61: Hypertension

An infant has a systolic blood pressure (BP) of >95 mm Hg. Normal blood pressure values depend on the infant's gestational age, postnatal age, and birthweight. Hypertension is commonly defined as a BP >2 standard deviations above normal values for age and weight, but other definitions exist. The Task Force on Blood Pressure Control in Children defines hypertension as 95% percentile or above on 3 separate occasions. For a rapid reference of blood pressure ranges for premature and term infants see Table 65–1. For estimated BP levels at the 95th and 99th percentiles in infants after 2 weeks of age see Table 61–1. For other detailed BP values see Appendix C. Normal blood pressure increases with birthweight, gestational age, and postconceptional age.

1. How was the BP taken? Verify that the BP reading is correct and the hypertension is real. As the first reading is usually the highest, it is best to take 2–3 confirmatory measurements. BP rises when the infant is feeding, sucking, or in an upright position. BP is lower in the prone versus supine position. Measure when the infant is calm. Most BP data is from measurements taken from the right arm.

   1. Blood pressure cuff size is important; it should encircle two-thirds of the length of the upper extremity. If the cuff is too narrow, the BP will be falsely elevated. The American Academy of Pediatrics (AAP) recommendations for BP cuff bladder width are as follows: newborn—4 cm; infant—6 cm. For length: newborn—8 cm; infant—12 cm. Maximum arm circumference: newborn—10 cm; infant—15 cm.

   2. BP reading from an indwelling catheter (radial or umbilical artery) is the most accurate (gold standard) of all methods. If measurements are taken by means of an umbilical artery catheter (UAC), be certain that the catheter is free of bubbles or clots and the transducer is calibrated; otherwise, erroneous results will occur.

   3. Automated oscillometric devices (electronic pressure sensor), common in the neonatal intensive care unit (NICU), can give lower pressures than intra-arterial catheters.

   4. BP protocols have been established to standardize blood pressure measurement in infants. One suggested by Nwankwo is to measure BP 1.5 hours after feeding or medical intervention, with the infant asleep or in a quiet state and lying prone or supine. Place an appropriate-sized cuff on the right upper arm, and let the infant rest undisturbed after cuff placement for 15 minutes. Measure by oscillometric device, and do 3 successive BP readings at 2-minute intervals.

   5. The AAP does not recommend universal screening but states it is important to screen blood pressure in those infants in whom coarctation of the aorta or renal disease is suspected.

2. Is an umbilical artery catheter in place, or has one been in place in the past? Incidence of hypertension is ∽ 9% with a UAC. Umbilical artery catheters are associated with an increased incidence of renovascular hypertension. The hypertension is probably related to the thrombus formation at the time of line placement. The following conditions are risk factors for thrombus formation in the aorta: bronchopulmonary dysplasia/chronic lung disease (BPD/CLD), patent ductus arteriosus, hypervolemia, and certain central nervous system (CNS) disorders. Improved catheters and the use of heparin have helped decrease the incidence of thrombus formation. Hypertension appears with equal frequency in high versus low catheters.

3. Are signs of hypertension present? Infants with hypertension may be asymptomatic or manifest the following: irritability, tachypnea, cyanosis, seizures, lethargy, increased tone, apnea, abdominal distention, fever, and mottling. They may also have congestive heart failure (CHF), failure to thrive, GI problems, and respiratory distress.

4. What is the BP in the extremities? The BP in a healthy infant should be higher in the legs than in the arms. If the pressure is lower in the legs, coarctation of the aorta may be the cause of the hypertension. Coarctation of the aorta is the most common heart malformation that causes hypertension in a neonate.

5. What is the birthweight, gestational age, and postnatal age of the infant? Normal BP values increase with increasing birthweight, gestational age, and post-conceptional age. Values rise ∼1–2 mm Hg/d during the first week of life and then ∼1–2 mm Hg/wk over the next 6 weeks.

6. Is the infant in pain or agitated? Pain from an invasive procedure, crying, agitation, or suctioning can cause a transient rise in BP. The systolic pressure can be 5 mm Hg lower in sleeping infants.

7. Does the infant have BPD/CLD or an intraventricular hemorrhage? Infants with BPD/CLD have a significant problem with hypertension (6% up to 40%). It often occurs after discharge from the nursery. Infants with an intraventricular hemorrhage (3% incidence) also have an increased risk of hypertension.

8. Does the infant have any risk factors that would be associated with the development of hypertension? Chronic lung disease, respiratory distress syndrome (RDS), prematurity, extremely low birthweight (ELBW), UAC placement, maternal hypertension, antenatal steroids, acute renal failure (acute kidney injury) in the postnatal period, and treatment with indomethacin are all associated with the development of hypertension in a neonate.

9. Were recent boluses of fluids or blood products given? Fluid overload is a common iatrogenic cause of hypertension, especially in infants with decreased urine output.

10. Was there maternal drug use (cocaine or heroin)? Maternal drug use of cocaine and heroin has been associated with hypertension in their newborn infants.

Hypertension is rare in the healthy term newborn infant. The incidence is from 0.2–3% (healthy newborn) to 40% (in infants with chronic lung disease). Hypertension in newborns is primarily of renal origin (renovascular and renal parenchymal diseases). BPD/CLD is the most common nonrenal cause.

1. Common causes of hypertension. See Table 61–2 for comprehensive list.

   1. Renal causes/vascular causes

      1. Renal artery stenosis. The infant is hypertensive from birth. This accounts for 20% of the cases of hypertension in infants. It can be secondary to fibromuscular dysplasia. Congenital rubella infection can cause arterial calcification and renal artery stenosis.

      2. Renal artery thrombosis. Most commonly related to umbilical artery catheterization, this is a relatively common cause of hypertension. The thrombi embolize to the kidneys causing infarction and increased release of renin.

      3. Renal vein thrombosis. Seen in hypovolemic or asphyxiated infants, infants of diabetic mothers, and infants with coagulopathies. Signs are hypertension, gross hematuria, thrombocytopenia, and a flank mass.

      4. Renal failure. Postnatal acute renal failure (acute kidney injury) is associated with hypertension. Acute tubular necrosis (ATN) secondary to perinatal asphyxia or sepsis is a common cause.

      5. Congenital renal disease. Autosomal dominant or autosomal recessive polycystic kidney disease can present in the neonate with hypertension and enlarged kidneys. Ureteropelvic junction obstruction can activate the renin-angiotensin system and cause hypertension.

   2. Bronchopulmonary dysplasia/chronic lung disease (BPD/CLD) is the most common cause of nonrenal hypertension in the neonate. Approximately 13–43% of patients with BPD/CLD have hypertension. The origin is unclear but is probably multifactorial (increased renin activity and catecholamine secretion and chronic hypoxemia may be associated with chronic lung disease). The majority of these infants develop hypertension after being discharged from the hospital.

   3. Coarctation of the aorta. A common cause of hypertension in newborns. Occurs with an increased incidence in Turner syndrome.

   4. Neurologic. Increased intracranial pressure and seizures can cause episodic hypertension. Intraventricular hemorrhage can cause increased intracranial pressure.

   5. Medications. Such as corticosteroids (antenatal and postnatal), theophylline, caffeine, adrenergic agents, and ocular phenylephrine. Maternal use of cocaine can cause damage to the kidneys. Drug withdrawal from heroin can cause hypertension.

   6. Fluid/electrolyte overload.

   7. Pain or agitation. This usually causes episodic hypertension.

   8. Other. Extracorporeal membrane oxygenation/extracorporeal life support (ECMO/ECLS) (up to 50% of infants), abdominal surgery (closure of an abdominal wall defect).

1. History. Evaluate maternal factors: Was cocaine or heroin used during pregnancy, or were antenatal steroids used? Does the infant have a predisposing illness that would account for the hypertension, eg, BPD/CLD, CNS disorder, PDA? Evaluate the current medication list, and determine if the infant has a UAC?

2. Physical examination. In most infants, hypertension is discovered on vital signs with no overt signs. Life-threatening presentations can include congestive heart failure with cardiogenic shock or seizures or few or no signs. Some infants present with apnea, feeding difficulties, failure to thrive, irritability, lethargy, unexplained tachypnea, and mottling of the skin. Check for tachycardia and flushing for hyperthyroidism.

   1. Check the femoral pulse in both legs, which are absent or decreased in coarctation of the aorta. Check blood pressure in all 4 extremities (blood pressure discrepancies between the upper and lower extremities, arterial hypertension in the upper extremities with normal to low blood pressure in the lower extremities).

   2. Are there any dysmorphic features that would indicate a genetic syndrome that would explain the hypertension? Consider Turner, Noonan, Williams, or Liddle syndrome.

   3. Do a complete cardiac examination to rule out congestive heart failure. Is there a heart murmur? Is there cyanosis? Is there tachycardia? Is there mottling and signs of vasomotor instability?

   4. Respiratory. Is there tachypnea or cyanosis?

   5. Examine the abdomen for masses and to determine the size of the kidneys. Is there abdominal distension? An enlarged kidney or flank mass may indicate tumor, polycystic kidneys, obstruction, or renal vein thrombosis. An epigastric bruit can indicate renal artery stenosis.

   6. Examine the genitalia to rule out congenital adrenal hyperplasia.

   7. Neurologic signs may include apnea, lethargy, tremors, seizures, asymmetric reflexes, or hypertonicity.

3. Laboratory studies. Few tests are usually needed and should be dictated by history and physical examination. Basic tests should include CBC and platelet count, serum electrolytes, and serum calcium. Abnormal sodium and potassium suggests endocrine causes. Elevated white blood cell count can be seen in pyelonephritis. High calcium validates hypercalcemia. Assessment of renal function is important and is as follows:

   1. Assessment of renal function with the following:

      1. Serum creatinine and BUN. Elevation suggests renal insufficiency, which may be associated with hypertension.

      2. Urinalysis. Red blood cells in the urine suggests obstruction, infection, or renal vein thrombosis.

      3. Urine culture. To evaluate for urinary tract infection (UTI) including pyelonephritis.

      4. Serum electrolytes and carbon dioxide. A low serum potassium level and a high carbon dioxide level suggest primary hyperaldosteronism.

      5. Urine protein/creatinine ratio, urine albumin/creatinine ratio. To evaluate significant proteinuria and renal parenchymal disease.

   2. Other useful tests in selected infants

      1. Plasma renin levels (plasma renin activity [PRA]) may be elevated in patients with renovascular disease. Levels will be low in primary hyperaldosteronism. Rarely elevated in normal infants, PRA can be falsely elevated because of medications such as aminophylline. Direct renin assay has been used, but normal neonatal values are not readily available.

      2. Thyroid studies (thyroid-stimulating hormone [TSH], free T4) to rule out hyperthyroidism.

      3. Serum cortisol.

      4. Serum aldosterone.

      5. Urine vanillylmandelic acid (VMA)/homovanillic acid (HVA). Twenty-four-hour urinary catecholamines to evaluate for pheochromocytoma or neuroblastoma.

      6. Urinary 17-hydroxysteroid and 17-ketosteroid levels to evaluate for Cushing syndrome and congenital adrenal hyperplasia.

      7. Urine toxicology screen.

      8. Coagulation panel.

4. Imaging and other studies

   1. Chest radiograph. May help in those infants with congestive heart failure and those with a murmur. Cardiomegaly can be seen.

   2. Renal/abdominal ultrasonography. Preferred screening test in neonates and should be done in all hypertensive infants to detect abdominal masses, assess adrenals, and check for renal vein thrombosis as well as kidney obstruction. Color Doppler flow ultrasonography can be used to screen for arterial or venous problems (thrombosis). Infants who had a UAC should have their aorta and renal arteries studied for thrombi.

   3. Cranial ultrasonography. To rule out intraventricular hemorrhage.

   4. Echocardiography. If a disease such as coarctation is suspected or to evaluate end-organ damage caused by hypertension (eg, left ventricular hypertrophy or decreased contractility).

   5. Further studies. The following procedures and studies are sometimes necessary to further evaluate the infant with hypertension:

      1. Angiography to evaluate renovascular disease, or venacavography to evaluate renal vein thrombosis. This is most commonly done through the umbilical artery catheter. Renal angiography/scan helps quantitate the function of each kidney. Magnetic resonance angiography (MRA) is the gold standard for renal vascular hypertension and is recommended in infants >3 kg.

      2. Abdominal CT scan if needed to obtain more specific anatomic information on an abdominal mass.

      3. Voiding cystourethrography if urinary tract pathology is possible.

      4. Radionuclide imaging (nuclear scan) can show renal perfusion abnormalities. It can also show decreased renal blood flow and increased isotope concentration in the abnormal kidney. A dimercaptosuccinic acid (DMSA) renal scan can rule out arterial infarctions.

      5. Renal biopsy to rule out any intrinsic renal disease.

1. General. First treat any obvious or correctable underlying cause of hypertension. Stop medications or adjust inotropic infusions if they are causing hypertension. Correct fluid overload by decreasing fluids and administering diuretics. Always check volume status and restrict sodium and fluid intake. Administer pain medications if necessary. Remove UAC if possible. Treat hypercalcemia. Hormone replacement should be started in those infants with endocrine disorders. Consultation with a pediatric cardiologist is recommended.

2. Drug therapy. (See Chapter 148.) To guide drug therapy, determine whether the hypertension is mild, moderate, or life threatening. Note that treatment thresholds are unclear, and many of the recommendations are controversial. More studies are necessary to establish guidelines in preterm infants. Many infants will require more than one medication. Some experts believe that any asymptomatic infant with hypertension with no end-organ involvement should only be observed.

   1. Life-threatening hypertension. See Table 61–1. If BP is extremely high (>99th percentile) this is considered a hypertensive crisis with or without signs (CHF, cardiogenic shock, seizures). Avoid too rapid of a decrease in the BP, as this may cause cerebral ischemia and hemorrhage. Monitor the BP every 10 minutes. The medications chosen depend on your institutional guidelines. With life-threatening hypertension, continuous intravenous infusions are preferred, as these can be titrated, and the BP should begin to fall within 15 minutes to an hour.

      1. Nicardipine. A calcium channel blocker, it is often considered a drug of choice because of its advantages and few side effects (reflex tachycardia). Initial dose is 0.5 mcg/kg/min constant IV infusion (see also Chapter 148).

      2. Labetalol. An α- and β-blocker. Relative contraindications are heart failure and BPD/CLD. Dose is 0.4–1 mg/kg/h IV infusion (3 mg/kg/h maximum).

      3. Esmolol. A short-acting β-blocker. Dose is 50 mcg/kg/min, increased by 25–50 mcg/kg/min every 5 minutes until target blood pressure reached (200 mcg/kg/min maximum).

      4. Sodium nitroprusside. A vasodilator. It is difficult to use but has a very short half-life, so its effect can be quickly reversed. Dose is 0.25–0.5 mcg/kg/min IV infusion. Titrate every 20 minutes to the desired response. Use for >72 hours or in infants with renal failure. It can cause thiocyanate toxicity. Usual dose is 3 mcg/kg/min; rarely >4 mcg/kg/min. Maximum is 8–10 mcg/kg/min.

      5. Fenoldopam mesylate. A new selective dopamine 1 receptor agonist. Widely studied in children over 5 kg and up to 12 years, it has been used for inadequate urine output after neonatal cardiopulmonary bypass.

   2. Moderate hypertension. See dosing in Chapter 148.

      1. Begin diuretics first such as furosemide, hydrochlorothiazide, or chlorothiazide.

      2. Add a second-line drug (eg, hydralazine or propranolol) if necessary. Choice of drug depends on your institution; propranolol is the most extensively used β-blocker and has a low risk of side effects.

      3. If a third drug is needed with propranolol. Hydralazine can be added.

      4. Give captopril alone or with a diuretic. This drug is contraindicated in infants with bilateral renovascular disease. Angiotensin-converting enzyme (ACE) inhibitors also may result in hypotensive events at initiation of therapy and after long-term use. Oliguria and some neurologic complications have been reported after captopril use; therefore, use cautiously.

   3. Mild hypertension. Usually managed by observation (recommended) or oral medications. Simple observation is best for asymptomatic patients with no readily identifiable cause and is supported in recent reviews. If needed, diuretics (such as chlorothiazide or hydrochlorothiazide) are preferred over furosemide because of fewer electrolyte disturbances. They work well in cases of volume overload but may cause hypotension when used with other agents. Spironolactone is a potassium-sparing diuretic that can also be considered.

   4. Patients with mild to moderate hypertension who cannot tolerate oral therapy because of gastrointestinal (GI) problems. These are good candidates for IV bolus or intermittently administered IV agents:

      1. Diuretics such as IV furosemide. Monitor electrolytes.

      2. Hydralazine (vasodilator) dose is 0.1–0.5 mg/kg/dose IV bolus every 6–8 hours (2 mg/kg/dose maximum). Side effects include tachycardia.

      3. Labetalol dose is 0.2–0.5 mg/kg/dose over 2–3 minutes IV intermittent bolus. Range: 0.2–1.0 mg/kg/dose, maximum 20 mg/dose. Side effects include heart failure. Avoid in BPD/CLD patients.

   5. Long-term oral antihypertensive medications. These are typically used in infants with moderate to severe hypertension who are ready to go on long-term oral therapy. Medication choice depends on your institution's preference. See Chapter 148 for more detailed information. The most common classes recommended are ACE inhibitors, α/β- and β-blockers, calcium channel blockers, vasodilators, and diuretics. Start all medications at the lowest dose.

      1. ACE inhibitors. Do not use if renal vascular disease is suspected.

         1. Captopril. A commonly used oral drug but because of the concern of renal development problems, especially in premature infants, it is preferred in infants at least 38 to 40 weeks (some state 44 weeks). Contraindicated in hyperkalemia, unilateral renal disease, and hyperkalemia.

         2. Enalapril. Start with 0.04–0.1 mg/kg/d every 24 hours. Close monitoring is recommended.

         3. Lisinopril. 0.07–0.6 mg/kg/d.

      2. β-Blockers, α/β-blockers. Do not use in infants with BPD/CLD.

         1. Propranolol (β-blocker). This is the most commonly used β-blocker and should not be used in infants with BPD/CLD.

         2. Labetalol (α/β-blocker). Avoid in infants with BPD/CLD.

         3. Carvedilol (α/β-blocker). May be good to use in heart failure. Start with 0.1 mg/kg/dose.

      3. Vasodilators

         1. Hydralazine. May cause increase in heart rate and flushing.

         2. Minoxidil. Most useful for refractory hypertension. Dose: 0.2–5 mg/kg/d divided 3 times a day.

      4. Calcium channel blockers

         1. Amlodipine. Due to its slow onset, it is useful in chronic hypertension. Dose is 0.1–0.3 mg/kg/d divided twice a day.

         2. Isradipine. Optimal dosing is difficult for smaller preemies due to the drug's ability to be made into a stable suspension. Dose is 0.05–0.15 mg/kg divided 4 times a day.

         3. Nifedipine. May cause tachycardia and rapid temporary drops in blood pressure and is not used long term because of side effects. It is also difficult to administer in small doses (best to avoid). Dose is 0.2 mg/kg/dose.

      5. Diuretics. Diuretics are good for hypertension with BPD/CLD. Monitor electrolytes.

         1. Hydrochlorothiazide.

         2. Chlorothiazide.

         3. Spironolactone (aldosterone antagonist) can cause hyperkalemia.

   6. Neonatal renovascular hypertension. Enalaprilat (IV dicarboxylate containing ACE inhibitor) has been used with some success but has to be used with extreme caution. Side effects are oliguric acute renal failure (acute kidney injury) and prolonged hypotension, and use may be limited because of these side effects.

3. Surgical intervention. Used for urinary tract obstruction, certain tumors (Wilms and neuroblastoma), unilateral renal vein thrombosis, renal arterial stenosis, rare cases of polycystic kidney disease, and coarctation of the aorta.