Pediatr Nephrol (2U00) © IPNA 2()()0

PRACTICAL PKDIATRIC NEPHROLOGY

Joseph T. Flynn

Neonatal hypertension: diagnosis and management

Received: 20 April 1999 / Revised: 2 August 1999 / Accepted: 13 August 1999

Abstract Hypertension in the term or preterm neonate tice of neonatology in general, have lead to an increased
may be seen in up to 2% of all infants cared for in the awareness of hypertension in modem neonatal intensive
modern neonatal intensive care unit. Although the defini- care units (NICUs). Since most hypertension in infants is
tion of hypertension in this age group has not been cotn- related to renovascular or renal parenchymal disease |2.
pleteiy standardized, recent studies have provided new 3|, the evaluation and management of neonatal hyperten-
normative data that may be used to facilitate identifica- sion frequently requires the expertise of a pediatric neph-
tion of such infants. Common causes of hypertcn.sion in rologist. This review will focus on Ihe differential diag-
neonates include thromboembolic events related to um- tiosis of hypertension in the neonate. the optimal diag-
bilical catheterization. congenital problems such as aor- nostic evaluation, and both acute and chronic antihyper-
tic coarctation. staictural renal malformations and reno- tensive therapy.
vascular disease, as well as acquired renal disease and
certain medications. A careful history and physical ex-
amination will usually identify the probable cause in
Definition and incidence of neonatal hypertension
nujst cases without Ihc need for extensive laboratory or
radiologic testing. Therapy of neonatal hypertension
Defining what is considered a normal blood pressure in
should be tailored to the severity of the blood pressure
newborn infants is a complex task. Just as blood pressure
elevation, and to the underlying cause of hypertension as
in older children has been demonstrated to increase with
appropriate. A wide range of therapeutic agents are now
increasing age and body size |4], studies in both term
available for management of neonatal hypertension in
and preterm infants have demonstrated that blood pres-
both the acute and chronic settings. In most cases hyper-
sure in neonales increases with both gestational and
tension will resolve, but some infants may require pro-
postconceptual age. as well as with binh weight l ^ - l l ] .
longed treatment.
Extremely useful data in this regard has recently been
published by Zubrow et al. 191, who prospectively ob-
Key words Hypertension Neonates • Premature infants tained serial blood pressure meastirements from 695 in-
Antihypertensive therapy fants admitted to several NICUs in a large metropolitan
area over a period of 3 months. From these data, they
were able to define the mean plus upper and lower 95%
Introduction confidence limits for blood pressure for the infants stud-
ied; their data clearly demonstrated increases in blood
Hypertension as a clinical problem in newborn infants pressure with increasing gestational age, binh weight
was first recognized in the 1970s [1]. However, recent and postconceptual age (Figs. 1-3). Based on these data,
advances in our ability to identify, evaluate and care for we would consider an infant's blood pres.sure to be ele-
hypertensive infants, coupled with advances in the prac- vated if it fell above the upper limit of the 95% confi-
dence interval for infants of similar gestational or post-
conceptual age and size.
J. T. Flynn For older infants found to be hypertensive following
Division oi Pediatric Nephrology, discharge from the NICU 112|. the percentile curves gen-
Depanmenl of Pediatrics and Communicable Diseases, erated by the Second Task Force (Fig. 4) [13) appear to
University of Michigan. Motl F6865 - Box 0297.
150.^ Simpson Rd. East. Ann .Arhor. Ml 48109, USA be the most useful. Based on serial hlood pressure mea-
e-mail: jttiynn@uniich.edu surements obtained from nearly 13.000 infants, these
Tel.: -^1-734-3321007, Fax: -*• 1-734-7636997 curves allow blood pressure to be characterized as nor-
 333
upper 95% CL Upper 95% CL
90- no
80- 100

tol icBP (mmHg)

90
70- ,--*'—"V^ 80
60-
70
50-
60
40- Lower 95% CL.
50 Lower 95% CL,
30- 40
20- >, 30
10- 20
0-VA 10
750 1.250 1.750 2,250 2.750 3,250 3.750
1.000 1.500 2.000 2.500 3.000 3.500 4.000 24 26 28 30 32 34 36 38 40 42 44 46
Birth weight (kg) Post conceptional age (weeks)

70- 100-]
CT 60- Upper 95% C.L Ol 90
^ 80 Upper 95% C L
I 50- g 70
a. 40- a. 60
m - 50
^ 30- ^ 40
o ^ 30
S 20- Lower 95% C.L. b 20 Lower 95% C L
Q lOH
10

750 1.250 1.750 12.250 2.750 | 3.250 3.750 24 26 28 30 32 34 36 38 40 42 44 46

1.000 1.500 2.000 2.500 3.000 3.500 4.000 Post conceptional age (weeks)
Birth weight (kg)

I'lg. I Lineiir regres.sion of mean systolic and diaslolic blood Fig. 3 Linear regression of mean systolic and diastolic blood
pressures by birth weight on day I of life, with 95% confidence pressures by postconceptual age in weeks, with 95% confidence
limits (upper and lower dashed lines). Reproduced from Ziibrow limits {upper and lower dasiwd lines). Reproduced from Zubrow
et al. [9|, with permission from the copyright holders, Stockton et ai. [9], with permission from tbe copyright holders. Stockton
Press, a division of Nature America Press, a divi.sion of Nature America

90- Upper95%C,L mal or elevated not only by age and gender, but also by
80- size, albeit to a somewhat limited extent. Hypertension
™- in this age group would be defined as blood pressure ele-
60- vation above the 95th percentile for infants of similar
50- age, size and gender.
40- Lower 95% CL. Although the upper limit of normal blood pressure
30- has been defined as the 95th percentile. the actual inci-
20- dence of hypertension in neonates is quite low, ranging
10- from 0.2% to 3% in most reports [I. 2, 14-16]. It is so
22 24 26 28 30 32 34 36 38 40 42 unusual in otherwise healthy term infants that routine
Gestational age (weeks) blood pressure detennination is not advocated for this
group | I 7 | . For premature and otherwise high-risk new-
boms admitted to modetn NICUs, however, the picture
Upper 95% C.L. can be quite different. In a review of over 3,000 infants
admitted to a Chicago NICU, the overall incidence of
hypertension was found to be 0.81% [ 16]. Hypertension
was considerably more cotnmon in infants with broncho-
pulmonary dysplasia. patent ductus arteriosus. intraven-
tricular hemorrhage or that had indwelling umbilical ar-
terial catheters. In this latter group, approxitnately 9% of
22 24 26 28 30 32 34 36 38 40 42 the infants studied developed hypertension.
Gestational age (weeks) Hypertension tnay also be detected well after dis-
charge from the NICU. In a retrospective review of over
Fig. 2 Linear regression of mean systolic and diastolic blood 650 infants seen in follow-up after discharge from a
pressures hy gestational age on day 1 of life, with 95'^ confidence
limits {upper and lower dashed lines). Reproduced from Z.uhrow teaching hospital NICU, Friedman and Hustead 112]
et al. [9], with permission from the copyright holders, Stockton found an iticidence of hypertension (defined as a systolic
Press, a division of Nature America blood pressure of greater than 113 mtiiHg on three con-
secutive visits over 6 weeks) of 2.6%. Hypertension in
this study was detected at a mean age of approximately
334
Age-specific percentiles of blood pressure Age-specific percentiles of blood pressure
measurements in boys birth to 12 months measurements in girls birth to 12 months
115- 115-
110- 95 th 110 •95 th
90 th •90th
105- 105
100 75 th
I 100- •75 th
95 E 95-
50 th E •50th
90- 90-
85- a. 85-
ca

lie
80- ao-
75- o
75-
70- 70-
65- 65-

5 6 7 9 10 11 12 0 I 5 6 7 9 10 n 12
Months Months
75- 75 n
-^ 70- ^ 70
oi
X X
E 65-1 75 th P 65
E 75 th
Q. 60- 50-
Q3
50 til
"5 55- =5 55- 50 th

5 50- D 50-

45 • 45-
0 1 5 6 7 10 n 12 0 1 5 6 7 9 10 11 12
90 Ih Peitenl Months 90 th Peicenrlle Months
Systolic BP 87 101 106 106 106 106 106 106 106 106 106 106 106 SyilolJc BP If, 98 101 104 105 106 106 106 106 tO6 106 105 105
Dlastoric BP 68 65 63 63 63 65 66 67 68 68 89 69 89 Dtastollc BP 68 65 M 64 6S 65 66 66 66 67 67 67 67
Height (cm) 51 59 63 66 68 70 72 73 7A 76 77 78 80 Height (cm) 54 56 56 58 61 63 66 68 70 72 74 7S 77
Weighi (kg) 4 4 5 5 6 7 8 9 9 10 10 11 11 Weight (kgi 4 4 4 3 5 6 7 8 9 9 10 10 It
Veaii 0 10 II 12

b
Fig. 4 Age-specifJL- percentiles for blood pressure in boys (a) and by Neal et al. [181. They performed aortography at the
girls (b) from birth lo 12 monihs of age. Reproduced with permis- time of umbilical artety removal in a group of 19 infants,
sion from 113|
demonstrating thrombus formation in 18 of the 19 in-
fants, as well as several instances of clot fragmentation
2 months post-term when corrected for prematurity. Al- and embolization. Thrombosis was also seen at autopsy
though the differences were not significant, infant.s in in 7 of 12 infants who had died, for an overall incidence
this study who developed hypertension tended to have of 25 out of 31 infants, or approximately 81% of infants
lower initial Apgar scores and slightly longer NICU studied.
stays than infants who remained normotensive. indicat- Following the report of Neal et al.. the association be-
ing a somewhat greater likelihood of developing hyper- tween utnbilical arterial catheter-associated thrombi and
tension in sicker babies, a finding similar to that of Singh the development of neonatal hypertension was confirmed
et al. 116]. Eveti with the increasing rates of survival of by several other investigators [19-241. Hypertension was
premature infants, however, hypertension remains a rela- demonstrated in infants whi) had undergone umbilical ar-
tively infrequetit clinieal problem that is primarily con- terial catheterization even when thrombi could not be
fitiecj to the NICU. demonstrated in the renal arteries. Rates of thrombus for-
mation have generally been much lower than in the re-
port of Neal et al.. typically in the range of 25% [19. 25.
Causes of hypertension in neonates 26). Although there have been several studies that have
examined duration of line placement and line position
As in older infants and children, the causes of hyperten- ("low" vs "high") as factors involved in throtnbus forma-
sion in neonates are numerous (Table I). with the two tion, these data have not been conclusive [25-27]. Thus,
largest categories being renovaseular and other renal pa- the assumption has been made that the cause of hyper-
renchymal diseases | l - 3 . 12. 14-16]. More specifically, tension in such cases is re[ated to thrombus formation at
umbilical artery catheter-as.sociated thromboemboiism the time of line placement, probably related to disruption
affecting either the aorta and/or the renal arteries proba- of the vascular endothelium of the umbilical artery. Sueh
bly accounts for the majority of eases of hypertension thrombi may then embolize to the kidneys, causing areas
seen in the typical NICU. A clear association between of infarction and increased renin release. A similar phe-
use of utnbilical arterial catheters atid development of ar- nomenon has been reported in infants with dilatation of
terial thrombi was first demon.strated in the early 1970s the ductus arteriosus [28J.
 335
Table I Causes of neonatal hypertension (ECMO cxtracorporeal nant and autosoma! recessive polycystic kidney disease
membrane oxygenation. HTN hypertension) (PKD) may present in the newborn period with severe
Medications/intoxicalions
nephromegaly and hypertension 135, 36[. With recessive
Renovascular
PKD for example, the majority of affected infants will be
riiromboembolism Infant
Renal artery slenosis
discovered to be hypertensive during the 1st year of life
Dexamethasone [3-'i|. The most severely affected infants with PKD are at
Mid-aortic coarctation Adrenergic agents
Renal venous thrombosis Vitamin D intoxication risk for development of congestive heart failure due to
Compression ot renal artery Theophylline severe, malignant hypertension. Although much less
Idiopathic arterial calcification Caffeine common than in PKD, hypertension has also been re-
Congenital rubella syndrome Pancuroniuin ported in infants with unilateral multicystic dysplastic
Renal parenchymal disease Phenylcphrine kidneys |I4, 37-39|. This is somewhat paradoxical, as
Congenital Malernal such kidneys are usually thought to be non-functional.
Polycystic kidney disease Cocaine Renal obstruction may be accompanied by hyperten-
Muliicyslic-dysplastic kidney Heroin sion, even in the absence of renal arterial compression.
disease
Neoplasia This has been seen for exarnple in infants with congeni-
Tuberous sclerosis
Ureleropelvic junction obstruction Wilms tumor tal ureteropelvic-junction obstruction [12, 14, 16], and
Unilateral renal hypoplasia Mesoblastic nephroma sometimes may persist following surgical correction of
Congenital nephrotic syndrome Neuroblastoma the obstruction [40]. Ureteral obstruction by other intra-
Acquired Neurologic abdominal masses may also be accompanied by hyper-
Acute iiibular necrosis Pain tension. The mechanism of hypertension in such instanc-
Cortical necrosis Inlracranial hypertension es is unclear, although the renin-angiotensin system has
Interstitial nephritis Seizures been implicated [41. 42[. Finally, unilateral renal hypo-
Hemolytie-uremic syndrome Familial dysautonomia plasia may also present with hypertension [43]. although
Obstruction (stones, tumors) Subdural hematoma
this is uncommon.
i'ulmonary Miscellaneous
Hypertension due to acquired renal parenchymal dis-
Bronchopulmonary dysplasia Total parenteral nutrition
ease is less common than that due to congenital rena! ab-
Pneutnothorax Closure of abdominal wall
normalities. However, severe acute tubular necrosis, in-
Cardiac defect terstitial nephritis or cortical necrosis may be accompa-
Adrenal hemorrhage
Hypercalceniia
Thoracic aortic coarctation nied by significant hypertension 114, 16]. usually on the
Traction basis of volume overload or hyperreninemia. Hemo!ytic
lindocrine ECMO
Congenital adrenal hyperplasia Birth asphyxia uremic syndrome, which has been described in both term
Hyperaldosteronism Essential HTN? and preterm infants, is usua!ly also accompanied by hy-
Hyperthyroidisiii pertension. Such hypertension may be quite difficult to
Pseudohypoaklosteronism type 11 control, requiring multiple agents [44|.
Hypertension as a consequence of bronchopulmonary
dysptasia (BPD) was first described in the mid-1980s by
Other renovascular problems may also lead to neona- Abman et al. [451. In a study of 65 infants discharged
lal hypertension. Renal venous thrombosis clussically from an NICU, the instance of hypertension in infants
presents with the triad of hypertension, gross hematuria, with BPD was 43%, versus an incidence of 4.5% in in-
and an abdominal mass. Hypertension may be quite se- fants without BPD. Investigators were unable to identify
vere in such ca.ses and may persist beyond the neonatal a clear cause of hypertension, but postulated that hypox-
period [13. 29, 30], Fibromuscular dysplasia leading to etnia tnight be involved. Over half of the infants with
renal arterial stenosis is another important cause of reno- BFD who developed hypertension did not manifest it un-
vascular hypertension in the neonate. Many of these in- til discharged frotn the NICU. highlighting the need for
fants may have tiiain renal arteries that appear fairly nor- measurement of blood pressure in NICU "graduates,"
mal on angiography but demonstrate significant branch whether or not they have lung disease [ 12[.
vessel disease that can cause severe hypertension |3I |. In The findings of Abman et al. have been reproduced by
addition, renal arterial stenosis may also be accompanied other investigators, most recent!y in 1998 by Alagappan
by mid-aortic coarctation atid cerebral vascular stenoses and Malloy [46[. who foutid that hypertension was twice as
|3I |. Other vascular abnormalities may also lead to hy- cotTitiion in very !ow birth weight infants with BPD com-
pertension in the neonate, including idiopathic arterial pared to the incidence in a!! very !ow birth weight infants.
calcification [32, 331 i»nd renal artery stenosis secondary Development of hypertension appeiired to be correlated
to congenital rubella infection [34|. Finally, mechanical with the severity of pu!moniU7 disease, as a!I of the hyper-
compression of one or both renal arteries by tumors, hy- tensive infants required supplemental oxygen and ami-
dronephrotic kidneys, or other abdominal masses may nophylline. A greater need for diuretics and bronchodila-
also lead to hypettension. tors has also been shown to correlate with the development
The next largest group of infants with hypeitension of hypetiension in infants with severe BPD [47]. These ob-
are neonates who have congenital renal parenchymal ab- servations reinforce the impression that infants with severe
normalities. It is well known that both autosoma! domi- BPD are clearly at increased risk and need close monitor-
336
itig for the development of" hypertension. This is especially have all been proposed as causative factors [61, 621.
true in infants who require ongoing treatment with theoph- Given the widespread use of ECMO both in neonales
ylline preparations and/or corlicosteroid.s, and in older children, this problem is ripe for further in-
Hypertension may also be seen in disorders of several vestigation.
other organ systems. Coarctation of the thoracic aorta is
easily delected in the newborn period, and has been re-
ported in numerous case series of neonatal hypertension Clinical presentation and diagnostic approach
[2, 3, 12, 14, 16], Hypertension may persist in these in-
fants even after surgical repair of the coarctation. Repair In many infants, hypertension will be discovered on rou-
early in infancy .seems to lead to an improved long-term tine monitoring of vital signs, particularly in the most
outcome compared to delayed repair |48]. Endocrinolog- acutely ill infants. However, other classic presentations
ic disorders, particularly congenital adrenal hyperplasia of neonalal hypertension have been described. Conges-
|49. 50], hyperaldosteronism 151| and hyperthyroidism tive heart failure and cardiogenic shock represent life-
|52] constituie easily recognizable clinical entities that threatening consequences of hypertension that may te-
are accompanied by hypertension. solve with appropriate blood pressure reduction [63]. In
Iatrogenic causes of hypertension constitute another the less acutely ill infant, feeding difficulties, unex-
important category of diagno.ses. Medications given to plained tachypnea. apnea. lethaigy. irritability, or sei-
infants for treatment of puhnonary disease such as dexa- zures may constitute symptoms of unsuspected hyperten-
methasone and aminophylline have clearly been .shown sion. In older infants who have been discharged from the
to elevate blood pressure [53, 54). In addition, high dos- nursery, unexplained instability or failure to thrive may
es of adrenergic agents, prolonged use of pancuronium. be the only manifestations of hypertension.
or adtninistration of phenylephrine ophthalmic drops No matter what the presentation, it is crucial that
\55\ may raise blood pressure. Stich hypertension typi- blood pressure is being measured accurately so that hy-
cally resolves when the offending agent is discontinued pertension will be correctly identified. Fortunately, in
or its dose reduced. For infants receiving prolonged paj'- most acutely ill neonates. blood pressure is usually mon-
enteral nutrition (TPN), hypertension may result from itored directly via an indwelling arterial catheter either in
salt and water overload, or from hypercalcemia caused the radial or umbilical artery. This method provides the
either directly by excessive calcium intake, or indirectly most accurate blood pressure readings, and is clearly
by vitamin A or D intoxication. preferable to other methods [64], In addition to accurate-
Substances ingested during pregnancy may also lead ly measuring blood pressures, such catheters are also
to significant problems with hypertension in Ihe neonate. crucial in careful management of hypertension, particu-
In particular, maternal cocaine use tnay have a number larly in infants with extremely severe blood pressure ele-
of undesirable effects on the developing kidney that may vation.
lead to hypertension I56|. Hypertension has also been re- Automated, oscillometric devices are the most com-
ported to occur in infants of drug-addicted mothers with- mon alternative method of blood pressure measurement
drawing from heroin. in tnost NICUs. Although readings obtained using such
Tumors, including neuroblastoma. Wilms tumor, and devices may differ slightly from intra-arterial blood pres-
mesoblastic nephroma tnay all present in the neonatal sure measurements [65], they are easy to use and provide
period and may produce hypertension, either because of the ability to follow blood pressure trends over time.
compression of the renal vessels or ureters, or because of They are especially useful for infants who require blood
production of vasoaetive substances such as catechola- pressure monitoring after discharge from the NICU [66[.
mines |12, 57-60], Neurologic problems such as sei- When using such devices, however, attention should be
zures, intracranial hypertension and pain constitute fairly paid lo using a properly sized cuff, and also to the ex-
common cau.ses of episodic hypertension. !n the modern tremity used. Most normative blood pressure data, not
NICU. postoperative pain must not be overlooked as a only in infants but also in older children, have been col-
cause of hypertension. Provision of adequate analgesia lected using blood pressures obtained in the right arm
may constitute the only required "antihypertensive" in |13|. Since blood pressures obtained in the leg may be
such infants. higher than those obtained in the arm [67, 68|, the use of
There are numerous other miscellaneous causes of other extremities for routine blood pressure determina-
hypertension in neonates. the most comtnon of which tion may complicate to some extent the evaluation of hy-
are listed in Table I. Of these, hypertension associated pertension. Nursing staff should document the extremity
with extracorporeal membrane oxygenation (ECMO) used for blood pressure determinations and try to use the
deserves comment. This may be seen in up to 50% of same extremity for subsequent determinations if possi-
infants requiring ECMO 161], and may result in serious ble. Finally, the infant's state of activity may also affect
complications, including intracranial hemorrhage |62]. the accuracy of blood pressure readings. Increased activ-
Despite e.Ktensive investigation, the exact pathogenesis ity, including oral feeding, increases blood pressure [5,
of this form of hypertension remains poorly under- 69|. It may. therefore, be important to obtain blood pres-
stood. Fluid overload, altered handling of sodium and sure readings while infants are sleeping to obtain the
water, and derangements in atrial baroceptor function most accurate readings.
 337
Table 2 Diagnostic testing in neonatal hypertension (CBC com- ly, plasma renin may be falsely elevated by medications
plete blood count. VMA/HVA vaiiillylniandelic acid/homovanillic that are commonly used in the NICU. such as aminoph-
acid. VCUG voiding cystourethrograms) yliine |721. Despite these difficulties, assessment of plas-
Generally useful Useful in selected infants ma renin activity may be helpful in the evaluation of
some infants, especially when elevated, and is therefore
Urinaiysis (± culture) Thyroid studies usually included as part of the initial laboratory evalua-
CBC and platelet count Urine VMA/HVA tion.
lilectrolytes Aldosterone
IHJN. creatinine Cortisol Ultrasound imaging of the genitourinary tract is a rel-
Echocardiogram atively inexpensive, noninvasive. and quick study that
Plasma renin Abdominal/pelvic ultrasound should be obtained in all hypertensive infants. An accu-
Chest X-ray VCUG rate renal ultrasound can help uncover potentially cor-
Renal ultrast)und with Dopplcr Aortography rectable causes of hypertension such as renal venous
Renal angiography
Nuclear scan (DTPA/Mag-.l) thrombosis 129], may detect aortic and/or renal arterial
thrombi | I 9 . 24|. and can identify anatomic renal abnor-
malities or other congenital renal di.seases. For these rea-
Diagnosing the etiology of hypertension is u fairly sons, ultrasound has largely replaced Intravenous pyel-
straightforward task in most hypertensive neonates. A ography. which has little if any use in the routine assess-
relatively focused history should be obtained, paying at- ment of neonatal hypertension.
tention to determining whether there were any pertinent For infants with extremely severe blood pressure ele-
prenatal exposures, as well as to the particulars of the in- vation, angiography may be necessary. In our experi-
fant's nursery course and any concurrent conditions. The ence, a formal angiogram utilizing the traditional femo-
procedures that the infant has undergone (e.g.. umbilical ral venous approach offers the most accurate method of
catheter placement) should be reviewed, and their cur- diagnosing renai arterial stenosis, particularly given the
rent medication list should be scrutinized. high incidence of intrarenal branch vessel disease in
The physical exarnination. likewise, should be fo- children with fibromuscular dysplasia |31 ]. In extremely
cused on obtaining pertinent information to assist in nar- small infants, it may be appropriate to defer angiography.
rowing the differential diagnosis. Blood pressure read- managing the hypertension medically until the baby is
ings should be obtained in all four extremities to rule out large enough for an angiogram to be perfortned safely.
coarctation of the thoracic aorta. The genera! appearance Although nuclear scanning has been shown in some
oi the infant should be assessed, with particular attention studies to demonstrate abnortnalities of renal perfusion
paid to the presence of dysmorphic features that may in- caused by thromboembolic phenomenon | l . 1,*^. 16. 23,
dicate an obvious diagnosis sueh as congenital adrenal 28], in our practice it has had little role in the as.sessment
hyperplasia. Careful cardiac and abdominal examination of infants with hypertension, primarily due to the diffi-
shouid be performed. The presence of a Hank mass or of culties in obtaining accurate, interpretable results in this
an epigastric bruit may point the clinician towards diag- age group. Other studies, including echocardiograms and
nosis of either ureteropelvic junction obstruction or renal voiding cystourethrograms. should be obtained as indi-
atlerial stenosis, respectively. cated.
In most instances, few laboratory data are needed in
the evaluation of neonatal hypertension, as the correct
diagnosis is usually suggested by the history and physi- Therapy of neonatal hypertension
cal examination. It is important to assess renal function.
as well as to examine a specimen of the urine to ascer- Today's clinician has available an ever-expanding list of
tain the presence of renal parenchymal disease. Chest agents that can be used for treatment of neonatal hyper-
x-ray may be useful as an adjunctivc test in infants with tension (Tables 3. 4). Prior to embarking on drug thera-
congestive heart failure, or in those with a murmur on py, however, the infant's clinical status should be as-
physical examination. Other diagnostic studies, such as sessed and any easily correctable ialrogenic causes of
cortisol, aldosterone. or thyroxine levels, should be ob- hypertension addressed, such as infusions of inotropic
tained when there is pertinent history (Table 2). agents, volume overload, or pain. Following this, an an-
Determination of plasma renin activity is frequently tihypertensive agent should be chosen that is most ap-
performed in the assessment of neonates with hyperten- propriate for the specific clinical situation. For the ma-
sion | I 4 | . although there are few data on what consti- jority of acutely ill infants, particularly those with severe
tutes normal values for infants, particularly for prema- hypertension, it bas been our experience that continuous
ture infants. The data that are available indicate that re- intravenous infusions are the most appropriate approach.
nin values are typically quite high in infancy, at least in While intermittently administered agents also have a role
term newborns |7(). 71]. Although renai arterial stenosis in the management of hypertension, the wide fluctua-
and thromboembolic phenomenon are typically consid- tions in blood pressure frequently seen when these
ered high renin forms of hypertension, a peripheral renin agents are utilized make them inappropriate for treat-
level may not be elevated in such infants despite the ment of severe hypertension. The advantage of intrave-
presence of significant underlying pathology. Converse- nous infusions are numerous, most importantly including
338

Table 3 Intravenous agents lor acule hypertension and hypertensive emergencies/urgencies iACE angioiensin converting enzyme. IV in-
travenous. BPD bronchopulmonary dysplasia)

Drue Class Route Cornmenis

Dia/oxide Vasodilalor 2-5 mg/kg per dose Rapid bolus injection Slow injeclion ineffective:
(aneriolar) duratit)n unpredictable:
use with caution - may cause
rapid hypotension
I^nalaprilat ACE inhibitor I5±5 |ig/kg per dose Injection over 5-10 min May cause prolonged hypotension
Repeat Q 8-24 h and acute renal insufficiency
Esmolol |3 blocker Drip: 100-300 |ag/kg IV infusion Very short-acting - constaDt infusion
per min necessary
Hydralazine Vasodilator Bolus: 0.15-0.6 mg/kg IV bolus or infusion Tachycardia frequent side-effect: musi
(arteriolar) per dose administer Q 4 h when given IV boltis
Drip: 0.75-5.0 )ig/kg
per min
Labfialol a & ^ blocker 0.20-1.0 mu/kg per dose IV bolus or constant Heart failure, BPD relative
0.25-3.0 mg/kg per h infusion contraindications
Nicardipine Ca^* channel 1-3 ).tg/kg per min May cause reflex tachycardia
blocker Constant infusion
Sodium nitroprusside Vasodilator 0.5-10 fig/kg per min Thiocyanate toxicity can occur
(aneriolar & Constant infusion with prolonged (>72 h) use or
venous) in renal failure

the ability quickly to increase or decrease the rate of in- Oral antihypertensive agents (Table 4) are best re-
fusion to achieve the desired level of blood pressure con- served for infants with less severe hypertension or in-
trol. As in patients of any age with tiiiilignant hypetten- fants whose acute hypertension has been controlled with
sion. care should be taken to avoid too rapid a reduction intravenous infusions and are ready to be transitioned to
in blood pressure [73. 74] to avoid cerebral ischemia and chronic therapy. Captopril in particular is a useful agent
hemorrhage, a problem that premature infants in particu- for many causes of neonatal hypertension and is our oral
lar are already at increased risk for due to the immaturity drug of choice for most infants seen in our unit. Care
of their periventricular circulation. Here again, continu- must be taken to avoid giving a dose that is too high to
OU.S infusions of intravenous anti hypertensives offer a premature infants, as they may have an exaggerated fall
distinct advantage. in blood pressure following captopril administration
Unfortunately, there are few data available regarding [80). For infants whose blood pressure is unable to be
the use of these agents in neonates. so in many cases the controlled by captopril alone, the addition of a diuretic
choice of agent will depend on the individual clinician's frequently will result in the desired degree of blood pres-
experience. Our experience [75] and that of others |76| sure control. Beta blockers may need to be avoided in
suggests that infusions of the calcium channel blocker chronic therapy of neonatal hypertension, particularly in
nicardipine tiiay be particularly useful in this population. infants with chronic lung disease. In such infants, diuret-
Other drugs that have been successfully used in neonates ics may have a beneficial effect not only in controlling
include esmolol [77], labetalol and nitroprusside [73|. blood pressure but also in improving pulmonary function
Whatever agent is used, blood pressure should be moni- [8IJ. Other drugs that we have found useful in some in-
tored continuously via an indwelling arterial catheter, or fants include hydralazine. minoxidil and the calcium
else by frequently repeated (Q 10-15 min.) cuff readings channel blocker i.sradipine 182]. When a vasodilator is
so that the dose can be titrated to achieve the desired de- indicated, isradipine tnay be superior to the older agents
gree of blood pressure control. hydralazine and minoxidil since it can be compounded
For some infants, intermittently administered intrave- into a stable suspension !83[ that can be dosed with ac-
nous agents do have a role in therapy. Hydralazine and curacy, even in tiny infants. We no longer use nifedipine
labetalol in particular may be useful in infants with mild- in our unit because of the difficulty in adtiiinistering
to-nioderate hypertension that are not yet candidates lor small doses, and because of the rapid, profound, and
oral therapy because of gastrointestinal dysfunction. short-lived drops in blood pressure that are typically pro-
Enalaprilat, the intravenous angiotensin converting en- duced by this agent.
zyme inhibitor, has also been reported to be useful in the Surgery is indicated tor treatment of neonatal hyper-
treattnent of neonatal renovascular hypertension [78. 79|. tension in a limited set of circumstances |841. In particu-
However, in our experience, this agent should be used lar, hypertension caused by uretera! obstruction or aortic
with great caution. Even doses at the lower end of pub- coarctation |48| is best approached surgically. For in-
lished ranges tnay lead to significant, prolonged hypo- fants with renal arteiial stenosis, it may be necessary to
tension and oLiguric acute renal failure. manage the infant medically until it has grown sufft-
 339

Table 4 Oral ugcnls useCul for liypeiiension in infants

Drug Class Dose Interval Comments

Cuptopiil ACE Inhibitor <6m: 0.01-0.5 mg/kg TID Drug ot choice for most neonatal HTN
per dose monitor serum creatinine and K*
Max 6 mg/kg per day
Clonidine Central a agonist 0.05-0.1 mg per dose BID-TID Side effects include dry mouth & sedation;
rebound hypertension with abrupt
discontinuation
Hydraiazine Vasodilator (arteriolar) 0.25-1.0 iTig/kg per dose TID-QID Suspension stable up to I week;
Max 7.5 mg/kg per day tachycardia & tluid retention common
side-effects; kipus-like syndrome may
develop in slow acetylators
Isradipine Ca'* channel blocker 0.05-0.15 mg/kg per dose QID Suspension may be compounded: useful
Max 0.8 mg/kg per day for both acute & chronic HTN
Amlodipine Ca'+ channel blocker 0.1-0.3 mg/kg per dose BID Less likely to cause sudden hypotension
Max 0.6 mg/kg per day ihan isradipine
Minoxidil Vasodilator (arleriolar) 0.1-0.2 mg/kg per dose BID-TID Most potent oral vasodilator; excellent
for refractory HTN
Propranolol P - blocker 0.5-1.0 mg/kg per dose TID Maximal dose depends on heati rate;
may go as high as 8-10 mg/kg per day
if no bradycardia. Avoid in infants
with BPD
l.abet;ilnl a and P blocker 1.0 tiig/kg per dose BID-TID Monitor heart rate; avoid in infants
Max. 10 mg/kg per day wilh BPD
Spironolactone Aldcsterone antagonist 0.5-1.5 mg/kg per dose BID Potas.sium "sparing"; monitor electrolytes.
Takes several days to see maximum
effectiveness
Hydrochlorothiazidc Thiazide diuretic 1-3 mg/kg per dose QID Monitor electrolytes
Chlorothia/ide Thia/ide diuretic 5-15 mg/kg per dose BID Monitor electrolytes

ciently to undergo definitive repair of the vascular abnor- pressure monitoring by the parents is a crucially impor-
malities [851- Outcome of such surgical procedures can tant component of this process. It is our standard of care
become quite good if performed at centers with a large to arrange for home blood pressute equipment, either a
experience [86]. Infants with hypertension secondary to Doppler or oscillotnetric device, for all infants dis-
Wilms tumor or neuroblastoma will require surgical tu- charged frotn the NICU on antihypertensive medications.
mor removal [57. 58. 84]. possibly following chemother- Some forms of neonatal hypertension may persist be-
apy. A case has also been made by some authors for re- yond infancy. In particular. PKD and other fomis of re-
moval of multicystic-dysplastic kidneys because of the nal parenchytnal disease may continue to cause hyper-
risk of development of hypertension |37-391. although tension throughout childhood 135, 36, 89]. Infants with
this is controversial. Infants with malignant hypertension renal venous thrombosis may also remain hypertensive
secondary to polycystic kidney disease may require bi- [30|, and some of these children will ultimately benefit
lateral nephrectomy. Fortunately, such severely affected from removal of the affected kidney [29. 30]. Persi.stent
infants are quite rare. or late hypertension may also be seen in children who
have undergone repair of renal arterial stenosis [86] or
thoracic aortic coarctation |48|. Reappearance of hyper-
Outcome of neonatal hypertension tension in these situations should protnpt a search for re-
stenosis by the appropriate imaging studies.
The long-term prognosis for infants with hypertension is
in most eases quite good, depending of course on the un-
derlying etiology of the infant's hypertension. For in- Conclusions
fants with hypertension related to an umbilical arterial
catheter, the hypertension will usually resolve over time Blood pressure in neonates depends on a variety of fac-
[87. 88). These infants may require increases in their an- tors, including gestational age. post-natal age and birth
tihypertensive medications in the first several months weight. Hypertension can be seen in a variety of situa-
following discharge from the nursery as they undergo tions in the tiiodern NICU, and is especially common in
rapid growth. Following this, it is usually possible to infants who have undergone umbilical arterial catheter-
wean their antihypertensives by making no further dose ization. A careful diagnostic evaluation should lead to de-
increases as the infant continues to grow. Home blood tetmination of the underlying cause of hypertension in
most intanls. Treatment decisions should be tailored to 20. Ford KT. Teplick SK. Clark RB (1974) Renal artery embolism
the severity of the hypertension, and may include intrave- causing neonatal hypertension. Radiology 113:169-170
nous and/or oral therapy. Most infants will resolve their 21. Bauer SB. Feldman SM. Gellis SS. Relik AB (1975) Neonatal
hypertension: a complication of umbilical-artery catheieri/a-
hypertension over time, although a small number may tion. N Engl J Med 293:1032-1033
have persistent blood pressure elevation throughout child- 22. Plumer LB. Kaplan GW. Mendoza SA (1976) Hy[Tertension in
hood. infants - a complicalion of umbilical arterial catheterization. J
Pediatr 89:802-805
B The author wishes lo acknowledge Drs. Davjd 23. Meilen DF Vogel JM. Adelman RD. Goet/man. BW. Bogren
Kershaw and Manha Nelson Tor their lht)ugh(ful review of ihe HG (1978) Renovascular hypertension as a complication of
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