Neonatal Hypertension 

Updated: Jan 03, 2016
Author: Joseph Flynn, MD, MS; Chief Editor: Ted Rosenkrantz, MD 

Overview

Background

Advances in the ability to identify, evaluate, and care for infants with hypertension, coupled with advances in the practice of neonatology in general, have led to an increased awareness of hypertension in modern neonatal intensive care units (NICUs). This article provides an overview of the differential diagnosis of hypertension in the neonate, the optimal diagnostic evaluation of the disease, and immediate and long-term antihypertensive therapy. (See Presentation, DDx, Workup, Treatment, and Medication.)

Blood pressure (BP) in newborns depends on various factors, including gestational age, postnatal age, and birth weight. Hypertension can be observed in various situations in the modern NICU and is especially common in infants who have undergone umbilical arterial catheterization. A careful diagnostic evaluation should lead to determination of the underlying cause of hypertension in most infants. (See Etiology, Presentation, and Workup.)

Etiology and Risk Factors

As in older infants and children, most cases of neonatal hypertension are of renal origin, with the 2 largest categories being renovascular and renal parenchymal diseases. Other predisposing factors include a history of umbilical catheterization and cardiac, endocrine, and pulmonary causes.

A 1992 study by Singh and colleagues clearly demonstrated that hypertension was considerably more common in infants with BPD, patent ductus arteriosus, or intraventricular hemorrhage or in those who had indwelling umbilical arterial catheters. Approximately 9% of the infants in their series who had indwelling umbilical arterial catheters developed hypertension.[1]

The complexity of the infant’s nursery course also appears to be important in the development of hypertension. Freidman et al studied hypertension in NICU graduates and reported that infants who developed hypertension tended to have lower initial Apgar scores and slightly longer NICU stays than did infants who remained normotensive, indicating that sicker babies have a somewhat greater likelihood of developing hypertension.[2]

A study by Blowey et al of 764 neonates diagnosed with hypertension indicated that the greatest hypertension risk was a high severity of illness as reflected in the APR-DRG (All Patient Refined Diagnosis Related Groups) scoring system. Extracorporeal membrane oxygenation, coexisting renal disease, and renal failure also posed high risks. (Infants with congenital cardiac disorders were excluded from the study.)[3]

Umbilical artery catheter–associated thromboembolism

With respect to renovascular disease, umbilical artery catheter–associated thromboembolism affecting the aorta, the renal arteries, or both probably is the most common cause of hypertension observed in the typical NICU. In 1972, Neal et al were the first investigators to demonstrate an association between the use of umbilical arterial catheters and development of arterial thrombi. Using aortography at the time of umbilical artery removal, as well as autopsy data, they demonstrated thrombus formation in 25 of 31 infants studied (81%).[4]

Following Neal's report, the association between umbilical arterial catheter–associated thrombi and the development of hypertension was confirmed by several other groups of investigators. Although potential predisposing factors, such as duration of line placement and line position (low versus high), have been studied, these studies have not been conclusive, leading to the assumption that the cause of hypertension in such cases is related to thrombus formation at the time of line placement, which is probably related to disruption of the vascular endothelium of the umbilical artery. Such thrombi may then embolize into the kidneys, causing areas of infarction and increased renin release.

Additional renovascular causes

Other renovascular problems that may lead to neonatal hypertension include renal venous thrombosis (RVT) and renal artery stenosis secondary to fibromuscular dysplasia (FMD). Many infants with FMD may have main renal arteries that appear normal on angiography but demonstrate significant branch vessel disease that can cause severe hypertension.

Other vascular abnormalities may also lead to hypertension in the newborn, including idiopathic arterial calcification and renal artery stenosis secondary to congenital rubella infection.

Finally, mechanical compression of 1 or both renal arteries by tumors, hydronephrotic kidneys, or other abdominal masses may also lead to hypertension.

Renal parenchymal conditions

Numerous congenital renal parenchymal abnormalities can lead to hypertension in the newborn period. For example, patients with autosomal dominant or autosomal recessive polycystic kidney disease (PKD) may present in the newborn period with severe nephromegaly and hypertension. The most severely affected infants with PKD are at risk for development of congestive heart failure (CHF) due to severe, malignant hypertension.

Although much less common than in PKD, hypertension has also been reported in infants with unilateral multicystic dysplastic kidneys. Renal obstruction may be accompanied by hypertension, even in the absence of renal arterial compression. This has been observed, for example, in infants with congenital ureteropelvic junction obstruction and in infants with ureteral obstruction by other intra-abdominal masses. The mechanism of hypertension in such instances is unclear, although the renin-angiotensin-aldosterone system (RAAS) may be involved.

Additional renal parenchymal causes of hypertension in the newborn period include severe acute tubular necrosis, interstitial nephritis, and cortical necrosis. Hemolytic uremic syndrome, although rare in the newborn period, is usually accompanied by hypertension that can be quite difficult to control, frequently requiring multiple agents.

Bronchopulmonary dysplasia (BPD)

The most important nonrenal cause of neonatal hypertension is BPD. This association was first described in 1984, by Abman et al, who studied 65 infants discharged from a NICU.[5] Abman et al reported that the incidence of hypertension in infants with BPD was 43% versus an incidence of 4.5% in infants without BPD. More than half of the infants with BPD who developed hypertension did not manifest it until following discharge from the NICU, highlighting the need for measurement of BP in NICU graduates. Investigators were unable to identify a clear cause of hypertension but postulated that hypoxemia may be involved.

These findings have subsequently been reproduced by several other investigators. For example, Alagappan found that hypertension was twice as common in very low birth-weight infants with BPD compared with the incidence in all very low birth-weight infants.[6] As in Abman's report, the development of hypertension appeared to be correlated with the severity of pulmonary disease because all of the hypertensive infants were receiving supplemental oxygen and aminophylline. These observations reinforced the impression that infants with severe lung disease are clearly at increased risk of developing hypertension and need close monitoring for this problem.

Additional causes of hypertension

Numerous other causes of hypertension in newborns are recognized. Of these, hypertension associated with coarctation of the thoracic aorta deserves further comment. This is perhaps one of the most easily detected forms of hypertension in the newborn period and has been included in the differential diagnosis of this problem since the earliest reported case series of neonatal hypertension. Repair early in infancy seems to lead to an improved long-term outcome compared with delayed repair, which may be followed by persistent hypertension.

Endocrinologic disorders that may produce hypertension in the newborn period include congenital adrenal hyperplasia (CAH), hyperaldosteronism, and hyperthyroidism.

Iatrogenic hypertension can be the result of medications administered to infants for treatment of pulmonary disease, such as dexamethasone and aminophylline, high doses of adrenergic agents, prolonged use of pancuronium, or administration of phenylephrine ophthalmic drops. Hypertension in such cases typically resolves when the offending agent is discontinued or its dose is reduced.

For infants receiving prolonged total parenteral nutrition (TPN), hypertension may result from salt and water overload or from hypercalcemia. Patients with certain tumors, including neuroblastoma, Wilms tumor, and mesoblastic nephroma, may present in the neonatal period, and the tumors may produce hypertension either because of compression of the renal vessels or ureters or because of production of vasoactive substances, such as catecholamines.

Neurologic problems, such as seizures, intracranial hypertension, and pain, constitute fairly common causes of episodic hypertension. Finally, illicit substances ingested by the mother during pregnancy, most notably cocaine and heroin, may also lead to significant problems with hypertension in the newborn either because of direct effects on the developing kidney or because of drug withdrawal.

Epidemiology

Occurrence in the United States

Although precise figures are difficult to obtain, available data suggest that the incidence of hypertension in newborns is low, with published figures ranging from 0.2-3%. In a recent study, hypertension requiring treatment was found in 1.3% of neonates admitted to a teaching hospital NICU.[7] Hypertension is so unusual in otherwise healthy term infants that routine blood pressure (BP) determination is not advocated for these patients.

Hypertension may also be detected following discharge from the NICU. Friedman and Hustead diagnosed hypertension (defined as a systolic BP >113 mm Hg on 3 consecutive visits over 6 wk) in 2.6% of infants discharged from a teaching hospital NICU.[2] The diagnosis of hypertension was made in these infants at a mean corrected age of approximately 2 months. Although the number of babies affected is likely to be relatively small, this study supports screening for hypertension in the follow-up for NICU graduates, especially those with more complicated NICU courses.

International occurrence

A study of approximately 2600 infants treated at a single center in Australia over a 4-year period demonstrated a prevalence of hypertension of 1.3%.[8] Antenatal steroids, maternal hypertension, umbilical arterial catheter placement, postnatal acute renal failure, patent ductus arteriosus, treatment with indomethacin, and chronic lung disease were associated with the development of hypertension.

Prognosis

The long-term prognosis for most infants with hypertension is quite good. For infants with hypertension related to an umbilical arterial catheter, the hypertension usually resolves over time. These infants may require increases in their antihypertensive medications in the first several months following discharge from the nursery as they undergo rapid growth. Following this, weaning the patient off antihypertensive therapy is usually possible by making no further dose increases as the infant continues to grow. Home blood pressure (BP) monitoring by the parents is a crucially important component of this process.

Provide proper equipment, either a Doppler or oscillometric device, for all infants discharged from the NICU on long-term antihypertensive medications. Such infants may benefit from referral to a comprehensive pediatric hypertension clinic if their primary care provider is inexperienced in managing hypertension.

Other forms of neonatal hypertension may persist beyond infancy. In particular, polycystic kidney disease (PKD) and other forms of renal parenchymal disease may continue to cause hypertension throughout childhood. Infants with renal venous thrombosis (RVT) may also remain hypertensive, and some of these children ultimately benefit from nephrectomy.

Persistent or recurrent hypertension may also be observed in children who have undergone repair of renal arterial stenosis or coarctation of the aorta. Reappearance of hypertension in these situations should prompt a search for restenosis using the appropriate imaging studies.

Complications

The long-term sequelae of neonatal hypertension on renal growth, renal function, and future BP are unknown at this time. Long-term effects related to certain antihypertensive medications (eg, angiotensin-converting enzyme [ACE] inhibitors, calcium channel blockers) are also unknown. Infants with neonatal hypertension may need to be monitored closely even after their hypertension has resolved, particularly with respect to renal growth and the redevelopment of hypertension in later childhood.

Patient Education

Educate the parents of infants who develop hypertension requiring drug therapy about the expected effects and side effects of their infant's antihypertensive medications. In addition, arrange home blood pressure (BP) monitoring equipment and educate the parents in its use prior to the infant's discharge from the NICU. Parents must monitor the BP of all infants discharged on antihypertensive medications on a regular basis (ie, usually daily); parents should call the prescribing clinician if the infant's BP exceeds or falls below the target range.

Patient education information on childhood hypertension can be found at the International Pediatric Hypertension Association web site.

For patient education information, see High Blood Pressure (Hypertension).

 

Presentation

History

In most newborns, hypertension is discovered on routine monitoring of vital signs. Other presentations of neonatal hypertension to be aware of in acutely ill infants include congestive heart failure (CHF) and cardiogenic shock, which are potentially life threatening. Fortunately, these consequences of hypertension gradually resolve with appropriate blood pressure (BP) reduction.

In the less acutely ill infant, feeding difficulties, unexplained tachypnea, apnea, lethargy, irritability, or seizures may constitute symptoms of unsuspected hypertension. In older infants who have been discharged from the nursery, unexplained irritability or failure to thrive may be the only manifestations of hypertension.

Focus the history on discovering any pertinent prenatal or postnatal exposures, as well as to the particulars of the infant's nursery course and any concurrent conditions. Review the procedures that the infant has undergone, especially umbilical catheter placement, and analyze the baby's current medication list. If the infant has been discharged from the nursery, the history should also cover symptoms related to possible underlying causes of hypertension (similar to the evaluation of hypertension in older children).

Physical Examination

The physical examination should begin with 4-extremity blood pressure (BP) measurements in order to rule out aortic coarctation. Assess the general appearance of the infant and pay particular attention to the presence of dysmorphic features that may indicate an underlying genetic syndrome. Perform careful cardiac and abdominal examinations to rule out congestive heart failure (CHF) or renal anomalies. Examine the genitalia to rule out congenital adrenal hyperplasia (CAH). Neurologic examination may also be helpful, particularly in infants with intraventricular hemorrhage.

Normal blood pressure levels

BP in newborn infants is influenced by various factors, including birth weight, gestational age, and postconceptual age. Excellent data illustrating the importance of these factors were generated by Zubrow et al, who prospectively obtained serial BP measurements from nearly 700 infants admitted to several NICUs in a large metropolitan area over 3 months.[9] The investigators used these data to define the mean plus upper and lower 95% confidence limits for BP; their data clearly demonstrated increases in BP with increasing gestational age, birth weight, and postconceptual age.

A more recent study of hemodynamically stable premature and term infants admitted to the NICU showed that BPs on day 1 of life correlated with gestational age and birth weight.[10] However, another study of more than 400 term infants admitted to a postnatal ward in Australia showed no difference in BP on day 1 of life based on birth weight, length, or gestational age.[11] Thus, there appears to be physiologic differences in premature infants with respect to BP level that need to be taken into consideration when considering whether a particular BP value is normal or elevated.

Data from these studies have recently been summarized by Dionne et al,[12, 13] who generated a table of BP values that can be used in assessing if a neonate’s BP is normal or elevated (see Table 1 below). For older infants, the percentile curves generated by the 1987 Second Task Force on Blood Pressure Control in Childhood remain the most useful reference of normal BP values (see the image below).[14] These curves allow BP to be characterized as normal or elevated not only by age and sex but also by size, albeit to a somewhat limited extent.

Normal blood pressure percentile curves for older Normal blood pressure percentile curves for older infants. From the Second (1987) Task Force on Blood Pressure Control in Childhood; National Heart, Lung, and Blood Institute.

Defining hypertensive-level BP

Hypertension in adults is defined based upon occurrence of hard cardiovascular endpoints such as myocardial infarction, stroke, and death. Since these events occur rarely in the pediatric age group, the definition of hypertension in infants, children, and adolescents is a statistical one based on databases of BP readings obtained in healthy subjects. Thus, BP in the young is considered normal if less than the 90th percentile for age, sex, and height, and is considered hypertensive if it is greater than or equal to the 95th percentile.

For infants, the same definitions should probably be applied, although the available data on normal BP values in infancy is limited. The table summarized below is a useful reference for premature infants, while the Second Task Force curves (see image above) can be used for term and older infants. However, there are obvious shortcomings for both of these references, highlighting the need for additional studies of normal BP in infancy.

Table 1. Neonatal Blood Pressures and Potential Treatment Parameters. Adapted from Dionne et al.* (Open Table in a new window)

Postconceptual Age

50th Percentile

95th Percentile

99th Percentile

44 weeks

 

 

 

SBP

88

105

110

DBP

50

68

73

MAP

63

80

85

42 weeks

 

 

 

SBP

85

98

102

DBP

50

65

70

MAP

62

76

81

40 weeks

 

 

 

SBP

80

95

100

DBP

50

65

70

MAP

60

75

80

38 weeks

 

 

 

SBP

77

92

97

DBP

50

65

70

MAP

59

74

79

36 weeks

 

 

 

SBP

72

87

92

DBP

50

65

70

MAP

57

72

77

34 weeks

 

 

 

SBP

70

85

90

DBP

40

55

60

MAP

50

65

70

32 weeks

 

 

 

SBP

68

83

88

DBP

40

55

60

MAP

49

64

69

30 weeks

 

 

 

SBP

65

80

85

DBP

40

55

60

MAP

48

63

68

28 weeks

 

 

 

SBP

60

75

80

DBP

38

50

54

MAP

45

58

63

26 weeks

 

 

 

SBP

55

72

77

DBP

30

50

56

MAP

38

57

63

 

*Estimated values for blood pressures after age 2 weeks in infants from 26-44 weeks postconceptual age. The 95th and 99th percentile values serve as a reference to identify infants with persistent hypertension that may require treatment. SBP, systolic blood pressure; DBP, diastolic blood pressure; MAP, mean arterial pressure.

 

DDx

Diagnostic Considerations

Cardiac conditions to consider in the differential diagnosis of neonatal hypertension include thoracic aortic coarctation. Renovascular conditions to consider in the differential diagnosis include the following:

  • Thromboembolism

  • Renal artery stenosis

  • Midabdominal aortic coarctation

  • Renal venous thrombosis

  • Compression of renal artery

  • Idiopathic arterial calcification

  • Congenital rubella syndrome

Renal parenchymal diseases to consider in the differential diagnosis of neonatal hypertension include the following:

  • Polycystic kidney disease

  • Multicystic dysplastic kidney disease

  • Tuberous sclerosis

  • Ureteropelvic junction obstruction

  • Acute tubular necrosis

  • Cortical necrosis

  • Interstitial nephritis

  • Hemolytic-uremic syndrome

Pulmonary conditions to consider in the differential diagnosis of neonatal hypertension include the following:

  • Bronchopulmonary dysplasia

  • Pneumothorax

Endocrine conditions to consider in the differential diagnosis of neonatal hypertension include the following:

  • Congenital adrenal hyperplasia

  • Hyperaldosteronism

  • Hyperthyroidism

  • Pseudohypoaldosteronism type II

Medications/intoxications to consider in the differential diagnosis of neonatal hypertension include the following:

  • Dexamethasone

  • Adrenergic agents

  • Vitamin D intoxication

  • Theophylline

  • Caffeine

  • Pancuronium

  • Phenylephrine

  • Maternal cocaine or heroin use

Tumors that should be considered in the differential diagnosis of neonatal hypertension include the following:

  • Neoplasia

  • Wilms tumor

  • Mesoblastic nephroma

  • Neuroblastoma

  • Pheochromocytoma

Neurologic conditions to consider in the differential diagnosis of neonatal hypertension include the following:

  • Pain

  • Intracranial hypertension

  • Seizures

  • Familial dysautonomia

  • Subdural hematoma

Miscellaneous conditions to consider in the differential diagnosis of neonatal hypertension include the following:

  • Closure of abdominal wall defect

  • Adrenal hemorrhage

  • Hypercalcemia

  • Traction

  • Extracorporeal membrane oxygenation

  • Birth asphyxia

  • Urologic neoplasms

Differential Diagnoses

 

Workup

Approach Considerations

Usually only a limited set of laboratory data are needed in the evaluation of neonatal hypertension. Obtain serum electrolyte, calcium, creatinine, and blood urea nitrogen (BUN) analysis, as well as urinalysis, in looking for renal parenchymal disease. Obtain endocrinologic studies, such as cortisol, aldosterone, or thyroxine, when pertinent history is noted.

Blood pressure measurement

Proper identification of hypertension in the newborn requires accurate blood pressure (BP) measurement. Fortunately, in most acutely ill infants, BP is usually monitored directly via an indwelling arterial catheter, either in the radial or umbilical artery. This method provides the most accurate BP readings and is clearly preferable to other methods.

In infants who do not have indwelling umbilical lines, automated oscillometric devices are an acceptable alternative method of BP measurement. Although BP readings obtained using such devices may differ slightly from intra-arterial readings, they are easy to use and facilitate the monitoring of BP trends over time. BP readings obtained using such devices are also useful for infants who require BP monitoring after discharge from the NICU. Repeat determinations are advised due to the tendency of oscillometric devices to inflate to a preset value on the first reading.

Pay attention to the size of the cuff and also to the extremity used. Most normative BP data, not only in infants but also in older children, have been collected using BP measurements obtained in the right arm. Because BP measurements obtained in the leg may be slightly higher than those obtained in the arm, the use of other extremities for routine BP determination may complicate the evaluation of hypertension. The nursing staff should document the extremity used for BP determinations and try to use the same extremity for all BP measurements, especially in infants who require antihypertensive treatment.[15]

Plasma Renin Activity

Measurement of plasma renin activity (PRA) is usually recommended as part of the laboratory assessment in newborns with hypertension, although elevated peripheral renin levels may not signify the presence of underlying pathology, because renin values are typically high in infancy. In addition, plasma renin levels may be falsely elevated by medications that are commonly used in the NICU, such as aminophylline. Keep these factors in mind when interpreting renin values.

Alternatively, suppressed PRA in an infant with hypertension is a significant finding, possibly indicating the presence of a genetic form of hypertension associated with volume overload, such as glucocorticoid-remediable aldosteronism or Liddle Syndrome.

Imaging Studies

Chest radiography may be helpful in infants with congestive heart failure (CHF) or in those with a murmur upon physical examination.

Perform renal ultrasonography with Doppler of the renal vessels in all hypertensive infants. Accurate renal ultrasonography may help to uncover potentially correctable causes of hypertension (eg, renal venous thrombosis [RVT]), it may detect aortic thrombi and/or renal arterial thrombi, and it may reveal anatomic renal abnormalities or other congenital renal parenchymal disease. Ultrasonography is fast, noninvasive, and relatively inexpensive. The modality has largely replaced intravenous pyelography, which has little, if any, use in the routine assessment of neonatal hypertension.

For infants with extremely severe blood pressure (BP) elevation, angiography may be necessary. Although some investigators have used aortography via the umbilical artery catheter, formal renal arteriography using the traditional femoral vascular approach is much more accurate for diagnosing renal arterial stenosis, primarily because of the high incidence of intrarenal branch vessel abnormalities observed in children with fibromuscular dysplasia. Depending on the expertise available, this may need to be deferred until the infant is larger. Magnetic resonance (MR) and computed tomography (CT) angiography are of little value in infants, as they do not provide sufficient resolution to identify branch vessel stenoses.

Nuclear scanning may demonstrate abnormalities of renal perfusion caused by thromboembolic phenomenon, although obtaining good studies in infants is difficult because of their immature renal function. Obtain other studies, including echocardiography and voiding cystourethrography, as indicated.

 

Treatment

Approach Considerations

Tailor treatment decisions, which may include intravenous therapy, oral therapy, or both, to the severity of the hypertension. Hypertension resolves in most infants over time, although a small number of infants may have persistent blood pressure elevation throughout childhood.

Numerous medications are available that may be used in the treatment of neonatal hypertension. Assess the clinical status of the infant and correct any easily correctable iatrogenic causes of hypertension (eg, infusions of inotropic agents, volume overload, pain) prior to instituting drug therapy. Next, choose an antihypertensive agent that is most appropriate for the specific clinical situation.[16]

Few medications are approved for use in treating hypertension in neonates; therefore, all such use must be considered off label.

Transfer

Occasionally, infants may need to be transferred to specialized centers for advanced diagnostic or therapeutic procedures, such as angiography or vascular surgery.

Diet

A low-sodium diet may assist in treatment of infants with persistent hypertension; however, because most infant formula is relatively low in sodium content, no special dietary modifications are usually necessary in the neonatal period.

Consultations

Consultation with a cardiologist may be indicated for performance of echocardiography and/or evaluation of congestive heart failure. Nephrologist consultation may be needed if parenchymal renal disease is diagnosed. Consultation with an interventional radiologist may also be needed in some cases for performance of renal angiography.

Deterrence and prevention

Although several studies have examined the role of placement of umbilical artery catheters (ie, low versus high lines), no definitive proof has emerged that changes in catheter placement can prevent thromboembolism and the subsequent development of hypertension.

Intravenous Antihypertensive Infusions

Usually, continuous intravenous infusions are the most appropriate initial therapy, especially in acutely ill infants with severe hypertension. The advantages of intravenous infusions are numerous, most importantly including the ability to quickly increase or decrease the rate of infusion to achieve the desired blood pressure (BP). In patients of any age with malignant hypertension, take care to avoid too rapid a reduction in BP, in order to avoid cerebral ischemia and hemorrhage; premature infants in particular are already at an increased risk because of the immaturity of their periventricular circulation.

Because of the paucity of available data regarding the use of intravenous antihypertensive infusions in newborns, the choice of agent depends on the individual clinician's experience.

Currently available drugs for continuous infusion include sodium nitroprusside, labetalol, esmolol, fenoldopam and nicardipine (see Table 1, below). Nicardipine, which is a dihydropyridine calcium channel blocker, has been reported to be effective most often in neonates; it appears to have some advantages compared with older drugs that may make it the drug of choice in the neonatal population.

Regardless of the drug chosen, continuously monitor BP via an indwelling arterial catheter or by frequently repeated (every 10-15min) cuff readings so that the rate of infusion can be titrated to achieve the desired degree of BP control.

Table 2. Intravenous Drugs for Severe Hypertension in Neonates [12] (Open Table in a new window)

Drug

Class

Intravenous (IV) Dosage

Comments

Esmolol

Beta blocker

100-300 mcg/kg/min IV infusion

Very short acting; constant IV infusion necessary

Hydralazine

Vasodilator (arteriolar)

0.15-0.6 mg/kg/dose IV bolus or 0.75-5mcg/kg/min IV constant infusion

Tachycardia is frequent adverse effect; must administer every 4 hours when administered as IV bolus

Labetalol

Alpha blocker and beta blocker

0.2-1 mg/kg/dose IV bolus or 0.25-3 mg/kg/h IV constant infusion

Heart failure, bronchopulmonary dysplasia (BPD), relative contraindications

Nicardipine

Calcium channel blocker

1-5 mcg/kg/min IV constant infusion

May cause reflex tachycardia

Sodium nitroprusside

Vasodilator (arteriolar and venous)

0.5-10 mcg/kg/min IV constant infusion

Thiocyanate toxicity can occur with prolonged use (>72 h) or in renal failure; usual maintenance dose is below 2 mcg/kg/min; may use 10 mcg/kg/min for short duration (ie, < 10-15 min)

Intermittently Administered IV Antihypertensive Agents

For some infants, intermittently administered intravenous agents have a role in therapy (see Table 1, above). Hydralazine and labetalol, in particular, may be useful in infants with mild to moderate hypertension who are not yet candidates for oral therapy because of gastrointestinal (GI) dysfunction. Enalaprilat, the intravenous angiotensin-converting enzyme (ACE) inhibitor, has also been reported to be useful in the treatment of neonatal renovascular hypertension; however, it should be used with great caution. No study has been performed to determine a safe and effective pediatric dose; furthermore, even doses at the lower end of published ranges may lead to significant prolonged hypotension and oliguric acute renal failure.

Oral Antihypertensive Agents

Oral antihypertensive agents (see Table 2, below) are best reserved for infants with less severe hypertension or infants whose acute hypertension has been controlled with intravenous drugs and who are ready to be converted to long-term therapy. Although captopril had once been considered by many authorities to be the oral drug of choice for neonatal hypertension, this has come under question because of the possibility of adverse effects on renal development, particularly in premature infants. It is probably acceptable for use in infants with a postconceptual age of 44 weeks and above.

Beta-blockers may need to be avoided in long-term antihypertensive therapy in infants with bronchopulmonary dysplasia (BPD). In such infants, diuretics may have a beneficial effect not only in controlling blood pressure (BP), but also in improving pulmonary function. Other drugs that may be useful in some infants include vasodilators, such as hydralazine and minoxidil (because it can be compounded into a stable suspension), and the calcium channel blocker isradipine, which may be superior to the older agents.

Nifedipine is a poor choice for long-term therapy because of the difficulty in administering small doses and because of the rapid, profound, and short-lived drops in BP that are typically produced by this agent.

Table 3. Oral Antihypertensive Agents Useful for Treatment of Neonatal Hypertension [12] (Open Table in a new window)

Drug

Class

Oral Dosage

Comments

Captopril

Angiotensin-converting enzyme (ACE) inhibitor

Under age 3 months: 0.01-0.5 mg/kg/dose 3 times daily; not to exceed 2 mg/kg/day

At or above age 3 months: 0.15-0.3 mg/kg/dose 3 times daily; not to exceed 6 mg/kg/day

Monitor serum creatinine and potassium levels

Clonidine

Central agonist

0.05-0.1 mg/dose 2-3 times daily

Adverse effects include dry mouth and sedation; rebound hypertension with abrupt discontinuation

Enalapril

ACE inhibitor

0.08-0.6 mg/kg/day, given once or twice daily

Monitor serum creatinine and potassium levels

Hydralazine

Vasodilator (arteriolar)

0.25-1 mg/kg/dose 3-4 times daily; not to exceed 7.5 mg/kg/day

Suspension stable up to 1 wk; tachycardia and fluid retention are common adverse effects; lupuslike syndrome may develop in slow acetylators

Isradipine

Calcium channel blocker

0.05-0.15 mg/kg/dose 4 times daily; not to exceed 0.8 mg/kg/d or 20 mg/day

Suspension may be compounded; useful for both acute and chronic hypertension

Amlodipine

Calcium channel blocker

0.1-0.3 mg/kg/dose twice daily; not to exceed 0.6 mg/kg/d or 20 mg/d

Less likely to cause sudden hypotension than isradipine

Minoxidil

Vasodilator (arteriolar)

0.1-0.2 mg/kg/dose 2-3 times daily

Most potent oral vasodilator; excellent for refractory hypertension

Propranolol

Beta-blocker

0.5-1 mg/kg/dose 3 times daily

Maximal dose depends on heart rate; may administer as much as 8-10 mg/kg/d if no bradycardia; avoid in infants with BPD

Labetalol

Alpha and beta blocker

1 mg/kg/dose 2-3 times daily, up to 12 mg/kg/d

Monitor heart rate; avoid in infants with BPD

Spironolactone

Aldosterone antagonist

0.5-1.5 mg/kg/dose twice daily

Potassium-sparing diuretic; monitor electrolytes; several days necessary to observe maximum effectiveness

Hydrochlorothiazide

Thiazide diuretic

2-3 mg/kg/d orally every day or divided twice daily

Monitor electrolytes

Chlorothiazide

Thiazide diuretic

5-15 mg/kg/dose twice daily

Monitor electrolytes

Surgical Care

Surgery is rarely indicated for the treatment of neonatal hypertension, except for specific diagnoses, such as ureteral obstruction, aortic coarctation, or certain tumors. Unilateral renal venous thrombosis is commonly treated with nephrectomy to avoid the need for long-term drug therapy.

For infants with renal arterial stenosis, managing the infant medically may be necessary until the patient’s growth is sufficient for the child to undergo definitive repair of the vascular abnormalities. Infants with malignant hypertension secondary to polycystic kidney disease may require bilateral nephrectomy. Fortunately, such severely affected infants are quite rare.

Monitoring

Monitor blood pressure (BP) regularly in neonates with hypertension until the infant is ready for discharge from the NICU. Infants treated with angiotensin-converting enzyme (ACE) inhibitors or diuretics should have electrolyte levels and renal function monitored periodically until discharge.

Arrangements for home BP monitoring should be part of the discharge plan for any infant sent home on antihypertensive therapy. The optimal device for home BP measurements in an infant is a Dinamap device or a similar oscillometric device. A second choice is a Doppler device: however, this only measures systolic BP and is difficult to teach parents to use. Therefore, oscillometric devices should be prescribed.

Include BP measurement at all follow-up visits for infants with neonatal hypertension. In addition, monitor infants with bronchopulmonary dysplasia at discharge and those who had complicated NICU courses for the development of hypertension following discharge.

Ultrasonography should be obtained 6-12 months after discharge in infants with hypertension to ensure that the kidneys are growing normally.

 

Medication

Medication Summary

Most medications discussed in this article have not been specifically studied in newborns; however, through the empiric use of these medications, reasonable clinical experience has been accumulated.

As previously stated, assess the clinical status of the infant and correct any easily correctable iatrogenic causes of hypertension (eg, infusions of inotropic agents, volume overload, pain) prior to instituting drug therapy. Next, choose an antihypertensive agent that is most appropriate for the specific clinical situation.[16]

A study by Blowey et al[3] assessing pharmacologic treatment in neonates with hypertension (excluding patients with congenial cardiac disorders) demonstrated that multiple drugs are commonly prescribed for hypertensive neonates; the distribution of medication classes used was as follows:

  • Vasodilators - 64.2% of patients

  • Angiotensin-converting enzyme (ACE) inhibitors - 50.8% of patients

  • Calcium channel blockers - 24% of patients

  • Alpha and beta blockers - 18.4% of patients

The authors also determined that more than 1 antihypertensive agent was used in 45% of the neonates with hypertension.

Vasodilators

Class Summary

These agents relax blood vessels, thereby decreasing peripheral vascular resistance.

Hydralazine

Hydralazine decreases systemic resistance through direct vasodilation of arterioles.

Sodium nitroprusside (Nitropress)

Sodium nitroprusside produces vasodilation and increases inotropic activity of the heart.

Calcium Channel Blockers

Class Summary

These agents block calcium channels in vascular smooth muscle, which leads to vasodilatation.

Amlodipine (Norvasc)

Amlodipine relaxes coronary smooth muscle and produces coronary vasodilation, which, in turn, improves myocardial oxygen delivery. This agent is a good choice for long-term outpatient treatment. It may be compounded into a stable suspension (1mg/mL).

Isradipine (DynaCirc CR)

Isradipine is a dihydropyridine calcium channel blocker. It binds to calcium channels with high affinity and specificity and inhibits calcium flux into cardiac and smooth muscle. The resultant effect is arteriole dilation, which reduces systemic resistance and blood pressure, with a small increase in resting heart rate. Isradipine has a rapid onset of action. It may be compounded into a stable suspension.

Nicardipine (Cardene)

Nicardipine relaxes coronary smooth muscle and produces coronary vasodilation, which, in turn, improves myocardial oxygen delivery and reduces myocardial oxygen consumption. Intravenous nicardipine is the drug of choice for initial management of severe neonatal hypertension.

Cardiovascular, Other

Class Summary

These agents decrease heart rate and cardiac output.

Labetalol (Normodyne, Trandate)

Labetalol blocks beta1-adrenergic, alpha-adrenergic, and beta2-adrenergic receptor sites, decreasing blood pressure.

Propranolol (Inderal, InnoPran XL)

Propranolol has membrane-stabilizing activity and decreases the automaticity of contractions.

It is not suitable for the emergency treatment of hypertension. Do not administer propranolol intravenously in hypertensive emergencies.

Esmolol (Brevibloc)

Esmolol is an excellent drug for use in patients at risk for experiencing complications from beta blockade, particularly individuals with reactive airway disease, mild to moderate left ventricular dysfunction, and/or peripheral vascular disease. Its short half-life of 8 minutes allows for titration to the desired effect and quick discontinuation if needed.

ACE Inhibitors

Class Summary

These agents inhibit the conversion of angiotensin I to angiotensin II.

Captopril

Captopril prevents the conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, and reduces aldosterone secretion.

Enalapril (Vasotec)

Enalapril is a competitive inhibitor of ACE. It reduces angiotensin II levels, decreasing aldosterone secretion.

Diuretics, Other

Class Summary

These agents decrease plasma volume and promote excretion of water and electrolytes by the kidneys. They may be used as monotherapy or combination therapy to treat hypertension.

Chlorothiazide (Diuril)

Chlorothiazide inhibits the reabsorption of sodium in the distal tubules, causing increased excretion of sodium and water as well as of potassium and hydrogen ions.

Hydrochlorothiazide (Microzide)

Hydrochlorothiazide inhibits the reabsorption of sodium in the distal tubules, causing increased excretion of sodium and water as well as potassium and hydrogen ions. It is a good second agent to add to angiotensin-converting enzyme (ACE) ̶ inhibitor or vasodilator therapy.

Spironolactone (Aldactone)

Spironolactone is a potassium-sparing diuretic that is used for the management of hypertension. It may block the effects of aldosterone on arteriolar smooth muscles.

Alpha2 Agonists, Central-Acting

Class Summary

These agents decrease central adrenergic output.

Clonidine (Catapres)

Clonidine stimulates alpha2-adrenoreceptors in the brain stem, activating an inhibitory neuron, which, in turn, results in reduced sympathetic outflow. These effects produce a decrease in vasomotor tone and heart rate.