1. family and parenting
2. children

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.
cardiology.theclinics.com
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
598
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,
599
600
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
601
Kavey
602
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
603
604
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
Kavey
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
605
Kavey
606
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
children and adolescents. Pediatrics 2004;114
(Suppl):555e76.
Muntner P, He J, Cutler JA, et al. Trends in blood
pressure among children and adolescents. JAMA
2004;291:2107e13.
McNiece KL, Poffenbarger TS, Turner JL, et al.
Prevalence of hypertension and pre-hypertension
among adolescents. J Pediatr 2007;150:640e4.
Sorof J, Daniels SR. Obesity hypertension inn
children: a problem of epidemic proportions. Hypertension 2002;40:441e7.
Urbina E, Alpert B, Flynn J, et al. Ambulatory blood
pressure monitoring in children and adolescents:
recommendations for standard assessment. Hypertension 2008;552:433e51.
Lande MB, Carson NL, Roy J, et al. Effects of
childhood primary hypertension on carotid intima
media thickness. A matched controlled study.
Hypertension 2006;48:40e4.
Lim SM, Kim HC, Lee HS, et al. Association between
blood pressure and carotid intima-media thickness.
J Pediatr 2009;154:667e71.
Daniels SR, Loggie J, Khoury P, et al. Left ventricular
geometry and severe left ventricular hypertrophy in
children and adolescents with essential hypertension. Circulation 1998;97:1907e11.
Chen X, Wang Y. Tracking of blood pressure from
childhood to adulthood: a systematic review and
meta-analysis. Circulation 2008;117:3171e80.
Raitakari OT, Juonola M, Kahonen M, et al. Cardiovascular risk factors in childhood and carotid artery
intima-media thickness in adulthood: the Cardiovascular Risk in Young Finns Study. JAMA 2003;290:
2277e83.
Li S, Chen W, Srinivasan SR, et al. Childhood cardiovascular risk factors and carotid vascular changes
in adulthood: the Bogalusa Heart Study. JAMA
2003;290:2271e6.
Gidding SS, Barton BA, Dorgan JA. Higher selfreported activity is associated with lower systolic
blood pressure: the Dietary Intervention Study in
Childhood (DISC). Pediatrics 2006;118:2388e93.
Niinikoski H, Jula A, Viikari J, et al. Blood pressure is
lower in children and adolescents with lowsaturated-fat diet since infancy: the Special Turku
Coronary Risk Factor Intervention Project. Hypertension 2009;53:918e24.
Hansen ML, Gunn PW, Kaelber DC. Underdiagnosis
of hypertension in children and adolescents. JAMA
2007;298(8):874e9.
Kaelber DC, Pickett F. Simple table to identify children and adolescents needing further evaluation of
blood pressure. Pediatrics 2009;123:e972e4.
Rosner B, Prineas R, Daniels SR, et al. Blood
pressure differences between blacks and whites in
relation to body size among US children and adolescents. Am J Epidemiol 2000;151:1007e19.
18. Reinehr T, Andler W, Denzer C, et al. Cardiovascular
risk factors in overweight children and adolescents:
relation to gender, age and degree of overweight.
Nutr Metab Cardiovasc Dis 2005;15:181e7.
19. Sorof JM, Lai D, Turner J, et al. Overweight, ethnicity
and prevalence of hypertension in school-aged
children. Pediatrics 2004;113:475e82.
20. Grebla RC, Rodriguez CJ, Borrell LN, et al. Prevalence and determinants of isolated systolic
hypertension among young adults: the 1999e2004
US National Health and Nutrition Examination
Survey. J Hypertens 2010;28:15e23.
21. Shear CL, Freedman DS, Burke GL, et al. Body fat
patterning and blood pressure in children and
young adults: the Bogalusa Heart Study. Hypertension 1987;9:236e44.
22. Rocchinin AP, Katch V, Kveselis D, et al. Insulin and
renal sodium retention in obese adolescents.
Hypertension 1989;14:367e74.
23. Rocchini AP, Key J, Bondie D, et al. The effect of
weight loss on the sensitivity of blood pressure to
sodium in obese adolescents. N Engl J Med 1989;
321:580e5.
24. Rocchini AP, Moorehead C, DeRemer S, et al.
Hyperinsulinemia and the aldosterone and pressor
responses to angiotensin II. Hypertension 1990;15:
861e6.
25. Jiang X, Srinivasan SR, Urbina E, et al. Hyperdynamic circulation and cardiovascular risk in children
and adolescents: the Bogalusa Heart Study. Circulation 1995;91:1101e6.
26. Sorof JM, Poffenbarger T, Franco K, et al. Isolated
systolic hypertension, obesity and hyperkinetic
hemodynamic states in children. J Pediatr 2002;
140:660e6.
27. Feig DI, Kang D-H, Johnson RJ. Uric acid and
cardiovascular risk. N Engl J Med 2008;359:
1811e21.
28. Feig DI, Johnson RJ. Hyperuricemia in childhood
primary hypertension. Hypertension 2003;42:
247e52.
29. Feig DI, Soletsky B, Johnson RJ. Effect of allopurinol
on blood pressure of adolescents with newly diagnosed essential hypertension: a randomized trial.
JAMA 2008;300:924e32.
30. Stabouli S, Kotsis V, Papamichael C, et al. Adolescent obesity is associated with high ambulatory
blood pressure and increased carotid intimalmedial thickness. J Pediatr 2005;147:651e6.
31. Rocchini AP, Moorehead C, Katch V, et al. Forearm
resistance vessel abnormalities and insulin
resistance in obese adolescents. Hypertension
1992;19:615e20.
32. Tuck MI, Sowers J, Dornfield L, et al. The effect of
weight reduction on blood pressure plasma renin
activity and plasma aldosterone level in obese
patients. N Engl J Med 1981;304:930e3.
High Blood Pressure in Children
33. Rocchini AP, Katch VL, Grekin R, et al. Role for
aldosterone in blood pressure regulation of obese
adolescents. Am J Cardiol 1986;57:613e8.
34. Sjostrom CD, Lissner L, Wedel H, et al. Differential
long-term effects of intentional weight loss on diabetes
and hypertension. Hypertension 2000;36:20e5.
35. Rocchini AP, Katch V, Anderson J, et al. Blood
pressure in obese adolescents: effect of weight
loss. Pediatrics 1988;82:116e23.
36. Kavey REW, Kveselis DA, Atallah N, et al. White coat
hypertension in childhood: evidence for end-organ
effect. J Pediatr 2007;150:491e7.
37. He FJ, Graham AM. Importance of salt in determining blood pressure in children. Meta-analysis of
controlled trials. Hypertension 2006;48:861e9.
38. Appel LJ, Moore TJ, Obarzanek E, et al. A clinical
trial of the effects of dietary patterns on blood
pressure. DASH Collaborative Research Group.
N Engl J Med 1997;336(16):1117e24.
39. Folsom AR, Parker ED, Harnack LJ. Degree of
concordance with DASH diet guidelines and
incidence of hypertension and fatal cardiovascular disease. Am J Hypertens 2007;20(3):
225e32.
40. Couch SC, Saelens BE, Levin L, et al. The efficacy of
a clinic-based behavioral nutrition intervention
emphasizing a DASH-type diet for adolescents with
elevated blood pressure. J Pediatr 2008;152(4):
494e501.
41. Kay JP, Alemzadeh R, Langley G, et al. Beneficial
effects of metformin in normoglycemic morbidly
obese adolescents. Metabolism 2001;50(12):
1457e61.
42. Srinivasan S, Ambler GR, Baur LA, et al. Randomized, controlled trial of metformin for obesity and
insulin resistance in children and adolescents:
improvement in body composition and fasting
insulin. J Clin Endocrinol Metab 2006;91(6):
2074e80.
43. Freemark M, Bursey D. The effects of metformin on
body mass index and glucose tolerance in obese
adolescents with fasting hyperinsulinemia and
a family history of type 2 diabetes. Pediatrics
2001;107(4):E55.
44. Maahs D, de Serna DG, Kolotkin RL, et al. Randomized, double-blind, placebo-controlled trial of orlistat
for weight loss in adolescents. Endocr Pract 2006;
12(1):18e28.
45. Chanoine JP, Hampl S, Jensen C, et al. Effect of
orlistat on weight and body composition in obese
adolescents: a randomized controlled trial. JAMA
2005;293(23):2873e83.
46. Ozkan B, Bereket A, Turan S, et al. Addition of orlistat to conventional treatment in adolescents with
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
severe obesity. Eur J Pediatr 2004;163(12):
738e41.
Berkowitz RI, Wadden TA, Tershakovec AM, et al.
Behavior therapy and sibutramine for the treatment
of adolescent obesity: a randomized controlled trial.
JAMA 2003;289(14):1805e12.
Garcı́a-Morales LM, Berber A, Macias-Lara CC,
et al. Use of sibutramine in obese Mexican adolescents: a 6-month, randomized, double-blind,
placebo-controlled, parallel-group trial. Clin Ther
2006;28(5):770e82.
Daniels SR, Long B, Crow S, et al. Sibutramine
Adolescent Study Group. Cardiovascular effects of
sibutramine in the treatment of obese adolescents:
results of a randomized, double-blind, placebocontrolled study. Pediatrics 2007;120(1):e147e57.
Tsai WS, Inge TH, Burd RS. Bariatric surgery in
adolescents: recent national trends in use and inhospital outcome. Arch Pediatr Adolesc Med 2007;
161(3):217e21.
Ippisch HM, Inge TH, Daniels SR, et al. Reversibility
of cardiac abnormalities in morbidly obese adolescents. J Am Coll Cardiol 2008;51:1342e8.
Flynn JT. Pediatric use of antihypertensive medications: much more to learn. Curr Ther Res Clin Exp
2001;62:314e28.
Roberts R, Rodriguez W, Murphy D, et al. Pediatric
drug labeling: improving the safety and efficacy of
pediatric therapies. JAMA 2003;290:905e11.
Dunne J. The European Regulation on medicines for
paediatric use. Paediatr Respir Rev 2007;8:177e83.
Ghulam A, Keen K, Tuleu C, et al. Poor preservation
efficacy versus quality and safety of pediatric
extemporaneous liquids. Ann Pharmacother 2007;
41:857e60.
Flynn JT, Meyers KC, Neto JP, et al. Pediatric Valsartan Study Group. Efficacy and safety of the angiotensin receptor blocker valsartan in children with
hypertension aged one to five years. Hypertension
2008;52:222e8.
Wühl E, Trivelli A, Picca S, et al. for the ESCAPE Trial
Group. Strict blood-pressure control and progression of renal failure in children. N Engl J Med
2009;361:1639e50.
Assadi F. Effect of microalbuminuria lowering on
regression of left ventricular hypertrophy in children
and adolescents with essential hypertension.
Pediatr Cardiol 2007;28:27e33.
Flynn JT, Daniels SR. Pharmacologic treatment of
hypertension in children and adolescents.
J Pediatr 2006;149:746e54.
Benjamin DK Jr, Smith PB, Jadhav P, et al. Pediatric
antihypertensive trial failures: analysis of end points
and dose range. Hypertension 2008;51:834e40.
607