Hypertensive Encephalopathy/Pheochromocytoma Case File

Hypertensive Encephalopathy/Pheochromocytoma Case File

Eugene C. Toy, MD, Gabriel M. Aisenberg, MD

Case 7

A 39-year-old man is brought to the emergency center by ambulance after he was found wandering in the street in a disoriented state. He is confused and agitated. Further history is obtained from his wife. She reports that for the last several months he has been complaining of intermittent headaches and palpitations. He has also experienced feelings of light-headedness when playing basketball. Three weeks ago, he was diagnosed with hypertension and was started on clonidine twice per day. He took the clonidine for 2 weeks, but the drug made him feel sedated. Five days ago, he was instructed by his primary care provider to stop the clonidine and to start taking metoprolol twice daily. On examination, he is afebrile, with a heart rate of 110 beats per minute (bpm), respiratory rate of 26 breaths per minute, oxygen saturation of 98% on room air, and blood pressure of 215/132 mm Hg in both arms. He is agitated and diaphoretic and is looking around the room but does not appear to recognize his wife. His pupils are dilated but reactive. On fundoscopic examination, he has papilledema and scattered retinal hemorrhages. He has no thyromegaly. Heart, lung, and abdominal examinations are normal. His pulses are bounding and equal in his arms and legs. He moves his extremities well, his reflexes are brisk and symmetric, and he is slightly tremulous. Noncontrast computed tomography (CT) of the head is negative for hemorrhage. Laboratory studies results include a normal leukocyte count and a hemoglobin level of 16.5 g/dL. Serum sodium is 139 mEq/L, potassium is 4.7 mEq/L, chloride is 105 mEq/L, HCO3 is 29 mEq/L, blood urea nitrogen (BUN) is 32 mg/dL, and creatinine is 1.3 mg/dL. Urinalysis is normal, and a urine drug screen is negative. Lumbar puncture is performed. The cerebrospinal fluid (CSF) has no red or white blood cells or xanthochromia, and it has normal protein and glucose levels.

▶ What is the most likely diagnosis?

▶ What is the underlying etiology?

▶ What is the next step?

ANSWERS TO CASE 7:

Hypertensive Encephalopathy/Pheochromocytoma

Summary: A 39-year-old-man with recently diagnosed hypertension presents with

• Altered mental status
• Critically elevated blood pressures
• Previous episodes of palpitations, headaches, light-headedness
• Recent medication change from clonidine to metoprolol
• Physical examination significant for dilated pupils, papilledema, and bounding peripheral pulses
• Negative urine drug screen and no evidence of intracranial hemorrhage or infection on CT scan and CSF studies

Most likely diagnosis: Hypertensive encephalopathy as evidenced by confusion, with systolic blood pressures > 180 mm Hg and diastolic blood pressures > 110 mm Hg.

Possible etiology: Pheochromocytoma, given the age of presentation and absence of major risk factors for idiopathic hypertension and previous episodes of palpitations, headaches, and light-headedness. Consider clonidine rebound hypertension due to recent medication change.

Next step: Admit to the intensive care unit (ICU), immediately lower blood pressure with a parenteral agent, and closely monitor the arterial pressure.

ANALYSIS

Objectives

1. Define and describe the management of hypertensive emergency and urgency. (EPA 10)
2. Understand the relationship between systemic blood pressure and cerebral blood flow. (EPA 3, 12)
3. Describe how to diagnose and medically treat a patient with a pheochromocytoma. (EPA 1, 4)

Considerations

Hypertensive encephalopathy, a symptom complex of severely elevated blood pressures, confusion, increased intracranial pressure, and/or seizures, is a diagnosis of exclusion; other causes for the patient’s acute mental decline, such as stroke, subarachnoid hemorrhage, meningitis, or mass lesion, must be ruled out. Knowing the specific etiology of the patient’s hypertension is not necessary to treat his encephalopathy; urgent blood pressure lowering is indicated. However, it may be harmful to normalize the blood pressure too quickly because it may cause cerebral hypoperfusion. Parenteral medications should be used to lower the blood pressure to the range of 160/100 to 110 mm Hg.

In addition, the patient has tachycardia, hypertension, diaphoresis, dilated pupils, and a slight tremor, all signs of a hyperadrenergic state. Pheochromocytoma must be considered as a possible underlying etiology of his hypertension. His antihypertensive medication changes may also be contributory—perhaps rebound due to discontinuation of clonidine. Moreover, in pheochromocytoma the use of beta-blockers promotes further hypertension due to the unopposed effect of alpha-adrenergic stimulation.

APPROACH TO:

Hypertensive Crises/Pheocromocytoma

DEFINITIONS

HYPERTENSIVE EMERGENCY: Acute elevation in blood pressure with associated end-organ damage.

HYPERTENSIVE URGENCY: Acute elevation in blood pressure to greater than 180 mm Hg systolic pressure and/or greater than 110 mm Hg diastolic pressure without evidence of end-organ damage.

CLINICAL APPROACH TO HYPERTENSIVE CRISIS AND EMERGENCY

Background

Hypertensive crises are critical elevations in blood pressure and are usually classified as either hypertensive emergencies or urgencies. The presence of acute end-organ damage constitutes a hypertensive emergency, whereas the absence of such complications is considered hypertensive urgency. Examples of acute end-organ damage include hypertensive encephalopathy, myocardial ischemia or infarction, aortic dissection, stroke, declining renal function with proteinuria, microangiopathic hemolytic anemia, pulmonary edema secondary to acute left ventricular failure, and vision loss with papilledema on examination.

Hypertensive emergencies require immediate reduction in blood pressure with hospitalization for close monitoring. Hypertensive urgencies also require prompt medical attention, but the blood pressure can be lowered over 1 to 2 days and monitored in the outpatient setting for patients with reliable follow-up.

Hypertensive crises are uncommon but occur most often in patients with an established history of essential hypertension (hypertension without an apparent underlying cause). A crisis may also be precipitated by use of sympathomimetic agents, such as cocaine, or by conditions that produce excess sympathetic discharge, such as clonidine withdrawal. Hypertensive crises also result from underlying diseases that cause hypertension, such as renovascular disease (eg, renal artery stenosis), renal parenchymal disease (eg, glomerulonephritis), and pheochromocytoma.

Pathophysiology

Although the pathophysiology is not completely understood, abrupt rises in vascular resistance are met with endothelial compensation by the release of vasodilator molecules such as nitric oxide. If the increase in arterial pressure persists, the endothelial response is overwhelmed and decompensates, leading to a further rise in pressure and endothelial damage and dysfunction.

Cerebral blood flow is a good example of vascular compensation by vasodilation or vasoconstriction in response to changes in arterial pressure (Figure 7–1). In normotensive adults, cerebral blood flow remains relatively constant over a range of mean arterial pressures between 60 and 120 mm Hg because cerebral vasoconstriction limits excessive cerebral perfusion. In patients with chronic hypertension, this regulation curve is shifted to the right due to the long-term change in pressure. As the mean arterial pressure increases beyond the normal range of cerebral autoregulation, there is cerebrovascular endothelial dysfunction and increased permeability of the blood-brain barrier. This leads to vasogenic edema and the formation of microhemorrhages that manifest as symptoms and signs of hypertensive encephalopathy, such as lethargy, confusion, headaches, or vision changes. Typical imaging findings on magnetic resonance imaging (MRI) include posterior leukoencephalopathy, usually in the parietooccipital regions, which may or may not be seen on CT scanning. Without therapy, hypertensive encephalopathy can lead to seizures, coma, and death.

Figure 7–1. Cerebral blood flow autoregulation. Cerebral blood flow is constant over a range of blood pressures. Chronic hypertensive patients have an adaptive mechanism that shifts the curve to the right.

Treatment

The definition of hypertensive emergency does not require numerical thresholds of arterial pressure but is based on end-organ effects. Autoregulation failure can occur in previously normotensive individuals at blood pressures as low as 160/100 mm Hg; however, individuals with long-standing hypertension frequently develop adaptive mechanisms (eg, cerebral arterial autoregulation) and may not show clinical manifestations until the blood pressure rises to above 220/110 mm Hg. Thus, emergent treatment of hypertensive encephalopathy (and indeed, all hypertensive emergencies) should focus on the symptoms rather than the numbers. In fact, it may be dangerous to “normalize” the blood pressure of patients with chronic hypertension too quickly. Rapid lowering of blood pressures may lead to decreased perfusion to the brain due to the rightward shift in the blood pressure autoregulation curve. This results in cerebral ischemia or infarction or in renal or coronary hypoperfusion. Usually, a reasonable goal is reduction of mean arterial pressures by no more than 20% or to a diastolic blood pressure of 110 to 120 mm Hg in the first hour and further 15% reduction in the following 23 hours.

Treatment of hypertensive emergencies usually necessitates parenteral medication without delay; direct blood pressure monitoring with an arterial catheter often is necessary. One of the most commonly used medications for treating hypertensive emergencies is sodium nitroprusside. It has the advantage of nearly instantaneous onset of action, and its dose can be easily titrated for a smooth reduction in blood pressure. However, its metabolite may accumulate, resulting in cyanide or thiocyanate toxicity when it is given for more than 2 to 3 days. Certain clinical situations may favor the use of other medications. Intravenous loop diuretics and vasodilators such as nitroglycerin decrease the preload (central venous pressure) in acute pulmonary edema. Myocardial ischemia or infarction is treated with intravenous nitroglycerin to improve coronary perfusion and beta-blockers to reduce blood pressure, heart rate, and myocardial oxygen demand. Patients with aortic dissection benefit from medications that reduce the shear forces affecting the aorta, which will help limit propagation of the dissection. A useful technique in treating these individuals is the use of intravenous nitroprusside to lower the arterial blood pressure and a beta-blocker to blunt reflex tachycardia. Alternatively, intravenous labetalol, a combined alpha- and beta-blocker, alone can be used. Patients presenting with acute cerebral infarction generally should not have acute blood pressure lowering unless the systolic blood pressure is greater than 220 mm Hg because of the possibility of worsening cerebral ischemia.

CLINICAL APPROACH TO PHEOCHROMOCYTOMA

Epidemiology

The vast majority of hypertension has no discernible cause (essential hypertension), but some patients have secondary causes, such as renal artery stenosis, hyperaldosteronism, or pheochromocytoma. Less than 10% of pheochromocytomas are familial, and these tend to be bilateral. One should consider screening for the presence of the RET proto-oncogene seen in multiple endocrine neoplasia type II (MEN II) or the VHL gene for von Hippel-Lindau syndrome, as well as screening family members for these diseases and for familial pheochromocytoma and neurofibromatosis.

Pathophysiology

Pheochromocytomas are catecholamine-producing tumors that arise from chromaffin cells of the adrenal medulla. The diagnosis of pheochromocytoma is established by measuring increased concentrations of catecholamines or their metabolites in either urine or plasma. Usually, a 24-hour urine collection is assayed for metanephrines and catecholamines. One-time measurement of plasma-free metanephrines is a convenient and fairly sensitive screening test. After the biochemical tests document the excess catecholamines, the next step is to locate the tumor for surgical removal. Approximately 90% of pheochromocytomas are in the adrenal gland, usually identified by CT or MRI. If the initial imaging is unrevealing, scintigraphic localization with 123I-metaiodobenzylguanidine (123I-MIBG) or an octreotide (somatostatin analog) scan is indicated.

Clinical Presentation

This patient’s history of paroxysmal hypertension with headaches, palpitations, and hyperadrenergic state (dilated pupils, diaphoresis) suggests the diagnosis of pheochromocytoma. Other symptoms may include episodic anxiety, tremor, and orthostatic hypotension caused by volume contraction from pressure-induced natriuresis. Although uncommon, accounting for only 0.01% to 0.1% of hypertensive individuals, these tumors have important therapeutic considerations.

Treatment

The treatment of choice for these tumors is surgical resection, but it is critical to reverse the acute and chronic effects of the excess catecholamines prior to excision (Figure 7–2). Alpha-adrenergic blocking agents, such as phenoxybenzamine, an irreversible, long-acting agent, are started 2 weeks prior to surgery to help prevent hypertensive exacerbations, which are especially worrisome during surgery. A liberal salt diet is initiated to expand the commonly seen contracted blood volume. Sometimes a beta-blocking agent is started, but only after alpha-blockade is established. The products of pheochromocytomas stimulate both the alpha- and beta-adrenergic receptors; thus, using a beta-blocker alone may worsen the hypertension because of unopposed alpha-adrenergic stimulation. Also, beta-blockade may result in acute pulmonary edema, especially in the presence of cardiomyopathy secondary to chronic catecholamine exposure.

CASE CORRELATION

• See also Case 6 (Hypertension, Outpatient) and Case 36 (Transient Ischemic Attack).

Figure 7–2. Pheochromocytoma evaluation and treatment flowchart.

COMPREHENSION QUESTIONS

7.1 A 50-year-old man with chronic hypertension presents at the clinic having run out of his medications, lisinopril and amlodipine, for more than a month. He is asymptomatic and has a blood pressure of 200/104 mm Hg. Which of the following is the best management?

A. Admit him to the hospital and initiate intravenous nitroprusside.

B. Prescribe clonidine 0.1 mg tid and recheck the blood pressure in 24 to 48 hours.

C. Restart his angiotensin-converting enzyme (ACE) inhibitor and calcium channel blocker and recheck blood pressure in 24 to 48 hours.

D. Refer to a social worker and do not prescribe any antihypertensive agent.

7.2 An 80-year-old woman with no significant past medical history undergoes surgery for a hip fracture. She tolerates the procedure well. On postoperative day 1 she reports moderate hip pain, but no chest pain, headache, shortness of breath, or palpitations. She is alert, awake, and oriented to person, place, and time. Her pulse is 95 bpm, temperature is 99.5 °F, respiratory rate is 18 breaths per minute, and blood pressure is 172/106 mm Hg. Over the past 24 hours, she has made 1000 mL of clear, yellow urine. Which of the following is the best next step?

A. Transfer the patient to the ICU, obtain cardiac enzyme levels, and lower the blood pressures to the 140/90 mm Hg range.

B. Control the pain and monitor the blood pressure.

C. Start the patient on a beta-blocker and monitor the blood pressure.

D. Restrict visitors and turn down the television, alarms, and other noise.

7.3 A 61-year-old man with a past medical history of coronary artery disease complains of progressive orthopnea, pedal edema, and dyspnea on exertion for the past 3 months. He is hospitalized with a pulse of 78 bpm, temperature of 98.6 °F, respiratory rate of 14 breaths per minute, and blood pressure of 190/105 mm Hg. He has bilateral 2+ pitting edema above the ankles. Cardiac enzyme levels and an electrocardiogram are normal, but an echocardiogram is still pending. Intravenous furosemide has been administered. Which of the following is the best next step?

A. Prescribe a beta-blocker to decrease myocardial oxygen demands.

B. Start intravenous dopamine.

C. Observe his clinical status.

D. Start an ACE inhibitor.

7.4 A 58-year-old woman with a past medical history of atrial fibrillation presents to the emergency room with aphasia and right arm weakness for the past 8 hours. She is nonadherent to her medication regimen. Pulse is 86 bpm, temperature is 99 °F, blood pressure is 162/98 mm Hg, and her respiratory rate is 14 breaths per minute. Cardiac examination shows an irregularly irregular rhythm. Pulmonary examination is normal. CT scan shows no intracranial hemorrhage. Which of the following is the best next step in management?

A. Normalize the blood pressure with beta-blockade.

B. Admit to the ICU with sodium nitroprusside.

C. Normalize the blood pressure with an ACE inhibitor.

D. Observe the blood pressure.

ANSWERS

7.1 C. This man has a hypertensive urgency—elevated blood pressures without end-organ symptoms. The appropriate treatment is reinitiation of blood pressure medications and reassessment in 24 to 48 hours. Answer A (hospitalization) would be indicated if the patient had symptoms of end-organ damage such as headache, chest pain, altered mental status, and so on. Answer B (clonidine) would not be good maintenance therapy, given questions regarding his compliance with treatment and the risk of rebound hypertension. Answer D (refer to social worker and do not prescribe antihypertensives) is incorrect because it is unethical not to treat this patient with critically high blood pressures. While the patient’s nonadherence should be explored and addressed, it is imperative to get the blood pressure controlled first.

7.2 B. Elevated blood pressure without symptoms may occur acutely after surgery, particularly because of postoperative pain. Answer C (starting beta-blocker therapy) would be appropriate only if the patient had critically elevated blood pressures (systolic blood pressure > 180 mm Hg and diastolic blood pressure > 110 mm Hg) or symptoms of end-organ damage. Blood pressure medications are usually not indicated when the pressures are below the malignant range; rather, pain control is the primary treatment. Lowering the blood pressure excessively can lead to orthostatic hypotension when the patient gets out of bed. Answer A (admitting to the ICU and obtaining cardiac enzymes) is not necessary in an asymptomatic patient whose increased blood pressure can be explained by postoperative pain. Answer D (restrict visitors, limit noise) would not treat the patient’s underlying pain.

7.3 D. Elevated blood pressures may exacerbate congestive heart failure and must be treated. Both ACE inhibitors and oral nitrates or intravenous nitroglycerine are used to treat acute heart failure. ACE inhibition reduces afterload, and oral nitrates or intravenous nitroglycerine reduce preload. Answer A (prescribing beta-blockers) would be inappropriate for this patient; beta-blockers are generally avoided when patients are volume overloaded because beta-blockers decrease myocardial contractility and can thus worsen acute heart failure. Answer B (treatment with intravenous dopamine) would be inappropriate for this patient because the dopamine may exacerbate the increased blood pressure and peripheral resistance. Answer C (observe the clinical status) is not appropriate with a blood pressure so high.

7.4 D. In general, blood pressure should not be acutely decreased (unless systolic blood pressure > 220 mm Hg) in an individual suspected of having an ischemic stroke because of the concern for cerebral hypoperfusion and worsening brain ischemia. If thrombolytic therapy is considered, blood pressure should be controlled to < 185/100 mm Hg, but this patient’s symptom duration precludes that consideration. In contrast, patients with intracerebral hemorrhage require urgent blood pressure decrease to values of 140 mm Hg systolic or less to decrease the propagation of the hemorrhage. Answers A (normalize the blood pressure with beta-blockade), B (admit to ICU with sodium nitroprusside), and C (normalize the blood pressure with an ACE inhibitor) are inappropriate in this patient with an ischemic stroke.

    CLINICAL PEARLS    

▶ Hypertensive urgencies are acute elevations of blood pressures > 180 mm Hg systolic and > 110 mm Hg diastolic.

▶ Asymptomatic patients with hypertensive urgency can be treated with an oral regimen and reassessed in the outpatient setting in 24 to 48 hours.

▶ A hypertensive emergency is defined as an episode of elevated blood pressure with acute end-organ damage or dysfunction.

▶ Patients with hypertensive emergencies require immediate hospitalization and a gradual decrease in blood pressure, with a focus on symptom resolution.

▶ The cerebral autoregulation curve of individuals with chronic hypertension is shifted to the right.

▶ Marked elevations in mean arterial pressure can exceed the ability of cerebral vessels to constrict, causing hyperperfusion, cerebral edema, and hypertensive encephalopathy.

▶ Pheochromocytomas may cause paroxysmal blood pressure elevation with episodic headaches, palpitations, and diaphoresis.

▶ Preoperative blood pressure control in pheochromocytoma resection is achieved with alpha-blockers. Beta-blockers used alone can paradoxically increase blood pressure because of unopposed alpha-adrenergic effects.

REFERENCES

Dluhy RG, Lawrence JE, Williams GH. Endocrine hypertension. In: Larsen PR, Kronenberg HM, Melmed S, Polonsky KS, eds. Williams’ Textbook of Endocrinology. 10th ed. Philadelphia, PA: Saunders; 2003:555-562. 

Elliot WJ, Varon J. Evaluation and treatment of hypertensive emergencies in adults. Foreman JP, ed. UpToDate. Waltham, MA: UpToDate Inc. https://www.uptodate.com. Accessed June 27, 2019. 

Kotchen TA. Hypertensive vascular disease. In: Longo DL, Fauci AS, Kasper DL, et al, eds. Harrison’s Principles of Internal Medicine. 20th ed. New York, NY: McGraw Hill; 2012:2066-2076. 

Neumann HP. Pheochromocytoma. In: Jameson JL, Fauci AS, Kasper DL, et al, eds. Harrison’s Principles of Internal Medicine. 20th ed. New York, NY: McGraw Hill; 2018:2962-2967. 

Pacak K, Linehan WM, Eisenhofer G, et al. Recent advances in the diagnosis, localization, and treatment of pheochromocytoma. Ann Intern Med. 2001;134:315-329. 

Vaughan CJ, Delanty N. Hypertensive emergencies. Lancet. 2000;356:411-417. 

Young WF, Kebebew E. Treatment of pheochromocytoma in adults. Martin KA, Chen W, eds. UpToDate. Waltham, MA: UpToDate Inc. https://www.uptodate.com/contents/treatment-of-pheochromocytoma-in-adults. Accessed June 27, 2019.

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