Patients with Acute Stroke
The majority of patients presenting with either acute is-chemic or hemorrhagic stroke have hypertension.97 The temporal profile is that of an initial acute rise in BP in the first 24 hours, followed by a slow decline over the next several days. On the whole, observational studies show that high BP at stroke onset is associated with an increased risk of death or dependency.98 However, this association is not evident in some studies, especially studies in patients with ischemic stroke.99
Unfortunately, at present there is little evidence from clinical trials to provide clear recommendations for the appropriate management of BP during acute stroke. Currently, there is consensus that in patients with acute intracranial hemorrhage, BP should be lowered if it exceeds 200/120 mm Hg, to prevent growth of the hematoma or rebleeding. Lowering of BP by less than 20% is suggested in this setting.100 Guidelines for BP management in acute ischemic stroke from the Stroke Council of the American Heart Association suggest that in patients who are not candidates for thrombolytic therapy, hypertension should be managed with observation alone if BP is less than 220 mm Hg systolic and 120 mm Hg diastolic, unless there is evidence of other acute target-organ injury (e.g., aortic dissection, acute myocardial infarction, pulmonary edema, hypertensive encephalopathy).101 For patients with systolic BP higher than 220 mm Hg or diastolic BP of 121 to 140 mm Hg, treatment with intravenous labetalol or nicardipine is recommended. Labetalol is given in a dosage of 10 to 20 mg over 1 to 2 minutes; the dose is repeated or doubled as needed every 10 minutes to a maximum dose of 300 mg. Nicardipine is given in an initial 5 mg/hr infusion and titrated to desired effect by increasing the dosage by 2.5 mg/hr every 5 minutes, to a maximum rate of 15 mg/hr. It is suggested that BP be lowered by 10% to 15%. Nitroprusside is recommended if diastolic BP is higher than 140 mm Hg; the dose should be titrated to lower BP by 10% to 15%.
In patients who are eligible for thrombolytic therapy, the Stroke Council suggests lowering BP before initiating thrombol-ysis if the BP is higher than 185 mm Hg systolic or 110 mm Hg diastolic. Treatment with labetalol, 10 to 20 mg intravenously over 1 to 2 minutes, is advised. If needed, this dose can be repeated once; or nitroglycerin paste, 1 to 3 inches, can be applied.
Table 13 Screening Options for Secondary Hypertension
|
Disorder |
Screening Tests (Sensitivity/specificity) |
Comments |
|
Captopril radionuclide renal scan (75%/85%) |
Advantage: no contrast allergy Disadvantages: renal dysfunction impairs interpretation, may miss accessory-or branch-vessel disease |
|
|
Duplex ultrasound (80%-90%/90%) |
Advantages: no contrast allergy, can be used in patients with renal dysfunction; calculation of resistive index identifies patients with renal dysfunction likely to benefit from intervention Disadvantages: failure to visualize both renal arteries; may miss accessory-or branch-vessel disease |
|
|
Renovascular hypertension112-114 |
Spiral CT angiography |
Advantages: excellent images of renal arteries; can identify dissection, accessory vessels, and fibromuscular disease Disadvantage: considerable contrast load precludes use in presence of renal dysfunction |
|
Magnetic resonance angiography (85%-100%/79%-98%) |
Advantages: contrast allergy and renal dysfunction; no radiation exposure Disadvantages: cost, may overstate degree of stenosis, claustrophobic patients may not tolerate test |
|
|
Renal angiography |
Gold standard Advantages: identifies accessory- and branch-vessel disease; percutaneous interventions can be performed as part of study Disadvantages: cost, contrast exposure, invasive (atheroemboli) |
|
|
Primary aldosteronism105-115 |
Measurement of serum sodium, potassium, PRA, and PAC; 24-hr urinary aldosterone, sodium, and PRA after 3 days of 200 mEq sodium diet |
Diagnosis confirmed if UNa > 200 mEq, UaMo > 12, and PRA < 1.0; 30% of patients with primary aldosteronism will be normokalemic at presentation Ratio of PAC/PRA > 20 (PAC >15 ng/dl and PRA < 2.0 ng/ml) Advantage: simple Disadvantages: many antihypertensive drugs can influence values of PRA and PAC; sensitive screen but not specific |
|
Pheochromocytoma107 |
Plasma free metanephrine (highly sensitive); 24-hr fractionated urinary metanephrines |
|
|
Cushing syndrome |
24-hr urinary free cortisol (95%-100%/97%-100%) |
Diagnosis certain if 24-hr urinary free cortisol level > 3x normal; diagnosis excluded if level normal; use low-dose dexamethasone suppression test if elevation < 3x normal |
|
Coarctation of the aorta |
Chest x-ray; transesophageal echocardio-gram; CT or MRI of the aorta |
Diagnostic findings on chest x-ray: "3" sign from dilation of aorta above and below the coarctation, rib notching from collateral vessels |
PAC— plasma aldosterone concentration
PRA—plasma renin activity
If antihypertensive treatment does not reduce BP to below 185/110 mm Hg, thrombolytic therapy is not advised. During and after thrombolytic treatment, BP should be monitored frequently (every 15 minutes for 2 hours, then every 30 minutes for 6 hours, and then every hour for 16 hours). During this period, treatment with nitroprusside is advised for diastolic BP higher than 140 mm Hg. For systolic BP higher than 180 mm Hg or diastolic BP of 105 to 140 mm Hg, intravenous labetalol in a dosage of 10 mg administered over 1 to 2 minutes is recommended; the dosage should be repeated or doubled every 10 minutes to a maximum of 300 mg, or a drip at a rate of 2 to 8 mg/min should be started.
Secondary Hypertension
Detection of secondary hypertension is important because, depending on the cause, it may be possible to cure the underlying condition or tailor therapy to achieve optimal BP control. Certain features suggest the presence of specific secondary forms of hypertension [see Table 4], which should then direct further testing [see Table 13].
Common reversible causes of hypertension include obesity, the use of drugs that raise BP [see Table 5], obstructive sleep apnea, and renal disease. Obstructive sleep apnea is prevalent in the population and is often associated with hypertension. Renal insufficiency from any etiology causes BP to rise. Elevated BP in turn accelerates loss of renal function, and a vicious cycle ensues. Traditional secondary causes of hypertension include renal vascular disease, coarctation of the aorta, the adrenal causes of primary aldosteronism, pheochromocytoma, and Cushing syndrome.
Renovascular hypertension
Renovascular hypertension is the most common form of potentially curable secondary hypertension. It probably occurs in 1% to 2% of the overall hypertensive population. The prevalence may be as high as 10% in patients with resistant hypertension, and even higher in patients with accelerated or malignant hypertension.
Stenosing lesions of the renal circulation cause hypertension through ischemia-mediated stimulation of the renin-angiotensin-aldosterone axis. Correcting renal ischemia eliminates excess renin production and improves or cures the hypertension. In unilateral disease, prolonged hypertension can cause nephro-sclerosis in the nonischemic kidney; nephrosclerosis lessens the likelihood of benefit from correction of the renal vascular lesion.
Fibromuscular disease is the most common cause of renovas-cular hypertension in younger patients, especially women between 15 and 50 years of age; it accounts for approximately 10% of cases of renovascular hypertension.102 Vascular lesions typically affect the middle and distal portions of the renal artery and often extend into branches. Three subtypes are defined on the basis of the layer of the vascular wall affected: (1) intimal hyperplasia (1% to 2% of cases), (2) medial fibromuscular dysplasia (95% of cases), and (3) periadventitial fibrosis (1% to 2% of cases). The most common subtype, medial fibromuscular dyspla-sia, presents as a classic string-of-beads (aneurysmal dilatations) on angiography; it progresses in 30% of cases. It is rarely associated with dissection or thrombosis. In contrast, the rarer forms can progress rapidly, and dissection and thrombosis are common. Fibromuscular dysplasia is a rare cause of renal artery occlusion.
Atheromatous disease is the most common cause of renovas-cular hypertension in middle-aged and older patients and accounts for approximately 90% of renovascular hypertension.102 Vascular lesions are usually in the proximal third of the renal arteries, often near or at the orifice. The prevalence of atheroma-tous renal artery disease increases with age and is common in older hypertensive patients, especially in those with diabetes or with atherosclerosis in other vascular beds. Most patients with atheromatous renal vascular disease and hypertension have essential hypertension. The disease is frequently bilateral (30%) and is often progressive. The likelihood of progression can be decreased by aggressive control of risk factors (e.g., dyslipi-demia, cigarette smoking, and hypertension).
The presentations of hemodynamically significant bilateral renal artery disease (ischemic nephropathy) include the following: an acute decline in renal function with use of an ACE inhibitor or ARB or with a sudden decrease in blood pressure; acute hypertension and pulmonary edema (flash pulmonary edema); or an unexplained subacute decline in renal function with or without worsening of hypertension.103 Bilateral atherosclerotic renal artery disease accounts for a small but increasing number of cases of end-stage renal disease in older persons.104
Atheroembolic renal disease can mimic renovascular hypertension and ischemic nephropathy, in that it may present as hypertension of acute onset or as a worsening of hypertension in conjunction with a subacute decline in renal function. Athero-embolic renal disease often occurs after angiography or vascular surgery. Physical findings include the presence of distal livi-do reticularis and peripheral emboli. Laboratory findings include an elevated erythrocyte sedimentation rate, anemia, hematuria, eosinophilia, and eosinophiluria.
Primary aldosteronism
The classic syndrome of primary aldosteronism consists of hypertension, hypokalemia from excessive renal excretion, alka-losis, suppressed plasma renin activity, and increased aldos-terone secretion.105 Hypokalemia is the abnormality that most often raises suspicion of this disorder, but approximately 30% of patients with primary aldosteronism present with normal serum potassium levels.
Although several subtypes of primary aldosteronism have been identified, the most common are unilateral aldosterone-producing adenoma, which comprises 30% to 40% of cases; and bilateral adrenal zona glomerulosa hyperplasia (also known as idiopathic hyperaldosteronism [IHA]), which comprises 60% to 70% of cases. Rare subtypes include glucocorticoid-suppressible hyperplasia, unilateral hyperplasia, and aldosterone-producing cortical carcinoma. The prevalence of primary aldosteronism is probably around 2%, but studies have suggested the prevalence to be as high as 15% of the hypertensive population. The higher prevalence estimates reflect an increase in the number of patients being diagnosed with IHA, a condition that may be part of the spectrum of essential hypertension.
Patients for whom the diagnosis of primary aldosteronism should be considered include the following: all hypertensive patients with spontaneous hypokalemia of renal origin (for a hypokalemic patient, a 24-hour urinary potassium level higher than 30 mEq/L is consistent with renal potassium wasting); most patients with excessive hypokalemia who are receiving usual doses of diuretics (serum potassium < 3.0 mEq/L); most patients with resistant hypertension, even if normokalemic; and all patients with hypertension and an adrenal mass.
Pheochromocytoma
Pheochromocytomas are rare tumors of chromaffin cell origin that produce excess amounts of catecholamines, which leads to paroxysmal or sustained hypertension. The incidence in the general population is 2 to 8 cases per million persons per year. The prevalence is about 0.5% in patients with hypertension who have suggestive symptoms, and approximately 4% in patients with adrenal incidentalomas. Most tumors are benign, but approximately 10% are malignant. Symptomatic paroxysms occur in less than 50% of patients. Episodes are characterized by symptoms of headache, diaphoresis, palpitations, and pallor associated with increases in blood pressure.106 Such paroxysms are usually rapid in onset, and offset and can be precipitated by a variety of activities (e.g., exercise, bending over, urination, defecation, induction of anesthesia, infusion of intravenous contrast media, smoking). A history of unintended weight loss is not uncommon. The hypertension may be associated with marked BP lability and orthostatic hypotension. Rarely, patients may present with catecholamine-induced cardiomyopathy, fever, or peripheral vasospasm. The hypertension can be severe and resistant to control.
Most pheochromocytomas are sporadic, but 10% are familial. Familial syndromes include a simple autosomal dominant form not associated with other abnormalities, the multiple endocrine neoplasias (type IIA [medullary thyroid carcinoma, hyperpara-thyroidism] and type IIB [medullary thyroid carcinoma, mucos-al neuromas, marfanoid habitus, thickened corneal nerves, intestinal gangliomatosis]), neurofibromatosis, and the von Hippel-Lindau syndrome (retinal hemangiomatosis, cerebellar hemangioblastomas, renal cell carcinoma). Familial pheochro-mocytomas can be bilateral.
Most pheochromocytomas (90%) are located in one or both adrenal glands. Extra-adrenal pheochromocytomas can occur anywhere along the sympathetic chain and, rarely, in other sites (i.e., the superior para-aortic region, the glomus jugulare, the inferior para-aortic region, the bladder, or the thorax). About 98% of pheochromocytomas are located in the abdomen.
Screening for pheochromocytoma should be selective and based on suggestive clinical features. Screening tests include measurement of catecholamines (i.e., epinephrine, norepineph-rine, dopamine) and their metabolites (i.e., metanephrine, nor-metanephrine, and vanillylmandelic acid [VMA]) in the plasma and urine. Traditionally, most experts have considered measurement of 24-hour urinary catecholamines or catecholamine metabolites to be the screening tests of choice.106 However, studies now suggest that measurement of plasma free metaneph-rines is a much more sensitive screening test (for hereditary tumors, sensitivity is 97%, versus 60% for urinary metanephrines; for sporadic tumors, sensitivity is 99%, versus 88% for urinary metanephrines).
Table 14 Causes for False Positive Screening Results for Plasma Free Metanephrines and 24-Hour Urinary Metanephrines
|
Category |
Sources |
Tests Affected |
|
Diet |
Coffee (including decaffeinated) |
Plasma metanephrines/urinary HPLC electrophoresis |
|
Acetaminophen (direct effect) |
Plasma metanephrines/urinary HPLC electrophoresis |
|
|
Caffeine (increases plasma catecholamines) |
All |
|
|
Unknown diet sources |
Plasma metanephrines/urinary HPLC electrophoresis |
|
|
Nicotine (increases plasma catecholamines) |
All |
|
|
Tricyclic antidepressants (norepinephrine and its metabolites) |
All |
|
|
Dibenzyline (norepinephrine and its metabolites) |
All |
|
|
Drugs containing catecholamines (decongestants) |
All |
|
|
Labetalol |
Urinary HPLC electrophoresis |
|
|
Withdrawal from clonidine |
All |
|
|
Drugs |
Withdrawal from alcohol |
All |
|
Withdrawal from benzodiazepines |
All |
|
|
Levodopa |
All |
|
|
Cyclobenzaprine |
All |
|
|
Amphetamines |
All |
|
|
Phenothiazines |
Unknown |
|
|
Benzodiazepines |
Unknown |
|
|
Physiologic stress |
Obstructive sleep apnea, heart failure |
All |
HPLC—high-pressure liquid chromatography
Also, this screening test obviates the concerns associated with obtaining an adequate 24-hour urine collection. Although the sensitivity of the plasma screen is higher than that of urinary tests, its specificity is lower with regard to screening for sporadic tumors (for sporadic tumors, specificity is 82% with the plasma test versus 89% with the urinary test; in hereditary tumors, specificity is 96% with the plasma test versus 97% with the urinary test). Plasma metanephrine assay should be strongly considered as the screening test of choice if a hereditary form of pheochromocytoma is suspected; it should also be considered the test of choice for patients with a history of pheochromocy-toma and for patients in whom the clinical suspicion is high. A negative result on either a plasma or urinary metanephrine test excludes the diagnosis in most cases.
Because of the low prevalence of pheochromocytomas in patients screened for this disorder, false positive results outnumber true positive results. This is of major concern because positive results from screening tests often lead to additional tests and anxiety on the part of the both the physician and the patient. There are three main factors associated with false positive results: diet, drugs, and physiologic stressors [see Table 14]. Specific dietary factors and drugs affect plasma screens and urinary metanephrine screens differently. Moreover, for urinary meta-nephrine screens, different drugs affect the results differently depending on the method of analysis used (i.e., high-pressure liquid chromatography [HPLC] versus mass spectrophotome-try). Anticipation of these potential problems and proper preparation of the patient can prevent many false positive results.
A positive screening test should prompt a search for the tumor if sources of a false positive result have been excluded. Abdominal imaging with computed tomography or magnetic resonance imaging is the initial test of choice, given that 90% of pheochromocytomas are on the adrenal glands and 98% are in the abdomen. Additional studies may be required if a tumor is not found with initial imaging.108 Medical treatment is required before surgical intervention. The mainstay of treatment is alpha blockade with phenoxybenzamine. Beta blockers can be used to control the tachycardia that occasionally follows adequate alpha blockade. Because pheochromocytomas can recur in 10% of patients, long-term biochemical follow-up is required.
Cushing syndrome
Cushing syndrome arises from excess production of gluco-corticoids. It is rare: the incidence of the ectopic adrenocorti-cotropic hormone (ACTH) syndrome is about 660 cases per million population; in 50% of these cases, the underlying cause is small cell lung cancer. The incidence of adrenal tumors is one to five cases per million population per year. The incidence of pituitary ACTH-dependent disease is estimated to be five to 25 cases per million population per year. The signs and symptoms of Cushing syndrome arise from long-term exposure to excess glucocorticoids. They include central obesity, skin atrophy, striae, acne, slow wound healing, proximal muscle wasting and weakness, osteoporosis, menstrual irregularity, hyperpigmen-tation (ACTH dependent), glucose intolerance, hypokalemia, and hypertension. Clinical manifestations vary on the basis of degree and duration of glucocorticoid excess, the presence or absence of androgen excess (in women, androgen excess produces hirsutism, decreased libido, virilization, and oily skin), and the cause of hypercortisolism (hyperpigmentation results from excessive ACTH; androgen excess is more common in adrenal carcinomas). States of pseudo-Cushing syndrome can result from significant stress, severe obesity, depression, and chronic alcoholism.109
Patients suspected of having Cushing syndrome should undergo measurement of 24-hour urinary free cortisol. Normal levels exclude the diagnosis, and levels higher than threefold normal confirm it. In patients with equivocal results, a low-dose dexamethasone suppression test can be used. For this test, the patient is given a 1 mg tablet at 11 P.M. Serum cortisol is measured on a specimen drawn the next morning at 8 A.M. A normal response is a serum cortisol level of less than 5 ^g/dl. An alternative method is to give a 0.5 mg tablet every 6 hours for eight doses and to measure 24-hour urinary cortisol excretion on the second day. A normal response is a urinary cortisol excretion of less than 10 ^g/24 hr and a serum cortisol level of less than 5 ^g/dl.
Coarctation of the aorta
Congenital constriction of the aorta accounts for approximately 7% of congenital cardiovascular diseases. Coarctation can occur anywhere along the aorta but most often occurs just distal to the takeoff of the left subclavian artery. The disorder is usually detected in childhood, but occasionally it escapes detection until adulthood. Symptoms include headache, cold feet, and claudication. The classic feature of coarctation is elevated blood pressure in the arms and low or unobtainable blood pressure in the legs. This finding can be identified by direct measurement. The presence of weak femoral pulses or a delay in sensing the femoral pulse when simultaneously palpating the radial pulse is cause to suspect coarctation. Other findings include visible pulsations in the neck or chest wall and murmurs in the front and back of the chest from collateral vessels. Physical findings may be subtle. If the diagnosis is suspected, screening tests include transesophageal echocardiography or MRI or CT imaging of the aorta. Treatment is surgical in most cases [see 1:XII Diseases of the Aorta].
Complications
Left untreated, hypertension leads to premature death or disability from complications of CV diseases, especially atheroscle-rosis.3-5 Hypertension affects blood vessels directly, inducing en-dothelial dysfunction, and acts in concert with other factors (e.g., smoking, hyperlipidemia, and diabetes) to promote the atherosclerotic process. Although the effect of hypertension on blood vessels is systemic, it expresses itself by characteristic effects on target organs—the heart, brain, kidneys, and eyes.
Hypertension increases the risk of myocardial infarction and sudden cardiac death twofold.3 It contributes to the risk of atrial fibrillation and is the single most important antecedent to the development of heart failure.87,88 These adverse effects of hypertension reflect both acceleration of atherosclerosis and the development of structural adaptation of the heart (LVH and left atrial enlargement) to increased afterload. The structural changes limit coronary reserve.
Heart failure can be the result of either systolic or diastolic dysfunction. Hypertension is commonly associated with abnormal diastolic relaxation, which can be demonstrated by echocar-diography. Progression of these effects on the heart can lead to symptoms of heart failure with preserved systolic function, a condition known as diastolic heart failure [see 1:IIHeart Failure]. In addition, long-standing hypertension leads to LVH and ventricular remodeling, which progresses to systolic dysfunction. This process is aggravated by myocardial infarction.
Hypertension is the single most important cause of stroke, which itself is the third leading cause of death in the United States.110 Hypertension increases the risk of stroke by aggravating atherosclerosis in the aortic arch and carotid and cerebral arteries (causing thrombotic or embolic ischemic strokes) and by inducing arteriosclerosis in small, penetrating subcortical cerebral vessels, leading to leukoaraiosis (periventricular leuko-enceophalopathy) and lacunar strokes. Severe hypertension is also associated with intraparenchymal and subarachnoid hemorrhage.
Hypertension in midlife is associated with an increased risk of cognitive dysfunction and dementia in later life.5 This may be a complication of multiple cerebral infarctions (multi-infarct dementia), but it also occurs in the absence of previous strokes. In some persons, cognitive dysfunction may arise from the effects of elevated BP on the small penetrating subcortical arterioles, leading to ischemic injury to white matter (visible as leukoaraio-sis on brain imaging studies). Although vascular dementia in the elderly is strongly related to hypertension, the relationship between BP and cognition is less clear in persons older than 75 years. In some cases, an inverse relationship has been noted. This may reflect a shift in cerebral autoregulation to a higher range in patients with hypertension-induced small vessel disease, making these patients more vulnerable to further ischemic brain injury when BP is lowered.
Hypertension is a risk factor for abdominal aortic aneurysm. In addition, the majority of patients with aortic dissection have hypertension. Aortic dissection arises from the combined effects of accelerated aortic atherosclerosis and increased pulsatile stress on the aortic wall. Hypertension increases the risk of peripheral vascular disease, especially in cigarette smokers and diabetic patients.
Hypertension is the second leading cause of end-stage renal disease.104 Arteriosclerotic changes lead to ischemic injury and loss of glomeruli and tubular elements, ultimately leading to the shrunken kidney of nephrosclerosis. End-stage kidney disease from hypertension is much more common in blacks. Malignant hypertension induces fibrinoid necrosis of renal arterioles and can lead to acute renal failure.
Hypertension-related vascular disease causes loss of vision through a variety of mechanisms.111 Chronic hypertension causes arteriosclerosis of retinal vessels. These changes at the site of arterial-venous crossings can lead to branch retinal vein occlusion. Central retinal vein occlusion can also occur. Ischemic optic neuropathy can be a complication of chronic hypertension or acute severe hypertension. Acute, severe elevations in BP can also cause retinal hemorrhages, exudates, and papilledema. Hypertension accelerates atherosclerosis. Atherosclerotic emboli can occlude central or branch retinal arteries, with sudden and irreversible visual loss. Reduced blood flow in the carotid or ophthalmic artery because of severe atherosclerosis can cause venous stasis retinopathy. Occlusive disease of retinal vessels can lead to cystoid macular edema, epiretinal membrane formation, and collateral vessel formation.
Prognosis
Effective treatment has a dramatic effect on the prognosis of patients with hypertension. Prospective treatment trials have established that BP reduction with drug therapy markedly reduces CV morbidity and mortality. Active treatment of hypertension lessens the tendency for BP to increase over time. For patients whose diastolic BP is 90 mm Hg more or whose systolic BP is 160 mm Hg or more, drug intervention has been shown to reduce the risk of stroke by 35% to 40%; the risk of myocardial infarction is reduced by 20% to 25%; and the risk of heart failure is reduced by over 50%. In hypertensive patients with chronic kidney disease, drug intervention reduces the risk of progression to dialysis, transplantation, and death. However, even when BP is brought down to current recommended levels, hypertensive individuals remain at higher risk for CV disease events compared with normotensive individuals. Patients with target-organ disease remain at even higher risk, despite good BP control. These observations argue for application of public health and individual patient strategies to prevent the development of hypertension and for early detection and effective treatment of high BP.
