Oct. 29, 2022

Lucinda M. Gruber, M.D., an endocrinologist at Mayo Clinic in Rochester, Minnesota, answers common questions about the preoperative management of patients with pheochromocytoma and paraganglioma. This is a basic framework for titrating medications before surgery for patients with pheochromocytoma and paraganglioma.

When should medication titration be started?

Allow 10 to 14 days prior to surgery to start and adjust medications. A slightly shorter time frame of seven days can be considered in patients with tumors under 3 cm in size where catecholamine levels are minimally elevated. Quicker titration also can be used for patients who are hospitalized.

What is the preferred alpha-adrenergic blockade?

Alpha-adrenergic blockade is started at least seven days prior to initiating beta-adrenergic blockade. Doxazosin (selective alpha-1 blockade) or phenoxybenzamine (nonselective alpha blockade) can be used. Doxazosin is more readily available and affordable than phenoxybenzamine. A starting dose is 1 mg at bedtime or 1 mg twice daily. Phenoxybenzamine is an irreversible, nonselective alpha-adrenergic blocker. It should be considered for patients with large tumors or those with high metanephrine and catecholamine concentrations. A starting dose of 10 mg daily or 10 mg twice daily is used. The effect of phenoxybenzamine seems to plateau at a total daily dose of 90 mg, typically administered as 30 mg three times a day, as seen in a 2021 study in The Journal of Clinical Endocrinology & Metabolism. Side effects include orthostatic symptoms and fatigue. Phenoxybenzamine also can cause nasal stuffiness.

What is the preferred beta-adrenergic blockade?

Beta-adrenergic blockade is generally added 2 to 3 days prior to surgery. Propranolol 10 mg every 6 to 8 hours can be used, but metoprolol succinate has the advantage of once-daily dosing. A starting dose of 25 mg daily is reasonable. Phenoxybenzamine can cause reflex tachycardia due to blockade of the alpha-2 receptors. For patients with pronounced tachycardia, beta-adrenergic blockade can be considered a week after alpha-adrenergic blockade is initiated.

What if a patient is on other antihypertensive medications?

Antihypertensive medications can be gradually stopped as alpha-adrenergic blockade is started. Generally, diuretics (hydrochlorothiazide, spironolactone) should be stopped right away to help increase intravascular volume. A few days into adjustment, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers or hydralazine should be tapered or typically stopped. If possible, calcium channel blockers should be continued, as they are associated with decreased morbidity and mortality.

How should medications be titrated?

Patients should measure their blood pressure and pulse twice a day in a seated and standing position. Alpha-adrenergic medications are adjusted daily to target a systolic blood pressure around 90 to 110 mm Hg. Doxazosin is typically increased by 1 to 2 mg each day, while phenoxybenzamine is titrated by 10 mg daily in most cases. Beta-adrenergic blockade is titrated to keep the heart rate under 90 beats per minute.

What should be done if a patient develops orthostatic vital signs?

Counseling patients on the importance of increased salt and water intake is vital to the process. Salt intake should be more than 5,000 mg each day. Patients with orthostatic vital signs should not have alpha-adrenergic blockade increased that day and should focus on salt and water intake for the next 24 hours.

What if a patient remains hypertensive and surgery is a few days away?

Some patients will remain hypertensive despite being on significant alpha-adrenergic blockade, for example, 20 mg of doxazosin. A couple of strategies can be used in this scenario. Doxazosin is typically administered as a twice-daily medication but splitting it into three doses a day (every eight hours) can be more effective. Consider this for a patient taking more than 10 mg of doxazosin each day. Adding a calcium channel blocker also can be considered, such as 2.5 mg or 5 mg of amlodipine daily. Lastly, some patients may require the addition of metyrosine.

What is the role of metyrosine?

Metyrosine is a helpful adjunct to standard alpha- and beta-adrenergic blockade in select patients. This medication inhibits tyrosine hydroxylase, which is the rate-limiting step in catecholamine synthesis. Metyrosine should be considered if a patient has suboptimal control of hypertension with medical therapy or intolerance to alpha-adrenergic blockade. It is also helpful if significant tumor manipulation is expected, for example, mediastinal paraganglioma.

Metyrosine can be started four days before surgery at a dose of 250 mg every six hours. The total daily dose is increased by 1,000 mg every day as tolerated to a target dose of 1,000 mg every six hours. An additional 1,000 mg dose is provided on the day of surgery. Side effects are typically fatigue, dizziness and extrapyramidal symptoms.

Metyrosine can be added for patients who are already on an alpha-adrenergic blockade without needing to reduce the dose of the alpha-adrenergic blocking medications. However, if a patient becomes hypotensive after starting metyrosine, alpha-adrenergic blockade can be reduced.

Although most studies reporting on the use of metyrosine are retrospective, they do suggest a lower risk of hypertensive crisis and severe hypertension during surgery as well as lower intraoperative hemodynamic variability.

For more information

Gruber LM, et al. The role for metyrosine in the treatment of patients with pheochromocytoma and paraganglioma. The Journal of Clinical Endocrinology & Metabolism. 2021;106:e2393

Refer a patient to Mayo Clinic.