Emergency Medicine

Update on Hypertension in Special Populations

The diagnosis and treatment of isolated systolic hypertension in the elderly, hypertension in chronic kidney disease and diabetes, hypertension in African Americans, renovascular hypertension, and hypertension due to secondary causes such as hyperaldosteronism are discussed.

By Errol D. Crook, MD, and Donnelly Howard, MD

Hypertension affects more than 60 million adults in the United States and more than one billion people worldwide, and all indications are that this already high prevalence will continue to increase. Hypertension is the most common modifiable cardiovascular risk factor, and the risk factor for which treatment can have the greatest impact on outcomes. Therefore, it is important that this condition be recognized and treated appropriately.

BLOOD PRESSURE GOALS

The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC-7), the International Society of Hypertension in Blacks (ISHIB), and the European Society of Hypertension-European Society of Cardiology (ESH-ESC) all recommend a systolic blood pressure goal of less than 140 mm Hg and a diastolic blood pressure goal of less than 90 mm Hg. In patients with diabetes or chronic kidney disease (CKD), it is recommended that blood pressures of less than 130/80 mm Hg be maintained. Achieving these goals reduces morbidity and mortality from hypertension-related cardiovascular disease, stroke, and kidney disease.

A majority of patients with hypertension will require at least two blood pressure-lowering medications to reach these goals. Therefore, the question of which single agent is most appropriate is of relatively less importance than how many agents are necessary to reach the recommended targets. It is clear that improved cardiovascular, cerebrovascular, and renal outcomes are achieved by reaching and maintaining the target blood pressure, regardless of which agents are used.

Unrecognized and poorly controlled hypertension is common among emergency department patients. There are estimates that half of these patients have elevated blood pressure and a third have severe elevations. Moreover, many of these patients, particularly in urban settings, will not be treated for their hypertension, nor will they even be told they have the condition. Therefore, the emergency department setting is important in the recognition and treatment of hypertension.

Several groups of individuals may require special consideration with regard to hypertension. In this article, we will look at hypertension in these special populations and provide clinical clues that will assist with the diagnosis and treatment of secondary causes of elevated blood pressure. Addressing the diagnosis and treatment of hypertensive urgencies and emergencies is beyond the scope of this article. It is important to note, however, that many patients in the groups discussed here will present to their primary care providers or emergency departments with hypertensive urgencies and emergencies that will require aggressive short- and long-term therapy.

Initial therapy for hypertension is always lifestyle modification. However, patients in certain high-risk groups have compelling indications for pharmacologic therapy on diagnosis. Moreover, patients with severe elevations in blood pressure (above 180/110 mm Hg) should have medical therapy initiated at the time of diagnosis. Notably, two drugs are recommended as initial therapy in those with JNC-7 stage 2 hypertension (above 160/90 mm Hg). In all patients presenting with hypertension, an evaluation of target organ damage should be done to determine appropriate follow-up and which first-line agents should be prescribed.

ISOLATED SYSTOLIC HYPERTENSION IN THE ELDERLY

Isolated systolic hypertension is an elevation in systolic blood pressure (above 140 mm Hg) in the presence of normal diastolic blood pressure. It is typically seen in older adults, with a prevalence increasing dramatically after the fifth decade of life. It is now recognized that an elevated systolic blood pressure is relatively more important than an elevation in diastolic pressure with regard to cardiovascular disease, particularly in persons over 50 years of age. The importance of systolic blood pressure has been recognized only recently and did not become a diagnostic criteria for hypertension until JNC-6. Approximately 5% to 10% of persons aged 55 to 65 years have isolated systolic hypertension, and the prevalence increases to 25% among U.S. adults over 75 years of age. Cardiovascular risk is highest in patients with a systolic blood pressure greater than 160 mm Hg and a diastolic blood pressure below 70 mm Hg. This observation was made in men aged 35 to 57 years who were followed for a mean of 12 years. Therefore, the enhanced cardiovascular morbidity and mortality seen with isolated systolic hypertension is not limited to persons over age 65.

Clinical trials have provided guidance as to which therapies are beneficial in patients with isolated systolic hypertension (see box below). Studies in elderly patients with isolated systolic hypertension revealed reductions in cardiovascular morbidity and mortality with regimens employing both thiazide-like agents and calcium antagonists as primary blood pressure-lowering therapy. Recently, the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), the largest clinical trial done on hypertension to date, also supported the use of a regimen based on a thiazide-like agent for reduction of cardiovascular mortality. However, perhaps the most important observation in all of these trials was that the degree of blood pressure lowering was the primary predictor of outcome.

Caution must be used in treating hypertension in older individuals. The geriatric population is at higher risk for orthostatic hypotension and other side effects of blood pressure-lowering medications. Therefore, clinicians should question geriatric patients about orthostatic symptoms and should not increase the dose of an antihypertensive agent too rapidly. In the elderly population, especially those with orthostatic symptoms, blood pressure should be measured with the patient sitting and at one and three minutes after standing. In individuals with elevated blood pressure when supine or seated and a significant drop (more than a 20 mm Hg reduction) in blood pressure on standing, care has to be taken with their antihypertensive regimen. All classes of antihypertensives are associated with orthostatic hypotension, so it is difficult to say that any one class may be less harmful than another, but it should be clearly determined that a diuretic is not causing intravascular volume depletion.

It is still important to achieve blood pressure goals in patients with symptomatic orthostatic hypotension because they are at high risk for cardiovascular events. In these patients, antihypertensives should be titrated to standing blood pressure. Alternatively, antihypertensives may be taken at night, but patients should be told to be careful when getting up to urinate during the night.

In summary, regardless of age, patients with isolated systolic hypertension should be treated until the recommended blood pressure goals are achieved. While the side effects of blood pressure-lowering medications may be more common in older individuals, the benefits of therapy appear to be greater in the elderly.

HYPERTENSION IN CHRONIC KIDNEY DISEASE

The most important factor in renal survival in patients with CKD is reduction of blood pressure. The Joint National Committee and other authorities recommend achieving a blood pressure goal of less than 130/80 mm Hg in CKD patients and even lower levels (below 125/75 mm Hg) if significant proteinuria is present. Depending on the severity of CKD, it typically requires three to four blood pres-sure-lowering medications to achieve these goals.

It is widely accepted that patients with and without diabetes who have proteinuria and CKD will experience improved renal survival with a renin-angiotensin system (RAS) inhibitor included in their therapeutic regimen. However, the ALLHAT trial revealed no significant differences in renal outcomes—specifically, end-stage renal disease or 50% loss of glomerular filtration rate (GFR)— between patients treated with a diuretic-based regimen compared to either lisinopril or amlodipine. Dihydropyridine calcium channel blockers may permit increases in urine protein excretion and should not be used as first-line therapy in patients with proteinuria.

Many practitioners have concerns about using RAS inhibitors in patients with severe CKD. In particular, concern over a worsening GFR and hyperkalemia often results in inappropriate withholding of these agents. A 20% to 30% reduction in GFR should be expected and accepted with initiation of an RAS inhibitor in patients with CKD. Data suggest that patients who have this response may have the most long-term benefit from continued therapy. Moreover, the association of CKD with high cardiovascular disease morbidity and mortality has been established, and the use of RAS inhibitors in patients with CKD appears to lower cardiovascular morbidity and mortality.

HYPERTENSION IN DIABETES

The prevalence of hypertension in patients with type 2 diabetes is greater than 70%. The evidence supporting a reduction in cardiovascular events by lowering blood pressure is strongest in patients with diabetes. The risk of cardiovascular events increases with a systolic blood pressure above 110 mm Hg and there is no evidence of a J phenomenon (that is, cardiovascular risk does not increase with low blood pressure). Therefore, the recommended blood pressure target for patients with diabetes is less than 130/80 mm Hg.

The association of lower blood pressure with reduced small vessel complications of diabetes such as nephropathy and retinopathy has been established. Patients who have evidence of albuminuria, even in microscopic amounts, should be treated with an RAS inhibitor. Among patients with diabetes, older data on cardiovascular protection was more convincing with angiotensin-converting enzyme (ACE) inhibitors than angiotensin receptor blockers (ARBs). However, the relative inferiority of ARBs in terms of cardiovascular protection was hypothesized to be related to inadequate dosing, and recent data has emerged supporting the role of ARBs in cardiovascular protection in diabetic patients. In type 2 diabetic nephropathy, there is clearly more evidence supporting ARBs because the definitive trials using ACE inhibitors were only done in patients with type 1 diabetes. Therefore, both ARBs and ACE inhibitors can be considered as initial therapy for hypertension in patients with diabetes.

Beta blocker therapy is also important in patients with diabetes as a means to reduce cardiovascular mortality. However, as with CKD, blood pressure reduction is relatively more important than the specific agent used.

HYPERTENSION IN AFRICAN AMERICANS

African Americans have the highest rate of hypertension of any ethnic or racial group in the world. In addition, the severity and complications of hypertension in this population are significantly worse than in other groups. For example, the prevalence of hypertension-related stroke (80% higher), kidney disease (more than 300% higher), and heart failure (50% higher) is significantly elevated in African Americans compared to whites. Therefore, emergency physicians must pay particular attention to achieving blood pressure targets in this high-risk group.

There has been controversy regarding the best initial therapy for treatment of hypertension in African Americans. Because these patients are typically described as having low renin levels and being salt-sensitive and volume-expanded, diuretics and calcium channel blockers have been shown to be effective. In general, the blood pressure-lowering effect of an RAS inhibitor is less on average in African Americans as a group compared with other racial groups. This has led to the underutilization of RAS inhibitors in African Americans with compelling indications for these medications. However, blood pressure response to RAS inhibition varies widely among African Americans and whites and must be addressed on an individual basis. This was illustrated in the ATIME (Quinapril [Accupril] Titration Interval Management Evaluation) study, where blood pressure response overlapped to a large extent between African Americans and whites. Therefore, practitioners should not use race or ethnicity as the sole criterion for selecting an antihypertensive regimen for an individual patient.

The recommendations set forth by JNC-7 and the ISHIB Working Group should be followed with particular attention focused on cardiovascular risk factors and other compelling indications. Where RAS inhibition is indicated, it should be used without regard to race.

SECONDARY CAUSES OF HYPERTENSION

As noted earlier, the degree of blood pressure control is the most important predictor of complications from hypertension. This is true even in cases where elevated blood pressure is related to a secondary and perhaps curable cause. In such cases, however, it may be possible to decrease the need for antihypertensive medications and to prevent other systemic effects that may be related to the secondary cause.

Less than 10% of cases of hypertension can be attributed to a secondary cause. Evaluation for such causes can be very expensive and may lead to invasive tests that carry their own risk. The results of these evaluations are not always clear and practitioners may find themselves in a quandary as to how to proceed. For that reason, in-depth evaluation for a secondary cause of hypertension is usually not practical in the emergency department. Here, we will briefly review the more common secondary causes of hypertension and discuss diagnostic and therapeutic approaches to these entities.

Secondary causes of hypertension should be considered in every patient with new-onset hypertension, particularly those younger than 25 or older than 55. It is now less common to find phases of accelerated hypertension in patients with chronic hypertension. Only about 1% of patients with hypertension will ever have an acceleration of blood pressure due to a natural disease progression. Therefore, when patients with chronic hypertension present with significantly increased blood pressure, a secondary cause should be considered. In most instances, a detailed history is sufficient to determine if a secondary cause is likely.

There are numerous secondary causes of hypertension (see box below). Today, obesity and obesity-associated obstructive sleep apnea are commonly associated with hypertension. The link between obesity and hypertension is multifactorial, involving neurohumoral and hemodynamic factors, as well as changes in renal sodium absorption and renal function. Renal parenchymal disease, also known as primary renal disease, is a disorder that is closely associated with hypertension and has a higher prevalence in certain populations, such as African Americans. Many African Americans will present with hypertension and kidney disease at a disproportionately young age. In such patients, it is often difficult to determine if the renal parenchymal disease was primarily caused by hypertension or if primary renal disease preceded the hypertension. Excessive alcohol consumption and use of illicit drugs are also associated with elevated blood pressure and should be a critical part of a history in any patient with new-onset hypertension or with an exacerbation of previously stable hypertension.

Unlike the conditions just mentioned, there are other secondary causes of hypertension that are not as easily identified with a history, physical examination, and laboratory tests. One such cause is pheochromocytoma. It is no longer recommended that all patients with new-onset hypertension or accelerated hypertension be screened for this tumor because of its low incidence. Screening should be reserved for patients with symptoms suggestive of pheochromocytoma such as paroxysmal or severe sustained hypertension, severe headaches, sweating, palpitations, and tachycardia. Measuring free metanephrines in the plasma is the recommended screen.

RENOVASCULAR HYPERTENSION

Considered by some to be the most common form of secondary hypertension, renovascular hypertension is defined as elevated blood pressure caused by stenosis, constriction, or lesions of the renal arteries. The condition may be unilateral or bilateral, and it may involve the small or large renal vessels. It results in activation of the RAS and impaired renal sodium excretion. The median age for patients diagnosed with renal artery disease is over 70 years, and most of these patients have preexisting renal disease.

Renovascular hypertension should be considered as a cause of elevated blood pressure in patients who present with new-onset hypertension before age 25 or after age 55. In the young, this is usually related to fibromuscular hyperplasia, which is more prevalent in females. In older individuals, it is typically related to atherosclerotic disease. Patients who had previously well-controlled blood pressure and present with significant elevations while on the same regimen should also be considered for renovascular hypertension.

More than 80% of patients with renovascular disease will have atherosclerosis as the primary cause and will therefore have other serious comorbid conditions. The physical exam may find abdominal bruits, retinopathy out of proportion to the degree and duration of the hypertension, and evidence of atherosclerotic disease in vascular beds other than the kidneys. In many cases, evidence of extrarenal atherosclerotic disease includes a history of stroke, myocardial infarction (MI), or peripheral vascular disease. Patients with renovascular disease may also experience an elevation in serum creatinine with blood pressure lowering. This is seen most often and to a greater extent with use of RAS inhibitors. Patients who present with sudden onset of pulmonary edema and a relative resistance to diuretics may also have renovascular disease.

There are several tests that can be used to screen for renal artery stenosis: renal artery duplex sonography; magnetic resonance angiography (MRA); computed tomographic (CT) angiography; nuclear renal scan with captopril, lasix, or both; and renal angiography (see table below). The latter test remains the goal standard and is often required prior to surgical intervention. However, CT angiography and MRA have higher specificity and have become highly utilized screening tests for renovascular disease. Ultrasound without duplex sonography of vessels is a poor test, but renal duplex sonography is highly dependent on the technician and reader.

There is still significant controversy over whether medical therapy is superior to revascularization, either with percutaneous transluminal angioplasty or surgery, in renal artery stenosis. At least half of patients with a greater than 60% stenosis of a renal artery will progress over four years. However, in those with pre-existing renal disease there does not appear to be a significant difference in renal outcomes if blood pressure goals are reached.

Because of the significant atherosclerotic burden and coexisting kidney disease, patients with renovascular disease are at high risk for MI and stroke. Ongoing studies are examining whether revascularization will lower cardiovascular risks. Almost all patients (more than 85%) who undergo revascularization will still require multiple medications to reach their blood pressure goal. However, blood pressure goals can be achieved with adequate medication, particularly with RAS inhibitors. Since blood pressure medications will still be required, renal outcomes are not likely to change, and excessive cardiovascular risk will still be present with revascularization, it is debatable whether all patients in whom atherosclerotic renal vascular disease is suspected should be screened. Therefore, it is best that these decisions are made by hypertension specialists and that screening be reserved for those patients who are likely to benefit from revascularization.

HYPERALDOSTERONISM

The presence of hypokalemia should raise suspicion for a secondary cause of hypertension. Hypokalemia may be seen with any state in which mineralocorticoid levels are elevated, such as in hyperaldosterone states and Cushing’s disease. Liddle’s disease is an inherited form of hypertension that also presents with hypokalemia; however, hypertension usually presents at an early age with this disease and there is usually a strong family history of early-onset hypertension.

Hyperaldosteronism is thought to be the most common secondary cause of hypertension due to an endocrinopathy. It has been estimated that up to 10% of patients with hypertension may have an elevated aldosterone level. The fact that normotensive individuals with high-normal levels of aldosterone are more likely to develop hypertension over four years further supports aldosteronism as a causative agent in the development of hypertension.

While hypokalemia may be what alerts the clinician to the possibility of an elevated aldosterone level, potassium levels are normal in up to 30% of patients with primary aldosteronism. In general, patients who have a potassium level below 3 mmol/L on a diuretic or less than 3.5 mmol/L without a diuretic should be evaluated for an elevated aldosterone state. The primary screening test is the serum aldosterone-to-renin ratio. A ratio greater than 20 is suspicious for hyperaldosteronism. However, it must be determined that the renin activity was measured appropriately; otherwise, it will be aberrantly low, making the ratio greater than 20 even with aldosterone levels that are not pathologic. Therefore, an aldosterone level of 15 ng/dl or higher and a ratio greater than 20 should be required to sustain the suspicion of hyperaldosteronism.

A definitive diagnosis is made through provocative testing that includes salt loading with measurement of urine aldosterone levels in the presence of replete potassium and the absence of medicines that inhibit the RAS. Aldosterone levels in the urine should be low with adequate salt loading; if they remain higher than 14 µg per 24 hours after three days of appropriate salt loading, hyperaldosteronism is very likely.

If hyperaldosteronism is strongly suspected, it is necessary to determine whether elevated aldosterone secretion is due to adrenal hyperplasia or an aldosterone-secreting tumor. Imaging via CT scanning can often show an isolated adrenal mass but may miss microadenomas. Renal vein renin sampling may be helpful in isolating the site of pathology when it is not clear. Patients with adrenal hyperplasia usually have a rise in their aldosterone levels when they stand up; those with aldosterone-producing tumors usually have no such change. Also, patients with aldosterone-producing tumors usually maintain the normal circadian rhythm of aldosterone levels, while those with adrenal hyperplasia may not.

In cases of primary hyperaldosteronism, treatment may proceed with surgical removal of the aldosterone-secreting tumor or with medical management using aldosterone inhibitors. In cases of adrenal hyperplasia, aldosterone inhibitors should be used. Long-term use of spironolactone is associated with the antiandrogenic effects of gynecomastia and impotence in males and menstrual disturbances in females, but newer aldosterone blockers (such as eplerenone) do not have these hormonal effects. There is some data suggesting a calcium antagonist may be beneficial in patients with bilateral adrenal hyperplasia.

While hyperaldosteronism is a common cause of hypertension, making a definitive diagnosis is challenging. Therefore, patients in whom hyperaldosteronism is suspected should be referred to a hypertension specialist so that appropriate provocative testing can be done and a definitive diagnosis made. It is not appropriate to go straight to an imaging study because the finding of an adrenal mass is not uncommon and does not necessarily mean that the patient has an aldosterone-secreting tumor. In such cases, functional assessment of the mass must be done prior to any surgical intervention.