Evaluation and Management of Children with Hypertensive Emergencies
Authors: James D. Swift, MD, FAAP, Assistant Professor of Pediatrics; Assistant Director Pediatric Critical Care, Loma Linda University Children's Hospital, Loma Linda, CA, Co-Director, Pediatric Critical Care, Sunrise Children's Hospital, Las Vegas, NV; Ronald M. Perkin, MD, MA, FAAP, FCCM, Professor of Pediatrics and Emergency Medicine; Director of Pediatric Critical Care, Inpatient Respiratory Services and Sleep Disorders Center, Loma Linda University Children's Hospital, Loma Linda, CA, Co-Director, Pediatric Critical Care, Sunrise Children's Hospital, Las Vegas, NV; J. Scott Pickren, BS Pharm, Clinical Coordinator, Department of Pharmacy Services, Sunrise Hospital and Medical Center & Sunrise Children's Hospital, Las Vegas, NV; Ralph Rivera, PharmD, Clinical Coordinator, Department of Pharmacy Services, Sunrise Hospital and Medical Center & Sunrise Children's Hospital, Las Vegas, NV
Peer Reviewer: Sharon J. Kaminer, MD, FAAP, FACC, Associate Professor Pediatric Cardiology, Medical College of Georgia, Augusta, GA
It seems to be a perennial question asked in emergency departments, "Must we check blood pressures on every child coming to the ED, and, if not, what is the appropriate age to start?" Unfortunately, undocumented and uncontrolled hypertension can be devastating to a child's health. Furthermore, medical staff inexperienced in the care of children can easily fail to recognize that a physiologically normal blood pressure for an adult may be a hypertensive urgency in an infant.
Although hypertension is infrequent in the pediatric population, early identification and appropriate management are critical. In 90% of the children with hypertension, a cause will be identified. The reduction of hypertension in pediatric patients requires a thorough understanding of available medications, indications, and potential complications. This article presents a comprehensive review of recognition and management of hypertension in pediatric patients.
-The Editor
Introduction
The measurement of blood pressure (BP) is now established as an important component of the routine pediatric physical examination; however, blood pressure in children has only recently been given serious attention.1 The first report of the Task Force on Blood Pressure Control in Children was published in 1977.2 Since publication of the 1977 task force report, new and more extensive epidemiological data on normal BP distributions and the natural history of BP throughout the pediatric age range have been published. These data, as well as advances in the diagnosis of and therapy for hypertension, prompted publication of the "Report of the Second Task Force on Blood Pressure Control in Children-1987."3 Since 1987, additional BP data in children and adolescents, the use of newer classes of drugs, and the role of primary prevention of hypertension have expanded the body of knowledge regarding the classification and treatment of hypertension in the young. A recent report is available that updates practitioners on new data on BP in children and calls attention to modifications that are recommended for the diagnosis, treatment, and prevention of hypertension in children.4
Definition of Hypertension
BP varies widely throughout the day in children, as well as in adults, because of normal diurnal fluctuation and changes in physical activity, emotional stress, and other factors.4 The second National Heart, Lung, and Blood Institute Task Force developed definitions based on the distribution of BP in healthy children as well as clinical experience and consensus.3 Normal BP is defined as systolic and diastolic BP less than the 90th percentile for age and sex. High-normal BP is defined as average systolic or diastolic BP greater than or equal to the 90th percentile but less than the 95th percentile. Hypertension is defined as average systolic or diastolic BP greater than or equal to the 95th percentile for age and sex measured on at least three separate occasions. However, recent data suggest that body size is also an important determinant of BP in childhood and adolescence.4 The concept is that the differential growth rates present in children require adjustment in interpretation of BP percentile for individual children. For example, tall children with pressures that seem to be elevated may actually be normotensive if their height for a given age is beyond the 90th height percentile. Recent reports have reanalyzed the national childhood BP data; the BP percentiles were redefined and based not only on sex and age but also on height to determine age-, sex-, and height-specific systolic and diastolic BP percentiles.4,5 This approach provides information that allows for consideration of different levels of growth in evaluating BP and demonstrates that BP standards that are based on sex, age, and height permit a more concise classification of BP according to body size.4,5 This approach avoids misclassifying children at the extremes of normal growth; very tall children will not be misclassified as hypertensive, and very short children with high normal BP or even hypertension will not be missed. Although BP clearly is also associated with obesity, this association is believed to be a causal one, wherein the obesity contributes to higher BP and increased risk for cardiovascular disease.
The update on the 1987 Task Force Report provides new normative BP tables for children and adolescents, which includes height percentiles, age, and gender.4 To use the tables in a clinical setting, the height percentile is determined from the standard growth charts. The child's measured systolic and diastolic BP is compared with the numbers provided for age, sex, and height percentiles. Modifications of these tables are provided (see Tables 1 and 2), but reference to the original data is recommended.4 The child is normotensive if BP is below the 90th percentile. If the child's BP (systolic or diastolic) is at or above the 95th percentile, the child may be hypertensive and repeated measurements are indicated.
The American Academy of Pediatrics now recommends that every child 3 years of age and older have a yearly blood pressure measurement. In addition, all acutely ill children, regardless of age, should have a blood pressure reading performed at the time of evaluation.1,3,6
Measurement of BP in Children
BP is most conveniently measured with a standard clinical sphygmomanometer, using a stethoscope placed over the brachial artery pulse, proximal and medial to the cubital fossa and below the bottom edge of the cuff. Correct measurement of BP in children requires the use of a cuff that is appropriate to the size of the child's upper right arm. The right arm is preferred for consistency and comparison with standard tables. The equipment necessary to measure BP in children 3 years of age through adolescence includes three pediatric cuffs of different sizes, as well as a standard adult cuff, an oversized cuff, and a thigh cuff for leg BP measurement. The latter two cuffs may be needed for use in obese children and adolescents. A technique to establish an appropriate cuff size is to choose a cuff having a bladder width that is approximately 40% of the arm circumference midway between the olecranon and the acromion. This will usually be a cuff bladder (length) that will cover 80-100% of the circumference of the arm.4 Use of an inappropriately small cuff may falsely elevate the BP reading, whereas the use of too large a cuff will give falsely low readings. However, if two cuffs are close in size to the measured width of the arm, the larger cuff should be selected; it is uncommon for a slightly large cuff to mask true hypertension, whereas use of a small cuff will often lead to elevated readings.1
Systolic BP is determined by the onset of the "tapping" Korotkoff sounds. The phase of the Korotkoff sounds that defines diastolic BP has been controversial. The American Heart Association has established the fifth Korotkoff sound (K5), or the disappearance of Korotkoff sounds, as the definitions of diastolic pressure.4,5,7 The change to a K5 definition of diastolic BP enables a uniform designation of diastolic BP for all ages. The BP Tables provided in recently published reports use K5 as the diastolic BP. In children, a difference of several millimeters of mercury is frequently present between the fourth Korotkoff sound, the muffling of Korotkoff sounds, and K5. In some children, Korotkoff sounds can be heard to OmmHg. When this occurs, it excludes diastolic hypertension.
There has been an increasing use of automated devices to measure BP in children. Those most commonly used devices use oscillometric methods to measure systolic, diastolic, and mean arterial BP. The advantage of these devices is their ease of use. While use of these devices is advantageous in the intensive care setting, the reliability of these instruments in a more standard clinical setting is less clear because of the need for frequent calibration of the instruments. Under most circumstances, the recommended method of BP measurement in children is auscultation.
Table 1. Blood Pressure Levels for the 90th and 95th Percentile-Girls
Age years |
BP (percentile |
Systolic BP by percentile of height (mmHG) |
Diastolic BP by percentile of height (mmHg) | ||||
10% |
50% |
90% |
10% |
50% |
90% | ||
1 |
90th |
98 |
100 |
103 |
53 |
54 |
56 |
95th |
102 |
104 |
107 |
57 |
58 |
60 | |
2 |
90th |
99 |
102 |
104 |
57 |
58 |
60 |
95th |
103 |
105 |
108 |
61 |
62 |
64 | |
5 |
90th |
103 |
106 |
108 |
66 |
67 |
68 |
95th |
107 |
110 |
113 |
70 |
71 |
72 | |
10 |
90th |
112 |
115 |
117 |
73 |
74 |
76 |
95th |
116 |
119 |
121 |
77 |
78 |
80 | |
15 |
90th |
121 |
124 |
126 |
78 |
79 |
81 |
95th |
125 |
128 |
130 |
82 |
83 |
85 | |
* Modified from: National High Blood Pressure Education Program Working Group on Hypertension Control in Children and Adolescents. Pediatrics 1996;98:649-658.
Blood Pressure: Infancy
Blood pressure is labile in infancy, and the definition of hypertensive is imprecise. Although reproducible hypertension is rare, clinical uncertainty concerning blood pressure measurements is not rare. Normal ranges can be difficult to specify because of different measurement techniques, the range of birth weights and gestational ages, rapidly changing body size, and the marked rise in blood pressure in the first hours and days of life.8 Automatic oscillometric methods are the most commonly used noninvasive methods, because auscultation of the brachial pulse is difficult in infants.8
Because the blood pressure in infants is so variable, every effort must be made to quiet infants during blood pressure measurement. Blood pressure rises during feeding, upright positioning, and sucking, so values obtained during feeding may not reflect baseline pressure.9
Table 2. Blood Pressure Levels for the 90th and 95th Percentile-Boys
Age years |
BP (percentile |
Systolic BP by percentile of height (mmHG) |
Diastolic BP by percentile of height (mmHg) | ||||
10% |
50% |
90% |
10% |
50% |
90% | ||
1 |
90th |
95 |
98 |
102 |
51 |
53 |
54 |
95th |
99 |
102 |
106 |
55 |
57 |
59 | |
2 |
90th |
99 |
102 |
105 |
55 |
57 |
59 |
95th |
102 |
106 |
109 |
59 |
61 |
63 | |
5 |
90th |
105 |
108 |
112 |
65 |
67 |
69 |
95th |
109 |
112 |
115 |
70 |
71 |
73 | |
10 |
90th |
112 |
115 |
118 |
74 |
75 |
77 |
95th |
115 |
119 |
122 |
78 |
80 |
81 | |
15 |
90th |
124 |
127 |
131 |
77 |
79 |
81 |
95th |
128 |
131 |
134 |
82 |
83 |
85 | |
* Modified from: National High Blood Pressure Education Program Working Group on Hypertension Control in Children and Adolescents. Pediatrics 1996;98:649-658.
The most widely used guidelines for neonatal hypertension are those of Adelman: Persistent blood pressures of more than 90/60 in the term infant and 80/50 in the preterm infant.10 Blood pressure distribution for the remainder of the first year is available from the 1987 Task Force Report.3 In children younger than 1 year, systolic BP has been used to define hypertension.5 The systolic blood pressure increases sharply between birth and 2 months. There is no significant difference between systolic blood pressure in infants between 2 months and 1 year. The 95th percentile value for systolic blood pressure in infants between 2 months and 1 year is 112 mmHg.3 As in older children, there is a significant correlation between the infants' systolic blood pressure and weight.
Causes of Hypertension. A differential diagnosis for hypertension in infancy is shown in Table 3. Renovascular disease has replaced coarctation of the aorta as the most common cause of hypertension in the newborn.8
Renovascular. Renovascular hypertension is caused by a lesion of the renal artery or of its branches. This can be iatrogenic or congenital. Renovascular hypertension secondary to complications of umbilical arterial catheterization was first described in 1975.11 The reported incidence of thrombus formation around umbilical artery catheters varies widely. The incidence is increased when the tip of the catheter is in a high position above the level of the renal arteries, but it may also occur with low-positioned catheters.12
Congenital renal artery stenosis accounts for about 20% of the cases of hypertension in newborns.
Coarctation of the Aorta. Coarctation of the aorta is the most common cardiovascular cause of hypertension.13 Coarctation is the fourth most frequent (7.5%) form of congenital heart disease that requires either cardiac catheterization or surgery during the first year of life.14
Table 3. Causes of Hypertension in Infancy
VASCULAR
Renal artery thrombosis
Aortic thrombosis
Congenital renovascular anomolies
Coarctation of the aorta
Hypoplasia of the aorta
RENAL
Infantile polycystic kidney
Hypoplastic kidney
Obstructive uropathy
Acute and chronic renal insufficiency
Renal tumors
Medullary cystic disease
Multicystic kidney
MISCELLANEOUS DISEASE
Bronchopulmonary dysplasia
Patent ductus arteriosus
Intraventricular hemorrhage
Neural crest tumors
Adrenogenital syndrome
Primary hyperaldosteronium
MEDICATION
Steroids
Intoxications (cocaine, amphetamines)
True coarctation is a distinct, shelf-like thickening or infolding of the aortic wall directly opposite, proximal, or distal to the ductus arteriosus. (See Figure 1.) A pressure gradient across the coarctation results. Many infants with coarctation do not present until the aortic end of the ductus arteriosus closes (the pulmonary end closes first).15 When ductal closure at the aortic end causes aortic constriction, a severe increase in left ventricular afterload results. In this acute situation, the left ventricular ejection fraction is decreased in response to higher afterload. Because the left ventricle is normal to small in size, there is not time for compensatory development of muscle hypertrophy that might improve ejection fraction. Systemic hypoperfusion, oliguria, and metabolic acidosis are observed on presentation in many infants.
Increased left ventricular afterload results in elevated ventricular wall tension, decreased myocardial perfusion pressure, and, in extreme cases, ischemic myocardium. The increased left ventricular end-diastolic pressure and increased left atrial pressure cause a left-to-right shunt at the foramen ovale and increased pulmonary blood flow. Pulmonary hypertension occurs as the result of increased blood flow and increased pulmonary venous pressures secondary to left atrial hypertension. Right heart enlargement ensues because of volume overload of the right ventricle. All these pathophysiologic events summate to produce the clinical picture of congestive heart failure of cardiogenic shock.
Infants younger than 3 months of age with coarctation have characteristic presenting signs. Congestive heart failure is present in up to 90%; poor peripheral perfusion, acidosis, tachypnea, and failure to thrive are common. Coarctation is difficult to diagnose early in infancy.15,16 Patients are often not referred until they are in shock or renal failure. Less than 30% of infants with physical findings of coarctation are referred with the correct diagnosis. Even in patients older than 1 year of age, diagnosis is usually delayed despite classic findings of murmur and upper extremity systemic hypertension.16
Table 4. Symptoms of Hypertension-Infants
· Failure to thrive
· Irritability
· Feeding problems, including vomiting
· Cyanosis
· Respiratory distress
· Cardiac failure
The hallmark physical finding in coarctation consists of discrepant arterial pulses and systolic blood pressure in the upper and lower extremities. Observations should be made from all four limbs. Arterial pulses below the coarctation are diminished in amplitude and delayed in timing compared to the proximal pulses. Systolic blood pressure is elevated in the extremities proximal to the coarctation, and a systolic pressure gradient is present between arm and leg that may be as high as 70-80 mmHg at rest. However, several clinical circumstances may arise that make the detection of pulse and pressure discrepancies difficult or impossible. First, the coarctation pressure gradient may be minimal. This may be due to a mild coarctation, but it also occurs in an infant with congestive heart failure and diminished cardiac output. Second, detection of arterial pulse and pressure differences may be difficult because of variations in brachiocephalic artery anatomy. An anomalous right subdavian artery arises distal to the coarctation in approximately 3-4% of cases. In these patients, the arterial pulse and blood pressure in the right arm are equal to those in the legs, and discrepancies will be detected only in the left arm. In other patients, the left subclavian artery arises adjacent to the coarctation and its orifice may be stenotic. In such patients, a bounding arterial pulse and elevated systolic pressure will be detected only in the right arm. Rarely, patients may present with an anomalous right subclavian artery in which the left subclavian artery is stenotic as well. In these patients, arterial differences in the four extremities will not be detected, although carotid artery pulsations will be bounding. Finally, in contrast to older children, infants presenting before 5 days of age rarely have upper extremity hypertension. After 5 days of age, hypertension becomes more common, and after 15 days of age, the incidence is 86%.17
Two-dimensional echocardiography with Doppler (echo Doppler) has become a sensitive and specific diagnostic method for children with coarctation. In experienced hands, diagnosis of coarctation of the aorta by echo Doppler achieves 95% sensitivity and 99% specificity.18,19
A pivotal time in the evolution of the treatment of infants with coarctation (as well as other anomolies of the aortic arch) was the late 1970s when prostaglandin E1 (PGE1) became available to maintain patency of the ductus arteriosus.20,21 This drug allows preoperative stabilization of critically ill neonates, who often present with heart failure, shock, and renal failure.
PGE1 is given initially in doses of 0.05 mcg/kg/min but can be increased gradually to 0.2 mcg/kg/min if not effective at the lower dose. Maximal response occurs 15 minutes to four hours after the start of the infusion.22 Initial studies of the drug's effectiveness reported clinical improvement in 80% of patients. The oldest infant to benefit was 36 days of age, but, in general, infants whose ductus closed before infusion showed no benefit.17,21,22 Symptomatic infants who are unresponsive to PGE1 have a high mortality. Side effects and complications of PGE1 include cutaneous vasodilation, hypotension, rhythm or conduction disturbances, jitteriness or seizure activity, fever, respiratory depression or apnea, diarrhea, and metabolic derangements. It is reasonable to administer PGE1 to every infant (< 3 months) in shock until critical coarctation or other ductal-dependent lesions have been excluded.
Blood Pressure: Children and Adolescents
Hypertension in infants and children is often due to an identifiable disease process.1 Hypertension in infants is usually related to renal or vascular disease, warranting an aggressive evaluation of the patient. Young infants may present in acute distress with signs and symptoms of congestive heart failure. (See Table 4.) In contrast, after infancy, hypertension is frequently silent and detected only during a routine physical examination. Symptoms or signs are rarely evident unless the level of BP is particularly high or hypertension has been present for years.
An underlying cause can be found in most children with hypertension who are 1-10 years old. In the majority of cases, renal diseases (either parenchymal or vascular) is the cause, although a number of less common causes exist. (See Table 5.) In adolescents, renal disease continues to be the most common cause of hypertension, although secondary causes are found much less frequently than in younger patients.1,23 Coarctation of the aorta needs to be ruled out in all patients with severe hypertension. In the hypertensive teenage girl, obstetric hypertension needs to be considered; reviews have shown that hypertension complicates 6-7% of all pregnancies.7 Drug side effects and the effect of drug withdrawal need to be considered. (See Table 6.) Illicit drug use, specifically cocaine and other sympathomomimetics, may precipitate severe hypertension. Since the incorporation of blood-pressure measurement into the routine physical examination, in junior and senior high school students, essential hypertension has been identified as an important and significant cause of hypertension in adolescents.1,23,24
Table 5. Causes of Hypertension in Children (1-10 years)
RENAL
Vascular
Hemolytic-uremic syndrome
Renal artery stenosis
Polyarteritis nodosa
Reflux nephropathy
Sickle cell nephropathy
Kawasaki disease
Nephritides
Henoch-Schonlein purpura
Postinfectious
glomerulonephritis
Systemic lupus nephritis
Membranoproliferative glomerulonephritis
Congenital malformation
Polycystic kidney disease
Tuberous sclerosis
Renal dysplasia
Miscellaneous
Intravascular volume overload
Renal transplant
CARDIOVASCULAR
Coarctation of the aorta
CENTRAL NERVOUS SYSTEM
Meningoencaphalitis
Tumor
Trauma/child abuse
Hydrocephalus
ENDOCRINE
Pheochromocytoma
Hypercalcemia
Mineralocorticoid excess
Hyperthyroidism
DRUGS
Corticosteroids
Cyclosporin A
Reserpine, amphetamines, phenylprine, phenylpropanolamine
Licorice
Selected drugs (recreational)
TUMORS
Neuroblasoma
Pheochromocytoma
Nephroblastoma (Wilms' tumor)
MISCELLANEOUS
Pain
Severe anxiety
Transient hypertension after urologic surgery
Hypertension secondary to immobilization (traction)
Sleep-apnea (chronic upper airway obstruction)
Morphologic Changes Induced by Hypertension
Hypertension and Progressive Renal Failure. There is a general agreement on the basis of experimental and clinical studies in adults that hypertension accelerates functional deterioration in all renal diseases and that effective blood pressure control can prevent or retard this deterioration.31 Increased arterial blood pressure can damage the kidney by stimulating myointimal hyperplasia or hypertrophy of renal arterioles and by increasing glomerular pressure. The first mechanism causes hypertensive microangiopathy with subsequent ischemia and death of nephrons downstream. The second mechanism, through barotrauma, causes albuminuria, mesangial expansion, and eventual glomerular sclerosis. At present, interest has focused on the latter mechanism, glomerular hypertension, as a cause of progressive hypertensive renal injury.
Glomerular pressure is directly proportional to efferent arteriole resistance and inversely proportional to afferent arteriole resistance.31 When renal perfusion pressure increases, afferent arteriole resistance normally rises, preventing transmission of systemic hypertension to glomeruli. Failure of this autoregulatory response will cause glomerular pressure to rise. Studies of several models of hypertensive renal disease support defective afferent arteriole constriction as an explanation of hypertension-induced glomerular damage.32 The mechanisms responsible for this vasoregulatory defect have not been established. Presumably, they involve either impaired vascular smooth muscle contraction mediated by stretch-induced changes in intracellular calcium or increased activity of vasodilatory prostaglandin I2 and nitric oxide.31
Glomerular pressure is also modulated by changes in efferent arteriole resistance. This segment of the glomerular microcirculation is highly sensitive to the vasoconstricting effect of angiotensin II.31,33 Suppression of angiotensin II reduces postglomerular vascular resistance and lowers glomerular capillary pressure. This physiologic action underlies the selection of ACE inhibitors as drugs of choice in hypertensive renal disease.32
The mechanisms by which glomerular hypertension leads to glomerulosclerosis remain unclear.34 Recent research suggests that the process could simply reflect the deleterious effect of physical stress on glomerular cell function.
The Heart in Hypertension. Hypertensive heart disease can be defined as the response of the heart to the afterload imposed on the left ventricle by the progressively increasing arterial pressure and total peripheral resistance produced by hypertensive vascular disease.35 Hypertension can cause or is related to various cardiac manifestations, including left ventricular hypertrophy, congestive heart failure, cardiac dysrhythmias, and ischemic heart disease.26,35-37
The heart maintains its chamber size in proportion to its workload and to body weight, growth, and maturation. The type of cardiac overload that is present determines the pattern of hypertrophy: volume overload produces increased ventricular cavitary volume in proportion to mass (eccentric hypertrophy), whereas pressure overload produces increased left ventricular mass out of proportion to volume (concentric hypertrophy).35
The increased peak systolic wall stress in pressure overload leads to replication of sarcomeres, increase in cell width, ventricular-wall thickening, and concentric hypertrophy without increasing the number of myocytes. Systolic function is usually preserved in patients with hypertension until late in the course of illness. Decompensation is characterized pathologically by the degeneration and lysis of myofibrils.
Table 6. Drugs that can Elevate BP
Amphetamines
Cocaine
Antihistamines
Diet pills
Steroids
Nicotine (cigarettes, smokeless tobacco)
Oral contraceptives
Beta-agonists (asthma therapy)
Imipramine
Caffeine
Ethanol
Methylphenidate (Ritalin)
Nonsteroidal anti-inflammatories (Ibuprofen)
Phencyclidine
Antidepressants (amitriptyline)
Decongestants
Factors other than hemodynamics are also important in the development of left ventricular hypertrophy. Humoral agents, such as norepinephrine and angiotensin, influence left ventricular hypertrophy. Generally, medications that reduce arterial pressure decrease left ventricular mass with prolonged treatment; however, those that reduce pressure without modulating the sympathetic or renin-angiotensin systems do not reverse left ventricular hypertrophy rapidly.35
Although concentric left ventricular hypertrophy maintains systolic function at a near-normal level, left ventricular relaxation is impaired with pressure overload, reflecting reduced distensibility of the left ventricle.26,36 Radionuclide scintigraphy and Doppler echocardiography studies have revealed a high prevalence of impaired early diastolic filling without systolic dysfunction in hypertensive patients. In these patients, overall diastolic filling is preserved by enhanced late filling during atrial systole. Enlargement of the left atrium may be detected by electrocardiography (P-wave abnormality) and echocardiography (diastolic-filling changes) even before there is electrocardiographic evidence of left ventricular hypertrophy.26 Diastolic filling abnormalities occur early in children with systemic hypertension and before there is evidence of left ventricular hypertrophy or systolic dysfunction.26,36
Multiple mechanisms for this pattern of abnormal diastolic function in the patient with hypertension have been proposed. Increased left ventricular chamber stiffness, changed geometry, and interstitial fibrosis serve to decrease ventricular compliance. Calcium metabolism also has been speculated as playing a role in diastolic dysfunction because ventricular muscle relaxation represents an active, energy-requiring process dependent on calcium balance. Defective calcium accumulative activities of the sarcoplasmic reticulum, increased calcium influx from the extracellular space, inadequate ATP supply, and impaired intracellular calcium shifts may all play a role in the abnormal diastolic function of the human with hypertension.26
Hypertension and the Brain. Cerebral blood flow remains constant over a wide range of systemic blood pressure by virtue of autoregulation. Unfortunately, our knowledge of this complicated system is incomplete, particularly in patients with central nervous system pathology. The effects of varied antihypertensive agents on the cerebral circulation are also incompletely studied.
Figure 2 shows cerebral blood flow autoregulation clearly exists, below which cerebral blood flow decreases. An upper limit also exists. As previously discussed, vascular remodeling with chronic hypertension includes structural changes in the cerebral vessels that result in a shift of the autoregulatory curve to the right.27-29 Thus, patients with chronic hypertension are able to tolerate higher levels of systemic arterial pressure, at least acutely. Over the long term, these vascular changes lead to increased risk of cerebrovascular disease. Chronic antihypertensive therapy can prevent and partially reverse these structural changes.28 Vigorous acute therapy can, however, lead to cerebral ischemia if systemic blood pressure is rapidly lowered below the autoregulatory threshold, which may be at normotensive pressures, because of the shift in autoregulation.7,38-42 This problem is clearly more relevant in the elderly; however, the potential exists in pediatric patients with chronic hypertension. Therefore, prior to treatment, determination of the chronicity of hypertension is important. Patients with chronic hypertension are less likely to develop acute symptoms even with severe BP elevation, but they are also less tolerant of acute drops in pressure.39,42 Previously, normal children are more likely to develop serious symptoms, such as hypertensive encephalopathy with mild-to-moderate elevations in BP. Evidence of end-organ damage, such as retinal changes, or left ventricular hypertrophy indicates chronic hypertension. This often can be determined by physical exam, although slit lamp examination and echocardiography may be required. In any child with chronic, severe hypertension, particularly with neurologic symptoms and signs, BP should be reduced in a controlled manner using infusion of short acting drugs.38,40
Evaluation of Hypertension
Medical History. The emphasis of the history and physical examination in a child with hypertension is to detect clues suggesting a secondary cause of hypertension or, alternatively, to establish a high likelihood of essential hypertension. A careful history and physical examination will narrow the differential diagnosis and guide further evaluation. In both first- and second-degree relatives, a history of essential hypertension, peripheral vascular disease, stroke, myocardial infarction, endocrine disease, and renal failure should be sought. Special emphasis should be placed on determining age of onset. More specifically, parents should be asked about inheritable conditions that predispose to hypertension (e.g., polycystic kidney disease, pheochromocytoma, neurofibromatosis, von Hippel-Lindau disease).
The birth history and neonatal course may provide important clues in determining the etiology of hypertension in infants and children. Prematurity and prolonged mechanical ventilation may suggest bronchopulmonary dysplasia, while a history for umbilical artery catheterization suggests the possibility of thromboembolic complications. A history of urinary tract infections is particularly important in children as a possible indication of reflux nephropathy. As always, hospitalizations, surgeries, and other known medical problems should be elicited.
All medications, including over-the-counter preparations, should be known. Hypertension typically occurs with vasoconstrictors such as those found in decongestants (e.g., pseudoephedrine, phenylpropanolamine). With adolescents, it is extraordinarily important to specifically (and tactfully) ask about the use of oral contraceptive pills, street drugs, chewing tobacco, ethanol, and cigarette smoking; this information rarely will be offered unsolicited. Diet and lifestyle should be explored.
A review of systems should focus on various symptom complexes for diseases that cause hypertension (e.g., headache, palpitations, and excessive sweating in pheochromocytoma). Most symptom complexes, aside from the additional finding of poor growth as a component of various diseases in children, are similar in adults and children. One note of caution with regard to headaches: Most children with headaches do not have elevated blood pressure, yet severe headaches that are occipital in location and occur with awakening may be indicative of hypertension, although a subarachnoid bleed must be considered.3,23 Some patients in hypertensive crisis may present primarily with gastrointestinal symptoms.43
Physical Examination. In addition to using appropriately sized cuffs, there are several important differences between the pediatric and adult physical examinations. First, the growth pattern should be assessed using the standard pediatric growth curve. Failure to grow at the expected rate (termed "falling off the growth curve") is an important indicator of overall health in children. Abnormalities in growth associated with hypertension can be caused by chronic renal disease, hyperthyroidism (causing primarily systolic hypertension), pheochromocytoma, adrenal disorders such as Cushing's syndrome, or genetic abnormalities such as Turner's syndrome. The possibility of a syndrome being present should be especially considered in patients with unusual facies or dysmorphic features. Syndromes are often linked with specific lesions that account for the hypertension. For example, in Turner's syndrome and Williams syndrome, both renovascular and cardiac lesions have been found to cause hypertension.
In the pediatric population, special note should be made of certain physical examination findings. To rule out coarctation, every child being evaluated for hypertension should have upper- and lower-extremity blood pressure measurements taken with appropriately sized cuffs. The diagnosis of coarctation can be established by finding a differential between the upper and lower extremity blood pressures. Normally the lower extremity blood pressure is slightly greater than the upper extremity blood pressure. A child with coarctation will have systolic hypertension in an upper extremity, and absent or decreased femoral pulses. In older infants and children, extensive collaterals may have developed so that femoral pulses are easily palpated; however, during simultaneous palpation of radial and femoral pulses, a delay in the femoral pulse timing would be noted. Another cardiac defect, patent ductus arteriosus, can cause primarily systolic hypertension in the young. These children will have signs of heart failure in association with a loud machinery-like murmur over the precordium.
Aberrant timing of secondary sexual characteristics, or inappropriate Tanner stage for chronologic age, may suggest an adrenocortical defect.
Evaluation. The primary purpose of the work-up of a hypertensive child is to uncover any secondary, potentially correctable, cause. The extent of the evaluation needs to be tailored to the individual child and depends on the likelihood that a secondary cause is present. While every child with elevated blood pressure will not require renal angiography, every child does require a thorough history and physical examination.
In general, children requiring comprehensive evaluations include those with significant or severe hypertension; a particular symptom complex discovered by history; abnormalities on physical examination, including "falling off the growth curve"; evidence of end-organ damage; sudden onset of hypertension; or the absence of family history for hypertension. The younger the child and the higher the blood pressure, the more likely a secondary cause is present.44
Certain factors increase the likelihood that a child has essential hypertension and, therefore, limit the extent of diagnostic studies. These include mild elevations in blood pressure, a strong family medical history of essential hypertension, a high resting heart rate, variable blood pressure on repeated measurements, and excess body weight. When clusters of these factors are present, the most probable diagnosis is essential hypertension.23,44
Because significant hypertension in the pediatric population is frequently caused by renal abnormalities, the initial evaluation in children should include a screen for renal dysfunction with a urinalysis, electrolytes, blood urea nitrogen and creatinine; some pediatric nephrologists would also include a urine culture and renal ultrasound in this initial "survey." A pregnancy test should be considered in adolescent females with unexplained hypertension. The other essential component to the initial evaluation is an assessment of end-organ damage, which provides evidence of chronicity and helps determine the need for therapy. Echocardiography is a sensitive means to detect interventricular septal wall thickening and posterior ventricular wall enlargement. A thorough ophthalmologic examination can also be useful.
Frequently Used Terms
In a discussion of the clinical aspects of severe hypertension, several frequently used terms need to be defined.45 Hypertensive urgency is an elevated BP that may be potentially harmful but is without evidence of end-organ damage or dysfunction requiring gradual lowering over 24-48 hours. Hypertensive emergency is a clinical syndrome in which elevated BP is associated with evidence of end-organ damage or dysfunction. Organs most affected include the central nervous system (hypertensive encephalopathy, cerebral infarction, hemorrhage), the cardiovascular system (congestive heart failure, myocardial ischemia, aortic dissection), and the kidneys with acute renal insufficiency. Hypertensive emergencies require immediate intervention to prevent progression to end-organ damage. In 1992, the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure proposed that such emergencies require lowering of the BP within one hour to decrease morbidity.46 It is important to note that no BP is given that automatically demands emergent treatment. It is the imminent compromise of vital organ function that dictates the necessity for immediate lowering of BP. Two subtypes of hypertensive emergency are frequently described: Accelerated hypertension occurs when elevated BP is associated with fibrinoid necrosis of arterioles; this is clinically evidenced by the presence of retinal exudates and hemorrhages. Malignant hypertension occurs when elevated BP is associated with papilledema. However, other clinically relevant features of malignant hypertension may exist, including other evidence of increased intracranial pressure (sixth cranial nerve palsy or diplopia), congestive heart failure, encephalopathy, and renal insufficiency.
Hypertensive Encephalopathy. Hypertensive encephalopathy is a neurologic syndrome that occurs in patients with elevated blood pressure.41-49 It is characterized by rapidly progressive signs and symptoms including headache, seizures, visual disturbances, altered mental status, and focal neurologic signs. Although the syndrome is usually reversible if the hypertension is treated early, it may be fatal if it is unrecognized and treatment is delayed.48 The clinical findings are sufficiently nonspecific, so that the diagnosis may be difficult to establish, particularly in patients who have other illnesses. Various neurologic conditions such as stroke, intracranial hemorrhage, venous thrombosis, and encephalitis can mimic hypertensive encephalopathy. Furthermore, the pathophysiologic changes of hypertensive encephalopathy are unclear, being ascribed either to marked vasospasm or to forced vasodilation of the cerebral vasculature.47,48
The most recent research supports the view that hypertensive encephalopathy is caused by breakthrough of autoregulation, with focal vasogenic edema. Characteristic findings include areas of reversible hypodensity on CT and increased T2 signal on MR, usually localized to the occipital lobes, with increased perfusion to these regions on SPECT (single-photon emission computed tomography).48
The susceptibility of the posterior circulation to the lesions of hypertensive encephalopathy is a well-known but poorly understood phenomenon. A likely explanation involves the regional heterogeneity of the sympathetic vascular innervation.48 In experimental studies, the sympathetic innervation of the intracranial arterioles has been shown to protect the brain from marked increases in blood pressure. Moreover, ultrastructural studies have shown that the internal carotid system is much better supplied with sympathetic innervation than is the vertebrobasilar system.48 Acute hypertension would, in this view, stimulate the perivascular sympathetic nerves, which would protect the anterior but not the more poorly innervated posterior circulation. This would result in breakthrough of autoregulation with edema mainly in the occipital lobes.
Management
Management of children presenting with hypertensive emergencies should proceed promptly, with definitive diagnostic studies delayed until BP has been lowered to "safe" levels. Unfortunately, a precise definition of "safe" has not been established. The implication is an obvious one; blood pressure should be reduced while maintaining vital organ perfusion. When facing a child with extreme hypertension and symptoms of end-organ damage, there is a temptation to rapidly reduce BP to normal levels. This practice, particularly when induced by administration of bolus antihypertensive agents, may result in permanent neurological damage.38,39
Traditional thinking is that hypertensive emergencies require the fastest possible reduction in BP, often by bolus antihypertensive therapy. However, Deal and colleagues suggest that in children, gradual, controlled reduction by incremental infusion is a safer and better approach.38 They reviewed their experience with both techniques (they changed from bolus intravenous injections of diazoxide or hydralazine to intravenous infusions of labetalol or sodium nitroprusside midway through the study period) in 110 children seen over 20 years. Overall, 57 children were treated by bolus injection, 13 developed hypotensive complications, and four suffered irreversible neurologic damage; by contrast 53 patients treated with gradual reduction suffered no neurologic impairment or serious irreversible side effects. The authors conclude that the key to safe BP reduction is probably not which drug is used but the method of administration and the rapidity with which BP falls.38
Severe hypertension of any cause leads to activation of autoregulatory mechanisms that serve to maintain normal perfusion of vital organs. This keeps blood flow to the heart, kidneys, and brain constant when mean arterial pressure (MAP) fluctuates within certain limits. With sustained hypertension, both the upper and lower limits of the tolerance range increase (see previous discussions). The lower limit of the autoregulatory range for BP in the central nervous system is usually 25% below the MAP, so acute reduction of an elevated BP by more than 20-25% of the MAP may cause cerebral ischemia.50 In the study by Deal et al, gradual lowering of BP using closely monitored intravenous infusions of labetalol, sodium nitroprusside, or both was a safe and effective method for treating hypertensive emergencies.38
Medications for Hypertensive Emergencies
Considerable experience has been gained with a variety of pharmacological agents for the treatment of hypertensive crisis and hypertensive urgency in the pediatric patients. Intravenous agents used for hypertensive emergencies include nicardipine, sodium nitroprusside, fenoldopam mesylate, and labetalol. Other intravenous agents are diazoxide, esmolol, and enalapril. Nifedipine, an oral agent, is also useful in controlling hypertension in the pediatric patient. (See Table 8.)
Nifedipine. Nifedipine is a dihydropyridine calcium antagonist that is available as short-acting capsules (immediate release) and in various slow-release formulations.51 Nifedipine lowers arterial pressure by peripheral vasodilation. The accompanying reflexive cardioacceleration usually overrides the mild negative inotropic and chronotropic effects. Because nifedipine is well absorbed from the gastrointestinal tract, blood pressure reduction is achieved shortly after its administration.41,51 The blood pressure response usually occurs within 5-15 minutes but can be unpredictable. The usual starting dose is 0.25-0.5 mg/kg.41,45
Nifedipine, in the form of short-acting capsules given sublingually or swallowed, is a common therapeutic intervention in the treatment of hypertensive emergencies. Despite the widespread use, no outcome data exist that allow careful assessment of the safety or efficacy of this intervention.51 To the contrary, numerous serious adverse effects have been reported after administration of nifedipine in adult patients. Also, sublingual absorption of nifedipine has been shown to be negligible, and most of the drug gets into the bloodstream by intestinal absorption.41,52
A recent literature review regarding nifedipine use for hypertensive emergencies revealed reports of serious adverse effects such as cerebrovascular ischemia, stroke, numerous instances of severe hypotension, acute myocardial infarction, and death.51 Elderly hypertensive patients with underlying structural vascular disease and target organ impairment tend to be more vulnerable to rapid and aggressive reduction in arterial pressure because of the shift in autoregulatory curves.51,53 Given the seriousness of the reported adverse events and the lack of any clinical documentation attesting to a benefit, researchers have argued that the use of nifedipine capsules for hypertensive emergencies should be abandoned.51
Abandoning the use of nifedipine in pediatric patients has important prehospital, ED, and intensive care unit implications because it is one of the only oral, rapidly acting antihypertensive agent available. Although enalapril, an angiotensin-converting enzyme inhibitor, has been recommended for treatment of hypertensive emergencies, it has a prolonged onset of action, even with intravenous administration.39,45 Nifedipine is widely used, particularly by pediatric nephrologists, to treat severe hypertension in children. There have not been any severe adverse events reported in the literature, and the consensus among pediatricians is that the drug is safe and effective.54 The criticism of the use of nifedipine in hypertensive emergencies begs answers to more important questions: In which patient is a rapid drop of blood pressure necessary? What is the proper velocity, magnitude, and duration of the decrease in arterial pressure in an individual pediatric patient?
Because of recent concerns about possible adverse effects of short-term calcium channel blockers in adults, it has been recommended that physicians treating children with severe hypertension exercise caution in their use.4 Newer calcium channel-blocking agents (nicardipine) seem to have fewer side effects, although their use in children has been limited.
Nicardipine. Nicardipine is the first intravenously administered calcium channel antagonist of the dihydropyridine class.40,55 Unlike other calcium channel antagonists, it has limited effects on the chronotropic and inotropic function of the myocardium.
Nicardipine provides easily titratable control of blood pressure in the pediatric patient.55-57 There have been a number of dosing schemes described in the literature for treating hypertensive crisis. Recommended continuous infusion rates range from 1-10 mcg/kg/min with 1-5 mcg/kg/min being the most common.39,55 If the patient's condition warrants a more rapid response, an initial bolus dose of 0.03 mg/kg can be administered.39 Clinical experience in pediatric patients documents that nicardipine has a rapid onset and offset of action.55
Nicardipine has been reported to produce equally effective control of blood pressure when compared to sodium nitroprusside.58 Thiocyanate and cyanide toxicity have also been associated with sodium nitroprusside at high infusion rates, which is not a problem encountered with nicardipine. This advantage may be of particular value in the treatment of hypertension associated with renal disease, or patients with hepatic dysfunction where accumulation of thiocyanate and cyanide may be more pronounced. The most common untoward effects of nicardipine are due to excessive vasodilation. These include dizziness, hypotension, headache, flushing, tachycardia, and nausea and vomiting. Extreme caution should be exercised when nicardipine is administered to patients with space-occupying intracranial lesions due to the risk of nicardipine causing cerebral vasodilation with associated increase in intracranial pressure.55
Sodium Nitroprusside. Sodium nitroprusside affords precise control of blood pressure. It is metabolized to nitric oxide, which is a potent direct acting vasodilator.29,39 Both arteries and veins are dilated, which results in reduction of both preload and afterload.45 The extremely short half-life of approximately 2-4 minutes provides a virtual instantaneous onset of activity with maximal effects observed in minutes.39 The blood pressure will also begin to rise immediately after stopping the infusion and reach pretreatment levels within seconds. The starting dose is 0.3-0.5 mcg/kg/min. The dose is then titrated upward until the desired blood pressure response is obtained with the usual effective dose being 3-4 mcg/kg/min.
A reflex stimulation of the sympathetic nervous system occurs in response to the drop in systemic vascular resistance, which can lead to tachycardia. Sodium nitroprusside should be used with caution in patients with increased intracranial pressure (ICP) or pulmonary disease.39 Increases in ICP with nitroprusside can be attenuated by administration with concomitant hypocarbia.29 Thiocyanate and cyanide toxicity may develop and can result in metabolic acidosis and neurologic symptoms that include vomiting, nausea, disorientation, hallucination, and anorexia.39,45
Labetalol. Labetalol is a competitive a- and b-adrenergic blocking agent that is useful in treating hypertensive crisis.45 After bolus intravenous administration, labetalol has a rapid onset of action within 2-5 minutes and a duration of actions that generally lasts up to 2-4 hours. Labetalol produces a combined decrease in systemic vascular resistance and a slight decrease in cardiac output that results in an overall reduction in blood pressure. The bolus dose is 0.3-1.0 mg/kg up to a maximum single dose of 20 mg.45 The bolus dose may be repeated every 10 minutes as needed to achieve the desired blood pressure. A constant infusion may also be instituted with an infusion dose of 0.4-1.0 mg/kg/h up to a maximum infusion dose of 3 mg/kg/h.39,45,59
Labetalol is contraindicated in asthmatics or patients with obstructive pulmonary disease due to the possibility of producing bronchospasm through b-adrenergic blocking activity.45,59
Fenoldopam Mesylate (Corlopam). Corlopam is a catecholamine that is structurally related to compounds such as dopamine and dobutamine.60 It is the first marketed, peripherally acting, selective dopamine-1 (D1) receptor agonist, but, unlike other dopaminergic agonists, it does not cross the blood-brain barrier and has no central nervous system activity.60-62
Corolopam is a parenteral, rapid-acting antihypertensive agent that results in vasodilation and lowers BP through D1 receptor agonist activity. Renal, mesenteric, coronary, and cerebral beds respond most prominently.60 In clinical studies, fenoldopam has been shown to rapidly and safely lower elevated BP. The renal effects of fenoldopam include increased renal blood flow, urine flow rate, and sodium excretion while glomerular filtration is maintained. Fenoldopam has been demonstrated to improve creatinine clearance, urine flow rate, sodium excretion, and potassium excretion while lowering blood pressure in severely hypertensive patients with impaired renal function.60
Corolopam is administered as a continuous infusion starting at rates of approximately 0.1 mcg/kg/min; doses below this rate have modest effects and appear only marginally useful.60,62 In general, as the initial dose increases, there is a greater and more rapid blood pressure reduction. Most of the effect of a given infusion rate is attained in 15 minutes.61,62 When infusions are stopped, blood pressure gradually returns to pretreatment values with no evidence of rebound hypertension. The offset of hypotensive effect begins within five minutes, and blood pressure returns to baseline within 15-30 minutes. Unfortunately, safety and effectiveness in children have not been established.
The most common adverse events reported as associated with Corolopam are tachycardia, headache, cutaneous dilation, nausea, and hypotension.60
Diazoxide. Diazoxide is a potent vasodilator of the arteriolar vasculature and has little effect on the venous vasculature. After bolus intravenous injection, diazoxide produces a prompt response in reduction of arteriolar blood pressure with maximal effects occurring at five minutes and lasting generally 3-12 hours. The usual dose is 2-5 mg/kg intravenously, with a maximum single dose of 150 mg.39 Marked hypotension, fluid retention, and hypoglycemia can be observed with diazoxide, which has resulted in limited use of this agent.39,45
Esmolol. Esmolol is a short acting b1-selective adrenergic blocking agent that decreases systolic and diastolic blood pressure.40 It has a short half-life of 10 minutes and is administered with an initial loading dose of 100-500 mcg/kg over one minute followed by a constant infusion of 25-100 mcg/kg/min.45 The infusion rate is then titrated to obtain the desired effect on blood pressure with the usual dosage range being 50-500 mcg/kg/min.63 A second loading dose may be administered if the desired blood pressure response is not initially obtained. As with labetalol, this drug may also cause bronchospasm in the patient with asthma or obstructive pulmonary disease. Other adverse effects that may be observed include nausea, vomiting, congestive heart failure, dizziness, and somnolence.40,45
Angiotensin Converting Enzyme Inhibitors. The renin-angiotensin cascade may contribute to many hypertensive states, including hypertensive emergencies.29,64 Angiotensin converting enzyme (ACE) inhibitors can be used for the chronic management of hypertension and for congestive heart failure. ACE inhibitors decrease total peripheral resistance and cause little change in heart rate, cardiac output, or pulmonary artery occlusion pressure in patients with hypertension.29 There are more than a dozen different ACE inhibitors, but only two are widely used in pediatrics-captopril and enalapril.64 The most common side effects of these agents are cough, rash, taste disturbance, angioedema, proteinuria, and, only rarely observed with the use of captopril, neutropenia.64
The most dramatic adverse effect of ACE inhibitors on the kidney is a severe reduction in glomerular filtration in patients with bilateral renal artery stenosis or renal artery stenosis in a solitary or transplanted kidney.41 In these situations, ACE inhibitors may precipitate acute renal failure.39 Because of these problems and a somewhat prolonged onset of action, even with intravenous administration, ACE inhibitors are not commonly used for hypertensive emergencies.39
Captopril therapy in infants with chronic hypertension has been associated with rapid drops in blood pressure, oliguria, and seizures.65 This illustrates that adaptive responses in the cerebral and renal microcirculations are altered in infants with chronic hypertension. Enalapril is also available for intravenous use. Enalapril has been used in hypertensive emergencies.45 However, the potential complications and the variable effectiveness of this therapy should limit its use in these circumstances. Enalapril should always be avoided in pregnant women.45
Conclusion
The etiology of hypertension in children is distinct and well documented. Most childhood cases (90%) are secondary to an identifiable process. Hypertensive crises occur in children and can be life-threatening. Prompt recognition and appropriate therapy are essential to decrease morbidity from these events. There are various options for safe and effective treatment of the acute hypertension, and close monitoring is required to ensure a successful outcome.
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