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Pediatr Nephrol (2U00)

PRACTICAL PKDIATRIC NEPHROLOGY

Joseph T. Flynn

Neonatal hypertension: diagnosis and management

© IPNA 2()()0

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

Abstract Hypertension in the term or preterm neonatemay be seen in up to 2% of all infants cared for in themodern neonatal intensive care unit. Although the defini-tion of hypertension in this age group has not been cotn-pleteiy standardized, recent studies have provided newnormative data that may be used to facilitate identifica-tion of such infants. Common causes of hypertcn.sion inneonates include thromboembolic events related to um-bilical catheterization. congenital problems such as aor-tic coarctation. staictural renal malformations and reno-vascular disease, as well as acquired renal disease andcertain medications. A careful history and physical ex-amination will usually identify the probable cause innujst cases without Ihc need for extensive laboratory orradiologic testing. Therapy of neonatal hypertensionshould be tailored to the severity of the blood pressureelevation, and to the underlying cause of hypertension asappropriate. A wide range of therapeutic agents are nowavailable for management of neonatal hypertension inboth the acute and chronic settings. In most cases hyper-tension will resolve, but some infants may require pro-longed treatment.

Key words HypertensionAntihypertensive therapy

Neonates • Premature infants

Introduction

Hypertension as a clinical problem in newborn infantswas first recognized in the 1970s [1]. However, recentadvances in our ability to identify, evaluate and care forhypertensive infants, coupled with advances in the prac-

J. T. FlynnDivision oi Pediatric Nephrology,Depanmenl of Pediatrics and Communicable Diseases,University of Michigan. Motl F6865 - Box 0297.150.̂ Simpson Rd. East. Ann .Arhor. Ml 48109, USAe-mail: [email protected].: -^1-734-3321007, Fax: -*• 1-734-7636997

tice of neonatology in general, have lead to an increasedawareness of hypertension in modem neonatal intensivecare units (NICUs). Since most hypertension in infants isrelated to renovascular or renal parenchymal disease |2.3|, the evaluation and management of neonatal hyperten-sion frequently requires the expertise of a pediatric neph-rologist. This review will focus on Ihe differential diag-tiosis of hypertension in the neonate. the optimal diag-nostic evaluation, and both acute and chronic antihyper-tensive therapy.

Definition and incidence of neonatal hypertension

Defining what is considered a normal blood pressure innewborn infants is a complex task. Just as blood pressurein older children has been demonstrated to increase withincreasing age and body size |4], studies in both termand preterm infants have demonstrated that blood pres-sure in neonales increases with both gestational andpostconceptual age. as well as with binh weight l ^ - l l ] .Extremely useful data in this regard has recently beenpublished by Zubrow et al. 191, who prospectively ob-tained serial blood pressure meastirements from 695 in-fants admitted to several NICUs in a large metropolitanarea over a period of 3 months. From these data, theywere able to define the mean plus upper and lower 95%confidence limits for blood pressure for the infants stud-ied; their data clearly demonstrated increases in bloodpressure with increasing gestational age, binh weightand postconceptual age (Figs. 1-3). Based on these data,we would consider an infant's blood pres.sure to be ele-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.

For older infants found to be hypertensive followingdischarge from the NICU 112|. the percentile curves gen-erated by the Second Task Force (Fig. 4) [13) appear tobe the most useful. Based on serial hlood pressure mea-surements obtained from nearly 13.000 infants, thesecurves allow blood pressure to be characterized as nor-

333

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750 1.250 1.750 12.250 2.750 | 3.250 3.7501.000 1.500 2.000 2.500 3.000 3.500 4.000

Birth weight (kg)

I'lg. I Lineiir regres.sion of mean systolic and diaslolic bloodpressures by birth weight on day I of life, with 95% confidencelimits (upper and lower dashed lines). Reproduced from Ziibrowet al. [9|, with permission from the copyright holders, StocktonPress, a division of Nature America

Upper 95% CL

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24 26 28 30 32 34 36 38 40 42 44 46

Post conceptional age (weeks)

Upper 95% C L

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Post conceptional age (weeks)

Fig. 3 Linear regression of mean systolic and diastolic bloodpressures by postconceptual age in weeks, with 95% confidencelimits {upper and lower dasiwd lines). Reproduced from Zubrowet ai. [9], with permission from tbe copyright holders. StocktonPress, a divi.sion of Nature America

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Gestational age (weeks)

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22 24 26 28 30 32 34 36 38 40 42Gestational age (weeks)

Fig. 2 Linear regression of mean systolic and diastolic bloodpressures hy gestational age on day 1 of life, with 95'^ confidencelimits {upper and lower dashed lines). Reproduced from Z.uhrowet al. [9], with permission from the copyright holders, StocktonPress, a division of Nature America

mal or elevated not only by age and gender, but also bysize, albeit to a somewhat limited extent. Hypertensionin this age group would be defined as blood pressure ele-vation above the 95th percentile for infants of similarage, size and gender.

Although the upper limit of normal blood pressurehas been defined as the 95th percentile. the actual inci-dence of hypertension in neonates is quite low, rangingfrom 0.2% to 3% in most reports [I. 2, 14-16]. It is sounusual in otherwise healthy term infants that routineblood pressure detennination is not advocated for thisgroup | I7 | . For premature and otherwise high-risk new-boms admitted to modetn NICUs, however, the picturecan be quite different. In a review of over 3,000 infantsadmitted to a Chicago NICU, the overall incidence ofhypertension was found to be 0.81% [ 16]. Hypertensionwas 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% ofthe infants studied developed hypertension.

Hypertension tnay also be detected well after dis-charge from the NICU. In a retrospective review of over650 infants seen in follow-up after discharge from ateaching hospital NICU, Friedman and Hustead 112]found an iticidence of hypertension (defined as a systolicblood pressure of greater than 113 mtiiHg on three con-secutive visits over 6 weeks) of 2.6%. Hypertension inthis study was detected at a mean age of approximately

334

Age-specific percentiles of blood pressuremeasurements in boys birth to 12 months

115-110-105-1009590-85-80-75-70-6 5 -

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87 101 106 106 106 106 106 106 106 106 106 106 10668 65 63 63 63 65 66 67 68 68 89 69 8951 59 63 66 68 70 72 73 7A 76 77 78 804 4 5 5 6 7 8 9 9 10 10 11 11

Fig. 4 Age-specifJL- percentiles for blood pressure in boys (a) andgirls (b) from birth lo 12 monihs of age. Reproduced with permis-sion from 113|

2 months post-term when corrected for prematurity. Al-though the differences were not significant, infant.s inthis study who developed hypertension tended to havelower initial Apgar scores and slightly longer NICUstays than infants who remained normotensive. indicat-ing a somewhat greater likelihood of developing hyper-tension in sicker babies, a finding similar to that of Singhet al. 116]. Eveti with the increasing rates of survival ofpremature infants, however, hypertension remains a rela-tively infrequetit clinieal problem that is primarily con-fitiecj to the NICU.

Causes of hypertension in neonates

As in older infants and children, the causes of hyperten-sion in neonates are numerous (Table I). with the twolargest categories being renovaseular and other renal pa-renchymal diseases | l - 3 . 12. 14-16]. More specifically,umbilical artery catheter-as.sociated thromboemboiismaffecting either the aorta and/or the renal arteries proba-bly accounts for the majority of eases of hypertensionseen in the typical NICU. A clear association betweenuse of utnbilical arterial catheters atid development of ar-terial thrombi was first demon.strated in the early 1970s

Age-specific percentiles of blood pressuremeasurements in girls birth to 12 months

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10 II 12

by Neal et al. [181. They performed aortography at thetime of umbilical artety removal in a group of 19 infants,demonstrating thrombus formation in 18 of the 19 in-fants, as well as several instances of clot fragmentationand embolization. Thrombosis was also seen at autopsyin 7 of 12 infants who had died, for an overall incidenceof 25 out of 31 infants, or approximately 81% of infantsstudied.

Following the report of Neal et al.. the association be-tween utnbilical arterial catheter-associated thrombi andthe development of neonatal hypertension was confirmedby several other investigators [19-241. Hypertension wasdemonstrated in infants whi) had undergone umbilical ar-terial catheterization even when thrombi could not bedemonstrated 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. 25.26). Although there have been several studies that haveexamined duration of line placement and line position("low" vs "high") as factors involved in throtnbus forma-tion, these data have not been conclusive [25-27]. Thus,the assumption has been made that the cause of hyper-tension in such cases is re[ated to thrombus formation atthe time of line placement, probably related to disruptionof the vascular endothelium of the umbilical artery. Suehthrombi may then embolize to the kidneys, causing areasof infarction and increased renin release. A similar phe-nomenon has been reported in infants with dilatation ofthe ductus arteriosus [28J.

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Table I Causes of neonatal hypertension (ECMO cxtracorporealmembrane oxygenation. HTN hypertension)

RenovascularriiromboembolismRenal artery slenosisMid-aortic coarctationRenal venous thrombosisCompression ot renal arteryIdiopathic arterial calcificationCongenital rubella syndrome

Renal parenchymal diseaseCongenitalPolycystic kidney diseaseMuliicyslic-dysplastic kidney

diseaseTuberous sclerosisUreleropelvic junction obstructionUnilateral renal hypoplasiaCongenital nephrotic syndrome

AcquiredAcute iiibular necrosisCortical necrosisInterstitial nephritisHemolytie-uremic syndromeObstruction (stones, tumors)

i'ulmonaryBronchopulmonary dysplasiaPneutnothorax

CardiacThoracic aortic coarctation

lindocrineCongenital adrenal hyperplasiaHyperaldosteronismHyperthyroidisiiiPseudohypoaklosteronism type 11

Medications/intoxicalionsInfantDexamethasoneAdrenergic agentsVitamin D intoxicationTheophyllineCaffeinePancuroniuinPhenylcphrine

MalernalCocaineHeroin

Neoplasia

Wilms tumorMesoblastic nephromaNeuroblastoma

Neurologic

PainInlracranial hypertensionSeizuresFamilial dysautonomiaSubdural hematoma

MiscellaneousTotal parenteral nutritionClosure of abdominal walldefectAdrenal hemorrhageHypercalceniiaTractionECMOBirth asphyxiaEssential HTN?

Other renovascular problems may also lead to neona-lal hypertension. Renal venous thrombosis clussicallypresents with the triad of hypertension, gross hematuria,and an abdominal mass. Hypertension may be quite se-vere in such ca.ses and may persist beyond the neonatalperiod [13. 29, 30], Fibromuscular dysplasia leading torenal arterial stenosis is another important cause of reno-vascular hypertension in the neonate. Many of these in-fants may have tiiain renal arteries that appear fairly nor-mal on angiography but demonstrate significant branchvessel disease that can cause severe hypertension |3I |. Inaddition, renal arterial stenosis may also be accompaniedby mid-aortic coarctation atid cerebral vascular stenoses|3I |. Other vascular abnormalities may also lead to hy-pertension in the neonate, including idiopathic arterialcalcification [32, 331 i»nd renal artery stenosis secondaryto congenital rubella infection [34|. Finally, mechanicalcompression of one or both renal arteries by tumors, hy-dronephrotic kidneys, or other abdominal masses mayalso lead to hypettension.

The next largest group of infants with hypeitensionare neonates who have congenital renal parenchymal ab-normalities. It is well known that both autosoma! domi-

nant and autosoma! recessive polycystic kidney disease(PKD) may present in the newborn period with severenephromegaly and hypertension 135, 36[. With recessivePKD for example, the majority of affected infants will bediscovered to be hypertensive during the 1st year of life[3-'i|. The most severely affected infants with PKD are atrisk for development of congestive heart failure due tosevere, malignant hypertension. Although much lesscommon than in PKD, hypertension has also been re-ported in infants with unilateral multicystic dysplastickidneys | I4, 37-39|. This is somewhat paradoxical, assuch kidneys are usually thought to be non-functional.

Renal obstruction may be accompanied by hyperten-sion, even in the absence of renal arterial compression.This has been seen for exarnple in infants with congeni-tal ureteropelvic-junction obstruction [12, 14, 16], andsometimes may persist following surgical correction ofthe obstruction [40]. Ureteral obstruction by other intra-abdominal masses may also be accompanied by hyper-tension. The mechanism of hypertension in such instanc-es is unclear, although the renin-angiotensin system hasbeen implicated [41. 42[. Finally, unilateral renal hypo-plasia may also present with hypertension [43]. althoughthis is uncommon.

Hypertension due to acquired renal parenchymal dis-ease is less common than that due to congenital rena! ab-normalities. However, severe acute tubular necrosis, in-terstitial nephritis or cortical necrosis may be accompa-nied by significant hypertension 114, 16]. usually on thebasis of volume overload or hyperreninemia. Hemo!yticuremic syndrome, which has been described in both termand preterm infants, is usua!ly also accompanied by hy-pertension. Such hypertension may be quite difficult tocontrol, requiring multiple agents [44|.

Hypertension as a consequence of bronchopulmonarydysptasia (BPD) was first described in the mid-1980s byAbman et al. [451. In a study of 65 infants dischargedfrom an NICU, the instance of hypertension in infantswith BPD was 43%, versus an incidence of 4.5% in in-fants without BPD. Investigators were unable to identifya clear cause of hypertension, but postulated that hypox-etnia tnight be involved. Over half of the infants withBFD who developed hypertension did not manifest it un-til discharged frotn the NICU. highlighting the need formeasurement of blood pressure in NICU "graduates,"whether or not they have lung disease [ 12[.

The findings of Abman et al. have been reproduced byother investigators, most recent!y in 1998 by Alagappanand Malloy [46[. who foutid that hypertension was twice ascotTitiion in very !ow birth weight infants with BPD com-pared to the incidence in a!! very !ow birth weight infants.Development of hypertension appeiired to be correlatedwith the severity of pu!moniU7 disease, as a!I of the hyper-tensive infants required supplemental oxygen and ami-nophylline. A greater need for diuretics and bronchodila-tors has also been shown to correlate with the developmentof hypetiension in infants with severe BPD [47]. These ob-servations reinforce the impression that infants with severeBPD are clearly at increased risk and need close monitor-

336

itig for the development of" hypertension. This is especiallytrue in infants who require ongoing treatment with theoph-ylline preparations and/or corlicosteroid.s,

Hypertension may also be seen in disorders of severalother organ systems. Coarctation of the thoracic aorta iseasily delected in the newborn period, and has been re-ported in numerous case series of neonatal hypertension[2, 3, 12, 14, 16], Hypertension may persist in these in-fants even after surgical repair of the coarctation. Repairearly in infancy .seems to lead to an improved long-termoutcome compared to delayed repair |48]. Endocrinolog-ic disorders, particularly congenital adrenal hyperplasia|49. 50], hyperaldosteronism 151| and hyperthyroidism|52] constituie easily recognizable clinical entities thatare accompanied by hypertension.

Iatrogenic causes of hypertension constitute anotherimportant category of diagno.ses. Medications given toinfants for treatment of puhnonary disease such as dexa-methasone and aminophylline have clearly been .shownto elevate blood pressure [53, 54). In addition, high dos-es of adrenergic agents, prolonged use of pancuronium.or adtninistration of phenylephrine ophthalmic drops\55\ may raise blood pressure. Stich hypertension typi-cally resolves when the offending agent is discontinuedor its dose reduced. For infants receiving prolonged paj'-enteral nutrition (TPN), hypertension may result fromsalt and water overload, or from hypercalcemia causedeither directly by excessive calcium intake, or indirectlyby vitamin A or D intoxication.

Substances ingested during pregnancy may also leadto significant problems with hypertension in Ihe neonate.In particular, maternal cocaine use tnay have a numberof undesirable effects on the developing kidney that maylead to hypertension I56|. Hypertension has also been re-ported to occur in infants of drug-addicted mothers with-drawing from heroin.

Tumors, including neuroblastoma. Wilms tumor, andmesoblastic nephroma tnay all present in the neonatalperiod and may produce hypertension, either because ofcompression of the renal vessels or ureters, or because ofproduction of vasoaetive substances such as catechola-mines |12, 57-60], Neurologic problems such as sei-zures, intracranial hypertension and pain constitute fairlycommon cau.ses of episodic hypertension. !n the modernNICU. postoperative pain must not be overlooked as acause of hypertension. Provision of adequate analgesiamay constitute the only required "antihypertensive" insuch infants.

There are numerous other miscellaneous causes ofhypertension in neonates. the most comtnon of whichare listed in Table I. Of these, hypertension associatedwith extracorporeal membrane oxygenation (ECMO)deserves comment. This may be seen in up to 50% ofinfants requiring ECMO 161], and may result in seriouscomplications, including intracranial hemorrhage |62].Despite e.Ktensive investigation, the exact pathogenesisof this form of hypertension remains poorly under-stood. Fluid overload, altered handling of sodium andwater, and derangements in atrial baroceptor function

have all been proposed as causative factors [61, 621.Given the widespread use of ECMO both in neonalesand in older children, this problem is ripe for further in-vestigation.

Clinical presentation and diagnostic approach

In many infants, hypertension will be discovered on rou-tine monitoring of vital signs, particularly in the mostacutely ill infants. However, other classic presentationsof neonalal hypertension have been described. Conges-tive heart failure and cardiogenic shock represent life-threatening consequences of hypertension that may te-solve with appropriate blood pressure reduction [63]. Inthe less acutely ill infant, feeding difficulties, unex-plained tachypnea. apnea. lethaigy. irritability, or sei-zures may constitute symptoms of unsuspected hyperten-sion. In older infants who have been discharged from thenursery, unexplained instability or failure to thrive maybe the only manifestations of hypertension.

No matter what the presentation, it is crucial thatblood pressure is being measured accurately so that hy-pertension will be correctly identified. Fortunately, inmost acutely ill neonates. blood pressure is usually mon-itored directly via an indwelling arterial catheter either inthe radial or umbilical artery. This method provides themost accurate blood pressure readings, and is clearlypreferable to other methods [64], In addition to accurate-ly measuring blood pressures, such catheters are alsocrucial in careful management of hypertension, particu-larly in infants with extremely severe blood pressure ele-vation.

Automated, oscillometric devices are the most com-mon alternative method of blood pressure measurementin tnost NICUs. Although readings obtained using suchdevices may differ slightly from intra-arterial blood pres-sure measurements [65], they are easy to use and providethe ability to follow blood pressure trends over time.They are especially useful for infants who require bloodpressure monitoring after discharge from the NICU [66[.When using such devices, however, attention should bepaid lo using a properly sized cuff, and also to the ex-tremity used. Most normative blood pressure data, notonly in infants but also in older children, have been col-lected using blood pressures obtained in the right arm|13| . Since blood pressures obtained in the leg may behigher than those obtained in the arm [67, 68|, the use ofother extremities for routine blood pressure determina-tion may complicate to some extent the evaluation of hy-pertension. Nursing staff should document the extremityused for blood pressure determinations and try to use thesame extremity for subsequent determinations if possi-ble. Finally, the infant's state of activity may also affectthe accuracy of blood pressure readings. Increased activ-ity, including oral feeding, increases blood pressure [5,69|. It may. therefore, be important to obtain blood pres-sure readings while infants are sleeping to obtain themost accurate readings.

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Table 2 Diagnostic testing in neonatal hypertension (CBC com-plete blood count. VMA/HVA vaiiillylniandelic acid/homovanillicacid. VCUG voiding cystourethrograms)

Generally useful Useful in selected infants

Urinaiysis (± culture)CBC and platelet countlilectrolytesIHJN. creatinine

Plasma reninChest X-rayRenal ultrast)und with Dopplcr

Thyroid studiesUrine VMA/HVAAldosteroneCortisolEchocardiogramAbdominal/pelvic ultrasoundVCUGAortographyRenal angiographyNuclear scan (DTPA/Mag-.l)

Diagnosing the etiology of hypertension is u fairlystraightforward task in most hypertensive neonates. Arelatively focused history should be obtained, paying at-tention to determining whether there were any pertinentprenatal exposures, as well as to the particulars of the in-fant's nursery course and any concurrent conditions. Theprocedures that the infant has undergone (e.g.. umbilicalcatheter placement) should be reviewed, and their cur-rent medication list should be scrutinized.

The physical exarnination. likewise, should be fo-cused on obtaining pertinent information to assist in nar-rowing the differential diagnosis. Blood pressure read-ings should be obtained in all four extremities to rule outcoarctation of the thoracic aorta. The genera! appearanceoi the infant should be assessed, with particular attentionpaid to the presence of dysmorphic features that may in-dicate an obvious diagnosis sueh as congenital adrenalhyperplasia. Careful cardiac and abdominal examinationshouid be performed. The presence of a Hank mass or ofan epigastric bruit may point the clinician towards diag-nosis of either ureteropelvic junction obstruction or renalatlerial stenosis, respectively.

In most instances, few laboratory data are needed inthe evaluation of neonatal hypertension, as the correctdiagnosis is usually suggested by the history and physi-cal examination. It is important to assess renal function.as well as to examine a specimen of the urine to ascer-tain the presence of renal parenchymal disease. Chestx-ray may be useful as an adjunctivc test in infants withcongestive heart failure, or in those with a murmur onphysical examination. Other diagnostic studies, such ascortisol, aldosterone. or thyroxine levels, should be ob-tained when there is pertinent history (Table 2).

Determination of plasma renin activity is frequentlyperformed in the assessment of neonates with hyperten-sion | I4 | . although there are few data on what consti-tutes normal values for infants, particularly for prema-ture infants. The data that are available indicate that re-nin values are typically quite high in infancy, at least interm newborns |7(). 71]. Although renai arterial stenosisand thromboembolic phenomenon are typically consid-ered high renin forms of hypertension, a peripheral reninlevel may not be elevated in such infants despite thepresence of significant underlying pathology. Converse-

ly, plasma renin may be falsely elevated by medicationsthat are commonly used in the NICU. such as aminoph-yliine |721. Despite these difficulties, assessment of plas-ma renin activity may be helpful in the evaluation ofsome infants, especially when elevated, and is thereforeusually included as part of the initial laboratory evalua-tion.

Ultrasound imaging of the genitourinary tract is a rel-atively inexpensive, noninvasive. and quick study thatshould be obtained in all hypertensive infants. An accu-rate renal ultrasound can help uncover potentially cor-rectable causes of hypertension such as renal venousthrombosis 129], may detect aortic and/or renal arterialthrombi | I9 . 24|. and can identify anatomic renal abnor-malities or other congenital renal di.seases. For these rea-sons, ultrasound has largely replaced Intravenous pyel-ography. which has little if any use in the routine assess-ment of neonatal hypertension.

For infants with extremely severe blood pressure ele-vation, angiography may be necessary. In our experi-ence, a formal angiogram utilizing the traditional femo-ral venous approach offers the most accurate method ofdiagnosing renai arterial stenosis, particularly given thehigh incidence of intrarenal branch vessel disease inchildren with fibromuscular dysplasia |31 ]. In extremelysmall infants, it may be appropriate to defer angiography.managing the hypertension medically until the baby islarge enough for an angiogram to be perfortned safely.

Although nuclear scanning has been shown in somestudies to demonstrate abnortnalities of renal perfusioncaused by thromboembolic phenomenon | l . 1,*̂ . 16. 23,28], in our practice it has had little role in the as.sessmentof infants with hypertension, primarily due to the diffi-culties in obtaining accurate, interpretable results in thisage group. Other studies, including echocardiograms andvoiding cystourethrograms. should be obtained as indi-cated.

Therapy of neonatal hypertension

Today's clinician has available an ever-expanding list ofagents that can be used for treatment of neonatal hyper-tension (Tables 3. 4). Prior to embarking on drug thera-py, however, the infant's clinical status should be as-sessed and any easily correctable ialrogenic causes ofhypertension addressed, such as infusions of inotropicagents, volume overload, or pain. Following this, an an-tihypertensive agent should be chosen that is most ap-propriate for the specific clinical situation. For the ma-jority of acutely ill infants, particularly those with severehypertension, it bas been our experience that continuousintravenous infusions are the most appropriate approach.While intermittently administered agents also have a rolein the management of hypertension, the wide fluctua-tions in blood pressure frequently seen when theseagents are utilized make them inappropriate for treat-ment of severe hypertension. The advantage of intrave-nous infusions are numerous, most importantly including

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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(aneriolar)

2-5 mg/kg per dose

I^nalaprilat ACE inhibitor I5±5 |ig/kg per doseRepeat Q 8-24 h

Esmolol |3 blocker Drip: 100-300 |ag/kgper min

Hydralazine Vasodilator Bolus: 0.15-0.6 mg/kg(arteriolar) per dose

Drip: 0.75-5.0 )ig/kgper min

Labfialol a & ^ blocker 0.20-1.0 mu/kg per dose0.25-3.0 mg/kg per h

Nicardipine Ca^* channel 1-3 ).tg/kg per minblocker

Sodium nitroprusside Vasodilator 0.5-10 fig/kg per min(aneriolar &venous)

Rapid bolus injection Slow injeclion ineffective:duratit)n unpredictable:use with caution - may causerapid hypotension

Injection over 5-10 min May cause prolonged hypotensionand acute renal insufficiency

IV infusion Very short-acting - constaDt infusionnecessary

IV bolus or infusion Tachycardia frequent side-effect: musiadminister Q 4 h when given IV boltis

IV bolus or constantinfusion

Constant infusion

Constant infusion

Heart failure, BPD relativecontraindicationsMay cause reflex tachycardia

Thiocyanate toxicity can occurwith prolonged (>72 h) use orin renal failure

the ability quickly to increase or decrease the rate of in-fusion to achieve the desired level of blood pressure con-trol. As in patients of any age with tiiiilignant hypetten-sion. care should be taken to avoid too rapid a reductionin blood pressure [73. 74] to avoid cerebral ischemia andhemorrhage, a problem that premature infants in particu-lar are already at increased risk for due to the immaturityof their periventricular circulation. Here again, continu-OU.S infusions of intravenous anti hypertensives offer adistinct advantage.

Unfortunately, there are few data available regardingthe use of these agents in neonates. so in many cases thechoice of agent will depend on the individual clinician'sexperience. Our experience [75] and that of others |76|suggests that infusions of the calcium channel blockernicardipine tiiay be particularly useful in this population.Other drugs that have been successfully used in neonatesinclude esmolol [77], labetalol and nitroprusside [73|.Whatever agent is used, blood pressure should be moni-tored continuously via an indwelling arterial catheter, orelse by frequently repeated (Q 10-15 min.) cuff readingsso that the dose can be titrated to achieve the desired de-gree of blood pressure control.

For some infants, intermittently administered intrave-nous agents do have a role in therapy. Hydralazine andlabetalol in particular may be useful in infants with mild-to-nioderate hypertension that are not yet candidates lororal therapy because of gastrointestinal dysfunction.Enalaprilat, the intravenous angiotensin converting en-zyme inhibitor, has also been reported to be useful in thetreattnent of neonatal renovascular hypertension [78. 79|.However, in our experience, this agent should be usedwith great caution. Even doses at the lower end of pub-lished ranges tnay lead to significant, prolonged hypo-tension and oLiguric acute renal failure.

Oral antihypertensive agents (Table 4) are best re-served for infants with less severe hypertension or in-fants whose acute hypertension has been controlled withintravenous infusions and are ready to be transitioned tochronic therapy. Captopril in particular is a useful agentfor many causes of neonatal hypertension and is our oraldrug of choice for most infants seen in our unit. Caremust be taken to avoid giving a dose that is too high topremature infants, as they may have an exaggerated fallin blood pressure following captopril administration[80). For infants whose blood pressure is unable to becontrolled by captopril alone, the addition of a diureticfrequently will result in the desired degree of blood pres-sure control. Beta blockers may need to be avoided inchronic therapy of neonatal hypertension, particularly ininfants with chronic lung disease. In such infants, diuret-ics may have a beneficial effect not only in controllingblood pressure but also in improving pulmonary function[8IJ. Other drugs that we have found useful in some in-fants include hydralazine. minoxidil and the calciumchannel blocker i.sradipine 182]. When a vasodilator isindicated, isradipine tnay be superior to the older agentshydralazine and minoxidil since it can be compoundedinto a stable suspension !83[ that can be dosed with ac-curacy, even in tiny infants. We no longer use nifedipinein our unit because of the difficulty in adtiiinisteringsmall doses, and because of the rapid, profound, andshort-lived drops in blood pressure that are typically pro-duced by this agent.

Surgery is indicated tor treatment of neonatal hyper-tension in a limited set of circumstances |841. In particu-lar, hypertension caused by uretera! obstruction or aorticcoarctation |48| is best approached surgically. For in-fants with renal arteiial stenosis, it may be necessary tomanage the infant medically until it has grown sufft-

339

Table 4 Oral ugcnls useCul for liypeiiension in infants

Drug Class Dose Interval Comments

Cuptopiil

Clonidine

Hydraiazine

Isradipine

Amlodipine

Minoxidil

Propranolol

l.abet;ilnl

Spironolactone

ACE Inhibitor

Central a agonist

Vasodilator (arteriolar)

Ca'* channel blocker

Ca'+ channel blocker

Vasodilator (arleriolar)

P - blocker

a and P blocker

Aldcsterone antagonist

Hydrochlorothiazidc Thiazide diureticChlorothia/ide Thia/ide diuretic

<6m: 0.01-0.5 mg/kg TIDper doseMax 6 mg/kg per day0.05-0.1 mg per dose BID-TID

0.25-1.0 iTig/kg per dose TID-QIDMax 7.5 mg/kg per day

0.05-0.15 mg/kg per dose QIDMax 0.8 mg/kg per day0.1-0.3 mg/kg per dose BIDMax 0.6 mg/kg per day0.1-0.2 mg/kg per dose BID-TID

0.5-1.0 mg/kg per dose TID

1.0 tiig/kg per dose BID-TIDMax. 10 mg/kg per day0.5-1.5 mg/kg per dose BID

1-3 mg/kg per dose QID5-15 mg/kg per dose BID

Drug ot choice for most neonatal HTNmonitor serum creatinine and K*

Side effects include dry mouth & sedation;rebound hypertension with abruptdiscontinuation

Suspension stable up to I week;tachycardia & tluid retention commonside-effects; kipus-like syndrome maydevelop in slow acetylatorsSuspension may be compounded: usefulfor both acute & chronic HTNLess likely to cause sudden hypotensionihan isradipineMost potent oral vasodilator; excellentfor refractory HTNMaximal dose depends on heati rate;may go as high as 8-10 mg/kg per dayif no bradycardia. Avoid in infantswith BPD

Monitor heart rate; avoid in infantswilh BPDPotas.sium "sparing"; monitor electrolytes.Takes several days to see maximumeffectiveness

Monitor electrolytesMonitor electrolytes

ciently to undergo definitive repair of the vascular abnor-malities [851- Outcome of such surgical procedures canbecome quite good if performed at centers with a largeexperience [86]. Infants with hypertension secondary toWilms tumor or neuroblastoma will require surgical tu-mor removal [57. 58. 84]. possibly following chemother-apy. A case has also been made by some authors for re-moval of multicystic-dysplastic kidneys because of therisk of development of hypertension |37-391. althoughthis is controversial. Infants with malignant hypertensionsecondary to polycystic kidney disease may require bi-lateral nephrectomy. Fortunately, such severely affectedinfants are quite rare.

Outcome of neonatal hypertension

The long-term prognosis for infants with hypertension isin most eases quite good, depending of course on the un-derlying etiology of the infant's hypertension. For in-fants with hypertension related to an umbilical arterialcatheter, the hypertension will usually resolve over time[87. 88). These infants may require increases in their an-tihypertensive medications in the first several monthsfollowing discharge from the nursery as they undergorapid growth. Following this, it is usually possible towean their antihypertensives by making no further doseincreases as the infant continues to grow. Home blood

pressure monitoring by the parents is a crucially impor-tant component of this process. It is our standard of careto arrange for home blood pressute equipment, either aDoppler or oscillotnetric device, for all infants dis-charged frotn the NICU on antihypertensive medications.

Some forms of neonatal hypertension may persist be-yond infancy. In particular. PKD and other fomis of re-nal parenchytnal disease may continue to cause hyper-tension throughout childhood 135, 36, 89]. Infants withrenal venous thrombosis may also remain hypertensive[30|, and some of these children will ultimately benefitfrom removal of the affected kidney [29. 30]. Persi.stentor late hypertension may also be seen in children whohave undergone repair of renal arterial stenosis [86] orthoracic aortic coarctation |48|. Reappearance of hyper-tension in these situations should protnpt a search for re-stenosis by the appropriate imaging studies.

Conclusions

Blood pressure in neonates depends on a variety of fac-tors, including gestational age. post-natal age and birthweight. Hypertension can be seen in a variety of situa-tions in the tiiodern NICU, and is especially common ininfants who have undergone umbilical arterial catheter-ization. A careful diagnostic evaluation should lead to de-tetmination of the underlying cause of hypertension in

most intanls. Treatment decisions should be tailored tothe severity of the hypertension, and may include intrave-nous and/or oral therapy. Most infants will resolve theirhypertension over time, although a small number mayhave persistent blood pressure elevation throughout child-hood.

B The author wishes lo acknowledge Drs. DavjdKershaw and Manha Nelson Tor their lht)ugh(ful review of ihemanuscript, and Ruth Primas for her secretarial a.ssistance.

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