Park's Pediatric Cardiology for Practitioners, 6th Ed.

Systemic Hypertension

Definition

For adults, the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7 Report, 2003) has recommended the following classification of blood pressure (BP) levels. BP level of 120/80 mm Hg, previously considered normal, is now classified as prehypertension; levels lower than 120/80 are now considered normal. Systolic pressure of 140 mm Hg and greater or diastolic pressure of 90 mm Hg and greater are now considered hypertension. Hypertension is further classified as stage 1 and stage 2 depending on the level of abnormalities (Table 28-1).

In children, hypertension is defined statistically because BP levels vary with age and gender and because outcome-based data are not available for children. The Fourth Report of the National High Blood Pressure Education Program (NHBPEP) Working Group on High Blood Pressure in Children and Adolescents (2004) has recommended the following definition (also see Table 28-1).

1. Hypertension is defined as systolic or diastolic pressure levels that are greater than the 95th percentile for age and gender on at least three occasions. As in adults, adolescents with BP levels of 120/80 mm Hg or above by auscultatory method are considered hypertensive even if they are below the 95th percentile.

2. Prehypertension is defined as an average systolic or diastolic pressure between the 90th and 95th percentiles for age and gender.

3. When the BP reading is above the 95th percentile, one further classifies the hypertension into stages 1 and 2 as follows.

a. Stage 1 hypertension is present when BP readings are between the 95th and 99th percentiles.

b. Stage 2 hypertension is present when BP readings are 5 mm Hg or more above the 99th percentile values.

4. White-coat hypertension is present when BP readings in health care facilities are greater than the 95th percentile but are normotensive outside a clinical setting. This condition may not be as benign as once thought to be, and regular follow-up is now recommended. This topic is discussed further later in this chapter.

TABLE 28-1

CLASSIFICATION OF BLOOD PRESSURE FOR ADULTS AND CHILDREN

image

BP, blood pressure.

 Adapted from Chobanian AV, Bakris GL, Black HR, et al: The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: The JNC 7 report. JAMA 21:2560-2572, 2003.

 Pediatric classification is according to the Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in Children and Adolescents. Pediatrics 111:555-576, 2004.

Normative Blood Pressure Standards

A prerequisite to the use of the above definition for pediatric hypertension is the availability of reliable normative BP standards. An unfortunate part of the problem is that there are no reliable evidence-based BP standards for children. The BP tables recommended by the Working Group of the NHBPEP are not as good as they were made to believe because (1) the BP data are not derived by the methodology recommended by the working group, (2) expressing BP levels by age and height percentiles is statistically unsound and unjustified, and (3) additional computation of BP levels by height percentile on such highly variable office BP readings are impractical and unproductive for busy practitioners (see Blood Pressure Measurement in Chapter 2 for further discussion). The NHBPEP’s statistical efforts on unscientifically obtained data do not improve their validity.

In addition, it is important to know that the BP standards of the NHBPEP cannot be used when BP is measured by an oscillometric device. BPs measured by the auscultatory method are not interchangeable with those measured by the oscillometric method, which is being used in increased frequency. In San Antonio Children’s Blood Pressure Study (SACBPS) using both the auscultatory and an oscillometric device (Dinamap Model 8100), BP levels obtained by Dinamap, an oscillometric device, were on average 10 mm Hg higher for the systolic pressure and 5 mm Hg higher for the diastolic pressures than those obtained by the auscultatory method (Park et al, 2001). Therefore, when BPs are obtained by an oscillometric device, one should not use the BP standards provided by the NHBPEP, which are based on the auscultatory method. Only normative BP standards by Dinamap Monitor are those from the SACBPS (Park et al, 2005), and they are presented in Appendix B (Tables B-6 and B-7) according to age and gender.

Kaelber et al (2009) have recommended a simplified table of BP levels according to age and gender (without height percentiles), above which further evaluation should be carried out for possible hypertension (see left half of Table 28-2 ). This is a more practical approach because in some BP screening sites, height is not always measured and because the inclusion of height percentile in BP evaluation has no statistical validity (as discussed in Chapter 2). Auscultatory BP levels presented in Table 28-2 agree very closely with the normative auscultatory standards reported by the SACBPS (Park et al, 2005). Because BP levels obtained by an oscillometric device are not interchangeable with those obtained by the auscultatory method, BP levels in the prehypertensive range by the oscillometric (Dinamap) method (Park et al, 2005) are shown in the right half of Table 28-2 for the same reasons.

Cause

Hypertension is classified into two general types, essential (or primary) hypertension, in which a specific cause cannot be identified, and secondary hypertension, in which a cause can be (Box 28-1).

1. The exact prevalence of essential hypertension in children and adolescents is not known. It is estimated that about 60% of pediatric patients with hypertension have essential hypertension. Among the patients with essential hypertension 75% of them are obese. Thus, the most common cause of pediatric hypertension appears to be obesity; about 10% to 30% of obese children are reported to have hypertension.

2. Among patients with secondary hypertension, more than 90% of the cases are caused by three conditions: renal parenchymal disease and renovascular diseases (both accounting for 70%) and coarctation of the aorta (COA) (20%). Fewer than 10% of secondary hypertension is caused by endocrine and other disorders.

3. In newborns, the causes of hypertension may include renal artery thrombosis, congenital renal malformation, and COA. Transient hypertension may be found in neonates with bronchopulmonary dysplasias, which resolves when oxygenation improves.

TABLE 28-2

BLOOD PRESSURE VALUES REQUIRING FURTHER EVALUATION ACCORDING TO AGE AND GENDER

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Diast, diastolic; Syst, systolic.

 From Kaelber DC, Pickett F: Simple table to identify children and adolescents needing further evaluation of blood pressure. Pediatrics 123(6):e972, 2009. For adolescents age 14 years and older, systolic pressure of 120 mm Hg is in prehypertensive range, as in adults.

 Data from Park MK, Menard SW, Schoolfield J: Oscillometric blood pressure standards for children. Pediatr Cardiol 26:601-607, 2005. These values were obtained by Dinamap model 8100 and in general fall between the 90th and 95th percentiles of blood pressure (prehypertension range). A systolic blood pressure of 130 mm Hg has been chosen for male teens 14 to 17 years old in this table.

In general, children with essential hypertension are older than 10 years of age, have mild hypertension, and are often obese. Secondary hypertension is suggested by a younger age, levels of hypertension (varying from mild to severe, especially stage 2 hypertension), and presence of clinical signs that suggest systemic conditions. Children with secondary hypertension are rarely obese and are often less than normal height. Table 28-3 lists the common causes of hypertension by age group in children. Box 28-1 lists the causes of secondary hypertension.

Diagnosis and Workup

Steps to Confirm the Diagnosis

1. The diagnosis of hypertension relies on accurate BP measurement and comparing the reading with reliable BP standards. In evaluating for possible diagnosis of hypertension, it is very important to remember that (a) the most common cause of high BP readings, especially of a single BP reading, in a health care facility is anxiety, called the white-coat phenomenon, and (b) BPs measured by the auscultatory and oscillometric methods are significantly different and thus are not interchangeable (as mentioned earlier). The following is one way of handling a case of high BP reading in the office setting.

a. If an abnormal reading is the result of single reading, two additional measurements should be made to help reduce the effects of anxiety associated with a visit to the doctor’s office.

b. If BP is still high, a repeat set of three readings at the end of the office visit may help identify some of the children with the white-coat phenomenon.

TABLE 28-3

COMMON CAUSES OF CHRONIC SUSTAINED HYPERTENSION

Age Group

Causes

Newborns

Renal artery thrombosis, renal artery stenosis, congenital renal malformation, COA, bronchopulmonary dysplasia

<6 yr

Renal parenchymal disease, COA, renal artery stenosis

6–10 yr

Renal artery stenosis, renal parenchymal disease, primary hypertension

>10 yr

Primary hypertension, renal parenchymal disease

COA, coarctation of the aorta.

Adapted from Report of the Second Task Force on Blood Pressure Control in Children—1987. Task Force on Blood Pressure Control in Children. National Heart, Lung, and Blood Institute, Bethesda, Maryland. Pediatrics 79:1-25, 1987.

BOX 28-1 Causes of Secondary Hypertension

Renal

Renal parenchymal disease

Glomerulonephritis, acute and chronic

Pyelonephritis, acute and chronic

Congenital anomalies (polycystic or dysplastic kidneys)

Obstructive uropathies (hydronephrosis)

Hemolytic-uremic syndrome

Collagen disease (periarteritis, lupus)

Renal damage from nephrotoxic medications, trauma, or radiation

Renovascular disease

Renal artery disorders (e.g., stenosis, polyarteritis, thrombosis)

Renal vein thrombosis

Cardiovascular

Coarctation of the aorta

Conditions with large stroke volume (patent ductus arteriosus, aortic insufficiency, systemic arteriovenous fistula, complete heart block) (these conditions cause only systolic hypertension)

Endocrine

Hyperthyroidism (systolic hypertension)

Excessive catecholamine levels

Pheochromocytoma

Neuroblastoma

Adrenal dysfunction

Congenital adrenal hyperplasia

11-β-Hydroxylase deficiency

17-Hydroxylase deficiency

Cushing’s syndrome

Hyperaldosteronism

Primary

Conn’s syndrome

Idiopathic nodular hyperplasia

Dexamethasone-suppressible hyperaldosteronism

Secondary

Renovascular hypertension

Renin-producing tumor (juxtaglomerular cell tumor)

Hyperparathyroidism (and hypercalcemia)

Neurogenic

Increased intracranial pressure (any cause, especially tumors, infections, trauma)

Poliomyelitis

Guillain-Barré syndrome

Dysautonomia (Riley-Day syndrome)

Drugs and chemicals

Sympathomimetic drugs (nose drops, cough medications, cold preparations, theophylline)

Amphetamines

Corticosteroids

Nonsteroidal antiinflammatory drugs

Oral contraceptives

Heavy-metal poisoning (mercury, lead)

Cocaine, acute or chronic use

Cyclosporine

Thyroxine

Tacrolimus

Miscellaneous

Hypervolemia and hypernatremia

Stevens-Johnson syndrome

Bronchopulmonary dysplasia (newborns)

c. Even if these BP readings are still high, a possibility of white-coat hypertension still exists. The diagnosis of hypertension should not be made until one confirms persistently elevated BP levels greater than the 95th percentile on three or more separate office visits over a period of time.

d. One should consider ways to identify cases of white coat hypertension by measuring BPs outside the health care facility.

(1) Some physicians advocate the use of the ambulatory BP measurement to rule out white-coat hypertension. Ambulatory BP measurement is costly, and it reflects BP readings on a single day; BPs vary from day to day.

(2) Having reliable school nurses to take daily BP for 3 to 4 weeks may be a cost-effective way to get the same information.

(3) Home BP monitoring can be an option. For adult patients, new position papers from the United States and Europe recommend home BP monitoring as a routine part of diagnosis and management of hypertension. They recommend recording an average of two (or three) BP readings taken in the morning and at night for 1 week, with a total of at least 12 readings being averaged to make clinical decisions. It is reasonable to try home BP measurement in children under certain circumstances using a protocol similar to the one described for adults.

(4) For home BP monitoring, the monitor should be checked for its accuracy, and the patient should be taught correct measurement technique and correct BP cuff size. Wrist monitors are not acceptable because the readings will reflect peripheral amplification of systolic pressure. In evaluating home BP readings, one should not use BP standards by NHBPEP, which are based on the auscultatory method. One may use the oscillometric BP data from the San Antonio Children’s Blood Pressure Study. Appendix B provides normative oscillometric BP values (Table B-6 for boys; Table B-7 for girls).

2. If multiple BP readings obtained outside the health care facility show persistently elevated BP levels above the 95th percentile most of the time, one could make a tentative diagnosis of hypertension and proceed with initial investigation for hypertension (as described below).

3. If the repeated BP measurements fall between the 90th and 95th percentiles (prehypertension), the patient should be followed on a regular basis (every 3 to 6 months) with repeat BP measurements.

4. When the diagnosis of hypertension is established:

a. One should evaluate the history (present, past, and family), perform careful physical findings, and proceed with initial investigation to look for the cause of hypertension.

b. The initial investigation should include urinalysis, serum electrolytes, renal function tests, uric acid, and electrocardiography (ECG) or echocardiography. The diagnosis of essential hypertension is made when the cause of hypertension is not found in a hypertensive patient older than 10 years of age.

c. One should also assess additional cardiovascular risk factors, including obesity, which is the most common associated finding in children with essential hypertension. Currently recognized cardiometabolic risk factors include:

(1) Family history of premature cardiovascular disease

(2) Obesity

(3) Dyslipidemias, such as hypercholesterolemia, hypertriglyceridemia, and low levels of high-density lipoprotein cholesterol (<40 mg/100 mL)

(4) Cigarette smoking

(5) Diabetes mellitus or prediabetic state

(6) Physical inactivity

History

Past and Present History

1. Present history

a. Most children with mild hypertension are asymptomatic, and hypertension is diagnosed as the result of routine BP measurement, highlighting the importance of accurate measurement of BP.

b. Children with acute severe hypertension may be symptomatic, such as that seen with acute glomerulonephritis (with headache, dizziness, nausea and vomiting, irritability, or personality changes). Occasionally, neurologic manifestations, congestive heart failure, renal dysfunction, and stroke may be the presenting symptoms.

c. Weakness and muscle cramp from hypokalemia may be seen with primary aldosteronism.

d. A history of palpitation, headache, and excessive sweating may suggest increased catecholamine levels.

e. Tachycardia with systolic hypertension may suggest hyperthyroidism or catecholamine excess.

2. Neonatal: Use of umbilical artery catheters (a possible cause of renovascular hypertension)

3. Cardiovascular: History of COA or surgery for it

4. Renal: History of obstructive uropathies; urinary tract infection; and radiation, trauma, or surgery to the kidney area

5. Medications: Corticosteroids, amphetamines, antiasthmatic drugs, cold medications, oral contraceptives, nephrotoxic antibiotics (e.g., aminoglycosides, sulfonamides, amphotericin B, trimethoprim, and others), cyclosporin, cocaine use, excessive dose of thyroxin, ingestion of large quantity of licorice. (Licorice inhibits 11β-hydroxysteroid dehydrogenase with a resulting increase in cortisol levels and producing hypokalemia.)

6. Habits: Smoking or consumption of excessive amount of coffee or tea

Family History

1. Essential hypertension, atherosclerotic heart disease, and stroke

2. Familial or hereditary renal disease (polycystic kidney, cystinuria, familial nephritis)

Physical Examination

1. Accurate measurement of BP is essential.

2. Complete physical examination also is essential, with emphasis on the following:

a. Delayed growth (renal disease)

b. Bounding peripheral pulse (patent ductus arteriosus or aortic regurgitation)

c. Weak or absent femoral pulses or BP differential between the arms and legs (COA). In normal children, systolic pressure in the lower limbs is more than 5 to 10 mm Hg higher than that in the upper limbs.

d. Abdominal bruits (renovascular)

e. Tenderness over the kidney (renal infection)

3. Children’s weight status, including body mass index percentile, should be obtained because obesity is a common cause of essential hypertension. Children with secondary hypertension from renal diseases are rarely obese, although those with hypertension from adrenocortical disorders may be obese.

Initial Investigation

1. The initial investigations should be directed toward detecting renal parenchymal disease and COA and therefore include the following (Table 28-4 ).

a. Urinalysis: Abnormal urinalysis with red blood cells or white blood cells suggests nephritis or infectious processes. Urine culture is indicated if urinalysis suggests infectious processes. Urinalysis is normal in essential hypertension, renovascular hypertension, and endocrine hypertension.

b. Serum electrolytes: Low potassium levels suggest aldosterone excess, either from primary aldosteronism or secondary hyperaldosteronism (including renovascular hypertension). Serum electrolyte changes also occur in endocrine disorders causing hypertension; hypokalemia may be seen with Cushing’s syndrome or certain (not all) types of congenital adrenal hyperplasias (11-β hydroxylase deficiency and 17-hydroxylase deficiency). Hypercalcemia suggests hyperparathyroidism.

c. Blood urea nitrogen (BUN) and creatinine: Abnormal values suggest renal parenchymal or renovascular disease, although renal function is usually not affected in renovascular hypertension. Normal BUN and creatinine do not rule out renovascular hypertension.

d. Uric acid level: Uric acid level above 5.5 mg/dL was found in 89% of subjects with primary hypertension, 30% of children with secondary hypertension, and 0% of children with white-coat hypertension and normal control participants. This finding suggests that uric acid level might have a role in the pathogenesis of primary hypertension (Feig et al, 2003). Furthermore, there is independent association between uric acid level and the severity of hypertension.

e. ECG, chest radiographs, and echocardiography: Echocardiography is useful in ruling out COA and evaluating end-organ damage, such as left ventricular (LV) mass.

2. When obesity is the likely cause of hypertension, metabolic aspects of risk factors should be evaluated (including fasting lipid profile, liver function test, blood glucose, and so on). Renal Doppler ultrasonography adds very little in obese children. The presence of metabolic abnormalities may help in convincing patients to adopt a healthy lifestyle.

3. In a nonobese child, younger than 10 years of age, who has moderate to severe hypertension, one should consider the possibility of renovascular hypertension. A history of umbilical catheterization and abdominal radiation is an important clue to renovascular hypertension. The following preliminary screening tests may be indicated.

a. Renal ultrasonography and renal Doppler sonography

b. Plasma renin activity (PRA)

c. 24-Hour urine collection for catecholamines and their metabolites

4. Thyroid function test (TSH, thyroxine) may be indicated when a rapid heart rate and hypertension coexist.

5. Depending on the results of the routine tests, more specialized tests have been used in the diagnosis of secondary hypertension (see Specialized Studies). The decision to undertake special tests and procedures depends on the availability of and familiarity with the procedure, severity of hypertension, age of the patient, and history and physical findings suggestive of a certain cause. For example:

a. Nonobese children younger than 10 years of age with sustained hypertension require extensive evaluation because identifiable, and potentially curable causes are more likely to be found.

b. Adolescents with mild hypertension and a positive family history of essential hypertension are more likely to have essential hypertension, and extensive studies are not cost effective.

c. In obese children with mild hypertension, renal Doppler ultrasound study does not add any clinical value.

6. When renovascular or renoparenchymal hypertension is a possibility, nephrology consultation is indicated because most of the specialized tests belong to the domain of nephrology. Consultation with endocrinology should be obtained when endocrine disorders are suspected to be the cause of hypertension.

TABLE 28-4

INITIAL AND SPECIAL LABORATORY TESTS AND THEIR SIGNIFICANCE

Investigations

Significance

Urinalysis, urine culture, BUN, creatinine, uric acid

Renal parenchymal disease

Serum electrolytes (hypokalemia)

Hyperaldosteronism (primary or secondary)

 

Adrenogenital syndrome

 

Renin-producing tumors

ECG, chest radiography, and possibly echocardiography

Cardiac cause of hypertension; also baseline function

Ultrasonography, radionuclide studies, CT or MRI of the kidneys, or IVP

Renal parenchymal disease

Renovascular hypertension

Tumors (neuroblastoma, Wilms’ tumor)

Plasma renin activity (peripheral)

High-renin hypertension (renovascular hypertension, renin-producing tumors, some Cushing syndrome, some essential hypertension)

 

Low-renin hypertension (adrenogenital syndrome, primary hyperaldosteronism)

24-hr urine collection for 17-ketosteroid and 17-hydroxycorticosteroids

Cushing syndrome

Adrenogenital syndrome

24-hr urine collection for catecholamine levels and VMA

Pheochromocytoma

Neuroblastoma

Aldosterone

Hyperaldosteronism (primary or secondary)

 

Renovascular hypertension

 

Renin-producing tumors

Renal vein plasma renin activity

Unilateral renal parenchymal disease

 

Renovascular hypertension

Abdominal aortogram

Renovascular hypertension

 

Abdominal coarctation of the aorta

 

Unilateral renal parenchymal disease

 

Pheochromocytoma

Intra-arterial digital subtraction angiography

Renovascular hypertension

BUN, blood urea nitrogen; CT, computed tomography; ECG, electrocardiogram; HT, hypertension; IVP, intravenous pyelography; MRI, magnetic resonance imaging; VMA, vanillylmandelic acid.

Specialized Studies

The following specialized studies may be indicated for the detection of causes of secondary hypertension (see Table 28-4).

1. Renal ultrasonography can provide a comparison of kidney size; the thickness and echogenicity of the renal cortex, medulla, and pyramids; and anatomic information of the collecting system. A smaller kidney may be seen with irreversible renal disease. The yield of this test in adolescents with obesity-associated hypertension is very low and not very cost effective (Tuli et al, 2005), although the test is definitely indicated in younger children with significant hypertension. This study has replaced intravenous pyelography.

2. Peripheral PRA is a useful screening test for a renal cause of hypertension. Whereas an elevated value (high-renin hypertension) suggests renal parenchymal or renovascular diseases, a suppressed value (low-renin hypertension) suggests excess mineralocorticoid effects such as seen with hyperaldosteronism. The usefulness of captopril-stimulated PRA is controversial at best.

3. A radionuclide renal scan is useful in distinguishing variation in perfusion and scarring of the two kidneys. Decreased flow to one kidney suggests arterial occlusion of that kidney.

4. Renal Doppler ultrasonography can demonstrate lesions in the main renal arteries and in the segmental branches. Computed tomography (CT) angiography and magnetic resonance (MR) angiography have higher sensitivity and specificity than Doppler ultrasonography for renovascular hypertension. However, renal arteriography is considered the gold standard for the diagnosis of renovascular hypertension.

5. PRA in blood collected from both renal veins and the inferior vena cava, at the time of angiography, is helpful in diagnosing unilateral or bilateral kidney disease.

6. Aldosterone levels in serum and urine are indicated in patients with hypokalemia for possible hyperaldosteronism.

a. High plasma aldosterone levels seen in primary aldosteronism are caused by a benign adrenal adenoma (Conn’s syndrome) or bilateral idiopathic adrenal hyperplasia.

b. Secondary hyperaldosteronism is caused by overactivity of the renin–angiotensin system. Examples of secondary hyperaldosteronism include juxtaglomerular cell tumor and renal artery stenosis (which increases renin levels). Other conditions, such as liver cirrhosis, heart failure, nephrotic syndrome, or a very low sodium diet may also increase aldosterone levels.

7. 24-Hour urine collection for catecholamine levels and their metabolites (metanephrine, normetanephrine, and vanillylmandelic acid [VMA]) is indicated when a catecholamine-secreting tumor (e.g., pheochromocytoma, neuroblastoma) is suspected. Collection of urine for 24 hours is preferable to plasma for the detection of increased levels of catecholamines or their metabolites because plasma levels of these fluctuate throughout the day.

8. 24-Hour urine collection for free cortisol and 17-ketosteroid: The former is elevated in Cushing’s syndrome, and the latter is elevated in congenital adrenal hyperplasia (adrenogenital syndrome).

Management of Essential Hypertension

Nonpharmacologic intervention

Nonpharmacologic intervention should be started as an initial treatment. Counseling should encourage weight reduction if the patient is overweight or obese, healthful diets, low-salt (and potassium-rich) foods, regular aerobic exercise, and avoidance of smoking and oral contraceptives.

Pharmacologic intervention

Drug therapy is not recommended initially. Drugs are used when nonpharmacologic approaches have not been found to be effective because the possible adverse effects of long-term drug therapy on growing children have not been evaluated adequately and because many antihypertensive agents have side effects.

Indications for drug therapy

Although there are no clear guidelines for identifying those who should be treated with antihypertensive drugs, the following are generally considered indications for initiating drug therapy in hypertensive children.

1. Severe symptomatic hypertension should be treated with intravenous (IV) antihypertensive medications.

2. Significant secondary hypertension, such as caused by renovascular and renoparenchymal diseases

3. Persistent hypertension despite nonpharmacologic measures

4. Hypertensive target-organ damage: LV hypertrophy; increased LV mass, and so on

5. Diabetes (types 1 and 2)

6. Family history of early complications of hypertension

7. Child who has dyslipidemia and other coronary artery risk factors

End-Organ Damage

The most reliable evidence of end-organ damage at this time appears to be the presence of LV hypertrophy revealed by echocardiographic studies. Increased LV mass by echocardiography may be an indication of LV hypertrophy, but the values are not very reproducible, and controversies exist as to how to express LV mass (i.e., by 2.7 power of height or by body surface area [BSA]). Other valuable markers of end-organ damage include carotid intima-media thickening and urinary albumin excretion. Although the latter two are frequently used in the evaluation of adult hypertension, they are infrequently used in the evaluation of pediatric hypertension. Carotid intima-media thickening is nonspecific and is also seen in children with familial hypercholesterolemia and obesity. Urinary albumin excretion is a sign of hypertension-related renal damage. Normal M-mode–derived LV mass data indexed by 2.7 power of height are available in Table D-7 in Appendix D. Normal two-dimensional echocardiography-derived LV mass data indexed by BSA are provided in Table D-8.

The Choice of Drug

In the past, most comparative studies in adult populations found that moderate doses of all classes of antihypertensive agents provided similar efficacy. However, more recent studies in adults suggest that beta-blockers are not as effective as other classes of antihypotensive agents. European studies have shown the superiority of calcium channel blockers (CCBs) over beta-blockers in lowering BP. Other studies have found that angiotensin-converting enzyme (ACE) inhibitors are definitely better than diuretics and are as effective as CCBs. It is known that diuretics and beta-blockers tend to raise blood glucose levels. Thus, CCBs and ACE inhibitors appear preferable to beta-blockers and diuretics, especially for overweight patients at risk of developing diabetes. Besides the BP-lowering effect of the drugs, ACE inhibitors and angiotensin receptor blockers (ARBs) are especially renoprotective and thus are recommended for patients with diabetes and other kidney diseases.

Currently, many adult cardiologists, especially those from European countries, strongly favor using ACE inhibitors (or ARBs) or CCBs as the choice of initial therapy in adult patients with hypertension. Some pediatric authorities now recommend ACE inhibitors (or ARBs) or CCBs as the initial drug for the treatment of hypertension in children and adolescents. Because ACE inhibitors are contraindicated in pregnancy, CCBs may be a better choice for female adolescents with hypertension. CCBs appear to be better choices for African Americans.

1. Adolescent boys

a. ACE inhibitors or ARBs: These agents alone or in combination with CCB (e.g., Lotrel, the combination of amlodipine and benazepril) are good choice in obese children with high glucose and triglyceride levels.

b. CCB are equally good as ACE inhibitors as the initial antihypertensive agent. CCBs do not raise blood glucose.

c. ACE inhibitors plus diuretics are a good combination because diuretics enhance ACE inhibitors’ effects. However, this combination is not recommended in obese patients with acanthosis nigricans because it could cause diabetes.

2. Adolescent girls and women of childbearing age

a. CCBs (e.g., amlodipine [Norvasc] or extended-release nifedipine) are good choices in women as they lack teratogenic effects.

b. Diuretics and beta-blockers are probably safe. However, blood glucose levels should be checked regularly because they raise glucose levels.

c. ACE inhibitors or ARBs should not be used in female adolescents because they are known teratogens. If one becomes pregnant, the drug should be discontinued; it may be resumed at the end of the third trimester if needed.

3. Coexisting conditions: The choice of initial therapy has been influenced by other conditions that frequently coexist with hypertension. Preferences, contraindications, and side effects of different classes of antihypertensive agents are summarized in Table 28-5, which may help in choosing the drug for initial therapy. Most of the information has been derived from adult experiences.

a. Migraine patients: Beta-blockers or CCBs are preferred. Beta-blockers appear to be more effective in the prevention of migraines than CCBs.

b. Patients with asthma: CCBs may be the drug of first choice. ARBs and diuretics may work well. ACE inhibitors may cause persistent dry cough in 10% of 20% of patients with asthma, and this may possibly cause bronchospasm. Beta-blockers are contraindicated in patients with asthma because they may cause bronchospasm.

c. Hyperthyroidism or hyperdynamic hypertension with fast heart rates: Beta-blockers are preferred. Beta-blockers are used as treatment adjuncts in hyperthyroidism.

TABLE 28-5

CLASSES OF ANTIHYPERTENSIVE AGENTS: PREFERENCES, CONTRAINDICATIONS, AND SIDE EFFECTS

image

d. Patients with diabetes: ACE inhibitors or ARBs are preferred. Thiazide diuretics and beta-blockers should not be used because they increase blood glucose levels.

e. Renal failure: CCBs or ACE inhibitors are preferred.

After the most appropriate agent for initial therapy has been selected, a relatively small dose of a single drug should be started, aiming for BP reduction of 5 to 10 mm Hg at each step of the dosage until the full dosage or the target BP is reached. If the first drug is not effective, a second drug may be added to, or substituted for, the first drug, starting with a small dose and proceeding to a full dose. In many situations, however, more than one drug is needed to control severely elevated BPs such as those seen in patients with renal disease, and thus starting with a combination of two drugs from classes with a complementary mechanism of action may be acceptable. A single daily dose of a long-acting agent improves adherence to the medication. Long-acting preparations are available within each class of antihypertensive drugs. Table 28-6 shows the dosage of antihypertensive drugs for children.

Classes of Antihypertensive Drugs

Diuretics

Diuretics are the oldest class of antihypertensive drugs. The thiazide diuretics (hydrochlorothiazide and chlorthalidone) have the longest history of being used in the treatment of hypertension, sometimes in combination with a potassium-sparing diuretic. The action of thiazide diuretics is related to a decrease in extracellular and plasma volume initially, and later the action is related to a decline in peripheral resistance. An important side effect of thiazide diuretics in children is hypokalemia, occasionally requiring potassium supplementation in the diet or as potassium salt. They may also increase glucose, insulin, and cholesterol levels. One should check serum electrolytes and glucose levels initially and periodically.

TABLE 28-6

ORAL DOSAGES OF SELECTED ANTIHYPERTENSIVE DRUGS FOR CHILDREN

image

Modified from The fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in Children and Adolescents. Pediatrics 114:555-576, 2004.

Aldosterone antagonists (or aldosterone receptor blockers), such as spironolactone, are weak potassium-sparing diuretics. Spironolactone antagonizes the action of aldosterone at mineralocorticoid receptors, with resulting inhibition of sodium resorption in the collecting duct of the nephron in the kidneys (by interfering with Na/K exchange with reduction of urinary potassium loss). This group of drugs is often used as adjunctive therapy, in combination with other drugs, for the management of chronic heart failure. It is also used in the management of hyperaldosteronism (including Conn’s syndrome).

Sodium channel blockers, such as triamterene (Dyrenium) and amiloride, are potassium-sparing diuretics used in combination with thiazide diuretics for the treatment of hypertension and edema. It directly blocks the epithelial sodium channel on the lumen side of the collecting tubule. Potassium-sparing diuretics (spironolactone, triamterene) may cause hyperkalemia, especially if given with ACE inhibitors or ARBs.

Adrenergic inhibitors

The mechanism of action of beta-blockers is not fully understood. It may involve suppressing cardiac contractility, decreasing systemic vascular resistance, or suppressing the renin–angiotensin system. Beta-blockers appear to be less effective than other classes of antihypertensives. β-Adrenergic blockers are contraindicated in patients with asthma (because of bronchospasm) and diabetes mellitus (because of hyperglycemic effects). Propranolol (Inderal) is a short-acting form requiring dosing three times a day. Atenolol (Tenormin) has the advantage of being a longer acting beta-blocker requiring only a single daily dose.

Angiotensin converting enzyme inhibitors

Captopril is a short-acting ACE inhibitor widely used in the treatment of pediatric hypertension. Enalapril and lisinopril are long-acting ACE inhibitors that have also been shown to be effective in children with hypertension. A diuretic clearly enhances the effectiveness of ACE inhibitors. Side effects of ACE inhibitors include rash, loss of taste, and leukopenia. Occasional side effects include cough, angioedema, hyperkalemia, and azotemia. If cough appears, an ARB may be used. ACE inhibitors are contraindicated in pregnancy because of their known teratogenic effects. Serum electrolytes and creatinine should be checked for hyperkalemia and azotemia.

Angiotensin receptor blockers

are new class of antihypertensive agents that act by displacing angiotensin II from its receptor, antagonizing all of angiotensin’s known effects with a resulting decrease in peripheral resistance. Cough is not a side effect, although angioedema can occur.

Calcium channel blockers

CCBs are being used increasingly in the treatment of adult hypertension. Nifedipine has the greatest peripheral vasodilatory action, with little effect on cardiac automaticity, conduction, or contractility. Concomitant dietary sodium restriction or the use of a diuretic agent may not be necessary because calcium antagonists cause natriuresis by producing renal vasodilatation. Recently, the safety and efficacy of amlodipine (Norvasc) have been reported for children with various forms of hypertension (Flynn et al, 2004). Occasional side effects include headache, flushing, and local ankle edema.

Vasodilators

Hydralazine (Apresoline), a direct-acting vasodilator, is popular in the treatment of acute hypertension in children. When used alone, it produces side effects related to increased cardiac output (flushing, headache, tachycardia, palpitation) and salt retention. Therefore, the concomitant use of a β-adrenergic blocker and a diuretic is recommended. Hydralazine can cause lupus-like syndrome. Minoxidil, a less commonly used vasodilator, can cause hypertrichosis when used on a chronic basis.

Follow-up Evaluation of Patients with Chronic Hypertension

1. Follow-up examinations should include ongoing monitoring of BP levels, target-organ damage, periodic serum electrolyte determination in children treated with ACE inhibitors or diuretics, counseling regarding other cardiovascular risk factors, and adherence with a newly adopted healthy lifestyle.

2. Goals of treatment

a. For children with uncomplicated primary hypertension without hypertensive end-organ damage, the goal of the treatment is reduction of BP to below the 95th percentile.

b. For children with chronic renal disease, diabetes, or hypertensive target organ damage, the goal is reduction of BP to below the 90th percentile.

3. A “step-down” therapy or cessation of therapy may be considered in selected patients with uncomplicated primary hypertension that is well under control, especially overweight children who successfully lose weight. Such patients require ongoing follow-up of their BP levels and their weight status.

Management of Secondary Hypertension

Treatment of secondary hypertension should be aimed at removing the cause of hypertension whenever possible. Table 28-7 lists curable causes of systemic hypertension.

Cardiovascular causes. Hypertension caused by mild coarctation is treated with beta-blockers. Surgical or catheter interventional correction may be indicated for COA.

Renal parenchymal disease. In nephritis, medical management should be instituted to lower BP in the same manner as has been discussed for essential hypertension. Salt restriction, avoidance of excessive fluid intake, and antihypertensive drug therapy can control hypertension caused by most renal parenchymal diseases. Concomitant antibiotic therapy for infectious processes and general supportive measures may be indicated, depending on the nature of the renal disease. If hypertension is difficult to control and the disease is unilateral, unilateral nephrectomy may be considered.

TABLE 28-7

CURABLE FORMS OF HYPERTENSION

Organ or System

Diseases and Conditions

Renal

Unilateral kidney disease (pyelonephritis, hydronephrosis, traumatic damage, radiation nephritis, hypoplastic kidney)

 

Wilms’ and other kidney tumors

Cardiovascular

Coarctation of the aorta

 

Renal artery abnormalities (e.g., stenosis, aneurysm, fibromuscular dysplasia, thrombosis)

Adrenal

Pheochromocytoma and neuroblastoma

 

Cushing syndrome (caused by adrenocortical or pituitary tumor)

 

Primary aldosteronism

Miscellaneous

Glucocorticoid therapy

 

Oral contraceptives

Hyperthyroidism

Renovascular disease. Renovascular disease may be cured by successful renal artery balloon angioplasty or surgery, such as reconstruction of a stenotic renal artery, autotransplantation, or unilateral nephrectomy. Further discussion of this topic follows.

Adrenal glands. Hyperaldosteronism caused by bilateral adrenal hyperplasia is treated with the mineralocorticoid antagonist, such as spironolactone or eplerenone. Hypertension caused by tumors that secrete vasoactive substances, such as pheochromocytoma and neuroblastoma, are treated primarily by surgery. Further discussion of this topic follows.

White-Coat Hypertension

White-coat hypertension is defined as persistent hypertension in a health care facility with concomitant normal BP during usual daily life. The prevalence of white-coat hypertension in children and adolescents is estimated to be about 30% to 50%.

White-coat hypertension may not be as benign as it was once thought to be. Several recent studies in adults and children suggest that about 30% to 40% of patients with white-coat hypertension spontaneously evolve into having hypertension with accompanying end-organ damage (e.g., increase in LV mass or increase in carotid intima-media thickness). Thus, white-coat hypertension can be considered a prehypertension. Therefore, it is important to identify individuals with white-coat hypertension before labeling them as hypertensive or dismissing them as normotensives. Patients with white-coat hypertension should be followed up on a regular basis.

How are individuals with white-coat hypertension identified, and how should they be followed? One needs a reliable way of accurately measuring BPs outside of health care facilities. There are at least two ways of identifying patients with white-coat hypertension.

1. Twenty-four-hour ambulatory BP measurements provide reliable BP readings outside the doctor’s office. The ambulatory BP values can then be compared with available ABP standards, such as those reported by Wühl and colleagues (2002), which provide both the 90th and 95th percentiles (see Table B-8 in Appendix B). It is noteworthy that the left ventricular mass index (LVMI) correlates well with ambulatory systolic pressures only but not well with ambulatory diastolic pressures or clinic BPs (Sorof et al, 2002). Ambulatory diastolic BP does not change much with increasing age. Drawbacks of ambulatory BP are that it is costly and reflects BP changes for only 1 day, but there are day-to-day variations in BP readings.

2. Another way of getting BP readings outside the doctor’s office is by having reliable outside persons, such as school nurses, to take daily BP measurements for 3 to 4 weeks. One then examines the overall distribution of BP readings and compares them with clinic BP readings as well as with normative BP standards to see if the readings are in the hypertensive range.

3. Home BP monitoring with an oscillometric device is controversial because the accuracy of many commercially available BP measuring devices is questionable. Besides, those that take BP on the wrist are more likely to cause confusion than solving the problem because of the well-known peripheral amplification of systolic pressure (discussed in depth in Chapter 2). The radial artery systolic BP is expected to be higher than the brachial artery BP, and there are no normal BP values for the wrist. Physicians should never recommend or use the wrist device.

Secondary Hypertension

Among patients with secondary hypertension, more than 90% of the cases of secondary hypertension are caused by chronic renal disease, renovascular diseases, and COA. The remaining 10% of cases are caused by other diseases and conditions listed in Box 28-1. In this section, renovascular hypertension and pheochromocytoma are discussed in some detail. Management of hypertension caused by COA is discussed in Chapter 13.

Renovascular Hypertension

Renovascular hypertension results from a lesion that impairs blood flow to a part or all of one or both kidneys. It is the second most common cause of correctable secondary hypertension, second only to COA. It accounts for 3% to 10% of children with hypertension.

Pathogenesis of Renovascular Hypertension

The renin–angiotensin–aldosterone system (RAAS) is involved in the pathogenesis of renovascular hypertension. Angiotensin and aldosterone together influence arterial pressure and cardiac output. Therefore, knowledge of the RAAS is essential in the management of renovascular hypertension by using such drugs as ACE inhibitors, ARBs, and aldosterone antagonists (see Fig. 28-1).

1. Renin is stored and released from juxtaglomerular (JG) cells associated with the afferent arteriole entering the glomerulus. Renin release from the JG cells of the kidney is stimulated by a reduction in BP in the afferent arteriole, such as is seen with renal artery stenosis or systemic hypotension; its release is inhibited by increased BP (see Fig. 28-1).

2. Renin causes the cleavage of angiotensinogen in circulation to form angiotensin I, which has no known biological activity. Angiotensin I is further broken down to angiotensin II by ACE. Angiotensin II is a potent vasoconstrictor, constricting arteries and veins and increasing BP.

3. Angiotensin II acts on the adrenal cortex to stimulate the secretion of aldosterone. Aldosterone in turn acts on the kidneys to increase the reabsorption of sodium and fluid retention, which may help sustain BP and lead to secondary suppression of renin release. Aldosterone stimulates the excretion of potassium in the distal tubule with resulting hypokalemia.

Causes

1. Fibromuscular dysplasia is the most common cause of renovascular hypertension, accounting up to 70% of the patients, in whom the media of the arterial wall is primarily affected. If the intima is most affected, the term intimal hyperplasia is used, which shows a “string of beads” appearance on angiography.

2. Rarely, renal artery stenosis is also seen in other systemic or inherited conditions, including Williams’ syndrome, Marfan’s syndrome, Kawasaki’s disease, and Takayasu’s disease; after neonatal renal artery thrombosis; as a sequela to abdominal radiation; and after renal transplantation.

Clinical Manifestations

Many children with renovascular hypertension are asymptomatic, and when symptoms are present, they are frequently nonspecific. However, when any or some of the following are found on workup, one should consider a possibility of renovascular hypertension.

1. Young age, usually younger than 10 years of age

2. History of umbilical catheterization in the newborn period or history of abdominal irradiation

3. Serum electrolyte abnormalities, notably hypokalemia, but occasionally hyponatremia may also be found. However, an absence of electrolyte abnormalities does not preclude the possibility of severe renovascular hypertension.

4. Some normal children may have abdominal bruit.

image

FIGURE 28-1 Renin–angiotensin–aldosterone system. See text for explanation. The sites of action of some antihypertensive agents are shown with open arrows. ARB, angiotensin receptor blocker; ACE, angiotensin-converting enzyme; BF, blood flow; BP, blood pressure; JECs, juxtaglomerular cells.

5. Severe hypertension or worsening of hypertension refractory to medical treatment. However, hypertension is not always severe in renovascular hypertension.

6. Unexplained impaired renal function in the presence of hypertension

7. Unequal kidney size on any clinical study. The affected kidney is usually smaller.

8. Rarely, polyuria and polydipsia may be present.

Diagnostic Workup

When renovascular hypertension is a possible cause, one generally needs most of the investigations listed earlier (see Table 28-4) except for endocrine tests.

1. BUN and creatinine are usually normal in renovascular hypertension unless there is severe renal artery involvement or accelerated hypertension.

2. There may be some hypokalemia caused by secondary hyperaldosteronism.

3. It is not uncommon to find a normal size and shape of the kidneys in renal ultrasonography.

4. PRA is increased in most (but not all) cases of patients with renovascular disease or pyelonephritic scarring. ACE inhibitors stimulate PRA selectively in patients with renovascular hypertension (“captopril-stimulated PRA test”), but the specificity of the test is controversial. Low PRA in a hypertensive child suggests mineralocorticoid excess or a salt and water overload for other reasons.

5. Renal vein renin measurement is an important diagnostic procedure and helps in identifying surgically curable forms of renal hypertension.

6. Doppler ultrasonography, CT angiography, and MR angiography are safe tests with high sensitivity and specificity for renovascular hypertension. However, renal arteriography is still considered the gold standard for the diagnosis of renovascular hypertension. The procedure is mandatory if surgical or transluminal angioplasty is being considered.

Management

1. While waiting for intervention, antihypertensive medication should be started to lower the BP.

a. ACE inhibitors are most effective, which minimizes the ischemia-induced rise in the angiotensin production. One needs to closely monitor renal function because ACE inhibitors can cause a drop in the glomerular filtration rate. ARBs may be equally effective.

b. CCBs provide control of hypertension in patients with less impaired function of the ischemic kidney. They may have beneficial long-term effects, but this remains uncertain.

2. Restoration of adequate renal blood flow can be accomplished by percutaneous transluminal angioplasty with or without stenting. This is a relatively safe procedure with a success rate up to 90%.

3. Surgical revascularization by using bypass graft may be performed. However, the widespread nature of the disease in children will not offer a benefit to many children. In adults, surgical revascularization was found to offer better long-term results than endovascular revascularization (Ham et al, 2010).

Pheochromocytoma

Pheochromocytoma is a catecholamine-secreting tumor that arises from chromaffin cells. The most common site of the tumor is the adrenal medulla, but it can occur anywhere along the abdominal sympathetic chain. It may be inherited as an autosomal dominant trait.

Hypertension results from excess secretion of norepinephrine and epinephrine. Paroxysmal hypertension typically suggests the disease, but hypertension in children is usually more sustained than paroxysmal. During attacks, the patient complains of headache, palpitation, abdominal pain, dizziness, vomiting, pallor, and sweating. Convulsion and other manifestations of hypertensive emergency may occur. Because of hypermetabolism, growth failure is striking, with frequent polydipsia and polyuria. BP may rise to 180 to 220 mm Hg.

The diagnosis is made by demonstration of increased levels of blood and urine catecholamines and their metabolites. Urinary excretion of VMA and metanephrine is increased. Adrenal tumors are easily detected by sonography, CT scan, or MR imaging, and they are often bilateral. However, in children, it often occurs in extraadrenal sites and in multiple sites, and thus, it may be difficult to detect and remove all tumors. Removal of these tumors results in cure, but the operation is very high risk. Preoperative α- and β-adrenergic blockade and fluid loading are required.

Hypertensive Crisis

In hypertensive crisis, BP is rapidly rising or a high BP level is associated with neurologic manifestations, heart failure, or pulmonary edema.

Classification

Hypertensive crisis may be loosely divided into the following subgroups.

1. Hypertensive emergencies

Situations in which immediate reduction of BP (within minutes) is needed, usually with parenteral therapy

2. Hypertensive urgencies

Situations in which reduction of BP is needed within hours, usually with oral agents

3. Accelerated malignant hypertension

Situations in which papilledema, hemorrhage, and exudate are associated with a markedly elevated BP; the diastolic pressure is usually above 140 mm Hg

4. Hypertensive encephalopathy

Situations in which markedly elevated BP is associated with severe headache and various alterations in consciousness. Hypertensive encephalopathy may be seen in a previously normotensive patient who suddenly becomes hypertensive, such as children with acute glomerulonephritis or young women with eclampsia. Chronically hypertensive patients less commonly develop encephalopathy and only at much higher pressures.

Treatment

Aggressive parenteral administration of antihypertensive drugs is indicated to lower BP.

1. Labetalol (alpha- and beta-blocker) 0.2 to 2 mg/kg/hour IV drip, diazoxide (Hyperstat), 3 to 5 mg/kg as an IV bolus, or nitroprusside (Nipride), 1 to 3 µg/kg per minute as an IV drip, is the treatment of choice.

2. If hypertension is less severe, hydralazine (Apresoline), 0.15 mg/kg IV or intramuscularly (IM), may be used. The onset of action is 10 minutes after an IV dose and 20 to 30 minutes after an IM dose. The dose may be repeated at 4- to 6-hour intervals. Nifedipine, 0.2 to 0.5 mg/kg (maximum, 10 mg), may be given orally every 4 to 6 hours in severe cases.

3. A rapid-acting diuretic, such as furosemide (1 mg/kg), is given IV to initiate diuresis.

4. Fluid balance must be controlled carefully, so intake is limited to urine output plus insensible loss.

5. Seizures may be treated with slow IV infusion of diazepam (Valium), 0.2 mg/kg, or another anticonvulsant medication.

6. When a hypertensive crisis is under control, oral medications replace the parenteral medications (see Table 28-5 for oral dosages of antihypertensive drugs).