Treatment algorithm

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

INITIAL

hypertensive crisis

1st line – antihypertensive therapy

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INITIAL
|
hypertensive crisis
1st line – 

antihypertensive therapy

May be a presenting feature or an intraoperative complication if the patient has not received adequate preoperative medical therapy.

A hypertensive crisis may be precipitated by drugs that inhibit catecholamine uptake, such as tricyclic antidepressants and cocaine; opiates; anesthesia induction; and radiographic contrast media. Possible consequences of a hypertensive crisis include cerebral hemorrhage, cardiac arrhythmias, myocardial infarction (MI), encephalopathy, and heart failure.[87]

Treatment includes immediate alpha blockade with an alpha-1 blocker (e.g., terazosin, doxazosin, or prazosin) or with the nonselective alpha-blocker, phenoxybenzamine. Intravenous agents (nitroprusside, phentolamine, or nicardipine) are short-acting and titratable, and can be used first line.[64] Nitroprusside, phentolamine, or nicardipine can be added, as required, to an oral alpha-1 blocker prescribed in the initial management of hypertensive crisis.[43]

Clinical presentation will inform prescribing decisions. Consult a specialist when deciding on the most appropriate regimen.

Primary options

terazosin: 1 mg orally once daily at bedtime, increase gradually according to response, maximum 20 mg/day in 1-2 divided doses

or

doxazosin: 1 mg orally (immediate-release) once daily at bedtime, increase gradually according to response, maximum 16 mg/day

or

prazosin: 1 mg orally two to three times daily, increase gradually according to response, maximum 20 mg/day

or

phenoxybenzamine: 10 mg orally twice daily initially, increase gradually according to response, maximum 120 mg/day in 2-3 divided doses

-- AND / OR --

nitroprusside: 0.3 to 0.5 micrograms/kg/minute intravenous infusion initially, increase by 0.5 micrograms/kg/minute every 5 minutes according to response, maximum 10 micrograms/kg/minute

More

or

phentolamine: 5 mg intravenously every 10 minutes when required according to response

or

nicardipine: 5 mg/hour intravenous infusion initially, increase by 2.5 mg/hour every 5-15 minutes according to response, maximum 15 mg/hour

ACUTE

without hypertensive crisis

1st line – alpha-blocker

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ACUTE
|
without hypertensive crisis
1st line – 

alpha-blocker

The first step in medical management is to block the effects of catecholamine excess by controlling hypertension and expanding intravascular volume.[1] This is achieved by first establishing adequate alpha blockade.[2][43]

Alpha-1 blockers (e.g., terazosin, doxazosin, or prazosin), or the nonselective alpha-blocker phenoxybenzamine, are recommended for initial pretreatment blockade.[2][43] These drugs lower BP by decreasing peripheral vascular resistance.[65]

A major disadvantage of phenoxybenzamine is that it blocks presynaptic alpha-2 receptors enhancing the release of norepinephrine, resulting in a reflex tachycardia.

Alpha-1 blockers have a shorter duration of action than phenoxybenzamine, making them particularly useful in the perioperative period. The dose of alpha-1 blocker can be rapidly titrated, avoiding postoperative hypotension. These drugs do not enhance the release of norepinephrine (noradrenaline) and therefore do not cause a reflex tachycardia.

Primary options

terazosin: 1 mg orally once daily at bedtime, increase gradually according to response, maximum 20 mg/day in 1-2 divided doses

OR

doxazosin: 1 mg orally once daily at bedtime, increase gradually according to response, maximum 16 mg/day

OR

prazosin: 1 mg orally two to three times daily, increase gradually according to response, maximum 20 mg/day

OR

phenoxybenzamine: 10 mg orally twice daily initially, increase gradually according to response, maximum 120 mg/day in 2-3 divided doses

Plus – beta-blocker (after alpha blockade)

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ACUTE
|
without hypertensive crisis
Plus – 

beta-blocker (after alpha blockade)

Treatment recommended for ALL patients in selected patient group

The main role of beta-blockers is to prevent tachycardia and arrhythmias. The commonly employed agents are beta-1 selective agents such as atenolol and metoprolol.

Beta-blockers must only be used after adequate alpha blockade is achieved preoperatively, as they can cause unopposed stimulation of alpha receptors leading to vasoconstriction and a possible hypertensive crisis.

Adverse effects include bradycardia, bronchospasm, hypotension, and vasoconstriction; therefore, caution is needed when commencing patients with asthma, cardiomyopathies (this is particularly important as cardiomyopathy is a complication of prolonged catecholamine exposure), heart failure, or atrioventricular (AV) conduction abnormalities on beta-blockers.

Primary options

atenolol: 25-100 mg orally once daily

OR

metoprolol tartrate: 50 mg orally (immediate-release) twice daily initially, increase according to response, maximum 450 mg/day

Plus – hydration and high-salt diet (>5 g per day)

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ACUTE
|
without hypertensive crisis
Plus – 

hydration and high-salt diet (>5 g per day)

Treatment recommended for ALL patients in selected patient group

Hydration and a high-salt diet (>5 g/day) are given for 7-14 days (or until the patient is stable) to offset the effects of catecholamine-induced volume contraction associated with alpha blockade.[43]

All patients should be volume expanded with isotonic saline. In surgical patients, postoperative hypotension may be avoided by adequate intravenous fluid replacement preoperatively.

Consider – calcium-channel blocker or metyrosine

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ACUTE
|
without hypertensive crisis
Consider – 

calcium-channel blocker or metyrosine

Treatment recommended for SOME patients in selected patient group

Dihydropyridine calcium-channel blockers can supplement alpha blockade should additional blood pressure control be required.[43] Monotherapy with dihydropyridine calcium-channel blockers is not recommended, but may be an option if the patient is unable to tolerate alpha blockade.[2][43]​​​ Nifedipine and amlodipine are the most commonly recommended calcium-channel blockers in the setting of perioperative pheochromocytoma BP control.[2]

Calcium-channel blockers lower BP by relaxing smooth muscle in peripheral arteries. This is achieved by inhibition of the norepinephrine-mediated release of intracellular calcium in vascular smooth muscle.

They do not cause orthostatic hypertension and, therefore, have a role in patients with episodic hypertension.

Metyrosine can be used in conjunction with alpha blockade to stabilize blood pressure. Metyrosine, an inhibitor of tyrosine hydroxylase, inhibits catecholamine synthesis. In patients with pheochromocytomas, metyrosine can reduce the biosynthesis of catecholamines by 35% to 80%.[66] This is particularly useful in patients with very high circulating levels of catecholamines, which can be cytotoxic to myocardial cells.

Metyrosine should be started 2 weeks prior to surgery. It can also be used when surgery is contraindicated.

Adverse effects of metyrosine often limit the use of this drug and include crystalluria, fatigue, diarrhea, depression, nightmares, and extrapyramidal signs.[88] Patients should be instructed on maintaining an adequate fluid intake in order to avoid metyrosine crystalluria.

Primary options

nifedipine: 30-60 mg orally (extended-release) once daily initially, increase gradually according to response, maximum 120 mg/day

OR

amlodipine: 5-10 mg orally once daily

Secondary options

metyrosine: 250 mg orally four times daily initially, increase by 250-500 mg/day increments according to response, maximum 4000 mg/day

Plus – surgical excision of tumor

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ACUTE
|
without hypertensive crisis
|
surgical candidate with benign tumor: following initial medical treatment
Plus – 

surgical excision of tumor

Treatment recommended for ALL patients in selected patient group

Hypertension should be controlled first with antihypertensives.

Postoperative hypotension may be avoided by adequate intravenous fluid replacement preoperatively.

Surgical treatment options include open or laparoscopic total adrenalectomy, adrenal-sparing, or partial adrenalectomy.

There is evidence in favor of cortical-sparing adrenalectomy in patients with hereditary pheochromocytomas.[2][70]​ This method can avoid the need for lifelong corticosteroid therapy; however, patients need to be monitored postoperatively for local recurrence.[86]

Plus – surgical debulking

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ACUTE
|
without hypertensive crisis
|
surgical candidate with malignant tumor: following initial medical treatment
Plus – 

surgical debulking

Treatment recommended for ALL patients in selected patient group

As in benign disease, surgical removal/debulking to improve symptoms is the primary therapy; however, this may not be possible if the tumor has extensive local or metastatic spread.[76]

Consider – postsurgical chemotherapy

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ACUTE
|
without hypertensive crisis
|
surgical candidate with malignant tumor: following initial medical treatment
Consider – 

postsurgical chemotherapy

Treatment recommended for SOME patients in selected patient group

Chemotherapy is given to all patients with metastatic disease after surgery.[61] Nonsurgical candidates with metastatic pheochromocytoma may also receive chemotherapy. Chemotherapy regimens usually consist of cyclophosphamide, vincristine, and dacarbazine.[43][61][77]

Temozolomide, an alkylating drug and an alternative to dacarbazine, can be used as monotherapy or in combination with other antineoplastic drugs in patients with malignant pheochromocytomas and SDHB mutations.[78][79]

See local specialist protocol for dosing guidelines.

Primary options

cyclophosphamide

and

vincristine

and

dacarbazine

Secondary options

temozolomide

Consider – iobenguane I-131, radiation, or ablative therapy

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ACUTE
|
without hypertensive crisis
|
surgical candidate with malignant tumor: following initial medical treatment
Consider – 

iobenguane I-131, radiation, or ablative therapy

Treatment recommended for SOME patients in selected patient group

Additional therapy may be required in some patients with residual tumor, such as multifocal or metastatic disease.[82]

The radiopharmaceutical, iobenguane I-131 (also known as I-131 metaiodobenzylguanidine [MIBG]), may be considered if I-123 MIBG scintigraphy was positive.[43]

See local specialist protocol for dosing guidelines.

Painful skeletal metastases can be treated with external beam radiation therapy.[80]

Radiofrequency ablation of hepatic and bone metastases may also be effective.[61][81]

Primary options

iobenguane I 131

Consider – enrollment in clinical trial

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ACUTE
|
without hypertensive crisis
|
surgical candidate with malignant tumor: following initial medical treatment
Consider – 

enrollment in clinical trial

Treatment recommended for SOME patients in selected patient group

In cases of malignant pheochromocytomas refractory to both radiation therapy and chemotherapy, enrollment in a clinical trial is suggested and other treatment options, such as tyrosine kinase inhibitors (e.g., sunitinib), peptide receptor radionuclide therapy (lutetium Lu 177 dotatate also known as 177Lu-DOTATATE), immunotherapy (e.g., pembrolizumab), and hypoxia-inducible factor 2 alpha inhibitors (e.g., belzutifan), considered on a case-by-case basis.[27][43][49][84]

Plus – continued medical treatment

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ACUTE
|
without hypertensive crisis
|
nonsurgical candidate with benign tumor: following initial medical treatment
Plus – 

continued medical treatment

Treatment recommended for ALL patients in selected patient group

Patients with benign tumors, who are unable to undergo surgery - for example, due to a high surgical risk because of heart failure - should receive long-term BP control using alpha- and beta-blockers, as well as calcium-channel blockers if needed. Metyrosine is a less-preferred option for controlling hypertension.

Consider – iobenguane I-131

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ACUTE
|
without hypertensive crisis
|
nonsurgical candidate with benign tumor: following initial medical treatment
Consider – 

iobenguane I-131

Treatment recommended for SOME patients in selected patient group

Iobenguane I-131 (also known as I-131 metaiodobenzylguanidine [MIBG]) may be considered in symptomatic patients with an unresectable tumor if I-123 MIBG scintigraphy was positive.[43]​[82]

See local specialist protocol for dosing guidelines.

Primary options

iobenguane I 131

Plus – continued medical treatment + chemotherapy

Back
ACUTE
|
without hypertensive crisis
|
nonsurgical candidate with malignant tumor: following initial medical treatment
Plus – 

continued medical treatment + chemotherapy

Treatment recommended for ALL patients in selected patient group

Symptomatic patients with extensive local or metastatic spread should receive long-term BP control using alpha- and beta-blockers, as well as calcium-channel blockers if needed. Metyrosine is a less-preferred option for controlling hypertension.

In addition, chemotherapy regimens (usually consisting of cyclophosphamide, vincristine, and dacarbazine) should be administered.[77] Temozolomide is an alkylating drug and an alternative to dacarbazine, which can be used as monotherapy or in combination with other antitumoral drugs in patients with malignant pheochromocytomas and SDHB mutations.[78][79]​ See local specialist protocol for dosing guidelines. 

Primary options

cyclophosphamide

and

vincristine

and

dacarbazine

Secondary options

temozolomide

Consider – iobenguane I-131, radiation, or ablative therapy

Back
ACUTE
|
without hypertensive crisis
|
nonsurgical candidate with malignant tumor: following initial medical treatment
Consider – 

iobenguane I-131, radiation, or ablative therapy

Treatment recommended for SOME patients in selected patient group

Iobenguane I-131 (also known as I-131 metaiodobenzylguanidine [MIBG]) may be considered in symptomatic patients with extensive local or metastatic spread if I-123 MIBG scintigraphy was positive.[61][43]​​[82][89][90] See local specialist protocol for dosing guidelines.

Painful skeletal metastases can be treated with external beam radiation therapy.[80]

Radiofrequency ablation of hepatic and bone metastases may also be effective.[61][81]

Primary options

iobenguane I 131

Consider – enrollment in clinical trial

Back
ACUTE
|
without hypertensive crisis
|
nonsurgical candidate with malignant tumor: following initial medical treatment
Consider – 

enrollment in clinical trial

Treatment recommended for SOME patients in selected patient group

In cases of malignant pheochromocytomas refractory to both radiation therapy and chemotherapy, enrollment in a clinical trial is suggested and other treatment options, such as tyrosine kinase inhibitors (e.g., sunitinib), peptide receptor radionuclide therapy (lutetium Lu 177 dotatate also known as 177Lu-DOTATATE), immunotherapy (e.g., pembrolizumab), and hypoxia-inducible factor 2 alpha inhibitors (e.g., belzutifan), considered on a case-by-case basis.[27][43][49][84]

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Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups. See disclaimer

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