Office Hypertension/Pseudohypertension
Office measures of BP may overestimate the usual or average level [see Ambulatory BP Monitoring, above]. Before embarking on further evaluation, the clinician should consider using out-of-office BP readings or ABPM to exclude a white-coat effect. Patients with white-coat hypertension are more likely to be younger (although cases of white-coat ISH do occur in elderly patients), female, and of normal weight. They often have no target organ injury and complain of fatigue and weakness (which are symptoms of hypotension) when drug doses are increased. One study suggested that up to 50% of hypertensive patients deemed resistant by office determinations of BP in fact had controlled hypertension.72
Some elderly patients may have pseudohypertension—false-ly elevated systolic and diastolic BP as determined by cuff measurement that results from atherosclerosis of the brachial artery. Because of the excessive stiffness of the vessel wall, higher cuff pressure must be applied to produce vascular occlusion. In addition, the accuracy of oscillometric devices is impaired under these circumstances. Such patients often have evidence of severe generalized atherosclerosis and remarkable elevations of systolic BP without concomitant symptoms. They may complain of weakness and fatigue with increases in drug doses. The ability to palpate the pulseless radial artery after cuff inflation (i.e., a positive Osler sign) increases the likelihood of pseudohy-pertension, but this is not a sensitive test.73 Confirmation of pseudohypertension requires intra-arterial measures of BP.
Secondary Hypertension
Secondary forms of hypertension are relatively uncommon in the general hypertensive population but may account for a significant proportion of cases of resistant hypertension. Once the other considerations have been eliminated, patients with resistant hypertension should be considered for further evaluation of secondary causes [see Secondary Hypertension, below].
Hypertensive crisis
An acute and severe rise in BP is a serious medical concern. Prompt therapy may be lifesaving. Clinically, acute and severe increases in BP can be classified as either hypertensive urgencies or emergencies (crises).42
The term hypertensive emergency or hypertensive crisis is defined as severely elevated BP associated with acute injury to target organs (i.e., brain, heart, kidneys, vasculature, and retina). Prompt hospitalization and reduction of BP with parenteral therapy is required. Examples of hypertensive emergencies include malignant hypertension, hypertensive encephalopathy, aortic dissection, eclampsia, unstable angina or acute myocar-dial infarction, pulmonary edema, and acute renal failure.
Malignant hypertension is an old term that describes a clinical syndrome associated with acute severe elevation of BP that may be fatal if not promptly treated. It is associated with a marked increase in peripheral vascular resistance caused by systemic (an-giotensin II) or locally generated (endothelin) vasoconstrictors. Any form of hypertension can progress to the malignant phase. Clinical characteristics include severe hypertension (diastolic BP > 130 mm Hg); hemorrhages, exudates, and papilledema on retinal examination; encephalopathy (i.e., headache, confusion, somnolence, stupor, visual loss, focal neurologic deficits, seizure, or coma); oliguria and azotemia; nausea, vomiting, and dyspnea; and physical findings of heart failure (rales, an S3 heart sound). Encephalopathy arises from the failure of cerebral au-toregulation of blood flow at critically high pressures, which results in cerebral vasodilation, hyperperfusion, vascular leakage, and cerebral edema. The hallmark vascular lesion of malignant hypertension is fibrinoid necrosis of arterioles that, in turn, increases both ischemic injury and further vasoactive substance release, setting up a vicious cycle. Microangiopathic hemolytic anemia with fragmentation of red cells and intravascular coagulation may occur in the setting of fibrinoid necrosis.
Hypertensive urgency is defined as severe hypertension without evidence of acute target organ injury that requires BP reduction over 24 to 48 hours. Oral therapy in the outpatient setting is often adequate. Examples include severe hypertension in a patient with known coronary artery disease, an aortic aneurysm (or aneurysm at another site), or a history of heart failure. The term accelerated hypertension is often used to describe a state of acute, severe hypertension with hemorrhages and exudates on retinal examination (but not papilledema) but without other findings of acute organ injury. This condition can be managed with oral therapy but may progress to malignant hypertension if left untreated.
The causes of hypertensive urgencies and emergencies include neglected essential hypertension (approximately 7% of untreated hypertension can progress to the malignant phase), sudden discontinuance of drug therapy (especially multiple drug regimens or regimens containing clonidine or beta block-ers), renovascular disease, collagen vascular disease (especially scleroderma), eclampsia, acute glomerulonephritis, and pheo-chromocytoma. Approximately 50% of hypertensive crises occur in patients with preexisting hypertension.
The goals of the initial evaluation are to assess for target organ injury and to define potential causes. The evaluation begins with a focused medical history and physical examination. In taking the history, the clinician must ask about compliance with prescribed antihypertensive medications and the use of drugs that can raise BP [see Table 5]. Retinal examination is a mandatory aspect of the physical examination. Immediate laboratory studies include a complete blood count (to check for anemia); blood smear (to look for fragmented red blood cells); serum cre-atinine and blood urea nitrogen assays; urinalysis; serum sodium, potassium, and glucose assays; a chest x-ray; and an electrocardiogram. In hypertensive crisis, evaluation for secondary hypertension should be deferred until the patient is stable. If a cause of the crisis is not apparent, such patients should eventually have an evaluation to exclude renal vascular disease, pheochromocytoma, scleroderma, and primary aldosteronism.
Table 12 Parenteral Therapy for Hypertensive Crisis
|
Drug |
Dosage |
Comments |
|
Sodium nitroprusside |
0.25-10.0 ^g/kg/min I.V. infusion |
General drug of choice; produces direct arteriolar and venous dilation; immediate onset and offset; side effects include metabolic acidosis, nausea, vomiting, agitation, psychosis, tremor (monitor thiocyanate levels) |
|
Labetalol |
Repetitive I.V. boluses of 20-80 mg q. 10 min or constant infusion of 0.5-2.0 mg/min |
Combination alpha/beta blocker; onset 5-10 min, offset 3-6 hr; useful in most settings, especially postoperative state, hypertensive crisis of pregnancy; avoid in acute heart failure; take beta-blocker precautions; side effects include scalp tingling, vomiting, heart block, orthostatic hypotension |
|
Glyceryl trinitrate |
5-100 ^g/min I.V. infusion |
Produces direct arteriolar and venous dilation; onset 5-10 min, offset 3-5 min; especially useful in acute coronary ischemia, CHF; tolerance with prolonged infusion; side effects include headache, flushing, nausea, methemoglobinemia |
|
Esmolol |
50-300 ^g/kg/min I.V. |
Cardioselective beta blocker, onset 1-2 min, offset 10-20 min; especially useful in postoperative state, aortic dissection, ischemic heart disease; take beta-blocker precautions; side effects include bradycardia, nausea |
|
Hydralazine |
10-20 mg I.V. bolus |
Causes direct arteriolar vasodilation; onset 10-20 min, offset 3-8 hr; used primarily for hypertensive crisis of pregnancy; avoid in acute MI, angina, aortic dissection; side effects include headache, flushing, nausea, vomiting, tachycardia, angina |
|
Enalapril |
1.25-5 mg I.V. bolus, q. 6 hr |
ACE inhibitor; onset 15 min, offset 6 hr; especially useful in acute heart failure in postoperative state; lower doses in renal disease; side effects include precipitous decline in BP (high-renin states), acute renal failure (presence of renal vascular disease) |
|
Nicardipine |
5-15 mg/hr I.V. infusion |
Dihydropyridine calcium antagonist; onset 5-10 min, offset 1-4 hr; especially useful in postoperative state; avoid in acute heart failure; side effects include headache, nausea, flushing, phlebitis |
|
Fenoldopam |
0.1-1.6 ^g/kg/min I.V. infusion |
Dopamine (DA1) agonist; onset 5 min, offset 30-60 min; especially useful in patients with impaired renal function because it increases renal blood flow and sodium excretion; side effects include nausea, vomiting, headache, flushing |
|
Phentolamine |
5-15 mg I.V. bolus |
Alpha blocker; onset instantaneous, offset 3-10 min; drug of choice for pheochromocytoma crisis; side effects include flushing, tachycardia |
|
Trimethaphan |
0.5-15 mg/min I.V. infusion |
Ganglionic blocker; onset 1-5 min, offset 10 min; tachyphylaxis common with prolonged infusion; side effects include urinary retention, paralytic ileus, dry mouth, blurred vision, orthostatic hypotension |
|
Diazoxide |
1-150 mg/kg I.V. bolus over 10 min; repeat at 10-15 min intervals if needed |
Considered obsolete; direct arteriolar dilator; onset 1 min, offset 3-18 hr; avoid in acute MI, aortic dissection; side effects include hyperglycemia, hyperuricemia, fluid retention |
ACE—angiotensin-converting enzyme
CHF—chronic heart failure
MI—myocardial infarction
Patients with hypertensive crisis should be hospitalized in an intensive care unit. The challenge of treatment is to lower BP without aggravating ischemia to vital organs. Parenteral therapy should be used [see Table 12]. Sodium nitroprusside is generally the drug of choice. Diazoxide is considered obsolete, because of the availability of newer and safer drugs. Mean BP should be lowered by 20% in the first hour (diastolic BP should be reduced to 100 to 110 mm Hg). As BP is lowered, the patient should be monitored for evidence of worsening cerebral, renal, or cardiac function. If the patient is stable, BP should be further lowered over the next 24 hours. Oral therapy can be started, and parenteral therapy gradually discontinued.
Treatment for specific patient groups
The Elderly
Approximately 60% to 70% of persons 60 years of age or older have hypertension.1 In this age group, systolic BP is the dominant predictor of adverse events, and ISH is the most common type of blood pressure disturbance.11,12 Treatment of hypertension in the elderly reduces CV disease event rates and lessens the risk of development and progression of cognitive dysfunction and dementia.7,74 The benefits of treatment have been shown for persons with either systolic-diastolic hypertension or ISH and for those older than 80 years. Although most elderly persons have primary hypertension, secondary forms of hypertension should be considered if the onset is recent or the hypertension is resistant.
There are special concerns regarding BP measurement in the elderly. Systolic BP is often quite variable, and the phenomenon of white-coat hypertension may be common in the elderly, especially in older women. Thus, readings of BP outside the office should be encouraged, as should selective use of ambulatory monitoring, especially if the patient has no target organ changes related to hypertension or complains of side effects that suggest hypotension with treatment. As noted, white-coat hypertension is an indication for ambulatory monitoring that is covered under Medicare.40 Orthostatic hypotension and postprandial hypotension are more common in the elderly, in most cases because of dysautonomia of aging. Systolic hypertension is a predictor of orthostatic hypotension, and diabetic patients are at greater risk because of autonomic neuropathy. Thus, BP measurement in the standing position is required in all elderly patients at all office visits. Pseudohypertension should be considered in elderly patients who have palpably stiff vessels, who lack significant target organ changes despite very high BP readings, and who complain of hypotensive symptoms with treatment. Such patients may require a direct intra-arterial measure of BP for clarification.
In general, treatment of hypertension in the elderly follows the same principles as treatment in younger patients. The BP goals are the same as for the general hypertensive population. However, because the benefit of treatment on longevity is less in most elderly patients, the costs of drugs, side effects, and quality of life are important considerations. Goal BP may be difficult to achieve in some patients with systolic hypertension, but any reduction is beneficial. Thus, in some patients, a higher systolic goal may be reasonable.
Modification of adverse lifestyle factors is beneficial in the elderly and should be encouraged.75 Salt sensitivity increases with age and with the reduction in renal function that is common in the elderly.76 In patients who require drugs, lower initial doses should be considered, especially in the presence of orthostatism or comorbid vascular diseases. However, many elderly patients ultimately require multiple drugs for BP control.
In the elderly with systolic-diastolic hypertension, placebo-controlled studies have shown that initial therapy with a diuretic or a beta blocker is beneficial. In one trial, treatment using newer drugs (calcium antagonists or ACE inhibitors) was not superior to treatment using diuretics and beta blockers.77 In another study, however, starting treatment with an ACE inhibitor rather than a diuretic was associated with better outcomes, particularly in men.65 Studies in patients with ISH have shown efficacy of thiazide diuretics and long-acting dihydropyridine calcium antagonists.7 In elderly patients with LVH, the LIFE (Losartan Intervention For Endpoint reduction in hypertension) trial demonstrated that, compared with therapy using a beta blocker (atenolol), use of an ARB (losartan) was associated with fewer CV events, including strokes.78 This observation was noted overall and in the subset of elderly patients with ISH. In elderly patients with a history of stroke or transient ischemic attack, the combination of indapamide and perindopril reduced the risk for subsequent stroke and progression to dementia.79 In many elderly patients, comorbid conditions will determine the use of specific drugs. Because of the problem of polypharmacy in the elderly, a goal should always be to keep the program as simple as possible.
Diabetic Patients
Patients who have both hypertension and diabetes have twice the risk of CV disease as nondiabetic hypertensive patients. In addition, hypertension increases the risk of diabetic retinopathy and nephropathy.80 Epidemiologic and observational studies have shown that the risk of BP-related CV disease and mortality in diabetic patients begins to rise when BP exceeds 120 / 70 mm Hg.80,81 There does not appear to be a thresh old value for risk associated with systolic BP in diabetic patients. In the Hypertension Optimal Treatment Trial (HOT), diabetic patients randomized to the lowest diastolic BP goal (s 80 mm Hg; the achieved diastolic BP was 82.6 mm Hg) had the best outcomes.56 In the United Kingdom Prospective Diabetes Study (UKPDS), a mean achieved diastolic BP of 82 mm Hg was beneficial, as compared with less aggressive BP reduction.82 On the basis of these data, the American Diabetes Association, the National Kidney Foundation, and the JNC 7 report recommend a goal BP of less than 130/80 mm Hg in hypertensive diabetic patients.8,81,83
All patients with diabetes should be encouraged to adopt lifestyle modifications [see Table 8]. Weight loss (if the patient is overweight or obese) and moderate exercise are especially beneficial in diabetic patients because in addition to lowering BP, these interventions improve insulin sensitivity and blood lipid levels. Many patients will require lifestyle modifications and three or more drugs to achieve the BP goals. Meeting these goals may be difficult in some patients. The clinician must balance benefit from lower BP with cost of medication, side effects, and risks associated with the lower goals in some patients. The American Diabetes Association recommends a trial of lifestyle modifications alone for up to 3 months if the initial systolic BP is 130 to 139 mm Hg or the diastolic BP is 80 to 89 mm Hg. Drug monotherapy should be considered initially along with lifestyle modifications if the initial systolic BP is 140 mm Hg or higher or if the diastolic BP is 90 mm Hg or higher.81 The JNC 7 report suggests that if the initial systolic BP is 150 mm Hg or higher or the initial diastolic BP is 90 mm Hg or higher, consideration should be given to starting therapy with a combination of two drugs, one of them a thiazide diuretic.8 Before initiating drug therapy, it is important to measure BP in the standing position to detect orthostatism, the presence of which may be a clue to autonomic neuropathy and would necessitate a modification to the treatment approach.
Placebo-controlled trials in diabetic patients have shown the efficacy of ACE inhibitors, ARBs, diuretics, and beta blockers as initial therapy. Numerous studies have shown the effectiveness of ACE inhibitors and ARBs in retarding progression of diabetic nephropathy.84,85 For diabetic patients with nephropathy, the American Diabetes Association guidelines recommend ACE inhibitors as initial drugs of choice in type 1 diabetes but ARBs in type 2 diabetes.81 It is unclear whether ARBs are as cardioprotec-tive in diabetic patients as ACE inhibitors have been shown to be. In some studies, the incidence of cardiac events has been higher in diabetic patients treated with dihydropyridine calcium antagonists, as compared with ACE inhibitors.86 Beta block-ers should be considered in the setting of coronary artery disease, a common comorbidity in patients with diabetes. On balance, treatment data suggest that reaching the goal BP in diabetic patients is probably more important than the choice of drugs used to achieve it.
Patients with Heart Disease
Ischemic heart disease is the most common cause of death in patients with hypertension. Poorly controlled hypertension also results in the development of LVH. Both LVH and ischemic injury lead to the development of heart failure from either systolic or diastolic dysfunction.87 Hypertension is the most common antecedent of heart failure.88 Hypertensive effects on the heart also increase the risk for atrial fibrillation.
For asymptomatic patients with known coronary artery disease, an ACE inhibitor should be considered initially because some studies (but not all) suggest that their use may be associated with a reduced risk of cardiovascular events.89 An ACE inhibitor would also be the initial drug of choice for patients with concomitant reduced systolic function or concomitant diabetes with renal involvement.81,84,90 If there is a history of myocardial infarction, the first drug should be a beta blocker.91 For hypertensive patients with previous myocardial infarction and reduced left ventricular function, combination therapy with a beta blocker and an ACE inhibitor should be considered.92 In addition, the aldosterone antagonist eplerenone has been shown to be effective.93 If eplerenone is used, serum potassium levels should be monitored carefully, especially in patients with renal dysfunction or if ACE inhibitors or ARBs are used.
The drug of choice in hypertensive patients with stable angina, both to lower BP and to relieve symptoms and ischemia, is a beta blocker. Long-acting dihydropyridine or nondihydropyri-dine calcium antagonists have been shown to relieve symptoms and are alternative agents if beta blockers are contraindicated; these alternative agents are also suitable as additional therapy for BP or symptom control. Newer vasoselective, long-acting di-hydropyridine calcium antagonists such as amlodipine or felodipine can be used safely to lower BP in patients with impaired left ventricular function. Nitrates can be used in combination with either beta blockers or calcium antagonists for symptomatic relief and may lower systolic BP. Beta blockers should be avoided in pure vasospastic angina, a disorder best managed with long-acting calcium antagonists or nitrates. Diuretics are safe antihypertensives for patients with coronary artery disease; they work well with other agents to lower BP. Hypokalemia should be avoided.
LVH is associated with a doubling of the risk of myocardial infarction and death in hypertensive patients.94 Effective BP control causes regression of LVH and improves prognosis. Weight loss and the use of antihypertensive drugs of all major classes have been shown to induce regression of LVH; however, increasing evidence suggests that ACE inhibitors and ARBs may be more effective than other agents.95
The goal of treating hypertensive patients with heart failure is a BP of less than 130/80 mm Hg. The American College of Cardiology/American Heart Association have developed guidelines for the evaluation and management of heart failure in adults that encompass a staging system and evidence-based treatment recommendations for patients with heart failure [see I:II Heart Failure].
Patients with Chronic Kidney Disease
Kidney disease is both a cause and a consequence of hypertension. Hypertension is the second most common cause of the development of end-stage kidney disease, and most people with kidney disease have hypertension. Aggressive control of elevated BP can slow progression of renal damage and delay or prevent the development of end-stage disease.83-85,96 The currently recommended goal BP for patients with kidney disease is a level below 130/80 mm Hg. Also, patients with chronic kidney disease are at high risk for CV morbidity and mortality. Therefore, in addition to elevated BP, other modifiable CV risk factors require management.
Chronic kidney disease is defined as either a GFR of less than 60 ml/min/1.73 m2 or the presence of albuminuria (> 300 mg/ day or > 200 mg albumin per gram of creatinine).83 The GFR can be estimated using the Cockcroft-Gault or MDRD equation [see Table 6]. Determination of creatinine clearance using timed urine collections generally does not improve upon the estimates of GFR obtained using these equations.
ACE inhibitors and ARBs may be more effective than other drugs in slowing progression of proteinuric kidney disease. Whether these agents provide a specific advantage in the absence of proteinuria is less certain.83 Serum creatinine concentrations often increase acutely when these drugs are used, so serum creatinine and potassium should be measured within several days of initiating treatment. An increase in creatinine is not a reason to stop the drug unless it is excessive or associated with severe hyperkalemia. Concomitant use of potassium-sparing diuretics, potassium supplements, or nonsteroidal anti-inflammatory drugs should be avoided. A persistent increase in creatinine with treatment raises the possibility of renal artery stenosis. Most patients with kidney disease will require a diuretic as part of the treatment regimen. If GFR is estimated to be less than 30 ml/min, thiazide diuretics are usually ineffective, and loop diuretics are required. Often, three or more drugs are required to control BP.
