Figure 64.1. Algorithm for JNC8 recommended first-line treatment of hypertension.

LIFESTYLE MODIFICATIONS

A recommended initial step is lifestyle modification. Components of lifestyle modification that have demonstrated effectiveness in reducing blood pressure include the following:

• Weight reduction in patients who are obese to achieve a body mass index of 18.5–24.9

• A decrease in daily sodium intake to <2.4 g

• Regular aerobic physical activity of 30 minutes daily on most days of the week

• Moderation of alcohol consumption

• Smoking cessation

Additionally, patients should be encouraged to adopt a diet rich in fruits, vegetables, and low-fat dairy products, with reduced content of total and saturated fat modeled on the Dietary Approaches to Stop Hypertension (DASH). The DASH diet has been demonstrated to be beneficial in reducing elevated blood pressure levels, particularly when combined with low sodium intake.

PHARMACOTHERAPY

The latest recommendations from the Joint National Commission (JNC8) depart from the previous iteration of these guidelines (JNC7) by de-emphasizing the use of a thiazide-type diuretic as treatment in hypertensive patients. In JNC7, thiazide-type diuretics were recommended as initial drug therapy for patients without a compelling condition. The use of calcium channel blockers (CCBs), ACE inhibitors, ARBs, and β-blockers is considered as an alternate but not first-line therapy. In JNC8, the options for first-line therapy are broadened to four classes for nonblack patients and two classes for black patients. First-line therapy for black patients consists of a thiazide-type diuretic, ACE inhibitor, ARB or CCB. Notably, the 2010 International Society on Hypertension in Blacks (ISHIB) guideline recommend an ACE inhibitor (or ARB)/CCB combination as an attractive option for black patients when BP is >15/10 mm Hg above the treatment threshold (e.g., systolic BP of 141 mm Hg in a black patient with diabetes). In JNC8 β-blockers are no longer recommended as first-line therapy because they seem to provide less protection against stroke. Furthermore, JNC8 essentially abandons the concept of defining compelling conditions like diabetes mellitus or chronic kidney disease in guiding antihypertensive therapy, but incorporates black race in guiding treatment choice (Figure 64.1).

    The treatment threshold also changes in JNC8. Whereas JNC7 recommended a treatment threshold of 140/90 mm Hg regardless of age, JNC8 raises the systolic threshold to 150 mm Hg at age 60. In addition, JNC7 recommended a lower treatment threshold (130/80 mm Hg) for patients with diabetes or chronic kidney disease, but JNC8 informed by the publication of recent randomized trials showing increased adverse risk associated with a lower target blood pressure abandons the lower BP threshold of 130/80 mm Hg. Because of lack of supportive evidence from randomized trials, JNC8 elected to not support the more aggressive blood pressure targets proposed in the 2010 ISHIB guidelines which recommended a treatment target of 135/85 mm Hg for most black hypertensive individuals and <130/80 mm Hg for those with additional comorbidity and/or target-organ disease.

HYPERTENSION SYNDROMES

HYPERTENSION EMERGENCIES

A hypertensive emergency is a condition in which elevated blood pressure results in target organ damage to one or more of the following: the cardiovascular system, the kidneys, and/or the central nervous system. Hypertensive emergencies are potentially life threatening and usually associated with blood pressures ≥180/120 mm Hg. Hypertensive urgency is defined as severely elevated blood pressure (i.e., systolic >220 mm Hg or diastolic >120 mm Hg) with no evidence of target organ damage. A hypertensive emergency requires immediate intervention and acute reduction in blood pressure to either reverse or attenuate further target organ damage. In contrast, the treatment of hypertensive urgency can be more deliberate.

Malignant Hypertension

Fewer than 1% of patients with essential hypertension develop malignant hypertension. The average age at diagnosis is 40 years, and men are affected more often than women. Risk factors for malignant hypertension include cigarette smoking, black race, medication nonadherence, and individuals with secondary hypertension. Prior to effective therapy, life expectancy was <2 years, with most deaths resulting from stroke, renal failure, or heart failure. With current therapy, including dialysis, the survival rate at 1 year is >90% and at 5 years is >80%. Malignant hypertension is characterized by severe hypertension with associated ophthalmological findings of retinal hemorrhages, exudates, and/or papilledema (Figure 64.2). Renal involvement manifests clinically with azotemia and an abnormal urinalysis—presence of hematuria, proteinuria, and red cell casts (Figure 64.3). Renal biopsy (if one is performed) usually demonstrates arteriosclerosis and fibrinoid necrosis. Neurological presentations include occipital headaches, cerebral infarct, cerebral hemorrhage, or hypertensive encephalopathy. Hypertensive encephalopathy is a symptom complex comprising of severe hypertension, headache, vomiting, visual disturbance, mental status changes, seizure, and retinopathy with papilledema. Focal signs and symptoms are uncommon and may indicate another process, such as cerebral infarct or hemorrhage. Gastrointestinal symptoms are nausea and vomiting. Diffuse arteriolar damage can result in microangiopathic hemolytic anemia.

    Patients with malignant hypertension are usually admitted to an intensive care unit for continuous cardiac monitoring and frequent assessment of neurological status and urine output. Blood pressure measurements should be measured in both arms. A rapid assessment for target organ damage is performed, both clinically and by a laboratory workup. The clinical workup must include a complete cardiac, neurological, and ophthalmoscopic examination. Hypertensive retinopathy is graded using the Keith-Wagner classification (table 64.2). Examination of the urine is also essential (see Figure 64.1). Proteinuria and hematuria are common. Red cell casts may be seen on urine sediment examination. An intravenous line is essential for medications. The initial goal of therapy should be to reduce the mean arterial pressure (MAP) by approximately 20–25% over the first 24–48 hours or to 110–120 mm Hg, whichever is higher. An intra-arterial line is helpful for continuous titration of blood pressure. Use of short-acting antihypertensive agents administered intravenously is recommended (table 64.3). The most widely used intravenous medications are nitroprusside, nitroglycerin, labetalol, and fenoldopam.

    Hypertensive urgencies do not mandate admission to a hospital. The goal of therapy is to reduce blood pressure within 24 hours, and this can be achieved as an outpatient, frequently with orally administered medications.

RESISTANT HYPERTENSION

The JNC7 defines resistant hypertension as failure to achieve goal BP (<140/90 mm Hg for the overall population and <130/80 mm Hg for those with diabetes mellitus or chronic kidney disease) when a patient adheres to maximum tolerated doses of three antihypertensive drugs including a diuretic. Resistant hypertension is present in 5% of patients with hypertension in a general practice setting, but it is much more common in specialty settings such as a renal clinic. An approach to resistant hypertension is shown in box 64.4. Because a suboptimal dosing regimen or inappropriate antihypertensive drug combination is the most common cause of resistant hypertension, the first step in management is to review the medication regimen. The most important intervention is to target subtle or clinically apparent extracellular volume expansion by either adding a diuretic agent or increasing the dose of diuretic, or by changing the diuretic class based on kidney function. A thiazide diuretic is preferred if the patient’s estimated GFR (eGFR) is >50 mL/min/1.73 m². Switching to a loop diuretic such as furosemide or bumetanide is recommended once the eGFR falls to <50 mL/min/1.73 m². In addition, the patient should be on a blocker of the RAS along with a calcium channel blocker. Options for a fourth agent include a vasodilator, a beta blocker, or a peripheral alpha blocker. Adding a complementary calcium channel blocker (e.g., adding diltiazem to nifedipine XL) has also been recommended. On the other hand, dual blockade with an angiotensin receptor blocker and an ACE inhibitor does not result in additive BP reduction and may be harmful.

Box 64.4 APPROACH TO PATIENT WITH RESISTANT HYPERTENSION

ENDOCRINE HYPERTENSION SYNDROMES

Endocrine hypertension includes the following disorders.

Primary Aldosteronism

Primary hyperaldosteronism is the most common form of endocrine hypertension. It affects 5–10% of all patients with hypertension. The two most common forms of primary aldosteronism are Conn syndrome, in which a single adrenal tumor produces excessive aldosterone, and bilateral adrenal hyperplasia, in which both adrenal glands are enlarged and cause hyperaldosteronism. Adrenal carcinoma is an extremely rare cause of primary hyperaldosteronism. Excessive aldosterone production by the adrenal glands leads to fluid retention, potassium loss that manifests as mild to moderate hypokalemia, metabolic alkalosis, and hypertension. Initial workup should include electrolytes, serum aldosterone, and plasma renin activity (PRA). A significant elevation of the plasma aldosterone-to-renin ratio to >30 may be found (normal ratio is 4–10). If the plasma aldosterone concentration is >20 ng/dL and the ratio is >30, the sensitivity and specificity for primary aldosteronism are >90%. Confirmatory testing should include either measurement of the serum aldosterone level after 3 days of an unrestricted sodium diet and 1 hour of full recumbency, or measurement of 24-hour urinary aldosterone excretion, or an oral or intravenous salt-loading test with measurement of serum aldosterone and PRA. Additional testing includes high-resolution, thin-slice (2–2.5 mm) adrenal computed tomography (CT) scanning with contrast and adrenal venous sampling. Adrenal venous sampling probably has its greatest utility in the setting of either totally normal adrenal imaging despite biochemical evidence for primary aldosteronism or settings in which bilateral adrenal pathology is present on imaging. MRI is not superior to contrast-enhanced CT scanning for adrenal visualization. Bilateral adrenal hyperplasia is best treated with medications such as spironolactone or eplerenone. Surgery is the treatment of choice for the lateralizable variants of primary hyperaldosteronism.

Cushing Syndrome

Cushing syndrome is caused by prolonged exposure to elevated levels of either endogenous or exogenous glucocorticoids. Cushing syndrome can be due to direct adrenal involvement (adrenal Cushing) or independent of adrenocorticotropic hormone (ACTH) secretion (i.e., ACTH-independent). ACTH-dependent Cushing disease is either secondary to an anterior pituitary tumor (in approximately 80%) or to ectopic ACTH production (box 64.5). Nonpituitary ectopic sources of ACTH include oat cell carcinoma, small-cell lung carcinoma, or carcinoid tumor. A more detailed discussion is provided in the endocrine section of this book (section 5, chapter 49).

Box 64.5 CAUSES OF CUSHING SYNDROME

Pheochromocytoma

This is a syndrome caused by tumors of the adrenal glands. Pheochromocytoma is rare. These tumors produce excessive amounts of epinephrine, norepinephrine, or other catecholamines. The classic triad of symptoms in patients with a pheochromocytoma consists of episodic headache, sweating, and tachycardia. Patients with a pheochromocytoma have episodic or sustained hypertension. About 10% of these tumors are located outside the adrenal glands (extra-adrenal) in various locations in the body. Extra-adrenal pheochromocytomas are also known as paragangliomas. About 10% of the tumors are malignant. Pheochromocytomas may present as a part of multiple endocrine neoplasia (MEN) syndromes (table 64.4). MEN syndromes can involve other endocrine organs such as the parathyroid glands, pituitary, and thyroid, as well as other organs such as the kidney, pancreas, or stomach. The MEN 2A and 2B syndromes, which are autosomally inherited, have been traced to germline mutations in the ret proto-oncogene. The ret proto-oncogene, located on chromosome 10, encodes a tyrosine kinase receptor involved in the regulation of cell growth and differentiation. Pheochromocytomas occur bilaterally in the MEN syndromes in as many as 70% of cases.

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