Correspondence *Neufeld Cardiac Research Institute, Sheba Medical Center, Tel-Hashomer, 52621, Israel

Email leorj@post.tau.ac.il

The case

A 52-year-old woman presented to the emergency department with recurrent episodes of chest and abdominal pain, dyspnea, palpitations and diaphoresis, which had begun 8 hours earlier. She had a 2-year history of type 2 diabetes mellitus that had been treated with oral hypoglycemic agents (5 mg glibenclamide taken three times per day), but did not have a history of hypertension or any other notable conditions. On arrival she was asymptomatic. Her blood pressure (BP) was 143/86 mmHg (normal 90–120/60–80 mmHg) and pulse was 88 beats/min. Physical examination did not reveal any abnormalities; the abdomen was soft on palpation and no unusual mass was detected. The patient's electrocardiogram and chest X-ray were both normal. Her blood test results are shown in Table 1.

Table 1 Summary of the patient's blood and urine test results.

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The patient was admitted to an internal medicine ward where she was initially treated with saline infusion (100 ml/h). Two hours later she developed chest pain and diaphoresis, and electrocardiography demonstrated a 4 mm ST-segment depression in the precordial leads. She was transferred to the Intensive Cardiac Care Unit with suspected acute myocardial ischemia. Upon arrival she was pale and apprehensive, and was experiencing abdominal and chest pain, dyspnea, palpitations, vomiting and profuse diaphoresis. Her BP was 300/160 mmHg, heart rate 74 beats/min and temperature 38.8 °C. She was treated with a bolus of nitroglycerin and metoprolol, and subsequently with nitroprusside infusion. Her systolic BP dropped to 50 mmHg, and nitroprusside infusion was discontinued. Before fluids and vasopressor agents could be administered, however, her systolic BP rose sharply to 300 mmHg and she developed a junctional rhythm of 70 beats/min. An arterial line was established to enable continuous intra-arterial pressure monitoring, which revealed unusual rhythmic alternation between phases of severe hypertension accompanied by a drop in heart rate (although not sufficiently low as to be classified as bradycardia), and phases of hypotension and tachycardia (Figure 1). Each complete cycle lasted around 15 min. Hypertensive episodes were accompanied by ST-segment depression on electrocardiography, which returned to baseline during the hypotensive phases.

Figure 1 Simultaneous recordings of the patient's heart rate and arterial blood pressure (BP).

The dotted line represents systolic arterial BP, the dashed line represents diastolic arterial BP and the solid line represents mean arterial BP. (A) Cyclic waves of severe hypertension and decreased heart rate alternating with hypotension and tachycardia were initially evident. (B) An intravenous bolus of phentolamine (5 mg; arrow), followed by continuous infusion, rapidly abolished the sinusoidal pattern. Abbreviation: BPM, beats/min.

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This cyclic hemodynamic crisis continued for the next 2 hours, during which time pheochromocytoma was considered as a possible diagnosis. Intravenous phentolamine (5 mg bolus, followed by continuous infusion) was administered—promptly eradicating the paroxysms (Figure 1). Treatment with the -blocker doxazosin (1 mg taken orally twice daily) was initiated. Laboratory tests performed 24 h later showed a urine vanillylmandelic acid level of 4.6 mg/24 h (normal range 1.9–9.8 mg/24 h). Echocardiography revealed a normally sized heart with a hyperdynamic left ventricle.

The patient spent a total of 7 days in hospital, and experienced no further attacks. She was discharged in good condition, and continued evaluation at the Cardiology and Hypertension outpatient clinic. Twenty-four hour urine analysis performed 3 months after discharge showed elevated metanephrine and epinephrine levels (Table 1). Abdominal CT revealed a 2.5 cm 2.0 cm mass on the right adrenal gland, and 131I m-iodobenzylguanidine (MIBG) scanning showed increased focal 131I activity that was consistent with right adrenal pheochromocytoma. The patient was advised to undergo surgical removal of the tumor but she refused, and surgery was postponed while she sought a second opinion. The patient continued to suffer from nonspecific chest pain but her BP was well controlled with doxazosin.

Two years after the initial diagnosis the patient underwent open right adrenalectomy. The operation was a success and the postoperative course was uneventful. Pathological examination of the excised tissue confirmed the presence of a 3.4 cm 2.5 cm adrenal tumor. Microscopic evaluation showed there was no spread of malignancy to the adjacent tissues and blood vessels. Ten years after surgery the patient remains stable and normotensive, and continues to take atenolol (50 mg/day), oral hypoglycemic agents and insulin.

Discussion of diagnosis

Pheochromocytomas are tumors originating in the catecholamine-producing chromaffin cells of the adrenal medulla.^{1, 2, 3, 4} Around 10% of pheochromocytomas are malignant, and the 5-year survival rate is about 50%. Typical pheochromocytomas mainly secrete norepinephrine along with smaller amounts of epinephrine but, in rare cases, can also produce dopamine and/or levodopa. The exact prevalence of this condition is unclear, but it can be found in 0.3–0.9% of the hypertensive population.⁵

The clinical presentation of pheochromocytoma can vary greatly, but hypertension, tachycardia, pallor, headache and feelings of panic or anxiety are typically evident.^{3, 4, 6} The signs and symptoms often occur in paroxysmal attacks—a consequence of the episodic nature of catecholamine secretion. Attacks typically last from several minutes to an hour, and can be brought on by anesthesia or physical manipulation of the tumor.

Diagnosis of pheochromocytoma can be difficult, as the symptoms often overlap with other conditions such as hyperthyroidism, carcinoid tumors, myocardial ischemia, arrhythmias, baroreflex failure, migraine, panic disorder and stroke.^{1, 4} Presentation with nonspecific signs (headache, abdominal discomfort, vomiting and nausea) in the absence of hypertension has previously led to misdiagnosis and a resultant poor outcome.⁶ Patients with tumors that predominantly secrete epinephrine can present with hypotension or even shock, caused by hypovolemia, desensitization of adrenergic receptors or abrupt cessation of catecholamine secretion owing to tumor necrosis.⁷ Such a presentation can mimic sepsis, encephalopathy or multi-organ failure.^{5, 8} Pheochromocytoma can also present with cardiovascular complications, including myocardial infarction, sudden death, heart failure, cathecholamine-induced cardiomyopathy, hypertensive encephalopathy and cerebrovascular accident.^{1, 4} Diagnosis in these patients is especially difficult, as these disorders are often accompanied by increased plasma catecholamine concentrations even if pheochromocytoma is absent.⁴

The initial testing for pheochromocytoma should include measurement of fractionated metanephrine levels (i.e. normetanephrine and metanephrine measured separately) in urine, plasma or both.^{3, 4, 9} Metanephrines are produced by the metabolism of catecholamines within chromaffin cells (norepinephrine is converted to normetanephrine, and epinephrine to metanephrine), which occurs independently of catecholamine release. There is no consensus as to whether testing of plasma or urine is preferable.³ Plasma metanephrines are usually measured in their free form, as released by tumors, whereas urinary metanephrines are commonly present as sulfate conjugates, produced by an enzyme localized mainly to gastrointestinal tissues.^{3, 9} Sensitivity is high for the measurement of both urinary fractionated metanephrine levels (97%) and plasma free-metanephrine levels (99%), so a negative result for either test can be considered to effectively rule out pheochromocytoma.^{3, 9, 10} Twenty-four hour urinary vanillylmandelic acid testing was traditionally used to screen patients but this test has a low sensitivity (64%),¹⁰ as exemplified by the negative result seen in the present case. Histological study of the tumor is not required for confirmation of the diagnosis, but can provide some clues as to whether the tumor has spread.¹¹ There is no histological feature that can conclusively differentiate between a benign and a malignant tumor, however, so prolonged patient observation is required in all cases.

Once a diagnosis has been confirmed, the location of the tumor should be established to facilitate the appropriate treatment. CT and MRI display excellent sensitivity (90–100%) for detecting catecholamine-producing tumors, but lack the specificity to definitively distinguish a pheochromocytoma from other adrenal tumors.⁴ Once a mass is detected using these techniques its identity can be confirmed with 123I MIBG scanning, which has a specificity of 95–100% and can identify pheochromocytomas regardless of their location.⁴ If 123I MIBG is unavailable, 131I MIBG can be used as an alternative, but the image quality is lower. This combination of imaging techniques could also facilitate detection of additional multifocal or metastatic tumors.⁴

Here, we report an unusual presentation of pheochromocytoma: cyclic waves of severe hypertension alternating with hypotension. Two further cases have been diagnosed since presentation of this case (SL Kobal, unpublished data; Table 2), and six others were identified in a literature search (Table 3). The length of the BP fluctuation cycles ranged from 5 to 21 min in all of these cases. Hypertension alternating with hypotension is rare in patients with pheochromocytomas, and is believed to be associated with tumors that primarily secrete epinephrine.^{4, 7, 12} The pathology of the patient described in this report seems to support this premise, as urine tests showed high levels of metanephrine and epinephrine but normal levels of normetanephrine. The precise mechanisms for these alternating attacks are unclear, but the concomitant cycles of hypertension and hypotension–tachycardia, and the rapid response to -blocker treatment (with phentolamine), suggest that the patient's baroreflex arc might have been involved. Prolonged exposure to high levels of epinephrine and norepinephrine could result in arterial and venous vasoconstriction, leading to a reduction in blood volume and cardiac output which would, in turn, stimulate excessive reflex catecholamine release, causing paroxysmal hypertension.^{5, 13} The increase in BP would stimulate baroreceptors in the blood vessel walls and activate a negative feedback loop, mediated by the sympathetic and parasympathetic nervous systems, which would respond by decreasing peripheral vascular resistance and lowering cardiac output—causing a subsequent reduction in BP. Baroreceptors are tonically active and can respond quickly to changes in BP, which could explain the rapid alternation between hypertension and hypotension seen in this patient.

Table 2 Test results from two further cases of pheochromocytoma presenting with cyclic attacks of hypertension alternating with hypotension (SL Kobal, unpublished data). These values suggest that patient 1 had a primarily epinephrine-secreting tumor, whereas patient 2 had a tumor that predominantly secreted norepinephrine.

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Table 3 Data from other cases of pheochromocytoma with alternating cycles of hypertension and hypotension.

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Treatment and management

Surgical resection is the definitive treatment for patients with pheochromocytoma.^{3, 4} The tumor is usually removed by laparoscopy, and it is recommended that only experienced surgeons perform the procedure.^{3, 4} Intraoperative and postoperative mortalities are both near zero.¹⁴ Open transperitoneal surgery is indicated when tumors are multiple, very large or difficult to remove by laparoscopy.

Plasma volume expansion is recommended before and after surgery, and liberal salt and fluid intake is encouraged.³ The patient must also be prepared for surgery by administration of -adrenergic receptor antagonists, which work to prevent catecholamine-induced vasoconstriction. Phenoxybenzamine, a long-acting nonselective noncompetitive blocker, has traditionally been used. Owing to the lack of evidence-based studies comparing different therapies, there are no specific recommendations on which channel blockers should be administered preoperatively—-adrenoceptor, calcium channel and angiotensin receptor antagonists are all recommended and seem beneficial.³ For patients with tachyarrhythmias, -adrenoceptor or calcium channel blockers are recommended. It is emphasized that -blockers should only be used after adequate pretreatment with -blockers.³ In the present case, the BP crisis was resolved by administration of the -blocker phentolamine, intravenous fluids and the oral -blocker doxazosin. Previous cases differed in their initial responses to treatment with -blockers, -blockers and fluid repletion (Table 3).

Conclusions

The case presented here should increase awareness of this unusual, life-threatening manifestation of pheochromocytoma. Early recognition is critical for selection of the most appropriate management strategy, which should aim to terminate the effects of catecholamine storm and expand plasma volume, while stabilizing the patient and preparing for surgical resection of the tumor.

References

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10. Lenders JW et al. (2002) Biochemical diagnosis of pheochromocytoma: which test is best? JAMA 287: 1427–1434 | Article | PubMed | ISI | ChemPort |
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Subject areas under which this article appears: Hypertension