Adrenal Medullary Sympathetic Hormone Excess: Pheochromocytoma

Less than 0.1% of all cases of hypertension are caused by pheochromocytomas, or catecholamine-producing tumors derived from chromaffin tissue.^[200] Nevertheless, these tumors are clearly important to the anesthetist inasmuch as 25% to 50% of hospital deaths in patients with pheochromocytoma occur during induction of anesthesia or during operative procedures for other causes.^[201] Though usually found in the adrenal medulla, these vascular tumors can occur anywhere, such as in the right atrium, the spleen, the broad ligament of the ovary, or the organs of Zuckerkandl at the bifurcation of the aorta.^[202] Malignant spread, which occurs in less than 15% of pheochromocytomas, usually proceeds to venous and lymphatic channels with a predisposition for the liver. This tumor is occasionally familial or part of the pluriglandular-neoplastic syndrome known as multiple endocrine adenoma type IIa or type IIb and is manifested as an autosomal dominant trait. Type IIa consists of medullary carcinoma of the thyroid, parathyroid adenoma or hyperplasia, and pheochromocytoma. What used to be called type IIb is now often called pheochromocytoma in association with phakomatoses such as von Recklinghausen's neurofibromatosis and von Hippel-Lindau disease and cerebellar hemangiobastoma. Often, bilateral tumors are found in the familial form. Localization of tumors can be achieved by MRI or CT scans, metaiodobenzylguanidine (MIBG) nuclear scanning, ultrasonography, or intravenous pyelography studies (in decreasing order of combined sensitivity and specificity).

Symptoms and signs that may be solicited preoperatively and preprocedurely and that are suggestive of pheochromocytoma are excessive sweating; headache; hypertension; orthostatic hypotension; previous hypertensive or arrhythmic response to induction of anesthesia or to abdominal examination; paroxysmal attacks of sweating, headache, tachycardia, and hypertension; glucose

TABLE 27-11 -- Characteristics of tests for pheochromocytoma

			Likelihood Ratio
Test/Symptoms	Sensitivity (%)	Specificity (%)	Positive Results *	Negative Result †
Vanillylmandelic acid excretion	81	97	27.0	0.20
Catecholamine excretion	82	95	16.4	0.19
Metanephrine excretion	83	95	16.6	0.18
Abdominal computed tomography scan	92	80	4.6	0.10
Concurrent paroxysmal hypertension, headache, sweating, and tachycardia ‡	90	95	18.0	0.10
Modified from Pauker SG, Kopelman RI: Interpreting hoofbeats: Can Bayes help clear the haze? N Engl J Med 327:1009, 1992.

*The ratio representing the likelihood of a positive result is obtained by dividing the sensitivity by 1 and then subtracting the specificity.
†The ratio representing the likelihood of a negative result is obtained by subtracting the sensitivity from 1 and then dividing by the specificity.
‡Data for concurrent paroxysmal symptoms are best estimates from available data.

Although no controlled, randomized, prospective clinical studies have investigated the value of preoperative and preprocedure use of adrenergic receptor blocking drugs, the use of such drugs is generally recommended before surgery. These drugs probably reduce the complications of hypertensive crisis, the wide BP fluctuations during manipulation of the tumor (especially until venous drainage is obliterated), and the myocardial dysfunction that occurs perioperatively. A reduction in mortality associated with resection of pheochromocytoma (from 40% to 60% to the current 0% to 6%) occurred when α-adrenergic receptor blockade was introduced as preoperative and preprocedure preparatory therapy for such patients^{[205] [206] [207] [208] [209] [210] [211]} ( Table 27-12 ).

α-Adrenergic receptor blockade with prazosin or phenoxybenzamine restores plasma volume by counteracting the vasoconstrictive effects of high levels of catecholamines. This re-expansion of fluid volume is often followed by a decrease in hematocrit. Because some patients may be very sensitive to the effects of phenoxybenzamine, it should initially be given in doses of 20 to 30 mg/70 kg orally once or twice a day. Most patients usually require 60 to 250 mg/day. The efficacy of therapy should be judged by the reduction in symptoms (especially sweating) and stabilization of BP. For patients who have carbohydrate intolerance because of inhibition of insulin release mediated by α-adrenergic receptor stimulation, α-adrenergic receptor blockade may reduce fasting blood sugar levels. For patients who exhibit ST-T changes on ECG, long-term preoperative and preprocedure α-adrenergic receptor blockade (1 to 6 months) has produced ECG and clinical resolution of catecholamine-induced myocarditis.^{[206] [207] [208] [209] [210] [211] [212]}

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β-Adrenergic receptor blockade with propranolol is suggested for patients who have persistent arrhythmias or tachycardia^{[206] [207] [208] [209] [210] [211] [212]} because these conditions can be precipitated or aggravated by α-adrenergic receptor blockade. β-Adrenergic receptor blockade should not be used without concomitant α-adrenergic receptor blockade lest the vasoconstrictive effects of the latter go unopposed and thereby increase the risk of dangerous hypertension.

The optimal duration of preoperative therapy with phenoxybenzamine has not been studied. Most patients require 10 to 14 days, as judged by the time needed to

TABLE 27-13 -- Incidence of perioperative complications in a randomized study of patients undergoing resectioning of pheochromocytoma under one of four anesthetic techniques

	Anesthetic *
	Enflurane (6)	Halothane (6)	Droperidol and Fentanyl (7)	Regional (5)
Ventricular tachycardia
Needing no treatment	5	5	6	5
Needing treatment	0	1	1	0
Vasodilator needed
Intraoperatively	6	6	7	5
Postoperatively	0	1 †	1 †	0
Vasopressor needed
Intraoperatively	0	1	1	0
Postoperatively	0	0	0	0
Myocardial infarction ‡	0	0	0	0
Renal failure ‡	0	0	0	0
Congestive heart failure ‡	0	1	1	1
Stroke ‡	0	0	0	0
Death ‡	0	0	0	0
Data from Roizen MF, Horrigan RW, Koike M, et al: A prospective randomized trial of four anesthetic techniques for resection of pheochromocytoma [abstract]. Anesthesiology 57:A43, 1982.

*Number of patients shown in parentheses.
†Not all the abnormally secreting tumor tissue was removed from the patient.
‡Occurring postoperatively.

1. No in-hospital BP reading higher than 165/90 mm Hg should be evident for 48 hours before surgery. We often measure arterial BP every minute for 1 hour in a stressful environment (our postanesthesia care unit). If no BP reading is greater than 165/90, this criterion is considered satisfied.
2. Orthostatic hypotension should be present, but BP on standing should not be lower than 80/45 mm Hg.
3. The ECG should be free of ST-T changes that are not permanent.
4. No more than one premature ventricular contraction (PVC) should occur every 5 minutes.

Other drugs, including prazosin, calcium channel blocking drugs, clonidine, and magnesium, have also been used to achieve suitable degrees of α-adrenergic blockade before surgery.

Although specific anesthetic drugs have been recommended, we believe that optimal preoperative preparation, gentle induction of anesthesia, and good communication between the surgeon and anesthesiologist are most important. Virtually all anesthetic drugs and techniques (including isoflurane, sevoflurane, sufentanil, remifentanil, fentanyl, and regional anesthesia) have been used with success. In fact, all drugs studied are associated with a high rate of transient intraoperative arrhythmias^[207] ( Table 27-13 ). We have avoided halothane because it sensitizes the myocardium and may increase arrhythmogenic

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Because of ease of use, we prefer to give phenylephrine hydrochloride (Neo-Synephrine) or dopamine for hypotension and nitroprusside for hypertension. Phentolamine (Regitine) has too long an onset and duration of action. Occasionally (five times in >80 pheochromocytoma resections), we have used a β-adrenergic blocking agent (esmolol is now the preferred agent) for severe tachycardia without hypertension or volume depletion. Painful or stressful events such as intubation often cause an exaggerated stress response in less than perfectly anesthetized patients who have pheochromocytoma. This response is caused by release of catecholamines from nerve endings that are "loaded" by the reuptake process. Such stresses may cause catecholamine levels of 200 to 2000 pg/mL in normal patients. For a patient with pheochromocytoma, even simple stress can lead to blood catecholamine levels of 2000 to 20,000 pg/mL. However, infarction of a tumor, with release of products onto peritoneal surfaces, or surgical pressure causing release of products can result in blood levels of 200,000 to 1,000,000 pg/mL—a situation that should be anticipated and avoided (ask for a temporary stay of surgery, if at all possible, while the rate of nitroprusside infusion is increased). Once the venous supply is secured and if intravascular volume is normal (as measured by pulmonary wedge pressure), normal BP usually results. However, some patients become hypotensive and occasionally require massive infusions of catecholamines. On rare occasion, patients remain hypertensive intraoperatively. Postoperatively, about 50% remain hypertensive for 1 to 3 days—and initially have markedly elevated but declining plasma catecholamine levels—at which time all but 25% become normotensive. It is important to interview other family members and perhaps advise them to inform their future anesthetist about the potential for such familial disease.