Surgical Hypertension

Logan R. McKenna, MD, John C. Eun, MD, Robert C. McIntyre, Jr., MD

CHAPTER 63

SURGICAL HYPERTENSION

1. What are the surgically correctable causes of hypertension? Renovascular hypertension, pheochromocytoma, Cushing’s syndrome, primary hyperaldosteronism (Conn’s syndrome), coarctation of the aorta, and unilateral renal parenchymal disease. Surgical hypertension accounts for 5%–10% of all hypertensive patients.  2. Which form of surgical hypertension is most common? Renovascular hypertension is the most common cause of surgical hypertension (approximately 3% of patients with hypertension), followed by primary hyperaldosteronism (1.5%), Cushing’s syndrome (0.5%), pheochromocytoma (0.1%–0.3%), and coarctation of the aorta (0.1%). However, in patients with resistant hypertension, defined as uncontrolled blood pressure despite the use of three or more antihypertensive agents, secondary forms of hypertension are much more prevalent. Renal artery stenosis may be present in up to 24% of patients with resistant hypertension. Also, primary aldosteronism is present 7%–20% of patients with resistant hypertension, particularly those with concurrent type 2 diabetes mellitus.  3. What are the most common causes of renovascular hypertension? The two major causes of renovascular hypertension are atherosclerosis and fibromuscular dysplasia. Atherosclerosis causes about 90% of cases and affects men twice as often as women. It usually involves the ostium and proximal third of the main renal artery, although, in advanced cases, segmental and diffuse intrarenal atherosclerosis may also be observed. The second most common cause is fibromuscular dysplasia (10%). Fibromuscular dysplasia may affect the intima, media, or adventitia, although 90% of cases involve the media. It tends to affect women between 15 and 50 years of age, frequently involves the distal two-thirds of the renal artery, and is characterized by a beaded, aneurysmal appearance on angiography.  4. What clinical criteria support the pursuit of investigative studies for suspected renovascular hypertension? Although no clinical characteristics are pathognomonic of renovascular hypertension, the following findings strongly suggest the presence of an underlying renal artery stenotic lesion: • Hypertension in very young individuals or in women younger than 50 years of age (suggestive of fibromuscular dysplasia) • Rapid onset of severe hypertension after age 50 years (suggestive of atherosclerotic renal artery stenosis) • Hypertension refractory to three-drug regimens • Accelerated or malignant hypertension • Deterioration of renal function after the initiation of antihypertensive agents, especially angiotensin-converting enzyme (ACE) inhibitors • Unilateral small kidney • Systolic or diastolic upper abdominal or flank bruits  5. What is the renin-angiotensin-aldosterone system (RAAS)? Renin is released from the juxtaglomerular apparatus of the kidney in response to changes in renal cortical afferent arteriolar perfusion pressure and sodium concentration. Renin acts locally and in the systemic circulation to cleave angiotensinogen, a nonvasoactive α2 globulin that is produced in the liver, to form angiotensin I. Angiotensin I undergoes enzymatic cleavage by ACE in the pulmonary circulation to produce angiotensin II, a potent vasopressor responsible for the vasoconstrictive element of renovascular hypertension. Angiotensin II increases adrenal gland production of aldosterone with subsequent retention of sodium, which acts to increase blood volume.  6. How do ACE inhibitors work? Direct inhibition of ACE decreases concentrations of angiotensin II, which leads to decreased vasopressor activity and decreased aldosterone secretion. Removal of angiotensin II mediated negative feedback on renin secretion leads to increased plasma renin activity. A similar class of drugs,

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278   ENDOCRINE SURGERY angiotensin receptor blockers (ARBs), antagonizes the action of angiotensin II at the angiotensin AT1receptor. Because there are enzymatic pathways capable of converting angiotensin I to angiotensin II independent of ACE, there is a theoretical advantage to direct inhibition of angiotensin II using ARBs.  7. How is renovascular hypertension diagnosed? The gold standard for diagnosis of renal artery stenosis remains renal arteriography, which is able to evaluate not only the degree of stenosis but also directly evaluate systolic pressure gradient. However, noninvasive methods should be used first for screening. Duplex ultrasound is the most common first study; however, it is extremely operator dependent, and lack of experienced providers may limit its use in some areas. If ultrasound is unavailable, computed tomographic angiography (CTA) is the next test of choice. Magnetic resonance angiography may be used in patients who cannot tolerate the contrast or radiation involved in CTA. Captopril renal scintigraphy, selective renal vein renin measurements, and plasma renin levels (with or without captopril administration) are not useful as initial diagnostic tests for renal artery stenosis. Generally, stenosis of >50%–70% is considered significant. Unfortunately, the degree of stenosis does not correlate well with severity of symptoms or predict response to therapy.  8. Should patients with renovascular hypertension be treated medically or surgically? In patients with symptomatic renal artery fibromuscular dysplasia, small trials demonstrate a roughly 50% cure rate with intervention, and the current standard of care is to pursue revascularization, usually by angioplasty. Surgical or percutaneous revascularization for atherosclerotic renovascular disease is more controversial. Several large, multicenter, randomized controlled trials have shown that revascularization does not improve blood pressure reduction, cardiovascular or renal outcomes, or overall mortality compared to medical therapy. However, these studies have been criticized for excluding high-risk patients. The current American Heart Association (AHA) guidelines (2006) recommend revascularization for the following patients: • Recurrent congestive heart failure or sudden unexplained pulmonary edema (Class I) • Unstable angina (Class IIa) • Accelerated hypertension, malignant hypertension, resistant hypertension (Class IIa) • Hypertension with unexplained unilateral small kidney (Class IIa) • Hypertension with intolerance to medication (Class IIa)  9. Should patients with renovascular hypertension undergo surgical or percutaneous revascularization? Small, randomized controlled trials demonstrate similar success, morbidity, and mortality rates for percutaneous transluminal renal angioplasty (PTRA) compared to surgical revascularization, and PTRA has gradually become first-line therapy over the last 10–20 years. PTRA may be performed with or without stenting; however, PTRA alone is associated with higher restenosis rates.  10. What findings on history and physical examination should lead to a suspicion of pheochromocytoma? Pheochromocytomas are neuroendocrine tumors that arise from paraganglia cells derived from the neural crest. Pheochromocytomas most often (75%–85%) arise in the chromaffin cells of the adrenal medulla. Extraadrenal pheochromocytomas most commonly occur around the inferior mesenteric artery or at the aortic bifurcation in the organ of Zucherkandl but can occur in any chromaffin tissue in the thorax, abdomen, or pelvis. Almost all pheochromocytomas produce catecholamines autonomously. About half of patients will present with sustained hypertension, but hypertension may be paroxysmal, or the patient may even be normotensive. Classically, patients describe episodes of headache, palpitations, sweating, anxiety, and flushing.  11. How is pheochromocytoma diagnosed? Initial biochemical evaluation should include measurement of either plasma-free metanephrines or 24-hour urinary fractionated metanephrines. Both tests are very sensitive, and there is no consensus on which is superior. Plasma-free metanephrines may be slightly more sensitive but less specific than urine levels, so some experts recommend measuring 24-hour urine fractionated metanephrines when suspicion for a pheochromocytoma is low (resistant hypertension, hyperadrenergic spells, or incidentaloma with imaging characteristics not consistent with pheochromocytoma) and plasma-free metanephrines when pretest probability for a pheochromocytoma is high (family history, presence of a predisposing genetic syndrome, previously resected pheochromocytoma, or adrenal mass with

Surgical Hypertension   279 imaging characteristics suspicious for pheochromocytoma). Twenty-four-hour urine samples are difficult to collect but are reliable. Plasma metanephrines are simple and convenient but must be drawn while the patient is supine, 15–20 minutes after intravenous catheter insertion to minimize false positive results. If metanephrine levels are normal, no further workup is required; if greatly elevated (>4× normal) the diagnosis of a pheochromocytoma is highly likely. Low levels of elevated metanephrines (1–3× normal) should undergo repeat testing or may be confirmed by a clonidine suppression test if required. Clonidine suppression testing is done by measuring plasma normetanephrine both before and 3 hours after clonidine administration. Elevated normetanephrine levels or a decrease of <40% from baseline confirms the diagnosis. The diagnosis of pheochromocytoma should be followed by studies to localize the tumor.  12. What is the best test to localize a pheochromocytoma? Adrenal protocol computed tomography (CT) is the first-line imaging modality once the diagnosis of pheochromocytoma is established. CT scans are highly sensitive (88%–100%) and are usually the only imaging study required to localize lesions and plan for resection. Magnetic resonance imaging (MRI) should be used as the initial imaging study in patients with known metastatic disease, skull base and neck paragangliomas, the presence of surgical clips causing artifact on CT, contrast allergy, or in patients in whom radiation exposure should be limited. MRI has superior sensitivity for extraadrenal tumors with most pheochromocytomas enhancing on T2-weighted imaging. If no tumor is found in the abdomen, CT of the chest and neck should be performed. CT is preferred over MRI in this case because of better resolution in the lungs on CT. If the tumor still cannot be localized, I131-metaiodobenzylguanidine (MIBG) imaging should be used. MIBG is a functional imaging modality that uses a radiolabeled norepinephrine analog that is taken up by sympathoadrenergic tissues. MIBG is recommended for patients with known metastatic disease, for patients with increased risk of metastatic disease (large tumor size, extraadrenal, multifocal, or recurrent disease), or for occult tumors that cannot be visualized on CT or MRI.  13. Describe the perioperative management of patients with pheochromocytoma All patients with functional pheochromocytoma should receive appropriate preoperative medical management to block the effect of catecholamine release during surgical removal of the tumor. There is no clear consensus regarding the preferred drug and clinical practice varies widely. The main goal of preoperative management is to normalize blood pressure, heart rate, and volume status, and prevent the effects of catecholamine storm during surgery. Most commonly, alpha-blockade with phenoxybenzamine, a nonselective alpha-blocker, is employed, although selective agents such as prazosin, terazosin, or doxazosin are alternatives. Calcium channel blockers have been used as an alternative at some centers with good results. Tachyarrhythmias may be treated with beta-blocking agents but should never be given without concurrent alpha-blockade, as this will result in unopposed alpha vasoconstriction, which may precipitate worsening hypertension, end-organ malperfusion, and heart failure. Whatever the chosen agent, preoperative therapy should begin well before the operation (7–14 days) and should also include salt loading and increased fluid intake to normalize volume status prior to surgery.  14. Should patients with pheochromocytoma be referred for genetic testing? Pheochromocytomas are associated with multiple genetic mutations and familial syndromes, most commonly, multiple endocrine neoplasia type 2 syndrome, von Recklinghausen disease/neurofibromatosis type 1, and von Hippel-Lindau disease. About 25% of presumably sporadic pheochromocytomas are found to have a germline mutation. While most experts do not recommend genetic testing for every patient, patients with concern for a clinical syndrome, extraadrenal tumors, multiple tumors, and age <45 years should be considered. In particular, patients with paragangliomas should be tested for mutations in succinate dehydrogenase (SDH), and patients with metastatic disease should be tested for mutations in SDH subunit B (SDH B).  15. How is primary hyperaldosteronism (Conn’s syndrome) diagnosed and treated? Conn’s syndrome, which results from autonomous mineralocorticoid hypersecretion, is characterized by hypertension, hypokalemia, hypernatremia, metabolic alkalosis, and periodic muscle weakness and paralysis. It is most often caused by an aldosterone-secreting adenoma but may also be caused by bilateral adrenal hyperplasia. Initial evaluation should include measurement of morning plasma aldosterone concentration (PAC) and plasma renin activity (PRA). The diagnosis of primary aldosteronism is suspected if the PAC/PRA ratio is >20 and PAC is >15 ng/dL. In patients with spontaneous hypokalemia, undetectable PRA, and PAC >20 ng/dL, the diagnosis is confirmed. However, in most

280   ENDOCRINE SURGERY patients, the diagnosis must be confirmed by further testing, such as an oral sodium loading test or saline infusion test. Persistently high aldosterone levels despite a large sodium challenge confirm the diagnosis. Once the diagnosis of primary aldosteronism is confirmed, patients should undergo adrenal CT to differentiate unilateral versus bilateral primary aldosteronism. Adrenal vein sampling (AVS) is done to confirm unilateral disease amendable to surgery. Some experts advocate for selectively performing AVS. In young patients (<35 years) with marked aldosterone excess and unilateral adrenal lesions, no further workup is necessary. However, most advocate for routinely performing AVS, and certainly patients over 35 years old with bilateral adrenal abnormality should undergo AVS. Patients with unilateral disease should undergo adrenalectomy when possible. Patients with bilateral disease, or those unable or unwilling to undergo surgery should be treated with a mineralocorticoid antagonist, most commonly spironolactone.  16. Why does Cushing’s syndrome cause hypertension? In the cardiovascular system, glucocorticoids produce increased cardiac chronotropic and inotropic effects, along with an increased peripheral vascular resistance. Receptors in the distal renal tubules respond to glucocorticoids by increasing tubular resorption of sodium. These receptors belong to a different class from receptors that mediate the more potent actions of aldosterone.  17. What findings suggest aortic coarctation? Lower blood pressure in the legs than in the arms and diminished or absent femoral pulses may suggest coarctation of the aorta. Rib notching may be evident on chest radiograph in patients with longstanding, hemodynamically significant coarctation. Bruits may be heard over the chest or abdominal wall. Adults may even develop congestive heart failure and renal failure.  18. How does aortic coarctation cause hypertension? No single cause has been identified. Mechanical obstruction to ventricular ejection is one component that leads to upper extremity hypertension. Hypoperfusion of the kidneys with resulting activation of the RAAS probably contributes. Abnormal aortic compliance, variable capacity of collateral vessels, and abnormal setting of baroreceptors have also been implicated.

K EY POIN T S: SU RGIC A L H Y P ERT EN S I O N 1. The causes of surgically correctable hypertension include renovascular hypertension, pheochromocytoma, Cushing’s syndrome, Conn’s syndrome, coarctation of the aorta, and unilateral renal parenchymal disease. 2. The most common cause of renovascular hypertension is atherosclerosis. 3. The diagnosis of pheochromocytoma is confirmed by measurement of plasma-free or 24-hour urine fractionated metanephrines. 4. Conn’s syndrome is characterized by hypertension, hypokalemia, hypernatremia, metabolic alkalosis, and periodic muscle weakness and paralysis.

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