of palpitations or hypertension and preventing catecholamine-related complications associated with future surgery. Near-term management focuses on surgical removal of the tumor. Long-term management focuses on symptom control, consideration of genetic testing, and surveillance.

A. Immediate management

1. Initiation of alpha blockade (or calcium channel blockers): Once the diagnosis of pheochromocytoma is confirmed, or once there is sufficient concern, prioritization should be given to managing the patient’s hemodynamic status. Beta-blockers should never be introduced prior to adequate alpha blockade (due to the risk of unopposed alpha receptor stimulation-adrenergic stimulation). Generally, alpha blockade is undertaken as soon as the diagnosis of pheochromocytoma is confirmed, and at least 1-2 weeks prior to surgery. Alpha-blockers should be uptitrated every 2-3 days with goal blood pressure of normotension while seated and systolic BP greater than 80-90 mmHg while standing. In patients with a long history of hypertension this BP target should be achieved gradually to avoid cerebral hypoperfusion or symptomatic orthostasis.

The most widely used agent is phenoxybenzamine, an irreversible, nonselective alpha-blocker. A dose of 10 mg twice daily is an appropriate starting point with a final dose of up to 1 mg/kg. Other options include use of selective alpha-1 blockers (e.g., doxazosin, prazosin) due to their lower cost and reduced incidence of post-operative hypotension. Combined alpha-beta blockers such as labetalol are not appropriate as initial treatment agents (they are typically more strongly beta than alpha).

Alternative regimens include calcium channel blockers (either to supplement the above or to replace it outright for patients with mild preoperative hypertension or those who cannot tolerate alpha-blockade); most commonly used is nicardipine, which has the benefit of oral formulation as an outpatient and intravenous for the peri-operative setting. It is much less expensive than phenoxybenzamine and these patients may experience less intraoperative and post-operative hypotension.

2. Volume expansion: Typically patients with pheochromocytoma are volume contracted due to catecholamine-mediated vasoconstriction. Two to three days after initiation of alpha blockade it is desirable to undertake volume expansion, which reduces risk of orthostatic hypotension and post-surgical hypotension. This can be achieved with intravenous normal saline in inpatients if desired, or by liberalized salt intake and oral fluids in the outpatient setting. It should be considered on a patient-to-patient basis, especially in patients with renal insufficiency or congestive heart failure.

3. Beta-blockade: Once alpha-blockade has been achieved, introduction of a beta-blocker may be appropriate especially for patients with tachyarrhythmias. Most clinicians recommend use of a non-specific betablocker such as propranolol starting at a low dose and titrated to resting heart rate of 65-75 bpm. It typically is recommended only to be introduced after several days of alpha blockade and at least 2-3 days before surgery.

Metyrosine: Some providers and institutions use metyrosine, which blocks catecholamine production. Because of an undesirable side effect profile including sedation, use of metyrosine is generally restricted to high-risk patients (e.g., metastatic tumors) in combination with alpha-beta blockade or in patients who cannot tolerate alpha-beta blockade.

B. Physical examination tips to guide management

Blood pressure should be controlled to normotension at rest as noted previously over several days. Care should be taken to measure orthostatic blood pressures as many patients will be intravascularly volume depleted, and volume repletion should be considered in all patients. Goal systolic blood when standing is > 80-90 mmHg.

C. Laboratory tests to monitor response to, and adjustments in, management

Patients should have metanephrine levels measured at two weeks and 6 months post-surgery, and then at least annually to monitor for recurrence.

D. Long-term management

Surgical Resection:

For most patients a laparascopic approach is the preferred means of surgical removal. For large tumors, however, an open incision may be required. Cortical-sparing surgery should be considered in all patients with genetic syndromes for whom a bilateral adrenalectomy may eventually be required.

Operative risks specific to pheochromocytoma:

Intraoperatively patients are at high risk for the development of hemodynamic instability (both hypertension and hypotension). For all patients intra-arterial blood pressure monitoring is recommended perioperatively. For patients who develop hypertensive crisis, nicardipine, nitroprusside or phentolamine may be utilized.

An additional complication of surgical removal of a pheochromocytoma is post-operative hypoglycemia due to rebound insulin secretion. Under normal circumstances catecholamines will suppress endogenous insulin levels, and as such surgical removal of the tumor may lead to hypoglycemia. All patients should have routine blood glucose monitoring for the first 24 hours following surgery.

E. Common pitfalls and side-effects of management

1. If initial imaging tests do not demonstrate an intraabdominal tumor, reconsider the diagnosis before proceeding to more advanced tests as there are a number of reasons for false positive laboratory tests and 95% of tumors are intraabdominal.

2. Beta-blocker therapy should be initiated at low dose and uptitrated gradually only after sufficient alpha-blockade. Patients often will not require high dose beta-blocker therapy.

3. Patients may experience hypoglycemia post-operatively.

IV. Management with co-morbidities

A. Renal insufficiency

Caution with intravascular volume expansion. For diagnosing pheochromocytoma, the plasma free fractionated metanephrines is the preferred test (urinary test is not reliable). Adjust medications appropriately.

B. Liver insufficiency

Caution with intravascular volume expansion. Adjust medications appropriately.

C. Systolic and diastolic heart failure

Caution with intravascular volume expansion. Care should be given during initiation of alpha and beta-blocker therapy.

D. Coronary artery disease or peripheral vascular disease

The risk of perioperative MI is increased in patients with a history of coronary artery disease. Encourage careful preoperative risk assessment with optimization and initiation of alpha and beta-blocker therapy. Preoperative evaluation with stress testing should be undertaken with caution in patients with pheochromocytoma.

E. Diabetes or other endocrine issues

Some patients will be at risk for post-operative hypoglycemia as endogenous suppression of insulin by catecholamine levels returns to normal. Insulin therapy may need to be adjusted following surgery.

F. Other Malignancy

No change in standard management; patients with incidental discovery of pheochromocytoma in the context of malignancy should have careful discussion around whether surgical resection of their tumors is indicated.

G. Immunosuppression (HIV, chronic steroids, etc)

No change in standard management.

H. Primary lung disease (COPD, asthma, ILD)

No change in standard management.

I. Gastrointestinal or nutrition issues

No change in standard management.

J. Hematologic or coagulation issues

No change in standard management.

K. Dementia or psychiatric illness/treatment.

No change in standard management.

V. Transitions of care

A. Sign-out considerations while hospitalized

If patient develops atrial arrhythmia requiring rate control (e.g., atrial fibrillation) do not initiate beta-blocker therapy until alpha-blockade well-established. As such, rate control with calcium channel blocker (verapamil or diltiazem) is preferred as initial therapy.

B. Anticipated length of stay

Initial length of stay can be quite variable and is dependent on how symptomatic patient is, and how responsive the hypertension is to treatment. With prompt and close follow-up much of the preoperative medical therapy can be undertaken as an outpatient.

C. When is the patient ready for discharge

If patient’s blood pressure, heart rate, and other symptoms are controlled, patient can be discharged with plans for follow up as outpatient.

D. Arranging for clinic follow-up

Patients should have follow-up with primary care for blood pressure management, endocrinology for assistance with management and discussion of genetic testing, and surgical consultation. An oncologist should be involved for patients with evidence of malignant tumors (by imaging or pathology).

E. Placement considerations

None specifically.

F. Prognosis and patient counseling

Most patients will do well with medications and surgical removal of the tumor, although there is a risk of recurrence (about 6% in 5 years). Large tumors or paragangliomas have some malignant potential and treatment for malignant tumors is limited. As discussed above, there is an association between pheochromocytoma and inherited genetic syndromes, and patients should discuss genetic testing with an endocrinologist (not routinely recommended for all patients).

VI. Patient safety and quality measures

A. Core indicator standards and documentation

None available.

B. Appropriate prophylaxis and other measures to prevent readmission

Given the potential for orthostasis patients should be advised about rising to stand gradually, and use of compression stockings should be considered. In the immediate post-operative period patients should be monitored for hypoglycemia.

VII. What’s the evidence?

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