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Pediatr Nephrol (2009) 24:11011112

DOI 10.1007/s00467-008-1000-1

REVIEW

Severe hypertension in children and adolescents:


pathophysiology and treatment
Joseph T. Flynn & Kjell Tullus

Received: 24 June 2008 / Revised: 18 August 2008 / Accepted: 19 August 2008 / Published online: 7 October 2008
# IPNA 2008

Abstract Severe, symptomatic hypertension occurs uncommonly in children, usually only in those with underlying congenital or acquired renal disease. If such
hypertension has been long-standing, then rapid blood
pressure reduction may be risky due to altered cerebral
hemodynamics. While many drugs are available for the
treatment of severe hypertension in adults, few have been
studied in children. Despite the lack of scientific studies,
some agents, particularly continuous intravenous infusions
of nicardipine and labetalol, are preferred in many centers.
These agents generally provide the ability to control the
magnitude and rapidity of blood pressure reduction and
shouldin conjunction with careful patient monitoring
allow the safe reduction of blood pressure and the
avoidance of complications. This review provides a
summary of the underlying causes and pathophysiology of
acute severe hypertension in childhood as well as a detailed
discussion of drug treatment and the optimal clinical
approach to managing children and adolescents with acute
severe hypertension.

J. T. Flynn
Pediatric Hypertension Program, Department of Pediatrics,
University of Washington School of Medicine,
Seattle, WA, USA
J. T. Flynn (*)
Division of Nephrology, A-7931,
Childrens Hospital & Regional Medical Center,
4800 Sand Point Way NE,
Seattle, WA 98105, USA
e-mail: joseph.flynn@seattlechildrens.org
K. Tullus
Great Ormond Street Hospital for Children,
Great Ormond Street,
London WC1N 3JH, UK

Keywords Children . Clonidine . Esmolol . Hydralazine .


Hypertension . Kidney disease . Labetalol . Nicardipine

Introduction
Hypertension in children and adolescents is defined as a
sustained systolic (S) and/or diastolic blood pressure (DBP)
elevation greater than or equal to the 95th percentile for
age, gender, and height [1]. Its severity can be further
classified according to the scheme in Table 1.
Severe hypertension, however, has not been as rigorously defined, which has led to some confusion with respect to
terminology. For the purposes of this review, severe
hypertension is defined as a BP elevation that fulfills (and
usually exceeds) the definition of stage 2 hypertension and
that is accompanied by severe symptoms; physical exam
and/or laboratory findings of accelerated hypertension are
frequently also present.
Severe hypertension has traditionally been divided into
hypertensive emergencies and hypertensive urgencies; the
former is associated with life-threatening symptoms and/or
target-organ injury, and the latter is associated with less
significant symptoms and no target-organ injury [2]. For
example, an adolescent with seizures and hypertensive
encephalopathy would be considered as experiencing a
hypertensive emergency, whereas a hypertensive child with
nausea and vomiting would be classified as a hypertensive
urgency. This distinction is not absolute and depends
somewhat on clinical judgment.
Peri-operative hypertension is commonly also classified
as a hypertensive urgency in order to emphasize the need
for prompt therapy to prevent complications [3]. Perhaps
the most significant aspect of any hypertensive urgency is

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Pediatr Nephrol (2009) 24:11011112

Table 1 Classification of normal and abnormal blood pressure in children and adolescentsa
Classification of blood pressure

SBP or DBP

Normal
Prehypertension
Stage 1 hypertension
Stage 2 hypertension

<90th percentileb
90th to <95th percentile, or if BP exceeds 120/80 in adolescents
95th percentile to 99th percentile plus 5 mmHg
>99th percentile plus 5 mmHg

SBP Systolic blood pressure, DBP diastolic blood pressure


a
Adapted from [1]
b
For age, gender, and height, as defined in [1]

that left untreated, as it may progress to a hypertensive


emergency, leading to more significant complications.
The above discussion aside, we feel that the confusion
regarding terminology/classification has received perhaps
too much emphasis in the hypertension literature. What is
most important is a careful assessment of patients presenting with severe hypertension, followed by the application
of meticulous treatment and monitoring. In this review, we
will briefly review the causes and pathophysiology of
severe hypertension in children and adolescents, review the
advantages and disadvantages of the drugs available to treat
severe hypertension, and then present a set of treatment
guidelines that should allow effective treatment of such
patients while avoiding complications.

Etiologies of severe hypertension in children and


adolescents
In a great majority of cases, hypertension in children has
traditionally been thought to be secondary to another
underlying disease. During the last decade, an increasing
proportion of children with hypertension has been found to
have primary hypertension that is in large part related to the
childhood obesity epidemic. In many centers, in particular
in the USA but less so in Europe, at least half of cases of
hypertension in older children are primary in origin [4].
Severe hypertension is, however, still in a large majority
of cases secondary, with renal disease being a predominant
cause (Table 2). Data to support this statement are
unfortunately limited. Deal et al. from Great Ormond Street
Hospital retrospectively reviewed their experience with
severe hypertension in children in 1992 [5]. The most
common causes of severe hypertension in their series
included reflux nephropathy, glomerular disease, renovascular disease, obstructive uropathy, and hemolytic-uremic
syndrome, which together accounted for 76% of the cases.
In a more recent, relatively large series of children with
severe hypertension treated with intravenous nicardipine
[6], causes included complications of organ transplantation,
multiorgan failure, renovascular disease, and acute renal
failure.

Severe fluid overload in dialysis patients (see below) or


non-compliance with antihypertensive therapy in patients
with established hypertension of any cause may also result
in severe, symptomatic hypertension requiring immediate
treatment. This was highlighted in a recent case series of
adults presenting to the Emergency Department of a
teaching hospital in the USA [7]. In that study, 90% of
patients requiring intervention for a hypertensive urgency
had a known diagnosis of hypertension; the most common
contributing factors to the severe BP elevation included
running out of prescribed medications and medication noncompliance. While no similar pediatric data exist, in our
judgment, this is not an infrequent situation in the young as
well, particularly for hypertensive children and adolescents
followed at referral centers. Finally, abrupt withdrawal of
either clonidine or a beta-adrenergic blocker may result in
severe rebound hypertension that may require prompt
intervention.

Table 2 Causes of severe hypertension in children and adolescents


Renal disease
Glomerulonephritis, especially membranoproliferative GN
Reflux nephropathy
Obstructive uropathy
Acute renal failure
Polycystic kidney disease
End-stage renal disease at presentation
Malignancy
Pheochromocytoma
Wilms tumor
Neuroblastoma
Vascular
Aortic coarctation (thoracic, abdominal)
Renal artery stenosis
Hemolytic-uremic syndrome
Other
Medication non-compliance in a patient with known
hypertension
Illicit substances (cocaine, MDMA)
Rapid withdrawal of clonidine or beta-adrenergic blockers
GN Glomerular nephritis, MDMA 3,4 methylenedioxymethamphetamine (Ecstacy)

Pediatr Nephrol (2009) 24:11011112

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Clinical presentation
Children with severe hypertension can present in many
different ways (Table 3). Some present with very severe
symptoms from heart failure or a cerebral insult, while
others are totally asymptomatic. The urgency to bring down
the BP will obviously also be influenced by the mode of
presentation. For example, we have seen a number of
children presenting with a systolic BP of 200 mmHg or
more which has been documented for many months and
occasionally several years that are still totally asymptomatic
when they come to us. These children clearly need their BP
lowered, but the urgency to do so is not as great as in
symptomatic children.
Children presenting with severe symptoms need to be
treated much more rapidly. However, it may be risky to
lower the BP too rapidly, especially in those whose
hypertension has been long-standing. In such patients, a
shift in cerebral autoregulation occurs (Fig. 1), which in the
hypertensive state protects the brain from excessive
perfusion [8]. A too rapid lowering of the BP in patients
with such alterations of cerebral flow might lead to
ischemic stroke from underperfusion of the brain. Unfortunately, little data are available to guide practitioners on the
safest rate of BP reduction in such patients. Based upon our
combined clinical experience and synthesis of available
data in adults, we normally recommend that the BP should
be reduced by 25% of the planned BP reduction over first
812 h, a further 25% over the next 812 h, and the final
50% over the 24 h after that.
Physical exam findings of accelerated hypertension (for
example, papilledema, congestive heart failure, pulmonary
edema) are usually only seen in hypertensive emergencies.
Additionally, many children with severe hypertension will
at presentation have signs of hypertensive end-organ
damage. In a group of 33 children with severe hypertension
needing angioplasty, we found evidence of left ventricular
hypertrophy in 22 children (66%), with three (9%) patients
in congestive cardiac failure [9]. Hypertensive retinopathy
was present in ten (33%) children at presentation.

Hypertensive encephalopathy is a very severe complication seen in some children with severe hypertension. This
condition is caused by a failure of the upper limit of the
autoregulation of cerebral blood flow (Fig. 1), which leads
to cerebral hypoperfusion. Seizures can be presenting
symptoms and also lethargy, confusion, headache, and
visual disturbances, including blindness [10]. Magnetic
resonance imaging will demonstrate characteristic findings
of posterior leucoencephalopathy predominantly affecting
the parieto-occipital white matter [11]. These findings are
potentially totally reversible after correction of the
hypertension.

Pathophysiology
Blood pressure is a function of cardiac output and
peripheral resistance. Several different pathophysiologic
mechanisms can lead to severe hypertension. Increased
cardiac output can be caused by increased stroke volume
and increased heart rate. The stroke volume is, among other
things, influenced by the extracellular fluid volume. We
will discuss these in this section and also emphasize
mechanisms that are most important in the development
of severe hypertension.
Reninangiotensin system
Renin is secreted from the juxtaglomerular apparatus in the
kidneys. It cleaves angiotensinogen to the deca-peptide
angiotensin I. Angiotensin-converting enzyme (ACE) then
converts angiotensin I further to the active component
angiotensin II (AII), which can cause hypertension through
several mechanisms [12]. Angiotensin II is a potent
vasoconstrictor agent through its binding to the angiotensin
II receptor I (AT 1). This binding also promotes several
other processes that cause hypertension, including include
sodium retention, vascular cell hypertrophy, and the
induction of several proinflammatory and profibrotic pathways. Polymorphisms of this receptor seem to be related to

Table 3 Presenting features in children with severe hypertension


(modified from [7])
Mode of presentation

Number

Incidental
Cardiac (congestive cardiac failure, palpitations, murmur)
Headache vomiting lethargy
Acute hypertensive encephalopathy
Cerebrovascular accident
Facial palsy
Poor feeding and failure to thrive
Other

9
7
6
3
2
2
2
2

Fig. 1 Altered cerebral autoregulation in chronic hypertension

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an increased risk, at least in adult patients, to develop


hypertension.
Angiotensin II also binds to another receptor, AT 2. This
binding produces effects that counteract those of AT 1, such
as vasodilation and natriuresis, among others, and this
binding thus reduces the BP. Angiotensin II also induces
the synthesis of aldosterone in the zona glomerulosa of the
adrenals, in various parts of the vascular tree (endothelial
cells and vascular smooth muscle cells), and in parts of the
brain. Aldosterone induces sodium retention and potassium
excretion and thus increases the circulating blood volume.
The sympathetic nervous system can be activated by
aldosterone. There is also evidence that AII has toxic
effects on the vessel wall via its proinflammatory action
[13].
High renin and high aldosterone levels have been found
to be the cause of hypertension in many kidney diseases,
but they are of particular importance in renovascular
hypertension. The underlying mechanism of the increased
secretion is often glomerular underperfusion, but reduced
sodium load or stimulation from the sympathetic nervous
system may also play a role.
Renin seems to be of particular importance in the
development of severe hypertension and the endothelial
dysfunction seen in such cases, as evidenced in animal
models. Rats that express the mouse renin gene Ren-2,
rapidly develop malignant hypertension compared to rats
from the same background population [14]. When such rats
were treated with an ACE inhibitor (I), only 4% developed
severe hypertension compared to 63% of the non-treated
controls [15]. Significantly less evidence of tissue injury,
such as intimal fibrosis, fibrinoid necrosis, and nephron
damage, was observed in the ACEi-treated group, and the
mortality among these treated rats was reduced to 4%
compared to 25% in the non-treated controls.
Fluid overload
Fluid overload is the most common mechanism leading to
hypertension in children with renal diseases. It is often
caused by acute renal failure with oliguria or anuria. Renindependent increased production of aldosterone and AIIstimulated sodium retention are also very important
contributors to the fluid overload. Increased vasopressin
levels can sometimes be found in patients with severe
hypertension and may indeed aggravate the hypertension
[16].
In children on dialysis, fluid overload is probably the
most important contributing factor to episodes of severe
hypertension. Fluid overload in dialysis patients often
results from poor adherence to dietary sodium and fluid
restrictions. Chronic under-dialysis and failure to consistently reach dry weight may lead to gradual fluid

Pediatr Nephrol (2009) 24:11011112

accumulation that can be clinically imperceptible until the


child presents with a hypertensive crisis. This may happen
even in the best dialysis center due to the difficulty in
assessing the fluid status in children and also because
differences in body weight may be attributed to growth
instead of to fluid accumulation.
Sympathetic stimulation
The sympathetic nervous system can be the main cause of
severe hypertension. This is particularly seen in children
with pheochromocytomas and other tumors that produce
vasoactive substances, including neuroblastoma [17]. Hemodialysis can contribute to a substantial increase in
catecholamines and also of renin, which in turn can
contribute to hypertension [18]. Increased sympathetic
activity can worsen severe hypertension in several conditions, including renovascular hypertension and polycystic
kidney disease, and seems to be unrelated to kidney
function. Renal ischaemia triggered by these diseases seems
to cause the systemic over-activation [19]. Activation of the
sympathetic nervous system leading to systemic vasoconstriction is generally accepted as the mechanism of severe
post-operative hypertension [3].
Other vasoactive systems may also be important in the
development of severe hypertension. Conflicting data are
found regarding the importance of endothelin [20]. Reduced levels of nitric oxide have been reported to contribute
to the hypertension, especially in the presence of renal
impairment [21].
Endothelial dysfunction
The endothelium seems to play a crucial role in the
development of severe symptomatic hypertension. Angiotensin II has many effects on the blood vessel wall that
result in endothelial dysfunction with a shift of endothelial
action toward reduced vasodilatation, a proinflammatory
state, and prothrombotic properties [22]. The mechanisms
that participate in the reduced vasodilatory response
include reduced nitric oxide generation and an oxidative
excess. The compensatory vasodilatation that occurs in
response to the raised blood pressure becomes overwhelmed, which leads to decompensation of the endothelium and a further rise of the blood pressureand a vicious
circle develops.
It has been shown in rats that AII mediates many of its
different actions over several transcription factors, most
notably NF-B. This transcription factor promotes the
production of a large number of proinflammatory molecules, including proinflammatory cytokines such as several
interleukins and tumor necrosis factor-, chemokines such
as MCP1, and vascular adhesion molecules. These all act in

Pediatr Nephrol (2009) 24:11011112

concert promoting inflammation of the blood vessel wall


[23]. Double transgenic rats with both the renin and
angiotensin genes have increased activation of NF-B and
marked renal and cardiac end-organ damage. When they
were treated with a substance that inhibits NF-B, their
blood pressure decreased significantly and so did their
cardiac hypertrophy index and 24-h proteinuria [24]. A
40% 7-week mortality in the untreated rats was also
prevented. Signs of an inflammatory response were also
attenuated; monocyte and macrophage infiltration in
kidneys and the heart was also reduced by 72 and 64%,
respectively. Findings in adult patients with malignant
hypertension also reveal endothelial activation; these
patients exhibit higher serum levels of both soluble Pselectin and von Willebrand factor [25].

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longer have patent protection and are unlikely to ever get


pediatric labeling [33].
Recent government initiatives in both the USA and
Europe offer the hope of improving this situation. Both the
FDA in the USA and the European Medicines Agency now
provide incentives to manufacturers to conduct clinical
trials of medications in children; this may result in new
pediatric labeling for the medications studied [33, 34].
Additionally, in the USA, the Best Pharmaceuticals for
Children Act [35] also provides a mechanism for studying
medications in children that no longer have patent
protection. With respect to medications for severe hypertension, there is now ongoing a study of intravenous
nitroprusside [ClinicalTrials.gov Identifier: NCT00135668]
that should provide important data regarding the efficacy
and safety of this agent in children.

Medications and other substances


There are numerous medications and other substances that
can acutely elevate blood pressure by a variety of
mechanisms. Although relatively uncommon in the pediatric age group, the ingestion of recreational drugs, such as
cocaine, amphetamine, or phencyclidine, can produce
severe acute hypertension via sympathetic overstimulation
[2]. Immunosuppressive medications used in solid organ
transplantation, specifically corticosteroids and calcineurin inhibitors, may also result in relatively severe
hypertension requiring prompt intervention [10]. Fluid
overload, activation of the reninangiotensin system, and
afferent glomerular arteriolar vasoconstriction are among
the medication-related mechanisms at play in such patients
[26]. For a more complete discussion, the interested reader
is referred to recent reviews on this topic [27].

Drugs used to treat severe hypertension


Availability of drugs with established efficacy in children
Therapeutic options for pediatric patients requiring treatment for severe hypertension are significantly limited: only
half of the intravenous antihypertensive medications currently marketed in the USA have pediatric labeling
approved by the Food and Drug Administration (FDA)
(Table 4). Of those agents with approved pediatric labeling,
one is no longer in routine use (diazoxide), and another was
demonstrated to have limited efficacy in children compared
to adults (fenoldopam) [28]. Because of this, practitioners
who care for children with severe hypertension have had to
use unapproved medications on an off-label basis. The
many recent reports of pediatric use of nicardipine [4, 29
32] are a salient example of this phenomenon. Another
example is the widespread use of medications that no

Intravenous agents currently used in children with severe


hypertension
A variety of intravenous antihypertensive agents are currently in widespread use for emergency reduction of acute
hypertension in children, including sodium nitroprusside,
labetalol, nicardipine, hydralazine, diazoxide, and esmolol.
Enalaprilat, the intravenous formulation of the ACE inhibitor
enalapril, has been utilized to a more limited degree in this
setting as well. Each of these agents has unique properties
and adverse effects that practitioners should be aware of.
Sodium nitroprusside is a direct vasodilator of both
arteriolar and venous smooth muscle cells. It is metabolized
to nitric oxide, which dilates both arterioles and venules,
resulting in both a reduced total peripheral resistance and
reduced venous return, thus decreasing both preload and
afterload. For this reason, this agent can be used in severe
congestive heart failure as well as in patients with severe
hypertension [36]. Nitroprusside has a rapid onset of action,
12 min, and a plasma half-life of <10 min, enabling it to
achieve rapid changes in blood pressure.
The metabolism of nitroprusside accounts for its primary
toxicity, cyanide accumulation, which results from the
conversion of nitroprusside to cyanide and thiocyanate.
The risk of toxicity increases after 2448 h or in patients
with renal insufficiency. While co-administration with
thiosulfate can be utilized to minimize this problem, most
authorities recommend that its use be limited to situations
where no other suitable agents are available or to brief
periods of time [2]. However, in addition to cyanide
accumulation, tachyphylaxis may develop with prolonged
use, making it necessary to switch to other agents when
prolonged treatment of hypertension is needed.
Labetalol is a combined 1 and -adrenergic blocking
agent that can be administered either orally or intravenously.
Due to its capacity to block 1 receptors, it produces

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Pediatr Nephrol (2009) 24:11011112

Table 4 Pediatric labeling status of intravenous antihypertensives


Agent

FDA-approved
pediatric label?

Label information on pediatric use

Reference

Diazoxidea

Yes

Package insert (Schering Corp.,


Kenilworth, NJ)

Enalaprilat

No

HYPERSTAT IV Injection is indicated for short-term use in the


emergency reduction of blood pressurein acute severe hypertension
in hospitalized children, when prompt and urgent decrease of diastolic
blood pressure is required.
Safety and effectiveness in children have not been established.

Esmololb

No

The safety and effectiveness of BREVIBLOC (Esmolol Hydrochloride)


in pediatric patients have not been established.

Fenoldopamc

Yes

Fenoldopam is indicated for the in-hospital, short-term (up to 4 hours)


reduction in blood pressure.

Hydralazine

Yes

Labetalol

No

Safety and effectiveness in pediatric patients have not been established


in controlled clinical trials, although there is experience with the use
of hydralazine hydrochloride in children. The usual recommended
parenteral dosage, administered intramuscularly or intravenously, is
1.73.5 mg/kg of body weight daily, divided into four to six doses.
Safety and effectiveness in children have not been established.

Nicardipine

No

Safety and efficacy in patients under the age of 18 have not been
established.

Sodium
nitroprussided

Yes

Contains weight-based dosing recommendations for patients 10 kg

Package insert (Merck & Co.,


West Point, PA)
Package insert (Baxter
Heathcare Corp., New
Providence, NJ)
Package insert (Abbott
Laboratories, North Chicago,
IL)
Package insert (American
Regent, Inc., Shirley, NY)

Package insert (Bedford


Laboratories, Bedford, OH)
Package insert (PDL
BioPharma, Redwood City,
CA)
Package insert (Hospira, Inc.,
Lake Forest, IL)

FDA, Food and Drug Administration


No longer recommended for use in children [1]
b
Pediatric trial completed but no pediatric labeling has been approved by FDA
c
Pediatric trial demonstrated relatively poor efficacy in children compared to adults [20]
d
Pediatric trial currently underway
a

vasodilatation; hemodynamic studies have demonstrated that


labetalol lowers peripheral resistance with little or no effect
on cardiac output. Administered intravenously, it is this
vasodilatation which accounts for labetalols efficacy in the
treatment of severe hypertension. The hypotensive effects of
a single dose of intravenous labetalol appear within 25 min
after administration, peak at 515 min, and last up to 24 h.
Intravenously administered labetalol has been extensively
studied in adults with severe hypertension [37], and case
series of successful use in children with severe hypertension
have been published [5, 38]. Adverse reactions are those
expected from a beta-adrenergic blocker, including bradycardia and bronchospasm. It is contraindicated in patients
with acute left ventricular failure. Intravenous labetalol can
be administered as a continuous infusion or by bolus
injection; repeated dosing of small doses has also been
described in adults and may be appropriate in selected
clinical settings, such as the Emergency Department [37].
Conversion to oral dosing is relatively straight-forward, but
the clinician should be aware that the alpha-to-beta blocking
ratio of the oral preparation is 1:3, whereas it is 1:7 for the
intravenous preparation.

Nicardipine is a second-generation dihydropyridine


calcium channel blocker that has been shown to be an
effective antihypertensive agent in numerous studies in
adults, comparing favorably to nitroprusside in terms of
overall efficacy [39]. It has high vascular selectivity and
strong cerebral and coronary vasodilatory activity; the latter
property probably accounts for its favorable effects on
myocardial oxygen balance. The initial onset of nicardipine
given intravenously occurs within 1 min, and the duration
of action after a single intravenous dose is approximately
3 h. Upon termination of infusions of nicardipine, plasma
concentrations rapidly decline, with at least a 50% decrease
during the first 2 h.
Many pediatric case series of intravenous nicardipine use
have been published [6, 2932]; in all of these, it has been
reported to be effective and well-tolerated. A multicenter trial
of intravenous nicardipine in hypertensive children that had
been initiated (ClinicalTrials.gov Identifier: NCT00528827)
was unfortunately recently terminated due to the sale of the
drug by the sponsor of the trial. Common adverse reactions
include phlebitis at the site of administration and tachycardia
which usually is not clinically significant. The conversion of

Pediatr Nephrol (2009) 24:11011112

nicardipine infusions to oral dosing has been reported in


adults [40], but no such data exist for children.
Hydralazine is a direct vasodilator of arteriolar smooth
muscle with an unclear mechanism of action, most likely an
alteration of intracellular calcium metabolism, leading to
interference with the calcium movements within the vascular
smooth muscle that are responsible for initiating or maintaining the contractile state. It does not affect coronary
arteries or venous smooth muscle, but its effects on arteriolar
smooth muscle stimulates the sympathetic nervous system,
leading to tachycardia, increased renin activity, and sodium
retention [41]. The average maximal decrease in blood
pressure usually occurs 1080 min after intravenous administration. An advantage of hydralazine compared to other
agents discussed herein is that it can be administered
intramuscularly, which can be useful in situations when
there is an immediate need to lower blood pressure but the
patient does not yet have intravenous access established.
Patients treated with intravenous hydralazine can be easily
converted to oral dosing; additionally, oral hydralazine may
be useful in patients with less severe hypertension who are
able to tolerate oral drugs. When administered orally,
hydralazine has an onset of action of 30 min to 2 h and an
unpredictable duration of action of 612 h. However,
prolonged treatment with hydralazine may be difficult to
maintain in young children given the limited stability of
extemporaneous suspensions of hydralazine [42].
Diazoxide is another direct vasodilator that acts by
increasing the permeability of the vascular smooth muscle
cell membrane to potassium ions. This increased permeability switches off voltage-gated calcium ion channels,
which in turn inhibits the generation of an action potential
[43]. Diazoxide has a long history of use for the treatment
of hypertensive emergencies in adults and has been utilized
in children with severe hypertension for many years as
well. In a multicenter study of 36 children with severe
symptomatic hypertension (BP >100 mmHg) of various
causes, mostly parenchymal renal disease, McCrory and
colleagues demonstrated that intravenous diazoxide
promptly reduced systolic and diastolic BP without significant adverse effects [44]. Reductions of about 2327% for
SBP and 3242% for DBP were achieved with initial
dosing; the BP subsequently rose slightly, but BP reduction
was sustained for about 6 hours. Diazoxide was successful
in 94% of the patients, including those who had failed prior
treatment with other agents. Diazoxide is rapidly and
extensively protein bound, so rapid injection is necessary.
However, the rapid injection of large bolus doses of
diazoxide can produce significant hypotension, so a
mini-bolus dosing regimen (doses of 13 mg/kg repeated
at intervals of 515 min) is currently recommended [45].
The duration of BP reduction produced by diazoxide can be
unpredictable, so repeat doses may be needed. Diazoxide

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can also transiently increase blood glucose levels [43], but


this is rarely a significant concern except in diabetics.
Esmolol is an ultra-short acting, cardioselective -1
adrenergic blocker that is particularly well-suited for the
management of intra-operative hypertension due to its rapid
onset of action (approx. 60 s) and relatively short duration
of action (1020 min) [36]. Esmolol pharmacokinetics have
been studied in children and are no different than in adults
[46]. Its rapid metabolism by an intracytoplasmic red blood
cell esterase is independent of both renal and hepatic
metabolism, making it potentially well-suited for critically
ill patients with multiorgan failure. It is typically administered by continuous infusion after an initial loading bolus
dose. One clinical trial of esmolol in hypertensive children
has been conducted to date: 118 children (neonates through
to 6-year-old children) with intraoperative and postoperative hypertension associated with repair of coarctation of
the aorta received one of three doses of esmolol (125, 250
or 500 g/kg per min, after respective loading doses of 125,
250 and 500 g/kg). The results showed a decrease in SBP
in all three dose groups, but there was no statistically
significant difference between groups in either the change
from baseline or percent change from baseline [28]. Despite
the lack of dose-response in the clinical trial setting, it is
likely that esmolol can be effectively titrated to achieve
control of BP in children with severe hypertension.
The final intravenous agent that has found use in
hypertensive children is enalaprilat, the only available
intravenous ACE inhibitor. With the exception of patients
with volume depletion, enalaprilat is reported to rapidly
lower BP without causing severe hypotension, and it is felt
to be especially effective in patients with renin-dependent
forms of hypertension [45]. There is one case series of
pediatric enalaprilat use [47] in which ten premature
neonates received doses of enalaprilat ranging from 7.4
22.9 g/kg per 24 h. Enalaprilat reduced mean arterial
pressure within 30 min of administration and remained
effective for a median of 12 h. Adverse effects included
prolonged hypotension, prolonged oliguria, and one case of
reversible acute renal failure. Although no correlations with
renal function or plasma renin activity were demonstrated,
these are the likely contributing factors, given the age of the
patients studied. Despite the reported efficacy of enalaprilat
in adults, the lack of pediatric data and the high incidence
of renovascular hypertension make us reluctant to recommend enalaprilat in children with severe hypertension.
Oral agents of potential use in children with severe
hypertension
Clonidine is a centrally-acting 2-adrenergic agonist that
reduces BP by reducing cerebral sympathetic output.
Compared to other centrally acting agents, it has a relatively

1108

rapid onset of effect, approximately 1530 min following


oral administration [48], making it attractive for use in the
management of acute hypertension. In adults, an initial dose
of 0.10.2 mg pf clonidine followed by repeated hourly
doses of 0.050.1 mg until the goal BP has been reached is
reportedly successful in managing urgent hypertension [48].
Although publications on the pediatric use of clonidine
have been limited to the treatment of chronic primary
hypertension [49], we have found it extremely useful in the
acute setting, particularly in hemodialysis patients, perhaps
due to the fact that it is minimally removed by hemodialysis
and does not require dose adjustment in renal failure [48].
Somnolence and dry mouth are the most common adverse
effects of clonidine, but these may be a relatively minor
consideration in the setting of severe hypertension, as other
agents can be used for chronic management of these
symptoms.
Isradipine is a second-generation dihydropyridine calcium channel blocker with a high specificity for the L-type
calcium channels found on vascular smooth muscle cell
membranes. It has a rapid onset of action, usually
producing BP within 1 h of administration, with its peak
effect occurring in 23 h [39]. Although the short-acting
formulation of isradipine is marketed as a twice-daily
medication, the rapid metabolism of isradipine, especially
in young children, usually necessitates three or even four
doses daily. A stable extemporaneous suspension of
isradipine can be compounded [50], thereby facilitating
precise dosing, even in infants and small children. Several
case series of isradipine use in chronic pediatric hypertension have been published [51, 52] that demonstrate its
efficacy even in children with secondary forms of hypertension. One study in adults [53] demonstrated that
isradipine is effective in the acute treatment of severe
hypertension; while no data for pediatric patients describing
such use are available, anecdotal experience indicates that
isradipine is extremely useful in children with severe
hypertension, and in one of the authors centers (JTF),
isradipine has become the drug of choice for oral therapy of
severe hypertension.
Minoxidil is a direct vasodilator that, like diazoxide,
opens potassium channels in smooth muscle cells, causing
potassium efflux, which in turn leads to hyperpolarization
and relaxation [43]. This drug acts primarily on arterioles
and does not produce venous dilatation. Minoxidil generally acts within 1 h, and its effects may last as long as 8
12 h. It is renally excreted and easily removed by dialysis;
therefore, dose adjustment may be needed in patients with
severe renal insufficiency, and it should be dosed after
dialysis [43]. Minoxidil has been shown to be effective in
children with severe chronic hypertension refractory to
other oral agents [54], and also in children with chronic
hypertension experiencing acute BP elevations [55]. It has

Pediatr Nephrol (2009) 24:11011112

well-known side effects of hirsutism and fluid retention that


are primarily seen with chronic use.
New agents for severe hypertension
Fenoldopam is a dopamine D1-like receptor agonist that
also binds to 2-adrenoceptors but not to other vascular
receptors, including D2-like receptors, 1 and adrenoceptors, 5HT 1 and 5HT 2 receptors, and muscarinic
receptors. Fenoldopam has been shown to have vasodilating effects in coronary, renal, mesenteric, and peripheral arteries and, when administered intravenously,
produces dose-dependent reductions in BP [56]. Fifty
percent of the maximal effect of fenoldopam is seen within
15 min after commencing an intravenous infusion, with
maximal BP reduction occurring at about 1 h. Studies in
adults have demonstrated a comparable efficacy of
fenoldopam and nitroprusside in various clinical settings,
including patients with severe hypertension and postoperative hypertension. One pediatric trial of fenoldopam
has been conducted; in this study, 77 children aged
1 month to 12 years of age undergoing surgical procedures
requiring controlled hypotension received one of four
doses of fenoldopam (0.05, 0.2, 0.8 or 3.2 g/kg per min).
According to the FDA analysis of the trial results [28],
fenoldopam produced modest reductions in DBP/SBP of
8.4 to 5.8/9.2 to 7.6 mmHg, with an increase in heart
of 12.5 to 20 beats per minute. The magnitude of the BP
reduction produced by fenoldopam was felt to be
significantly smaller than that reported in published
studies in adults.
Clevidipine is a recently developed, ultra-short-acting
dihydropyridine calcium channel antagonist with a high
specificity for vascular smooth muscle. Unlike oral dihydropyridine calcium channel antagonists, such as amlodipine, that have long durations of action, clevidpine
administration lowers the BP within 2 min after initiation
of a continuous infusion and has a rapid offset once
infusion is discontinued, with a half-life of just a few
minutes [57]. This makes its pharmacokinetics similar to
those of sodium nitroprusside; indeed, comparative studies
of clevidpine and sodium nitroprusside in adults following
coronary artery bypass have confirmed a similar clinical
efficacy of these two agents [58]. Clevidipine may be
superior to both sodium nitroprusside and to intravenous
nicardipine due to its decreased tendency to produce
tachycardia compared to nitroprusside and its more rapid
offset of action compared to nicardipine. Although originally developed for the control of BP during surgical
procedures, it is probable that clevidipine may also find a
role in the management of hypertensive emergencies.
Pediatric studies of clevidipine are anticipated to begin
within the next few years.

Pediatr Nephrol (2009) 24:11011112

Urapidil is a peripheral postsynaptic alpha-adrenoceptor


antagonist with a central agonistic action at serotonin 5-HT
receptors [59]. It reduces BP by decreasing peripheral
vascular resistance. Intravenous urapidil reduces BP in
patients with pre-eclampsia or hypertension in pregnancy
and in patients with hypertensive crises or peri- or
postoperative hypertension. The decrease in BP in adults
is similar to that observed after other intravenous antihypertensives, including enalaprilat, sodium nitroprusside,
and hydralazine. It has been shown to have an efficacy
equivalent to oral captopril in the Emergency Department
setting [60]. The heart rate is less likely to be altered by
urapidil than with some comparator drugs. At present, there
is no published pediatric experience with urapidil.

Approach to management in ambulatory and inpatient


settings
The child with acute severe hypertension requires prompt
evaluation and therapy in order to avoid the development of
the complications discussed earlier in this article. In most
such children, the underlying diagnosis will be obvious
from the medical history. In a child who is already
hospitalized, sufficient information can usually be gleaned
by review of the medical record. Similarly, for children
with a prior known history of hypertension or other
conditions predisposing to the development of severe
hypertension, little additional information will be needed
other than determining the severity of symptoms the patient
is experiencing, as this will guide treatment. For patients
newly presenting with severe hypertension who have no
prior history, then in addition to assessing symptom
severity, questions will need to be asked regarding the
onset of symptoms as well as recent and past medical
history, focusing on eliciting clues to the conditions listed
in Table 2.
Usually only a brief physical examination is necessary in
evaluating children with acute severe hypertension. It is
important to confirm that the BP has been accurately
measured. The examination should then focus on an
assessment of volume status, cardiac status, and neurologic
status. Other parts of the examination will help to narrow
the differential diagnosis in those children without prior
histories of hypertensionfor example, the presence of an
abdominal mass in a young child with severe hypertension
could be a clue to the presence of a Wilms tumor. For a
more detailed discussion of physical exam findings in
childhood hypertension, the interested reader is referred to
more comprehensive references [1].
Extensive diagnostic studies will not be necessary in
most patients, but laboratory assessment of renal function,
urinalysis (if possible), electrolyte determination, and an

1109

assessment of cardiopulmonary status by chest X-ray and/or


echocardiography should be obtained. Renal or abdominal
ultrasonography may be helpful in confirming the findings
on physical examination but usually can be deferred until
the BP has been lowered to a safe level. Other diagnostic
studies suggested by the physical examination or initial
laboratory tests can also be obtained at a later stage of
management.
A decision will need to be made quite early in the
patients clinical course as to how rapidly to lower the BP,
what the goal BP should be, and whether to pursue the goal
BP with either parenteral or oral medications. There are
advantages and disadvantages to each potential route of
administration. For example, intravenous agents can be
easily titrated to the desired effect, but their use requires a
certain degree of skill that may not be available in all
clinical settings. Oral agents are certainly easier to
administer, but their onset of action and magnitude of
effect can be unpredictable. In our collective experience,
the intravenous route is preferred in the majority of children
with severe hypertension. For some patients, the choice of
route will be obviousan example is the child with
hypertensive encephalopathy whose level of consciousness
is waxing and waning. Similarly, those symptomatic
children that require slow reduction of BP are best treated
with an intravenous infusion of one of the agents discussed
previously that can be titrated to the desired effect. A
proposed algorithm for initial management is outlined in

Severe Acute
Hypertension

Life-Threatening
Symptoms
(Seizures, CHF, etc)

Minor Symptoms
(Nausea, Headache,
Vomiting)

Hypertensive
Emergency

Hypertensive
Urgency

Bolus dose of IV
hydralazine or labetalol
followed by nicardipine
or labetalol infusion

Able to tolerate PO
medication:
Isradipine or clonidine

Unable to tolerate PO
medication:
IV hydralazine or
labetalol

Fig. 2 Proposed algorithm for initial management of children with


severe hypertension. CHF Congestive heart failure, IV intravenous,
PO oral

1110

Pediatr Nephrol (2009) 24:11011112

Fig. 2. Suggested doses for intravenous agents useful in


managing patients with severe hypertension can be found in
Table 5.
Oral agents may be appropriate in selected circumstances, usually in patients without severe (especially
central nervous system) symptoms and in those who do
not need as rapid a reduction in BP. Given the frequency of
volume overload as the basis for acute severe hypertension,
almost all oral agents useful in managing patients with
severe hypertension are vasodilators. In addition to the
agents listed in Table 5, other oral antihypertensive
medications that have been reported to be effective in acute
hypertension include captopril, hydralazine, labetalol, and
prazosin. The interested reader should consult more
comprehensive references for dosing guidelines for these
other drugs.
Whatever route of administration is selected, ongoing
monitoring of BP is of crucial importance in management.
For the severely symptomatic patient, continuous intra-

arterial BP monitoring is appropriate. If an arterial access


cannot be established, an acceptable alternative is to use
an oscillometric device programmed to take BP every
12 min. Although such devices have well-known shortcomings, one of their advantages is that they accommodate to the patients BP when used for repeated readings,
so they are extremely useful for following trends in BP over
time. Oscillometric devices are also suitable for less
severely ill patients on the inpatient ward or Emergency
Department, where they again can be programmed to take
repeated measurements of BP at short intervals. Finally, in
some situations, manual BP measurement every 515 min
may also be appropriate, depending on the patients clinical
status.
Finally, once the patients severe hypertension has been
brought under control and the initial target BP reached, the
institution of chronic oral antihypertensive treatment can be
initiated. As discussed above, several of the drugs considered useful for the management of severe hypertension

Table 5 Antihypertensive drugs for management of severe hypertension in children 117 yearsa
Drug

Class

Dose

Useful for severely hypertensive patients with life-threatening symptoms


Esmolol
-adrenergic
100500 mcg/kg per min
blocker
Hydralazine
Direct vasodilator
0.20.6 mg/kg per dose
Labetalol

Nicardipine
Sodium
Nitroprusside

- and adrenergic
blocker
Calcium
channel blocker
Direct vasodilator

Bolus: 0.201.0 mg/kg per dose, up to


40 mg/dose
Infusion: 0.253.0 mg/kg/hr
Bolus: 30 mcg/kg up to 2 mg/dose
Infusion: 0.54 mcg/kg per min
0.510 mcg/kg per min

Useful for severely hypertensive patients with less significant symptoms


Clonidine
Central -agonist
0.050.1 mg/dose, may be repeated up
to 0.8 mg total dose
Enalaprilat
ACE inhibitor
0.050.10 mg/kg per dose up to 1.25
mg/dose

Route

Comments

IV infusion

Very short-actingconstant infusion


preferred. May cause profound bradycardia
Should be given every 4 h when given IV
bolus
Asthma and overt heart failure are relative
contraindications

IV, IM
IV bolus or
infusion
IV bolus or
infusion
IV infusion

May cause reflex tachycardia

PO

Side effects include dry mouth and drowsiness

IV bolus

May cause prolonged hypotension


and acute renal failure, especially in
neonates
Produced modest reductions in BP
in a pediatric clinical trial in patients
up to 12 years
Extemporaneous suspension stable for only 1
week
Stable suspension can be compounded

Fenoldopam

Dopamine
receptor agonist

0.20.8 mcg/kg per min

IV infusion

Hydralazine

Direct vasodilator

0.25 mg/kg per dose up to 25 mg/dose

PO

Isradipine

Calcium channel
blocker
Direct vasodilator

0.050.1 mg/kg per dose up to 5 mg/


dose
0.10.2 mg/kg per dose up to 10 mg/
dose

PO

Minoxidil

PO

ACE Angiotensin-converting enzyme, IM intramuscular, IV intravenous, PO oral.


a
Adapted from [1]

Monitor cyanide levels with prolonged (>72 h)


use or in renal failure; or
co-administer with sodium thiosulfate

Most potent oral vasodilator;


long-acting

Pediatr Nephrol (2009) 24:11011112

have oral counterparts, and patients can be converted from


the intravenous to the oral formulation. In many cases,
intravenous and oral treatment will need to be overlapped
for several days until steady control with oral medications
can be achieved. This time interval can also be utilized for
the completion of any portions of the patients diagnostic
evaluation that had to be deferred initially.

1111

12.

13.

14.

Conclusion
Severe hypertension is a potential medical emergency that
needs to be addressed immediately. After a brief evaluation
of the possible etiology, antihypertensive treatment should
be initiated. This is mostly done with intravenous agents, of
which a number of options, albeit many not documented in
children, exist. The aim is to gradually normalize BP in 2
3 days and after that switch to oral treatment.

15.

16.

17.

18.
Statement of Disclosure Joseph Flynn is a consultant to Boehringer
Ingelheim Pharmaceuticals, Novartis Pharmaceuticals, and Pfizer, Inc.
Kjell Tullus has no consulting relationships to disclose.

19.

20.

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