23: Hypertension

First, what is normal BP, and when is a patient hypertensive? The first step is accurately measuring the BP. Table 23-1 summarizes guidelines for obtaining valid BP measurements.

Consensus guidelines classify BP as follows, based on the mean of 2 seated BP measurements on each of 2 or more office visits:

1. Optimal: systolic BP (SBP) < 120 mm Hg and diastolic BP (DBP) < 80 mm Hg

2. Normal: SBP 120–129 mm Hg and DBP 80–84 mm Hg

3. High normal: SBP 130–139 mm Hg or DBP 85–89 mm Hg

4. Grade 1 hypertension: SBP 140–159 mm Hg or DBP 90–99 mm Hg

5. Grade 2 hypertension: SBP 160–179 mm Hg or DBP 100–109 mm Hg

6. Grade 3 hypertension: SBP ≥ 180 mm Hg or DBP≥ 110 mm Hg

7. Isolated systolic hypertension: SBP ≥ 140 mm Hg and DBP < 90 mm Hg

Hypertension is either primary (essential) or secondary (resulting from a specific identifiable cause). Causes of secondary hypertension can be organized using an organ/system framework:

1. Primary (essential) hypertension

2. Secondary hypertension

   1. Endocrine

      1. Primary aldosteronism

      2. Pheochromocytoma

      3. Thyroid disease

      4. Hyperparathyroidism

      5. Cushing syndrome

   2. Renal

      1. Chronic kidney disease (CKD)

      2. Acute kidney injury

   3. Vascular

      1. Renovascular disease

      2. Coarctation of the aorta

   4. Pulmonary: sleep apnea

   5. GI: obesity

   6. Drug-induced or drug-related

      1. Prolonged corticosteroid therapy

      2. Nonselective nonsteroidal antiinflammatory drugs (NSAIDs)

      3. Cyclooxygenase (COX)-2 inhibitors

      4. Cocaine

      5. Alcohol

      6. Sympathomimetics (decongestants, anorectics)

      7. Oral contraceptives

      8. Cyclosporine and tacrolimus

      9. Erythropoietin

      10. Stimulants (modafinil, amphetamines)

Ninety-five to 99% of patients with hypertension have essential hypertension. A family history of hypertension increases the pretest probability of essential hypertension and is a pivotal clue in Mr. U’s history. Patients between the ages of 20 and 50 have about twice the risk of developing hypertension if they have 1 first-degree relative with hypertension; the relative risk is 3–4 if 2 first-degree relatives have hypertension. Common conditions that can contribute to or cause hypertension include obesity, hyperthyroidism or hypothyroidism, acute kidney injury or CKD, excessive alcohol use, sleep apnea, and the use of drugs listed previously. Other secondary causes are quite rare in unselected populations, with estimated prevalences of 0.18–4.4% for renovascular hypertension, 0.04–0.2% for pheochromocytoma, 0.01–0.4% for primary hyperaldosteronism, and 0.3% for Cushing syndrome. These conditions are more prevalent in populations of patients with resistant hypertension. Table 23-2 lists the differential diagnosis.

Leading Hypothesis: Essential Hypertension

Textbook Presentation

Essential hypertension generally presents as the gradual onset of elevated BP, most often in middle-aged people with positive family histories. Coexisting diabetes or obesity is common.

Disease Highlights

1. Patients who are normotensive at age 55 have a 90% lifetime risk of developing hypertension.

2. Across the BP range of 115/75 mm Hg to 185/115 mm Hg, each increment of 20 mm Hg systolic BP or 10 mm Hg diastolic BP doubles the risk of cardiovascular disease.

Evidence-Based Diagnosis

The evaluation of patients with hypertension focuses primarily on assessing other cardiovascular risk factors and assessing the presence or absence of target organ damage (TOD). Extensive testing for secondary causes is generally not done unless the patient has specific symptoms strongly suggestive of a specific secondary cause or if BP control cannot be achieved. Therefore, there are 3 objectives of testing in patients with hypertension:

1. Objective 1: Assess presence or absence of TOD (Table 23-3).

2. Objective 2: Assess presence or absence of other cardiovascular risk factors.

   1. Smoking

   2. Obesity (BMI > 30 kg/m²)

   3. Physical inactivity

   4. Dyslipidemia

   5. Diabetes

   6. Microalbuminuria or estimated glomerular filtration rate (GFR) < 60 mL/min

   7. Age (> 55 for men, > 65 for women)

   8. Family history of premature cardiovascular disease (men < 55, women < 65)

   9. Calculate a global risk score such as the Framingham Risk Score (see Chapter 2, Screening & Health Maintenance)

3. Objective 3: Identify secondary hypertension.

   1. In the absence of any of the clinical clues listed previously, it is unlikely that the patient has renal artery stenosis, hyperaldosteronism, or pheochromocytoma.

   2. Testing should focus on screening for more common causes or contributors to hypertension, such as kidney or thyroid disease, that are easily diagnosed with simple blood tests.

Initial testing in a patient with hypertension and no clinical clues should include an ECG, electrolytes, BUN, creatinine, calcium, TSH, urine albumin–creatinine ratio, fasting glucose, and fasting lipid panel (total cholesterol, high-density lipoprotein [HDL], triglycerides, low-density lipoprotein [LDL]).

Treatment

1. Goal 1: reduce BP to recommended target (2013 European Society of Hypertension guidelines)

   1. The SBP goal is < 140 mm Hg in all patients, including those with diabetes and CKD, except

      1. In patients 65–80 years of age, a SBP of 140–150 mm Hg is acceptable; a target of < 140 mm Hg should be considered in patients with high functional status and the ability to tolerate additional medication.

      2. In patients over 80 years of age, the target SBP is 140–150 mm Hg.

         • (1) All of the studies of hypertension treatment in the elderly included only patients with SBP ≥ 160 mm Hg.

         • (2) Decisions regarding whether to treat hypertension and target SBP in the elderly should be adapted based on the patient’s functional status, comorbid conditions, and medication side effects.

   2. The DBP goal is < 90 mm Hg in all patients except

      1. In patients with diabetes, the DBP target is < 85 mm Hg.

      2. The American Diabetes Association recommends a DBP target of < 80 mm Hg.

   3. Lifestyle changes (Tables 23-4 and 23-5) should be initiated in all patients with any grade of hypertension, and in patients with high normal BP plus additional cardiovascular risk factors, CKD, diabetes mellitus, or TOD.

      1. Low-risk patients (grade 1 hypertension, no other cardiovascular risk factors, no TOD) should be given several months to achieve their target BP with lifestyle changes.

      2. Moderate-risk patients (grade 1–2 hypertension with < 3 other risk factors) should start taking medication if goal BP is not achieved after several weeks of lifestyle changes. Many clinicians would start medication simultaneously with the initiation of lifestyle changes.

      3. High-risk patients (grade 3 hypertension, lower grade hypertension with multiple risk factors, TOD, CKD stage 3, or diabetes mellitus) should start taking medication simultaneously with the initiation of lifestyle changes.

   4. Selecting antihypertensive medication: general principles

      1. Monotherapy is successful in a limited number of patients.

      2. Combining 2 agents from any 2 classes reduces BP more than increasing the dose of a single agent.

         • (1) Low-risk and many moderate-risk patients can be given 1 medication initially.

         • (2) Patients with grade 3 hypertension or high cardiovascular risk may be given 2 medications initially.

      3. Current randomized trial evidence does not demonstrate major differences in clinical cardiovascular outcomes for different antihypertensive classes.

      4. Some patients have specific conditions that guide medication selection.

      5. Diuretics (thiazides, chlorthalidone, and indapamide), beta-blockers, dihydropyridine calcium antagonists, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin receptor blockers (ARBs) can all be used as initial monotherapy in patients with no indications for specific agents; beta-blockers are possibly somewhat less effective in preventing cardiovascular outcomes than the other classes.

      6. Preferred 2 drug combinations include diuretics plus dihydropyridine calcium antagonists, diuretics plus ACE inhibitors or ARBs, and dihydropyridine calcium antagonists plus ACE inhibitors or ARBs

      7. ACE inhibitors and ARBs should not be used together since the combination has been shown to accelerate CKD.

      8. If target BP is not achieved using 1 of the preferred 2 drug combinations, add the class not already being used (diuretic, ACE inhibitor or ARB, or dihydropyridine calcium antagonist).

      9. If target BP is not achieved using the 3 preferred drug classes, the next class added is usually beta-blockers, followed by spironolactone, direct vasodilators (such as hydralazine), or alpha-adrenergic blockers.

      10. Antihypertensive therapy for patients with specific indications

          • (1) Left ventricular hypertrophy: ACE inhibitors/ARBs, dihydropyridine calcium antagonists

          • (2) Heart failure: loop diuretics, ACE inhibitors/ARBs, beta-blockers, spironolactone (see Chapter 15, Dyspnea, for a more detailed discussion of the treatment of heart failure)

          • (3) Ischemic heart disease

            • (a) Stable angina: beta-blockers

            • (b) Acute coronary syndromes: use beta-blockers and ACE inhibitors

            • (c) Postmyocardial infarction: use beta-blockers, ACE inhibitors or ARBs

          • (4) Diabetes mellitus: ACE inhibitors/ARBs

          • (5) CKD or microalbuminuria: ACE inhibitors/ARBs

2. Goal 2: Optimize other cardiovascular risk factors

   1. Lipid lowering: The American College of Cardiology/American Heart Association (ACC/AHA) issued updated cholesterol treatment guidelines in 2013, based on the following findings:

      1. Statin therapy has been shown to reduce atherosclerotic cardiovascular disease (ASCVD) events in both primary and secondary prevention populations.

         • (1) The relative risk reduction is about the same in all populations.

         • (2) However, the number of events avoided per 1000 patients treated is smaller in lower risk populations (Figure 23-1).

      2. There was no randomized controlled trial evidence to support titrating drug therapy to a certain target LDL or to support the use of non-statin therapy in patients who can tolerate statins.

      3. High intensity statins lower LDL by ≥ 50% (Table 23-6).

      4. Moderate intensity statins lower LDL by 30–50% (Table 23-6).

      5. Low intensity statins lower LDL by < 30%.

   2. The guidelines are found in Table 23-7.

   3. There are no recommendations for patients with NYHA class II–IV ischemic systolic heart failure or patients receiving maintenance hemodialysis, since these patients were not included in the clinical trials; it is possible they would also benefit.

   4. All patients should be counseled regarding exercise and diet.

   5. Smoking cessation

   6. Antiplatelet therapy (aspirin 81 mg daily, or clopidogrel in aspirin-allergic patients) if the Framingham Risk Score is > 10%

Based on Mr. U’s history, physical exam, and initial laboratory test results, it is not necessary to do any further testing for secondary causes of hypertension. He does have other modifiable cardiovascular risk factors (smoking, obesity, and hypercholesterolemia), and some evidence for TOD (early retinopathy and left ventricular hypertrophy).

Mrs. X’s BP is uncontrolled. She could have resistant hypertension, which is defined as a failure to reach a BP goal despite the use of 3 optimally dosed antihypertensive medications of different classes, ideally including a diuretic. Alternatively, she could have “pseudoresistance,” meaning that her BP is uncontrolled due to poor BP measurement technique, poor adherence, white-coat effect, or an inadequate treatment regimen. The first steps in assessing patients with uncontrolled BP include repeating the BP measurement with a properly sized cuff (if the cuff is too small, the systolic BP can be elevated as much as 15 mm Hg), reviewing medication adherence, obtaining home BP measurements, and reviewing the medication regimen itself. Mrs. X is adherent to her medications, is taking optimal doses of 3 medications from different classes including a diuretic, and has consistent BP readings at home and in the office. Thus, she meets the criteria for resistant hypertension.

After establishing that a patient has resistant hypertension, the next step is to consider the many potential causes (Table 23-8). Lifestyle factors are common contributors to resistant hypertension. Elderly patients, African-American patients, and those with CKD tend to be particularly salt sensitive. About 12–14% of people consuming more than 2 drinks/day are hypertensive. For every 10% increase in body weight, systolic BP increases by 6.5 mm Hg. Secondary causes of hypertension are more common in patients with resistant hypertension referred to hypertension specialty clinics, with about 20% having an identifiable secondary cause.

The clinical clues in Mrs. X’s presentation include her vascular risk factors, suggesting she is at risk for renal artery stenosis. In addition, she does have preexisting CKD, a common cause of resistant hypertension. Her obesity is a risk factor for obstructive sleep apnea, another common cause. Hyperaldosteronism should be considered since it is found in 15–20% of patients with resistant hypertension. She has no symptoms to suggest a rare cause of secondary hypertension, pheochromocytoma (0.1–0.6% of patients). Table 23-9 lists the differential diagnosis.

Leading Hypothesis: Atherosclerotic Renal Artery Stenosis

Textbook Presentation

Patients generally have either very abrupt hypertension, hypertension that worsens over 6 months, or hypertension refractory to treatment with 3 drugs. The classic patient with atherosclerotic renal artery stenosis has other vascular disease (cerebrovascular disease, coronary artery disease, peripheral arterial disease) or risk factors such as smoking or diabetes.

Disease Highlights

1. Must distinguish renovascular disease from renovascular hypertension

   1. Renovascular disease means significant stenosis of 1 or both renal arteries.

      1. Can be due to fibromuscular dysplasia (most commonly in young women) or atherosclerosis (90% of cases)

         • (1) Atherosclerotic renal artery stenosis (ARAS) is present in 1–6% of unselected patients with hypertension.

         • (2) ARAS is found in more than 30% of patients undergoing cardiac catheterization.

      2. Does not necessarily cause hypertension and can exist in patients with essential hypertension.

   2. Renovascular hypertension means hypertension caused by renal hypoperfusion as a result of renal artery stenosis.

      1. Stenosis leads to renal ischemia, activating the renin–angiotensin system, which leads to release of renin and production of angiotensin II.

      2. Although plasma renin levels are high initially, they decrease over time.

      3. Aldosterone secretion and vasoconstriction then occur, leading to hypertension.

      4. Aldosterone secretion also causes salt and water retention and hypokalemia.

      5. Ischemic nephropathy occurs when renal blood flow is so reduced that GFR decreases and there is loss of renal function.

      6. Some patients with bilateral renal artery stenosis present with episodic, unexplained pulmonary edema (“flash pulmonary edema”); echocardiograms in such patients show normal systolic function.

2. About 50% of patients with renal artery stenosis have renovascular hypertension.

Evidence-Based Diagnosis

1. Clinical clues to identify patients with high risk of having ARAS

   1. Onset of hypertension before age 30, or severe hypertension after age 55

   2. Accelerated, resistant, or malignant hypertension

   3. New azotemia or worsening renal function after use of an ACE inhibitor or ARB

      1. A reversible increase in serum creatinine can develop in some patients with bilateral renal artery stenosis (or unilateral stenosis in patients with only 1 functioning kidney) when starting ACE inhibitor therapy.

         • (1) The peak creatinine occurs somewhere between 4 days and 2 months.

         • (2) Creatinine returns to baseline within 1 week of stopping the ACE inhibitor.

      2. One study reported that, in a population of high-risk patients, a 20% increase in creatinine had 100% sensitivity and 70% specificity for the diagnosis of renal artery stenosis (defined as > 50% bilateral stenosis).

   4. Unexplained atrophic kidney or size discrepancy of > 1.5 cm between the kidneys

   5. Sudden, unexplained pulmonary edema; unexplained heart failure; refractory angina

   6. Multivessel coronary artery disease or peripheral arterial disease

   7. Unexplained renal dysfunction

2. Abdominal bruits may be present.

   1. Should listen over all 4 abdominal quadrants and also spine and flanks between T12 and L2

   2. Must differentiate between systolic bruits and continuous (systolic and diastolic) bruits

      1. Systolic bruits occur in 4–20% of healthy persons, more commonly in people under 40 years of age.

         • (1) May originate from the celiac artery

         • (2) Modestly increase the likelihood of renal artery stenosis: LR+, 5.6; LR–, 0.6

      2. Continuous systolic-diastolic bruits often radiate to the side and strongly increase the likelihood of renal artery stenosis: LR+, 38.9; LR–, 0.6.

3. Family history of hypertension is often absent.

4. Hypokalemia is often seen as a result of stimulation of aldosterone release; metabolic alkalosis is also often seen.

5. Imaging studies

   1. Intra-arterial digital subtraction angiography is the gold standard.

      1. Can also be therapeutic through performance of angioplasty or placement of stent in the rare cases this is indicated

      2. Complications include bleeding, dissection, embolization, and contrast nephropathy.

   2. Duplex ultrasonography (2-dimensional ultrasound imaging combined with Doppler flow measurements)

      1. Results can vary depending on the level of experience of the technician and the body habitus of the patient.

      2. Accuracy ranges from 60% to 90%

      3. In optimal circumstances, sensitivity is 85% and specificity, 92% (LR+, 10; LR–, 0.16)

   3. Magnetic resonance angiography with gadolinium

      1. The largest single study found that for ARAS the sensitivity was 78% and specificity was 88% (LR+ = 6.5, LR− = 0.25); for fibromuscular dysplasia, the sensitivity was only 22% but the specificity was 96%.

      2. Smaller studies report sensitivities and specificities over 90%.

   4. CT angiography

      1. Preferable to avoid in patients with CKD due to the necessary IV contrast (see Chapter 28, Acute Kidney Injury)

      2. In the large study noted above, for ARAS, the sensitivity was 77% and specificity was 94% (LR+ = 12.8, LR− = 0.24); for fibromuscular dysplasia, the sensitivity was 28% and specificity was 99%.

      3. Smaller studies report sensitivities and specificities over 90%.

Treatment

1. All patients with ARAS should have optimal medical therapy with ACE inhibitors or ARBs, statins, and aspirin.

2. Most patients require multiple antihypertensive medications to reach BP goals.

3. Patients should stop smoking, and diabetes should be optimally controlled.

4. The role of renal artery revascularization is limited.

   1. Randomized, controlled trials have not shown that stenting is better than medical therapy with regard to preventing progression of renal disease or cardiovascular events.

   2. ACC/AHA guidelines recommend considering revascularization in patients with hemodynamically significant bilateral ARAS (or unilateral in patients with 1 kidney) and recurrent, unexplained heart failure or pulmonary edema. Other potential indications include progressive CKD, resistant or accelerated hypertension, and unstable angina.

Worsening CKD, lifestyle factors, and medications/drugs have been ruled out by the history and unchanged serum creatinine. Primary aldosteronism needs to be considered in patients with resistant hypertension, especially those with hypokalemia.

Alternative Diagnosis: Primary Hyperaldosteronism

Textbook Presentation

Primary hyperaldosteronism is usually diagnosed when a patient with hypertension has unexplained hypokalemia or when a patient has resistant hypertension.

Disease Highlights

1. Etiology

   1. Results from a unilateral aldosterone-producing adenoma in 30–35% of cases (Conn syndrome)

   2. Results from idiopathic bilateral adrenal hyperplasia in most other patients (60–70%)

   3. Rarer causes include microadenomas, unilateral adrenal hyperplasia, and adrenal carcinoma.

2. The overall prevalence, based on community cohorts, is about 11%.

   1. Prevalence of 8–15.5% in patients with grade 2 hypertension (160–179/100–109 mm Hg) and of 13–19% in patients with grade 3 hypertension (≥ 180/≥ 110 mm Hg)

   2. Found in 17–23% of patients with resistant hypertension

   3. Prevalence uncertain in patients with hypertension and unprovoked hypokalemia; 1 study reported a prevalence of 50%

3. Pathophysiology

   1. High aldosterone levels lead to salt and water retention and potassium wasting.

   2. Because aldosterone is being produced autonomously, it is not suppressed by volume expansion, as it is normally.

   3. Volume expansion suppresses plasma renin levels.

4. Most patients have a normal potassium level; 48% of those with aldosterone-producing adenomas and 17% of those with bilateral adrenal hyperplasia are hypokalemic.

A normal potassium level does not rule out hyperaldosteronism.

Evidence-Based Diagnosis

1. The Endocrine Society recommends screening for primary hyperaldosteronism in hypertensive patients with moderate-severe hypertension (BP > 160/100 mm Hg), resistant hypertension, unprovoked (by diuretics) hypokalemia associated with renal potassium wasting, an adrenal incidentaloma, diuretic-associated hypokalemia (especially in treatment resistant patients or when hypokalemia persists when potassium-sparing diuretics, ACE inhibitors, or ARBs are used), a family history of early onset hypertension, or cerebrovascular accident at < 40 years of age.

2. There are 3 steps in the diagnosis of primary hyperaldosteronism: screening, confirmatory testing, and determining the subtype.

   1. The plasma aldosterone concentration/plasma renin activity ratio (ARR) is the most commonly used screening test; since patients with primary hyperaldosteronism have elevated levels of aldosterone and suppressed renin levels, the ratio should be elevated.

      1. The ARR can be affected by potassium status, dietary sodium, medications, and age.

      2. Ideally, prior to measurement, the patient should have a normal potassium level and liberal sodium intake.

      3. Medications that minimally affect aldosterone levels include verapamil, hydralazine, and alpha-adrenergic blockers; other antihypertensive medications and NSAIDs should be stopped for 2–4 weeks when possible.

      4. The optimal cut point is unclear; a ratio > 20–30 is generally considered a positive test.

      5. Sensitivity ranges from 73% to 87%, with a specificity of about 75%.

   2. If the ARR is abnormal, the patient should be referred to an endocrinologist for confirmatory testing (oral sodium loading, saline infusion, fludrocortisone suppression, or captopril challenge).

   3. Patients with abnormal confirmatory testing should undergo adrenal CT, possibly followed by adrenal vein sampling.

Treatment

1. Laparoscopic adrenalectomy should be considered when lateralized aldosterone excess is demonstrated by adrenal vein sampling.

2. Otherwise, treat with the aldosterone antagonist spironolactone.

Mr. J’s BP clearly needs to be lowered, and the primary question is how quickly this needs to be accomplished. In other words, is this a hypertensive emergency or hypertensive urgency? These syndromes are defined by the degree of BP elevation and whether there is acute end organ damage.

A hypertensive emergency exists when there is severe BP elevation and acute target organ involvement: acute neurologic syndromes (encephalopathy, cerebrovascular accident, intracerebral or subarachnoid hemorrhage), acute aortic dissection, acute coronary syndrome, acute pulmonary edema, acute kidney injury, severe preeclampsia/eclampsia, microangiopathic hemolytic anemia, or acute postoperative hypertension.

In hypertensive urgency, there is severe BP elevation without any acute TOD. The exact definition of “severe BP elevation” has not been established, but many experts use a cutoff of > 180/110–120 mm Hg. Common causes of hypertensive urgency and emergency include medication nonadherence, abrupt cessation of clonidine, CKD, renovascular disease, drugs (cocaine, PCP), systemic lupus erythematosus, eclampsia, and postoperative state; Cushing disease and pheochromocytoma are less common causes.

A hypertensive emergency is defined by the presence of TOD, not by the degree of BP elevation.

To some extent, the degree of the acute TOD in patients with very elevated BP depends on the time course of the BP elevation. For example, normotensive women in whom acute hypertension develops from eclampsia can have significant TOD at pressures of 160/100 mm Hg, whereas patients with chronic hypertension can be asymptomatic at much higher pressures. So, despite his very elevated BP, it is quite likely that Mr. J falls into the “hypertensive urgency” rather than the “hypertensive emergency” category. Nevertheless, hypertensive emergency is always the “must not miss” diagnosis in such patients (Table 23-10).

Leading Hypothesis: Hypertensive Urgency

Textbook Presentation

A patient with chronic hypertension has extremely high BP; by definition, patients have no symptoms or signs of acute TOD.

Disease Highlights

1. Hypertensive urgency or emergency occurs in about 1% of adults with hypertension; with urgency occurring in three-quarters of these patients.

2. The most common presenting symptoms are headache (22%), epistaxis (17%), faintness (10%), psychomotor agitation (10%), chest pain (9%), and dyspnea (9%).

Evidence-Based Diagnosis

1. Must rule out acute TOD through history, physical, and selected laboratory tests.

2. BP should be measured in both arms, and pulses palpated in both the upper and lower extremities; all patients should have a complete cardiovascular and neurologic exam, including fundoscopic exam.

3. All patients should have a serum creatinine and urinalysis performed.

4. Patients with symptoms suggestive of myocardial ischemia or pulmonary edema should have an ECG, chest radiograph, and cardiac enzymes.

5. Patients with neurologic signs or symptoms need a head CT scan and sometimes a brain MRI.

Treatment

1. In stable outpatients with chronically elevated BP, there is NOT an urgent need to reduce the BP, and it is fine if it takes several days for the BP to be reduced.

2. There are several ways to approach treatment, depending on the overall condition of the patient, whether the patient has been treated previously, and the ability of the patient to return for follow-up.

   1. In patients who have stopped their medications, it is usually sufficient just to restart them.

   2. In previously untreated patients, options include

      1. Starting 2 long-acting agents, such as a diuretic and either a calcium channel blocker or ACE inhibitor

      2. Beginning treatment with more rapid-acting agents, such as oral labetalol or clonidine, and then transitioning to longer acting agents; patients can be observed for several hours to assess their response to the short-acting agents.

3. Too rapid reduction of BP can lead to hypotension and cerebral hypoperfusion with stroke.

4. IV and sublingual medications can have unpredictable effects on BP and should be avoided in asymptomatic patients.

   1. IV hydralazine causes a progressive and sometimes precipitous fall in BP 5–15 minutes after administration.

   2. Although the circulating half-life of hydralazine is only 3 hours, the half time of its effect on BP is 10 hours.

   3. Sublingual nifedipine causes completely unpredictable lowering of BP and should never be used.

Do not be in a hurry to normalize BP in patients without acute TOD!

Alternative Diagnosis: Hypertensive Emergencies

Patients with hypertensive emergencies frequently present with chest pain (27%), dyspnea (22%), and neurologic deficits (21%). Cerebral infarction is found in about 24% of patients, with about 22% having pulmonary edema, 16% hypertensive encephalopathy, and 12% heart failure.

Acute coronary syndromes, aortic dissection, subarachnoid hemorrhage, and pulmonary edema are discussed in other chapters. This section focuses on hypertensive encephalopathy.

Textbook Presentation

Patients present with the acute or subacute development of lethargy, confusion, headache, and visual disturbances, sometimes followed by seizures (focal or generalized) and coma. The syndrome can occur with or without proteinuria and retinopathy.

Disease Highlights

1. Cerebral blood flow is autoregulated within specific limits.

   1. In normotensive people, cerebral blood flow is unchanged between mean arterial pressures (MAP) of 60–120 mm Hg (MAP = [(2 × diastolic) + systolic]/3)

      1. Cerebral vasoconstriction limits hyperperfusion up to a MAP of 180 mm Hg.

      2. Above a MAP of 180 mm Hg, autoregulation is overwhelmed.

   2. In hypertensive patients, cerebral blood flow can be maintained at MAPs of up to 200 mm Hg.

      1. Thought to be due to arteriolar thickening

      2. Such patients also need higher MAPs to maintain adequate cerebral blood flow (ie, abrupt lowering of the BP to a MAP of < 100–110 mm Hg can potentially lead to cerebral ischemia).

2. Failure of autoregulation leads to cerebral vasodilation, endothelial dysfunction, and cerebral edema.

3. The classic MRI finding in hypertensive encephalopathy is subcortical vasogenic edema.

   1. Also called reversible posterior leukoencephalopathy syndrome (RPLS)

   2. Generally in the posterior regions of the brain due to relatively sparse sympathetic innervation of the vertebrobasilar territory leading to more disruption of autoregulatory mechanisms, increased perfusion, and edema

   3. Can also see changes in the brainstem and anterior brain

   4. In 1 series, 92% of patients with RPLS presented with encephalopathy, 39% with visual symptoms, and 53% with headache; 87% of patients had seizures.

   5. Also seen with eclampsia and use of some immunosuppressive agents and cytotoxic drugs; in 1 series, 68% of patients with RPLS had hypertension, 11% eclampsia, 11% immunosuppressive use, and 11% other causes

   6. Reversible with treatment of hypertension or removal of inciting agent, with MRI findings resolving in days to weeks; long-term antiepileptic therapy is not necessary.

Evidence-Based Diagnosis

1. Hypertensive encephalopathy is primarily a clinical diagnosis.

2. A head CT should be done to exclude intracranial hemorrhage (intracerebral or subarachnoid bleeding).

3. An MRI should be done to exclude acute ischemic stroke and to look for RPLS.

MRI is much more sensitive than CT (83% vs 16% sensitivity; specificity of both > 95%) for the diagnosis of acute ischemic stroke.

Treatment

1. Hypertensive encephalopathy and other hypertensive emergencies should be treated in the ICU with parenteral, titratable antihypertensive agents.

2. There is little evidence to guide the choice of agents; commonly used medications include labetalol, esmolol, fenoldopam, clevidipine, nitroprusside, and nicardipine.

3. Generally, the BP should be reduced by about 10% in the first hour, and by another 15% in the next 2–3 hours; patients can often be transitioned to oral agents within 12–24 hours.

   1. The BP should be reduced more quickly in acute aortic dissection, with a goal of < 120/80 mm Hg within 20 minutes.

   2. Neurology consultation should be obtained for guidance regarding BP lowering in the setting of acute stroke.

Mr. J’s previous regimen was hydrochlorothiazide, 25 mg; lisinopril 40 mg; and amlodipine, 10 mg. You instruct him to fill his prescriptions after he picks up his son at school, to take the amlodipine tonight, and then to take all 3 medications in the morning. When he returns in 2 days, his BP is 160/100 mm Hg; 3 weeks later it is 145/90 mm Hg.

Pheochromocytoma

Textbook Presentation

The classic presentation is a patient with attacks of paroxysmal hypertension, headache, palpitations, and sweating occurring several times daily, weekly, or every few months. Patients generally have orthostatic hypotension on physical exam.

Diseases Highlights

1. 95% of patients have headache, sweating, or palpitations.

2. 10% of pheochromocytomas are malignant and tend to have a less typical presentation.

3. 10–15% are familial (multiple endocrine neoplasia type 2, von Hippel-Lindau disease, neurofibromatosis); these are more often asymptomatic (and normotensive) than sporadic cases.

4. Table 23-11 lists symptoms, taken from a series of patients with pheochromocytoma, about half of whom presented with paroxysmal hypertension and about half of whom had persistent hypertension.

Evidence-Based Diagnosis

1. Pretest probability of 0.5% in hypertensive patients who have suggestive symptoms, and of 0.2% in unselected hypertensive patients

2. Pretest probability of 4% in patients with incidentally discovered adrenal masses

3. Plasma free metanephrine is the single best test to rule out pheochromocytoma (Table 23-12).

   1. Patients should fast overnight and be supine for 20 minutes prior to the blood draw.

   2. Because caffeine and acetaminophen interfere with the assay, patients should avoid caffeine for 12 hours and acetaminophen for 5 days prior to testing.

   3. The standard upper limit of normal for plasma metanephrines is 61 ng/L.

      1. The overall (sporadic and hereditary cases) sensitivity at this cut off is 99% with a specificity of 89%.

      2. A plasma metanephrine > 236 ng/L is 100% specific for the diagnosis of pheochromocytoma.

4. Patients with positive biochemical testing should undergo adrenal imaging.

   1. CT: sensitivity of 93–100% for detecting adrenal pheochromocytomas, 90% for extra-adrenal tumors; specificity 50–70%

   2. MRI: sensitivity 90%; specificity also 50–70%; better than CT for identifying vascular invasion

   3. ¹³¹I-MIBG or positron emission tomography scanning is sometimes used when the biochemistry is positive and both CT and MRI are negative.

Treatment

1. Surgery is the definitive treatment.

2. Must give both alpha- and beta-blocking agents preoperatively

   1. The alpha-blocker opposes catecholamine-induced vasoconstriction.

   2. The beta-blocker opposes the reflex tachycardia that occurs with alpha-blockade.

   3. Unopposed beta-blockade causes inhibition of epinephrine-induced vasodilation, leading to increased BP, left heart strain, and possibly heart failure.

   4. Should be done in consultation with an endocrinologist because of the complexities of ensuring adequate alpha-blockade

      Never give a patient with a pheochromocytoma a beta-blocker without first giving an alpha-blocker.

3. 27–38% of patients have residual hypertension.

4. Patients with familial pheochromocytoma often have multiple, bilateral tumors; the optimal approach to therapy is not clear.