Management of High Blood Pressure in Children and Adolescents

Management of H i g h B l o o d Pres s u re i n C h i l d re n a n d Adolescents Rae-Ellen W. Kavey, MD, MPHa,*, Stephen R. Daniels, MD, PhDb,c, Joseph T. Flynn, MD, MSd KEYWORDS  High blood pressure  Hypertension  Children  Adolescents  Management

from epidemiologic studies and randomized trials indicates that healthy lifestyle choices in childhood are convincingly associated with lower BPs later in life.13,14 A series of randomized trials summarized in the most recent pediatric BP Task Force report from the National Heart, Lung and Blood Institute (NHLBI) have shown the safety and efficacy of BP lowering drugs in children and adolescents.2 This section describes an approach to diagnosis and management of the important and increasingly common problem of hypertension in childhood.

DIAGNOSIS OF HYPERTENSION Because hypertension is a largely asymptomatic condition, it can be diagnosed only by routine measurement of BP. The Fourth Report on Childhood Blood Pressure from the NHLBI recommends that BP be measured routinely for all health care encounters in children aged 3 years and older.2 This is not happening regularly for all children, and even when BP is measured, it may not be interpreted correctly.15 Without appropriate measurement and interpretation, increased BP

a Department of Pediatrics, Division of Cardiology, Golisano Children’s Hospital, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY 14642, USA b Department of Pediatrics, University of Colorado, School of Medicine, 13123 East 16th Avenue, B065, Aurora, CO 80045, USA c Department of Pediatrics, The Children’s Hospital, 13123 East 16th Avenue, B065 Aurora, CO 80045, USA d Division of Nephrology, Seattle Children’s Hospital, 4800 Sandpoint Way North East, Seattle, WA 98105, USA * Corresponding author. Division of Pediatric Cardiology, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY 14642. E-mail address: [email protected]

Cardiol Clin 28 (2010) 597–607 doi:10.1016/j.ccl.2010.07.004 0733-8651/10/$ e see front matter Ó 2010 Elsevier Inc. All rights reserved.

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Primary hypertension is an increasingly common diagnosis in children and adolescents.1 In the past, hypertension in childhood was considered rare and usually secondary to an identifiable underlying cause, but epidemiologic studies have established reliable norms for blood pressures (BPs) measured in an outpatient setting, and BP screening, particularly in relation to the obesity epidemic, has identified increased BPs in 2% to 5% of American children and adolescents.2e5 In the past, increased BPs in the medical setting were often attributed to anxiety but use of ambulatory monitoring with established norms has allowed assessment of BPs throughout the day in the home environment and therefore, confirmation of true hypertension even in young children.6 Ultrasound applications have shown the presence of subclinical organ damage as evidence of the effect of hypertension in childhood.7e9 At a prevalence as high as 5%, hypertension is one of the most common chronic diseases of childhood. Further, detection of hypertension in childhood identifies an individual at defined risk for hypertension as an adult and at increased risk for accelerated atherosclerosis and future premature cardiovascular disease.10e12 By contrast, new information

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Kavey cannot be recognized and necessary treatment strategies cannot be implemented. There are several important issues to consider in the measurement of BP in children. Because children are growing and because of increasing obesity in childhood, appropriate cuff size can vary substantially among children of the same age. The cuff bladder should have a width that covers approximately two-thirds of the upper arm and a length that encircles at least 80% of the upper arm, preferably 100%. Ideally, BP should be measured by auscultation, using a mercury sphygmomanometer. Using an automated oscillometric device is acceptable for initial measurement, but elevated readings should be confirmed by auscultation. Once an accurate BP measurement is obtained, the interpretation of that BP is important. The definition of elevated BP for children is based on percentiles derived from population studies of healthy children. BP increase is defined as systolic or diastolic BP at or higher than the 95th percentile based on sex, age, and height percentile. Complete normative tables are available with these percentile values.2 Hypertension is defined as BP persistently higher than that level on 3 or more occasions. If hypertension is present, it can be further classified as stage 1 if the BP is between the 95th percentile and the 99th percentile plus 5 mm Hg. Stage 2 hypertension is BP persistently higher than the 99th percentile plus 5 mm Hg. Prehypertension is defined as systolic or diastolic BP between 90th and 95th percentile for sex, age, and height. However, during puberty the 90th percentile is higher than the adult definition of prehypertension (120/80 mm Hg). So, in this age range, BPs higher than 120/80 mm Hg and lower than the 95th percentile should be considered prehypertension. The definitions for increased BP are presented in Table 1. The BP tables from the most recent NHLBI Task Force Report2 are the most complete and accurate normative pediatric BP values available but they are lengthy and detailed, with knowledge of the patient’s height percentile needed for interpretation of measured BP. Recently, a simplified table (Table 2) has been created based on age and gender using systolic and diastolic BP measurements higher than the 90th percentile norms for the lower limit of height from the NHLBI Task Force Report to identify children and adolescents in whom BP requires further evaluation.16 This is a useful tool for screening BPs in children and adolescents. White-coat hypertension is a concern in children and adolescents. This form of hypertension occurs when BPs are increased in a clinic or office setting,

Table 1 Categorization of BP for pediatric patients Category

Definition

Normal BP

Systolic or diastolic BP below the 90th percentilea Systolic or diastolic BP above the 90th percentile (or 120/80 mm Hg), but below the 95th percentile Systolic or diastolic BP higher than or equal to the 95th percentile, but lower than the 99th percentile plus 5 mm Hg Systolic or diastolic BP higher than or equal to the 99th percentile plus 5 mm Hg

Prehypertension

Stage 1 hypertension

Stage 2 hypertension

a

All BP percentiles are based on sex, age, and height percentiles.

but are normal at home. White-coat hypertension can be evaluated in pediatric patients with established hypertension on clinic measurements by 24-hour ambulatory BP monitoring or home BP measurements. Standards have been established for pediatric ambulatory BPs.6 There may also be concerns about secondary forms of hypertension in children. Secondary hypertension can be caused by renal parenchymal disease, renal vascular disease, endocrine abnormalities, the use of certain medications, coarctation of the aorta, and certain neurologic conditions. Secondary hypertension probably represents about 5% of hypertension in children and adolescents and is more likely to be present in younger children, children with higher BP, and children who have little or no family history of hypertension. Most causes of secondary hypertension can be identified, or at least a strong suspicion developed, from a complete history and physical examination. Based on those results, confirmatory tests can be performed. When secondary hypertension is present, specific treatment can be initiated for the underlying abnormality. Another circumstance that raises concern about potential secondary hypertension occurs when pharmacologic treatment of hypertension is unsuccessful. The most common reason for this lack of success is poor adherence, but this difficulty in achieving successful treatment may also be a clue to an underlying secondary cause

High Blood Pressure in Children

Table 2 BP values requiring further evaluation, according to age and gender BP (mm Hg) Male

Female

Age (y) Systolic Diastolic Systolic Diastolic 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

100 102 104 105 106 107 109 111 113 115 117 120 120 120 120 120

59 62 65 68 70 71 72 73 74 74 75 75 76 78 80 80

100 101 103 104 106 108 110 112 114 116 117 119 120 120 120 120

61 64 66 68 69 71 72 73 74 75 76 77 78 78 78 80

These values represent the lower limits for abnormal BP ranges, according to age and gender. Any BP readings equal to or greater than these values represent BPs in the prehypertensive, stage 1 hypertensive or stage 2 hypertensive range and should be further evaluated by a physician. Data from Kaelber DC, Pickett F. Simple table to identify children and adolescents needing further evaluation of blood pressure. Pediatrics 2009;123:e972e4.

of the BP increase. The initial standard laboratory evaluation for pediatric hypertension includes checking blood urea nitrogen and creatinine levels, urinalysis, and a complete blood count. These tests are particularly useful for excluding renal causes of hypertension. Once a diagnosis of hypertension is made, it is also important to consider whether target-organ damage is present. The most useful way to evaluate target-organ damage is by assessing left ventricular (LV) mass using echocardiography. LV hypertrophy can result from prolonged exposure of the left ventricle to increased afterload caused by increased systemic BP. In this context, increased LV mass may be seen as adaptive, in adults LV hypertrophy is also a risk factor for adverse cardiovascular outcomes, including myocardial infarction, stroke, congestive heart failure, and sudden death. LV hypertrophy in the context of hypertension in children and

adolescents may be as prevalent as 40%, with more severe LV hypertrophy present in approximately 10%.9 Identification of LV hypertrophy may suggest the need for more urgent and more aggressive treatment of hypertension. Hypertension should be easily recognizable during health maintenance visits in children and adolescents. The prevalence of hypertension of as high as 5% in the general childhood population indicates that this diagnosis should not be uncommon for pediatricians and family physicians. However, to accomplish this diagnosis, correct measurement of BP is necessary. The observed BP must be compared with percentile values to determine if it is increased. This process often does not occur routinely in pediatric primary care.

OBESITY-RELATED HYPERTENSION As described earlier, secondary hypertension is rare in childhood and presents most frequently in children less than 10 years of age with severe BP elevation. By contrast, hypertension associated with obesity is now the most common presentation in children and adolescents, with prevalence increasing as both age and the degree of obesity increase. Analysis of pooled data from 8 large epidemiologic studies involving more than 47,000 children revealed that regardless of race, gender, and age, the risk of increased BP was significantly higher for children in the upper compared with lower decile of body mass index (BMI, calculated as weight in kilograms divided by the square of height in meters).17 Among obese children with BMI higher than the 90th percentile for age/sex in an obesity treatment program, the prevalence of hypertension averaged 30%.18 However, in the most severely obese group with BMI higher than the 99.5th percentile, obesity prevalence was reported to be 45%. In a school-based survey in the United States published in 2004, the overall prevalence of hypertension among adolescents was 4.5%.19 However, in the group with BMI higher than the 95th percentile, hypertension was reported in 34% of subjects. From epidemiologic studies, a serial analysis of combined National Health Examination Survey and National Health and Nutrition Examination Survey (NHANES) data showed that the prevalence of hypertension in children trended downward on each survey obtained between 1976 until 1988, after which prevalence progressively increased, coincident with the onset and progression of the obesity epidemic.1 Between 1988 and 2002, prehypertension increased significantly by 2.3% and hypertension by 1%. In 1999 to 2002, hypertension prevalence was 4.2% for blacks, 3.3% for whites,

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Kavey and 4.6% for Mexican-Americans. Higher BMI and waist circumference both significantly increased the likelihood of hypertension. This trend continues into young adult life, with NHANES data from 1999 to 2004 showing that in individuals aged 18 to 39 years, the prevalence of both isolated systolic hypertension and combined systolic and diastolic hypertension has increased compared with results from 1988 to 1994 and that hypertension correlates significantly with obesity, smoking, and low socioeconomic status.20 Hypertension is common among obese children and adolescents, involving at least onethird of all subjects when findings from epidemiologic and specific population studies are considered.

Mechanisms for Obesity-Related Hypertension The mechanisms by which obesity contributes to the development of hypertension are multiple, complex, and, as yet, incompletely understood. As in adults, an upper body fat distribution has been shown to correlate with the development of hypertension in children.21 Sodium retention is believed by many to be the common pathway leading to obesity-related hypertension. Hyperinsulinemia and/or insulin resistance, often seen with abdominal obesity, can result in chronic sodium retention by direct effects on the renal tubules and indirectly through stimulation of the sympathetic nervous system (SNS) and augmentation of aldosterone secretion.22e24 Insulin is also believed to be the signal that links dietary intake and nutritional status to SNS activity, with increased SNS activity reported in obese individuals in multiple studies.25,26 Hypertension is commonly seen in association with hyperuricemia, and this may also be related to hyperinsulinemia. However, recent studies in adults have shown that hyperuricemia independently predicts development of hypertension, suggesting that increased uric acid may play a causative role.27 In adolescents with essential hypertension, almost 90% were reported to have increased uric acid levels compared with only 30% of adolescents with secondary hypertension and no normotensive controls.28 A recent randomized, double-blind, placebo-controlled, crossover trial of allopurinol in children with newly diagnosed essential hypertension showed a significant reduction in BP associated with reduction of uric acid levels.29 Alterations in vascular structure and function have been described in obese children and adolescents; these may be primary and therefore contributory to pressure increase or secondary to

established hypertension. Findings include increased carotid artery intimal-medial thickness (cIMT) and reduced forearm blood flow response to ischemia with increased minimum vascular resistance.30,31 Increased cIMT has been shown to occur with obesity alone and to a greater extent with obesity and hypertension. Increased vascular resistance has been shown to correlate directly with fasting insulin levels and to improve with weight loss. Stimulation of the renin-angiotensinaldosterone system (RAAS) is also believed to contribute to the development of hypertension in obese individuals. The RAAS is an important modulator of efferent glomerular arteriolar tone and of tubular reabsorption of sodium. Plasma renin activity and aldosterone levels both decrease with weight loss in obese adults.32 In obese adolescents, Rocchini and colleagues33 reported significantly higher supine and upright aldosterone levels with no difference in plasma renin levels. However, a given increment in plasma renin activity produced a greater change in aldosterone levels in obese than in nonobese patients. In this study, weight loss resulted in a significant decrease in plasma aldosterone in the obese adolescent patients. Weight loss has been consistently shown to lower BP in multiple studies in obese adults and children.23,34,35 The BP change has been shown to be independent of sodium restriction.

Diagnosis of Hypertension in Obese Children and Adolescents The principles of BP measurement and interpretation outlined in the preceding section apply equally to obese children. Care must be taken to select an appropriate cuff size, which can be challenging for patients with large arms. White-coat hypertension is at least as common among obese children as it is in nonobese children, so ambulatory BP monitoring is an important way to confirm the diagnosis of hypertension, especially if drug treatment is being considered.30,36 Assessment for evidence of LV hypertrophy should be performed if a diagnosis of hypertension is made. Echocardiographic determination of LV mass is based on standard measurements indexed for body size using height to the 2.7 power. This method has been shown to most closely account for lean body mass, excluding the effects of obesity. Increased LV mass has been reported in obese children and in 34% to 38% of children with untreated hypertension. Outcome-based standards are not available for children. A conservative cut point for the presence of increased LV mass is 51 g/m2;7 this is higher than the 99th

High Blood Pressure in Children percentile throughout childhood and adolescence, and in adults with hypertension has been shown to be associated with increased morbidity.9

Treatment of Hypertension in Obese Children and Adolescents Weight loss is the cornerstone of hypertensive management in obese children and adolescents. Several recent studies have addressed the role of diet specifically as it relates to BP. A metaanalysis of the effect of reducing salt intake on BP in children and adolescents found that a modest reduction in salt intake did decrease BP, with a significant effect size of 1.17 mm of mercury (mm Hg) for systolic BP and 2.47 mm Hg for diastolic BP in normotensive children aged 8 to 16 years; in infants, salt reduction decreased systolic BP by 2.47 mm Hg.37 In the Dietary Approaches to Stop Hypertension (DASH) intervention trial in adults, a diet rich in fruits and vegetables, low-fat or fat-free dairy products, whole grains, fish, poultry, beans, seeds, and nuts and lower in salt and sodium, sweets and added sugars, fats, and red meat than the typical US diet substantially reduced both systolic and diastolic BP among hypertensive and normotensive individuals.38 Sustained adherence to a DASH-style diet has been shown to be associated with lower risk of coronary heart disease and stroke on long-term follow-up.39 A randomized controlled trial of the DASH diet was assessed in 57 adolescents with prehypertension or hypertension. At 3-month follow-up, the DASH group had a significantly greater decrease in systolic BP associated with higher intake of fruits, low-fat dairy products, potassium, and magnesium and a lower intake of total fat than did the usual care group.40 Maximal decreases in BP have been achieved when a weight loss program combines diet change with physical conditioning. When diet, exercise, and behavior counseling are not effective in reducing weight and controlling BP, drug therapy to support weight loss can be considered. Drug treatment of obesity to manage hypertension has not been specifically studied but pharmacologic treatment of obesity has been investigated in a series of randomized controlled trials in adolescents. For male and female adolescents with severe increase of BMI and insulin resistance, including females with polycystic ovarian syndrome, the addition of metformin to a comprehensive multidisciplinary weight loss program significantly reduced weight and BMI and improved insulin resistance and lipid levels at 4- to 6-month follow-up41e43 For adolescents older than 12 years, the addition of orlistat, which

causes fat malabsorption through inhibition of enteric lipase, to a comprehensive multidisciplinary weight loss program improved weight loss and BMI at 6- to 12-month follow-up in 3 of 4 studies.44e46 However, orlistat therapy was associated with a high reported rate of gastrointestinal symptoms. In 12- to 16-year-old adolescents with severe elevation of BMI (32e44 kg/m2), the addition of sibutramine, a serotonin reuptake inhibitor, to a comprehensive multidisciplinary weight loss program improved weight loss, BMI, and measures of metabolic risk at 12-month follow-up.47,48 A large multicenter randomized controlled trial of sibutramine versus placebo in obese adolescents specifically addressed the cardiovascular effects of sibutramine.49 At the 12-month end point, the sibutramine group had a significantly greater decrease in BMI and both groups had small mean decreases in heart rate and BP. However, tachycardia was reported as an adverse event in significantly more patients treated with sibutramine. Discontinuation of treatment did not differ between the 2 groups and no patient treated with sibutramine required discontinuation of treatment because of hypertension. Recent small case series of adolescents with a BMI higher than the 95th percentile with significant comorbidities and adolescents with a BMI 35 kg/m2 or greater, at or above the 97th percentile, who had failed a weight loss program indicate that bariatric surgery in conjunction with a comprehensive multidisciplinary weight loss program can improve weight loss, BMI, insulin resistance, glucose tolerance, and BP.50,51 Drug therapy to control hypertension is described in the next section.

PHARMACOLOGIC TREATMENT OF CHILDHOOD HYPERTENSION Nonpharmacologic measures (dietary changes, exercise, and weight loss) have long been recommended as primary therapy for childhood hypertension,2 especially in those with primary hypertension or obesity-related hypertension (see preceding section). The efficacy of these measures has been subject to question, however, primarily because of high rates of nonadherence with prescribed lifestyle changes. Thus, some hypertensive children and adolescents, including those with secondary hypertension, require pharmacologic treatment.

Medications Available for Use in Children A major issue related to use of antihypertensive medications in young people is the availability of safety and efficacy data. Historically, few drug

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trials were conducted in children, with the consequence that many drugs had to be used empirically, without the benefit of specific pediatric efficacy, safety, or dosing information. Given the low incidence of hypertension in childhood, it is not surprising that this situation was especially true for antihypertensive medications.52 The passing of the US Food and Drug Administration Modernization Act (FDAMA) in 1997, which contained a provision that granted 6 additional months of patent protection to drug manufacturers if they conducted pediatric trials, has had an enormous effect on pediatric drug development.53 Subsequent legislation (Best Pharmaceuticals for Children Act, Pediatric Research Equity Act, FDA Amendments Act of 2007) has extended this provision and has led to other initiatives, including public posting of internal FDA pharmacology and efficacy reviews on the Internet, and mechanisms to promote studies of medications with lapsed patent protection. These initiatives have led to many pediatric clinical trials of antihypertensive medications and have also increased the number of such medications with specific pediatric labeling (Table 3), correcting a significant deficiency for antihypertensive medications and increasing the amount of clinically useful information for practitioners. More recently, the European Medicines Agency has enacted the so-called pediatric rule, which requires manufacturers to study medications in children to be able to market them in Europe.54 Because many children cannot swallow standard pills and capsules, drug formulation is

another important issue for pediatricians and others who care for hypertensive children. The FDAMA and related legislation do not contain provisions to mandate marketing of liquid preparations of medications studied in children, leaving this need unfulfilled. However, several of the recent pediatric drug trials have incorporated an extemporaneous suspension into the study design, and the suspensions used have subsequently been incorporated into the FDAapproved label information for these compounds. Although this does provide some useful information for these medications, there are many unresolved questions with respect to stability of extemporaneously prepared suspensions that highlight the problems faced in prescribing most antihypertensive medications to children.55

Indications for Use of Antihypertensive Medications in Children Because there has never been a natural history study of untreated primary hypertension in the pediatric age group, the long-term consequences of untreated hypertension in an asymptomatic, otherwise healthy child or adolescent remain unknown.2 In addition, aside from one recent study of an angiotensin-receptor blocker (ARB),56 there is an almost complete lack of data on the long-term effects of antihypertensive medications on the growth and development of children. Therefore, consensus organizations have recommended that use of pharmacologic therapy be limited

Table 3 Pediatric labeling of antihypertensive medications: effect of the FDAMA and successor legislation

a b c

Had Pediatric Labeling Before FDAMA

New Pediatric Labeling Since FDAMAa

Under Study, Awaiting Labeling, or Anticipated Future Study

Captoprilb Chlorothiazide Diazoxideb Furosemide Hydralazine Hydrochlorothiazide Methyldopa Minoxidil Propranolol Spironolactone

Amlodipine Benazepril Enalapril Eplerenonec Fenoldopam Fosinopril Irbesartanc Losartan Lisinopril Metoprolol Valsartan

Aliskiren Candesartan Olmesartan Ramipril Sodium nitroprusside Telmisartan

Does not include medications studied and granted exclusivity but not pediatric labeling. No specific dose recommendations included in label. Label specifically states drug not effective in hypertensive children.

High Blood Pressure in Children to children and adolescents with one of the following indications2:     

Symptomatic hypertension Secondary hypertension Hypertensive target-organ damage Diabetes (types 1 and 2) Persistent hypertension despite nonpharmacologic measures.

There are some subpopulations of children in which the benefits of pharmacologic treatment are reasonably clearly established, making the decision to prescribe more likely to produce a clinical benefit. Chief among these are children with chronic kidney disease (CKD), in whom it has recently been shown that lower BP reduces the rate of CKD progression.57 In addition, one recent small study has shown that pharmacologic treatment can reduce LV mass index and urinary microalbumin excretion in a group of mostly obese children and adolescents with primary hypertension.58 However, in other groups of children a conservative approach still seems warranted given the lack of evidence of benefit and the concern over possible adverse medication effects unique to the pediatric age group.

Approach to Prescribing Antihypertensive Medications in the Pediatric Patient The approach to prescribing antihypertensive medications in the hypertensive child or adolescent has several differences from the approach usually followed in adults. The first of these differences relates to choice of initial medication. Although many individual antihypertensive compounds have now been studied in the pediatric age group, no pediatric studies comparing different agents have been conducted. Therefore, it is unknown whether one class of agent is better than another in children and adolescents. This situation leaves the prescriber without evidencebased guidance for choice of drug. This is reflected in the most recent consensus guidelines, which state that any class of agent is acceptable for use in children and adolescents.2 Given this state of affairs, various approaches for choice of initial medication have been proposed, including tailoring drug choice to the patient’s underlying pathophysiology and presence of concurrent conditions.59 The second difference from drug prescribing in adults is that most medications in children are dosed based on body weight; the one-size-fits-all approach used in adults is not followed in pediatrics. Ideally, such prescribing is based on the results of appropriately conducted clinical trials

designed to establish a dose response for the compound under study. Many of the recent pediatric trials of antihypertensive medications have failed to show a dose response because of design flaws.60 Nevertheless, as illustrated in Table 4, most antihypertensive medications used in children and adolescents do have accepted dose ranges based on body weight. This finding forms the basis for the stepped-care approach to drug treatment outlined in Fig. 1. Stepped care allows for the individualization of therapy according to the needs of the patient and also facilitates detection of adverse effects when drug doses are increased or new agents added. It has been endorsed by the last 3 pediatric working groups of the National High Blood Pressure Education Program as an appropriate approach to the use of antihypertensive drugs in children and adolescents.2 Another difference related to prescribing of antihypertensive medications in the pediatric age group is that ideally, drugs prescribed for use in children and adolescents should have FDA-approved pediatric labeling and should be indicated for pediatric use. As discussed earlier, many agents do not have such labeling, despite the recent legislative efforts that have been made to address this issue.52,53,56 Given this situation, and given that essentially all classes of antihypertensive agents have now been studied in children (with the exception of commonly used diuretics), it is reasonable to limit prescribing to those agents that are labeled for use in children and adolescents.

Long-term Considerations for Use of Antihypertensive Medications in Children and Adolescents As in adults, antihypertensive therapy in children and adolescents must be monitored closely both for efficacy and for potential adverse effects. BP should be measured in the office every 2 to 4 weeks until good control is achieved. For children with uncomplicated primary hypertension and no hypertensive target-organ damage, goal BP should be less than the 95th percentile for age, gender, and height, whereas for children with secondary hypertension, diabetes, or hypertensive target-organ damage, goal BP should be less than the 90th percentile for age, gender, and height.2 These goals are consistent with current recommendations for therapy for hypertension in adults and also parallel the prescribing practices of many pediatric nephrologists. Once control is achieved, then office BP measurement every 3 to 4 months is appropriate. Home BP

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Class

Drug

Starting Dose

Interval

Maximum Dosea

Aldosterone receptor antagonists

Eplerenone Spironolactoneb Benazeprilb Captoprilb Enalaprilb Fosinopril Lisinoprilb Quinapril Candesartan Losartanb Olmesartan Valsartanb

25 mg/d 1 mg/kg/d 0.2 mg/kg/d up to 10 mg/d 0.3e0.5 mg/kg/dose 0.08 mg/kg/d 0.1 mg/kg/d up to 10 mg/d 0.07 mg/kg/d up to 5 mg/d 5e10 mg/d 2e4 mg/d 0.75 mg/kg/d up to 50 mg/d 2.5 mg/d 1.3 mg/kg/d up to 40 mg/d <6 y: 5e10 mg/d 2e3 mg/kg/d 0.1 mg/kg/dose up to 12.5 mg BID 0.5e1 mg/kg/d 0.04 mg/kg/d up to 2.5/6.25 mg/d 1e2 mg/kg/d 1 mg/kg/d 0.06 mg/kg/d 2.5 mg/d 0.05e0.15 mg/kg/dose 0.25e0.5 mg/kg/d 5e10 mg/kg/d 5e10 mg/d 0.3 mg/kg/d 0.5e2.0 mg/kg/dose 0.5e1 mg/kg/d 0.25 mg/kg/dose 0.1e0.2 mg/kg/d

QD-BID QD-BID QD BID-TID QD QD QD QD QD QD QD QD

100 mg/d 3.3 mg/kg/d up to 100 mg/d 0.6 mg/kg/d up to 40 mg/d 6 mg/kg/d up to 450 mg/d 0.6 mg/kg/d up to 40 mg/d 0.6 mg/kg/d up to 40 mg/d 0.6 mg/kg/d up to 40 mg/d 80 mg/d 32 mg/d 1.4 mg/kg/d up to 100 mg/d 40 mg/d 2.7 mg/kg/d up to 160 mg/d <6 y: 80 mg/d 10e12 mg/kg/d up to 1.2 g/d 0.5 mg/kg/dose up to 25 mg BID 2 mg/kg/d up to 100 mg/d 10/6.25 mg/d 6 mg/kg/d up to 200 mg/d 16 mg/kg/d up to 640 mg/d 0.3 mg/kg/d up to 10 mg/d 10 mg/d 0.8 mg/kg/d up to 20 mg/d 3 mg/kg/d up to 120 mg/d 25 mg/kg/d up to 0.9 mg/d 20 mg/d 2 mg/kg/d up to 50 mg/d 6 mg/kg/d 3 mg/kg/d up to 50 mg/d 7.5 mg/kg/d up to 200 mg/d 1 mg/kg/d up to 50 mg/d

ACE inhibitors

ARBs

a and b-adrenergic antagonists b-adrenergic antagonists

Calcium channel blockers

Central a-agonist Diuretics

Vasodilators

Labetalolb Carvedilol Atenololb Bisoprolol/ HCTZ Metoprolol Propranolol Amlodipineb Felodipine Isradipineb Extended-release nifedipine Clonidineb Amiloride Chlorthalidone Furosemide HCTZ Hydralazine Minoxidil

Abbreviations: BID, twice daily; HCTZ, hydrochlorothiazide; QD, once daily; QID, 4 times daily; TID, 3 times daily. a The maximum recommended adult dose should never be exceeded. b Information on preparation of a stable extemporaneous suspension is available for these agents.

BID BID QD-BID QD BID BID-TID QD QD TID-QID QD-BID BID-TID QD QD QD-BID QD TID-QID BID-TID

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Table 4 Doses for selected antihypertensive agents for use in hypertensive children and adolescents

High Blood Pressure in Children

Fig. 1. Stepped-care approach to antihypertensive drug therapy in children and adolescents.

measurement should also be incorporated into the treatment plan, as this may help improve compliance with treatment, as well as achievement of goal BP. Periodic laboratory monitoring may also be required, particularly if a diuretic or agent affecting the renin-angiotensin system is prescribed, or if the hypertensive child or adolescent has underlying renal disease as the cause of their hypertension. Women of childbearing potential should be counseled regarding the need to use an effective method of contraception if treatment with an angiotensin-converting enzyme (ACE) inhibitor or ARB is indicated. Adherence to treatment is an important longterm issue in the treatment of hypertension in children and adolescents because most patients have so few symptoms. In adolescents, this situation is particularly difficult because they often do not like to take their medications and do not like to be perceived as different from their peers. If BP control can be achieved with a single drug that is taken once a day, this improves the likelihood of compliance and this should be taken into consideration when the initial agent is chosen. The adverse effect profile of the medication may also affect adherence; newer agents such as long-acting calcium channel blockers and agents affecting the renin-angiotensin system have lower rates of adverse effects than older agents such as

b-adrenergic blockers, and may therefore be preferable in the pediatric age group. A few hypertensive children and adolescents, specifically those obese patients who make significant progress with lifestyle modification, may be candidates for withdrawal of therapy after a period of sustained BP control. Parents may be especially interested in attempting this goal to avoid an indefinite period of drug therapy beginning at a young age. Home BP monitoring and monitoring for resolution of hypertensive target-organ damage are especially important if withdrawal of medications is contemplated. Antihypertensive medications lower BP in hypertensive children and adolescents. What remains for future study is whether use of antihypertensive drugs in the young results in prevention or amelioration of the long-term cardiovascular sequelae of hypertension.

REFERENCES 1. Din-Dzietham R, Liu Y, Bielo MV, et al. High blood pressure trends in children and adolescents in National Surveys, 1963 to 2003. Circulation 2007;116:1488e96. 2. National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and Adolescents. The fourth report on the diagnosis, evaluation and treatment of high blood pressure in

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