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Diagnosis and Treatment of Hypertension in Children
Symposium on Pediatric Nephrology
Diagnosis and Treatment of Hypertension in Children
Mark Mentser, M.D.*
Within the past decade, awareness of and interest in the diagnosis and treatment of childhood hypertension has increased. 37• 43 • 46 Prior to 1970, most reported series emphasized the importance of a comprehensive diagnostic evaluation in hypertensive children, reporting that a secondary cause could be found in more than 80 per cent. 44 • 67 • 81 More recent studies indicate that primary (essential) hypertension does occur in children and that a thoroughly comprehensive, expensive, and invasive evaluation need not be performed in all. z, 38,47 With the recommendation of the Task Force on Blood Pressure Control in Children that blood pressure measurements be obtained annually in children three years of age and older, 75 an increasing number of asymptomatic children with blood pressure levels at or exceeding the 95th percentile will be identified. Over the coming decade efforts will need to be directed toward determination of the upper limit of "normotension," selection criteria for institution of antihypertensive therapy, and long-term consequences of prolonged pharmacologic treatments in growing children.
Measurement of Blood Pressure Accurate determination of blood pressure in children requires selection of the proper equipment and minimization of variables that may affect the measurements. Appropriate cuff selection is essential to accurate blood pressure recordings by indirect sphygmomanometry and one should not settle for the cuff that is readily available but not the most suitable. The inflatable bladder within the cuff should cover at least two thirds of the length of the upper arm, allowing room for comfortable placement of the stethoscope over the brachial artery. The length of the bladder should be sufficient to completely, or nearly completely, encircle the arm.1,75 Selection of the proper cuff depends on the size of the child's arm and not on the child's age. The child should be approached in a nonthreatening manner, and sufficient time should be allowed for recovery from recent noxious stimuli. The child should be in a comfortable sitting position (infants should be supine) with the arm fully exposed and at heart level. The observer should *Assistant Professor of Pediatrics, Ohio State University College of Medicine; Section of Nephrology, Children's Hospital, Columbus, Ohio
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have an unobstructed view of the manometer, which should be parallel to his eyesight to avoid effects of parallax. The cuff is inflated approximately 20 to 30 mm Hg above the point at which the palpable pulse disappears, and is then released at a rate of 2 to 3 mm Hg per second. As the pressure falls, the Korotkoff sounds become audible and pass through the five recognized phases. Phase 1 is marked by the onset of a clear tapping sound, slowly increasing in intensity as the cuff is slowly deflated. There is general agreement that phase 1 indicates the systolic pressure. Determination of the diastolic pressure is controversial as there is disagreement as to which phase (fourth or fifth) best correlates with direct intra-arterial measurement. The onset of muffiing is the fourth phase and is regarded by many as the best index of diastolic pressure in children. 1• 58• 75 The fifth phase is the point at which all sounds disappear and is regarded as the best index of diastolic pressure in adults.'· 27 • 89 Blood pressure measurements in newborn and small infants is difficult. Various techniques have been applied to this problem including the flush method, palpation, auscultation, and Doppler ultrasound. To measure blood pressure by the flush method, a suitable cuff is wrapped around the extremity (arm or leg) and that portion distal to the cuff is wrapped with an elastic bandage. The manometer is then inflated above the estimated systolic pressure, the bandage is removed, and the pressure is allowed to fall at 3 to 5 mm Hg per second. The point at which capillary filling occurs is noted as the flush pressure and most nearly reflects the mean arterial pressure. 59 The Doppler ultrasound provides a reliable and reproducible measurement of systolic blood pressure in infants.U· 29 By the Doppler method ultrasonic energy is beamed from and received by a transducer positioned over the underlying artery. The frequency of the reflected ultrasound waves is dependent upon the motion of the vessel walls produced by the velocity of blood flow. With deflation of the occluding cuff, the artery snaps open, causing a change in the frequency of reflected sound waves, and produces an amplified audible signal, the systolic pressure. As the diastolic pressure is approached the audible signal changes to a softer and fainter sound. Accurate determination of the diastolic pressure is difficult and comparisons with direct intraarterial measurements question the reliability of such determinations. 93 Sources of error in the measurement of blood pressure include cuff selection, 19· 60 deficiencies in the examiner's technique, and variations in the condition of the subject. 46 Blood pressure measurements taken in the thigh, lower leg, and forearm compare reasonably well to levels obtained in the upper arm provided appropriate equipment and techniques are employed. 65
Interpretation of Blood Pressure Levels Strict criteria for establishing the upper limit of "normotension" in children are not available at the present time. Blood pressure distribution curves by age demonstrate a gradual increase both in systolic and diastolic levels through adolescence, 38• 48 • 75• 90 but the absolute upper limit of normal for a given age remains arbitrary. In addition, lack of standardized techniques including patient position, use of single or multiple measurements, and identification of the diastolic pressure creates confusion when selecting a reference standard for clinical use. Nevertheless, physicians must select a
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set of reference standards and meticulously adhere to the techniques used for establishing them. The Task Force on Blood Pressure Control in Children has developed blood pressure charts similar to the height and weight curves familiar to pediatricians (Fig. 1). Blood pressures should be taken in a quiet environment with the correct size cuff and the fourth phase used as the diastolic pressure. Measurements exceeding the 95th percentile for age should be repeated on at least three separate occasions, and if persistently elevated, should be considered "abnormal." Hypertension is arbitrarily defined as a diastolic blood pressure greater than 90 mm Hg for children three to 12 years old and a diastolic pressure greater than 100 mm Hg for those over 12 years of age.
Causes of Hypertension Renal disease accounts for nearly 80 per cent of secondary hypertension in children. 49 Acute elevations in blood pressure are commonly seen in acute poststreptococcal glomerulonephritis, 39 in hemolytic-uremic syndrome, 40 and in vasculitic diseases such as systemic lupus erythematosus 3 or HenochSchonlein purpura. 56 In acute glomerulonephritis, salt and water retention with subsequent extracelluar fluid volume expansion contributes to the increase in systemic pressure. 74 Acute glomerulonephritis is generally a selflimited disease and chronic hypertension is an infrequent sequela.61 Mild to severe hypertension is often present in hemolytic-uremic syndrome and elevated blood pressure levels may persist even as renal function improves. 20 High peripheral renin activity has been found in some patients 70 and probably contributes to the hypertension by increased generation of the pressor compound angiotensin 11. 86 Hypertension may be seen in diffuse proliferative nephritis secondary to systemic lupus erythematosus3 or as a complication of intake of high dose corticosteroids even in the absence of significant renal involvement. Henoch-Schonlein purpura is a multisystem vasculitis characterized by a purpuric rash, arthralgia, crampy abdominal pain, and nephritis. Hypertension is usually present only in those children with severe nephritis and decreased renal function, but on occasion elevated blood pressure has been observed even in the absence of hematuria, proteinuria, or azotemia. 9 Renal parenchymal and renovascular diseases are most often associated with chronic hypertension. 5 2 Children with chronic pyelonephritis or obstructive uropathy commonly experience an increase in blood pressure associated with progressive deterioration of renal function. Normal blood pressure levels are maintained until the glomerular filtraton rate (GRF) is significantly reduced, at which point sodium retention leads to an expanded blood volume. The onset of hypertension in these patients often heralds the accelerated progression to end-stage renal disease. Children with chronic glomerulonephritis are often hypertensive at the onset of disease even when renal function is relatively well preserved. Focal glomerulosclerosis and membranoproliferative glomerulonephritis are commonly associated with moderate to severe hypertension which may be exacerbated by corticosteroid therapy. Renovascular hypertension is second only to coarctation of the aorta as a cause of surgically correctable high blood pressure in children. Renal artery stenosis has been diagnosed in very young children as in the case reported
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PERCENTILES OF BLOOD PRESSURE MEASUREMENT (RIGHT ARM, SEATED)
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AGE Figure 1. Percentiles of blood pressure measurement in children. A, males; B, females. (From Report of the Task Force on Blood Pressure Control in Children. Pediatrics, 59(Suppl.):803, 1977, with permission.)
by Rahill et al. of a four month old infant whose blood pressure was 290 mm Hg systolic, 185 diastolic when referred for evaluation of a heart murmur; 72 Other reports of renovascular hypertension in infants stress signs and symptoms usually not thought to be caused by hypertension, including failure to thrive, anorexia, vomiting, irritability, convulsions, and congestive heart failure. 51 Older children often are discovered to be hypertensive on routine examination with the diagnosis being made by appropriate investigatory studies, including angiography. Fibromuscular dysplasia is the cause of the renovascular lesions in most children and is pathologically different from the medial dysplasia or arteriosclerotic lesions common to adults. 35 Radiologically, the lesions are most often focal, discrete areas of narrowing, distinctly different from the "string of beads" appearance typically found in adult females. 80 The lesions are often progressive 21 and multiple vessels, including the abdominal aorta, may be involved. 63
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PERCENTILES OF BLOOD PRESSURE MEASUREMENT (RIGHT ARM, SEATED)
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AGE Figure 1.
Continued.
Other renal conditions associated with hypertension include reninsecreting tumors, 91 renal transplantation, 5 3 radiation nephritis, 5° and genitourinary surgery.• Coarctation of the aorta is the most common surgically remediable cause of hypertension in children. In the newborn period, coarctation is often associated with other cardiac abnormalities and infants usually do well for the first few days or weeks of life until the development of congestive heart failure. Diagnosis is established by cardiac catheterization and at surgery the. "infantile" or preductal form of coarctation is found. 33 In spite of vigorous medical and/or surgical management the mortality in these infants is high. After the first year of life, most children with coarctation are asymptomatic. Hypertension is usually discovered on a routine physical examination in an otherwise healthy child. Diagnosis is made from the characteristic physical examination revealing a reduced blood pressure in the lower extremities with absent, diminished, or delayed femoral pulses, a systolic ejection murmur
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heard best over the base of the heart, and sometimes a palpable thrill over the suprasternal notch. Children with this clinical presentation are usually found to have the "adult" or postductal type of coarctation consisting of a short narrowed aortic segment terminating distally to the ductus arteriosus. Abnormalities of the adrenal cortex or medulla are rare causes of secondary hypertension in the pediatric age group. The 21-hydroxylase deficiency is the most common of the adrenogenital syndromes, but children with this disorder are normotensive unless excessive mineralocorticoid has been administered.B" The ll- and 17-hydroxylase deficiencies are associated with hypertension. Females with the ll-hydroxylase deficiency present as virilized infants or adolescents, whereas males usually present within the first five years of life with precocious puberty and gynecomastia. 22 A deficiency in the 17-hydroxylase enzyme results in females with primary amenorrhea and genotypic males presenting as phenotypic females. 85 Both deficiencies are associated with elevated levels of desoxycorticosterone (DOC), which presumably produces hypertension secondary to its mineralocorticoid effects. Other adrenal causes of hypertension include Cushing's syndrome, primary hyperaldosteronism, and pheochromocytoma. Cushing's syndrome, secondary to either a tumor or adrenal hyperplasia, presents with growth retardation, obesity, hirsutism, and hypertension. Biochemical diagnosis is made by demonstrating loss of the diurnal variation of plasma cortisol, increased urinary metabolites, and variable suppression after administration of dexamethasone. 54 The pathogenesis of the hypertension is unknown but may be related to elevated levels of plasma renin substrate with subsequent generation of increased angiotensin. 32 Primary hyperaldosteronism in children is usually secondary to bilateral adrenal hyperplasia with prominent clinical features of severe hypertension and polyuria. 23 Elevated urinary aldosterone secretion, suppressed plasma renin activity, and potassium wasting constitute supportive diagnostic criteria. 14 Long-term administration of spironolactone is the recommended treatment. 15 Pheochromocytoma is a catecholaminesecreting tumor arising from the adrenal medulla and/or any location along the sympathetic chain. Children are likely to have sustained rather than paroxysmal hypertension along with episodes of sweating, palpitations, headache, and abdominal pain. 79 The diagnosis is confirmed by identifying elevated levels of urinary vanillylmandelic acid (VMA), norepinephrine, or epinephrine. 8 The tumor(s) may be localized preoperatively by excretory urogram, angiography, and CT scan,'8 but no investigatory procedures should be performed prior to pharmacologic treatment with alpha-blocking and in some cases beta-blocking agents. 73 Additional causes of secondary hypertension in children include Liddle's syndrome, 36 hyperthyroidism, 92 hyperparathyroidism, 88 dexamethasone-suppressible aldosteronism, 82 low renin hypertension/6 neurofibromatosis, 84 Guillain-Barre syndrome, 57 burns, 68 and leg traction. 41 Physicians caring for children should not be reluctant to make the diagnosis of primary hypertension. While it is generally true that the younger the child and the higher the blood pressure the more likely a secondary cause will be found, prepubertal children will be seen in whom extensive diagnostic evaluations are negative. The more common clinical situation is the asymptomatic adolescent with blood pressure levels at or just above the 95th percentile. Recent studies indicate that extensive evaluations of such
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individuals generally do not identify a significant number with abnormalities;45 therefore, as will be discussed in subsequent paragraphs, limited hypertensive workups are recommended. Epidemiologic studies reveal numerous factors associated with essential hypertension. A genetic influence has been established by finding a close correlation of blood pressure levels in twins, siblings, and between parents and their children. 73 The role of stress and diet (salt and obesity) remains unclear, but an increasing amount of data supports the influence of these environmental factors on the development of essential hypertension. 64 The etiology of essential hypertension is unknown. Arterial blood pressure is regulated by the simultaneous operation and interaction of the sympathetic nervous system, the renin angiotensin system, and body water composition (blood volume). Studies of these mechanisms in hypertensive adults are conflicting and little information in young people is available. Elevated urinary 12 or plasma catecholamines 13 in some adults suggest hyperactivity of the adrenergic nervous system. Renin profiling has been used to identify subgroups of adult hypertensives, 34 but the significance of these data with respect to mechanism and prognosis remains disputed. Measurements of extracellular fluid volume have generally been normal or decreased in the few published studies."'
Diagnostic Evaluation of Hypertensive Children The evaluation of hypertensive children should be individualized and a policy of establishing absolute indications for specific tests is to be discouraged. Proper use of equipment and blood pressure curves will identify children with blood pressure levels at or exceeding the 95th percentile for age and sex. Minimal evaluation should include a thorough family history with emphasis on the occurrence of essential hypertension and identification of immediate family members with evidence of target organ damage, e.g., stroke, heart attack, or renal failure. The child's history should be extensively reviewed for signs and symptoms associated with secondary causes of hypertension. Polyuria, dysuria, or enuresis may suggest an underlying renal disease; while palpitations, flushing, sweating, or abdominal pain may be secondary to excessive catecholamine production (pheochromocytoma). A history of drug use or abuse should be obtained in all adolescents, asking specifically about use of amphetamines and oral contraceptives. The physical examination should include blood pressure measurements in both arms and one leg, a diligent search for signs of secondary causes of hypertension, and detection of target organ damage by cardiac and funduscopic examination. Many endocrine causes of hypertension are distinguishable by characteristic stigmata, which, in their absence, will obviate the necessity of costly laboratory studies. Coarctation of the aorta is generally recognized by a discrepancy between upper and lower extremity blo~d pressures while the presence of an abdominal bruit is "suggestive" of renal artery stenosis. If the history and physical examination are not suggestive of a secondary cause for the hypertension, the "basic" laboratory tests should include urinalysis, hematocrit, and serum creatinine. Serum lipid and uric acid levels are often obtained in large prospective studies, but the value of these tests in individual patients remains unclear. M-mode echocardiography is probably the most sensitive indicator of early myocardial inv.olvement in the hyper-
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tensive process 94 and may eventually be shown to provide objective evaluation of the physiologic effects of "mildly" elevated blood pressure. However, until further standardized data are available for mild hypertensives, the clinical applicability of these studies is limited. Additional studies are generally indicated in children and adolescents with unequivocal hypertension, that is, prepubertal children with diastolic pressure greater than 90 mm Hg and postpubertal children with diastolic levels persistently equal to or greater than 100 mm Hg. If the urine contains red and white cells, protein, or casts, studies applicable to the diagnosis of glomerulonephritis (complement, ASO, etc.) or pyelonephritis (urine culture, specific gravity) should be performed. Since a renal condition is frequently the cause of secondary hypertension, an intravenous urogram is recommended in these children as part of the initial evaluation. Obstruction, renal scarring, or asymmetric kidney size, all readily apparent on intravenous urogram, may establish obstructive uropathy or chronic pyelonephritis as the cause of the hypertension. Although intravenous urography does not visualize the arterial vascular system, evidence suggesting unilateral renovascular disease may be obtained from a properly performed rapid sequence study. Differences in the appearance, concentration, and excretion of contrast material, discrepancy of at least 1.5 em between the two kidneys, hyperconcentration of contrast material in the affected kidney, and ureteral notching are useful signs of unilateral renal artery stenosis. In adults with angiographically proven renovascular disease, the rapid sequence intravenous urogram gives a 70 to 75 per cent positive detection rate, 6 while in children a 50 to 60 per cent incidence of positive studies is reported. 80 Since the visualized abnormalities depe~d on different blood flow rates to the two kidneys, this study will generally miss bilateral or segmental intrarenal vascular disease. Radionuclide studies cannot replace the intravenous urogram for evaluation of renal anatomy, but they may supplement the preliminary evaluation of suspected renovascular disease. The abdominal aorta and renal arteries may be visualized by rapid injection of technetium-labeled compounds followed by serial imaging. Renography using 1311-labeled Hippuran may provide presumptive evidence of unilateral renal artery stenosis if a discrepancy in the relative renal blood flow to the two kidneys is discovered. The incidence of positive studies in children with proven renovascular disease is similar to that with intravenous urography, about 50 per cent. 80 Renal angiography and sampling of renal venous blood for plasma renin activity are used to identify renovascular disease and to assist in the selection of patients for whom corrective surgery is indicated. Although the morbidity associated with these procedures when performed by experienced personnel is low, the decision whether to proceed is often difficult. While probably not indicated for individuals with mildly elevated blood pressure levels, in the absence of other secondary causes these studies should be obtained in prepubertal and postpubertal children with diastolic pressure levels exceeding 100 and llO mm Hg respectively. The study should include the abdominal aorta, origins of both renal arteries, and careful examination of small, intrarenal vessels. Hypertension secondary to renovascular disease is often curable, but assessment of the hemodynamic significance of a lesion should be included in the diagnostic evaluation prior to surgery. A physiologically significant
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lesion will cause increased release of renin from the affected kidney with suppression of renin production by the contralateral kidney. A preoperative prediction exceeding 80 per cent for surgical cure is possible in unilateral renal artery stenosis if the ratio of renal venous renin exceeds 1.5 : 1. 35• 80 With bilateral or segmental renal artery disease, selective renin sampling is less helpful in preoperative assessment but surgical cure or improvement of blood pressure control can be achieved in some cases.
Treatment Many therapeutic decisions must be made in the absence of supporting scientific or epidemiologic data. The VA cooperative study clearly established the effectiveness of antihypertensive treatment in reducing morbidity and mortality in adult males with diastolic blood pressure greater than 115 mm Hg, 13 and preliminary studies of the hypertension detection and follow-up program cooperative group suggest a reduced morbidity in treated adults with less severe diastolic hypertension. 27 Since the upper limits of "normotension" are yet to be defined in children and the incidence of cardiovascular disease in adults whose blood pressure levels tracked at the 95th percentile as youngsters is unknown, selection of the lowest "treatable" blood pressure remains arbitrary. Antihypertensive treatment of children less than 12 years of age with diastolic levels greater than 90 mm Hg and adolescents with levels greater than 100 mm Hg would appear justified at the present time, but future studies may prove these recommendations too conservative. For the asymptomatic child with mild essential hypertension, treatment begins with a nutritional and exercise program prior to the use of pharmacologic agents. Epidemiologic studies suggest a close correlation of salt intake and prevalence ofhypertension30 and blood pressure levels do fall in subjects adhering to a salt restricted diet."8 Recommendations to avoid adding salt during food preparation or at the table and limiting the intake of highly salty foods (pork products, canned or "fast" foods) are achievable goals in motivated patients. Controlled exercise programs in adults have produced a significant reduction in diastolic pressure 7 and there is no reason to believe that such activities should not be pursued in mildly hypertensive children. Isometric exercises and weight lifting should probably be discouraged since hypertensive adolescents attain a significant increase in diastolic blood pressure following isometric handgrip exertion. 16 Thiazide diuretics remain the agents of choice for the initiation of pharmacologic therapy in patients with mild hypertension. Chlorothiazide at 10 to 20 mg per kg per day or hydrochlorothiazide at 1 to 2 mg per kg per day lowers blood pressure initially through diuretic and natriuretic effects, but the sustained hypotensive action probably results from a reduction in peripheral vascular resistance. 10 Side effects are generally minimal but acute symptomatic volume depletion and decreased serum potassium within the first two weeks should be watched for. The more potent "loop" diuretics, furosemide and ethacrynic acid, should be reserved for patients with reduced renal function since urinary water and electrolyte losses are excessive. Following the stepped approach to antihypertensive therapy, a vasodilator or beta-blocker should be added if satisfactory blood pressure control is not achieved with the diuretic alone. Hydralazine and minoxidil lower blood pressure by reducing vascular resistance through direct relaxation of
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arteriolar smooth muscle. 31• 42 Hydralazine given at 1 to 5 mg per kg per day, administered in 2 to 4 divided doses, lowers blood pressure effectively in patients with mild to moderate hypertension. Side effects of tachycardia, flushing, headache, and palpitations limit its clinical usefulness and may necessitate reduction in dosage or withdrawal of the drug; however, addition of a beta-blocker may prevent the adverse cardiac effects and permit the use of higher doses. Minoxidil is an extremely potent vasodilator that should be reserved for patients with severe hypertension resistant to standard drug therapy. Succcessful reductions of blood pressure in children with chronic renal failure, systemic vasculitis, and after transplantation have been lifesaving;66 however, diuretic therapy or dialysis is required to control sodium retention. Hypertrichosis has led to discontinuation of treatment in many patients, but the dosage should be decreased gradually since severe rebound hypertension has been observed following abrupt withdrawal of the drug. 5 2 Propranolol, a nonselective beta-adrenergic blocking agent, has been used to treat mild essential and severe renal hypertension in adolescents and children.59· 71 Plasma renin activity is lowered in patients taking propranolol, but a direct effect on the central vasomotor center is also a postulated mode of action. 26 Bradycardia may be observed shortly after initiating treatment and all children should be tested for their ability to increase cardiac output on exertion. Insomnia, bad dreams, and hallucinations are occasionally observed and warrant prompt withdrawal of the drug. Propranolol is contraindicated in asthmatics and should be used with caution in diabetics. Metoprolol, a more cardioselective beta-blocker, and nadolol, a long-acting drug, are being evaluated in hypertensive adults but are not currently recommended for children. Methyldopa, guanethidine, clonidine, prazosin, and reserpine are additional antihypertensive agents with no established superiority over those drugs previously mentioned. 78 Captopril, the first orally active inhibitor of angiotensin I converting enzyme, offers specific pharmacologic therapy for hyperreninemic hypertension by blocking the conversion of angiotensin I to angiotensin II. The hypotensive action is secondary to reduction of this potent vasopressor compound, but elevation of bradykinin and suppression of aldosterone may also contribute to its effectiveness. 90 Leukopenia, hyperkalemia, proteinuria, rash, and taste disturbances are the major reported side effects. Captopril has been used effectively in children with severe hypertension, 17 but until further information is obtained regarding the potential effects of chronically elevated levels of renin and angiotensin I, as well as suppression of aldosterone, this agent should be reserved for treatment of severe resistant hypertension. Children with unilateral renal artery stenosis in whom selective renal venous renins lateralize to the affected kidney should be afforded the opportunity of a definitive curative procedure. Nonsurgical treatment with percutaneous transluminal angioplasty has been quite effective in hypertensive adults 24 • 77 and employed successfully in a 3V2 year old child. 55 Avoidance of surgery and the ability to repeat the procedure if hypertension recurs make this a promising therapeutic modality for renovascular disease in children.
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REFERENCES 1. American Heart Association: Recommendations for human blood pressure determination by sphygmomanometers, 1981. 2. Aschinberg, L. C., Zeis, P. M., Miller, R. A., et a!.: Essential hypertension in childhood. }.A.M.A., 238:322, 1977. 3. Baldwin, D. S., Lowenstein, J., Rothfield, N. F., eta!.: The clinical course of the proliferative and membranous forms of lupus nephritis. Ann. Intern. Med., 73:929, 1970. 4. Berns, S. C., Linde, L. M., and Goodwin, W. E.: Transitory hypertension following urologic surgery in children. Pediatrics, 38:194, 1966. 5. Biron, P., and Mongeau, J.: Familial aggregation ofblood pressure and its components. PEDIATR. CLIN. NORTH AM., 25:29, 1978. 6. Bookstein, J. J., Abrams, H. L., Buenger, R. F., et a!.: Cooperative study of renovascular hypertension. Radiologic aspects of renovascular hypertension. The role of urography in unilateral renovascular disease. ].A.M.A., 220:1225, 1972. 7. Boyer, J. L., and Kasch, F. W.: Exercise therapy in hypertensive man. }.A.M.A., 211:1668, 1970. 8. Bravo, E. L., Tarazi, R. C., Gifford, R. W., et a!.: Circulating and urinary catecholamines in pheochromocytoma. N. Engl. J. Med., 301:681, 1979. 9. Bryn, J. R., Fitzgerald, J. F., Northway, J. D., et a!.: Unusual manifestations of HenochSchonlein syndrome. Am. J. Dis. Child., 130:1335, 1976. 10. Conway, J., and Lauwers, P.: Hemodynamic and hypotensive effects oflong-term therapy with chlorothiazide. Circulation, 21:21, 1960. 11. Elseed, A. M., Shinebourne, E. A., and Joseph, M. C.: Assessment of technique for measurement of blood pressure in infants and children. Arch. Dis. Child., 48:932, 1973. 12. Esler, M. D., and Neste!, P. J.: Renin and sympathetic nervous system responsiveness to adrenergic stimuli in essential hypertension. Am. J. Cardiol., 32:643, 1973. 13. Esler, M. D., Julius, S., Zweifter, A., eta!.: Mild high-renin essential hypertension. New Engl. J. Med., 296:405, 1977. 14. Ferris, J. B., Beevers, D. G., Brown, J. ]., eta!.: Clinical, biochemical and pathological features of low-renin ("primary") hyperaldosteronism. Am. Heart]., 95:375, 1978. 15. Ferris, J. B., Beevers, D. G., Boddy, K. K., et a!.: The treatment of low-renin ("primary") hyperaldosteronism. Am. Heart J., 96:97, 1978. 16. Fixler, D. E., Laird, W. P., Browne, R., eta!.: Response of hypertensive adolescents to dynamic and isometric exercise stress. Pediatrics, 64:579, 1979. 17. Friedman, A., Chesney, R. W., Ball, D., et a!.: Effective use of captopril (angiotensin !converting enzyme inhibitor) in severe childhood hypertension. J. Pediatr., 97:664, 1980. 18. Ganguly, A., Henry, D. P ., Yune, H. Y., eta!.: Diagnosis and localization of pheochromocytoma. Am. J. Med., 67:21, 1979. 19. Geddes, L.A., and Whistler, S. J.: The error in indirect blood pressure measurement with the incorrect size of cuff. Am. Heart J., 96:4, 1978. 20. Gianantonio, C. A., Vitacco, M., Mendilaharzu, F., et a!.: The hemolytic-uremic syndrome. Renal status of 76 patients at long-term follow-up. J. Pediatr., 72:757, 1968. 21. Goncharenko, V., Gerlock, A. ]., Shaff, M. 1., eta!.: Progression of renal artery fibromuscular dysplasia in 42 patients as seen on angiography. Radiology, 139:45, 1981. 22. Gregory, T., and Gardner, L. 1.: Hypertensive virilizing adrenal hyperplasia with minimal impairment of synthetic route to cortisol. J. Clin. Endocrinol. Metab., 43:769, 1976. 23. Grim, C. E., McBride, A. C., Glenn, J. F., eta!.: Childhood primary hyperaldosteronism with bilateral adrenocortical hyperplasia: Plasma renin activity as an aid to diagnosis. J. Pediatr., 71:377, 1976. 24. Gruntzig, A., and Kumpe, D. A.: Technique of percutaneous transluminal angioplasty with the Gruntzig balloon catheter. Am. J. Roentgenol., 132:541, 1979. 25. Heel, R. C., Brogden, R. N., Speight, T. M., et a!.: Captopril: A preliminary review of its pharmacological properties and therapeutic efficacy. Drugs, 20:409, 1980. 26. Holland, 0. B., and Kaplan, N. M.: Propranolol in the treatment of hypertension. N. Engl. J. Med., 294:930, 1976. 27. Hypertension Detection and Follow-up Program Cooperative Group: Five year findings of the hypertension detection and follow-up program. I. Reduction in mortality of persons with high blood pressure including m~ld hypertension. }.A.M.A., 242:2562, 1979. 28. Kemper, W.: Treatment of hypertensive vascular disease with rice diet. Am. J. Med., 4:545, 1948. 29. Kirkland, R. T., and Kirkland, J. L.: Systolic blood pressure measurements in the newborn infant with the transcutaneous Doppler method. J. Pediatr., 80:52, 1972. 30. Knudsen, K. D., and Dahl, L. K.: Essential hypertension. Inborn error of sodium metabolism? Postgrad. Med. J., 42:148, 1966.
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31. Koch-Weser, J.: Drug therapy: Hydralazine. N. Engl. J. Med., 295:320, 1976. 32. Krakoff, L., Nicolos, G., and Amsel, B.: Pathogenesis of hypertension in Cushing's syndrome. Am. J. Med., 58:216, 1975. 33. Krovetz, L. J., Gessner, I. H., and Schiebler, G. L.: Handbook of Pediatric Cardiology. New York, Harper and Row, 1969. 34. Laragh, J. H., and Sealey, J. E.: Renin-sodium profiling: Why, how, and when in clinical practice. Cardiovasc. Med., 2:1053, 1977. 35. Lawson, J. D., Boerth, R., Foster, J. H., et a!.: Diagnosis and management of renovascular hypertension in children. Arch. Surg., 122:1307, 1977. 36. Liddle, G. W.: A familial renal disorder simulating aldosteronism but with negligible aldosterone secretion. Trans. Assoc. Am. Phys., 76:199, 1963. 37. Lieberman, E.: Childhood hypertension: Evaluation and management. Cardiovasc. Med., Oct., 1976, p. 124. 38. Lieberman, E.: Essential hypertension in children and youth: A pediatric perspective. J. Pediatr., 85:1, 1974. 39. Lieberman, E., and Donnell, G. N.: Recovery of children with acute glomerulonephritis. Am. J. Dis. Child., 109:398, 1965. 40. Lieberman, E.: Hemolytic-uremic syndrome. J. Pediatr., 80:1, 1972. 41. Linshaw, M. A., Stapleton, F. B., Gruskin, A. B., et a!.: Traction-related hypertension in children. J. Pediatr., 95:994, 1979. 42. Linas, S. L., and Nies, A. S.: Minoxidil. Ann. Intern. Med., 94:61, 1981. 43. Loggie, J. M. H., New, M. I., and Robson, A. M.: Hypertension in the pediatric patient: A reappraisal. J. Pediatr., 94:685, 1979. 44. Loggie, J. M. H.: Hypertension in children and adolescents. I. Causes and diagnostic studies. J. Pediatr., 74:331, 1969. 45. Loggie, J. M. H.: Prevalence of hypertension and distribution of causes. In New, M. I., and Levine, L. S. (eds.): Juvenile Hypertension. New York, Raven Press, 1977. 46. Londe, S., and Goldring, D.: High blood pressure in children: Problems and guidelines for evaluation and treatment. Am. J. Cardiol., 37:650, 1976. 47. Londe, S., Bourgoignie, J. J., Robson, A.M., eta!.: Hypertension in apparently normal children. J. Pediatr., 78:569, 1971. 48. Londe, S.: Blood pressure in children as determined under office conditions. Clin. Pediatr., 5:71, 1966. 49. Londe, S.: Causes of hypertension in the young. PEDIAT. CLIN. NoRTH AM., 25:55, 1978. 50. Madrazo, A.: Radiation nephritis. In Edelmann, C., Jr.: Pediatric Kidney Disease. Boston, Little, Brown and Co., 1978. 51. Makker, S. P., and Lubahn, J. D.: Clinical features of renovascular hypertension in infancy: Report of a 9-month-old infant. Pediatrics, 56:108, 1975. 52. Makker, S. P., and Moorthy, B.: Rebound hypertension following minoxidil withdrawal. J. Pediatr., 96:762, 1980. 53. Malekzadeh, M. H., Brennan, L. P., Payne, V. C., eta!.: Hypertension after renal transplantation in children. J. Pediatr., 86:370, 1975. 54. McArthur, R. G., Cloutier, M. D., Hayles, A. B., eta!.: Cushing's disease in children. Mayo Clin. Proc., 47:318, 1972. 55. McCook, T. A., Mills, S. R., Kirks, D. R., et a!.: Percutaneous transluminal renal artery angioplasty in a 3V2 year old hypertensive girl. J. Pediatr., 97:958, 1980. 56. Meadow, S. R., Glasgow, E. F., White, R. H. R., eta!.: Schonlein-Henoch nephritis. Quart. J. Med., 163:241, 1972. 57. Mitchell, P. L., and Meilman, E.: The mechanism of hypertension in the Guillain-Barre syndrome. Am. J. Med., 42:986, 1967. 58. Moss, A. J., and Adams, F. H.: Index of indirect estimation of diastolic blood pressure. Muffiing versus complete cessation of vascular sounds. Am. J. Dis. Child., 106:364, 1963. 59. Moss, A. J., Liebling, W., Austin, W. 0., eta!.: An evaluation of the flush method for determining blood pressure in infants. Pediatrics, 20:53, 1957. 60. Nielsen, P. E., and Janniche, H.: The accuracy of auscultatory measurements of arm blood pressure in very obese subjects. Acta Med. Scand., 195:403, 1974. 61. Nissenson, A. R., Mayon-White, R., Potter, E. V., et a!.: Continued absence of clinical renal disease seven to 12 years after poststreptococcal acute glomerulonephritis in Trinidad. Am. J. Med., 67:255, 1979. 62. Olson, D. L., and Lieberman, E.: Renal hypertension in children. PEDIAT. CLIN. NoRTH AM., 23:795, 1976. 63. Onat, T., and Zeren, E.: Coarctation of the abdominal aorta: Review of 91 cases. Cardiology, 54:140, 1969. 64. Page, L. B.: Epidemiologic evidence of the etiology of human hypertension and its possible prevention. Am. Heart J., 91:527, 1976.
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65. Pascarelli, E. F., and Bertrand, C. A.: Comparison of blood pressures in the arms and legs. N. Engl. J. Med., 270:693, 1964. 66. Pennisi, A. J., Takahashi, M., Bernstein, B. H., eta!.: Minoxidil therapy in children with severe hypertension. J. Pediatr., 90:813, 1977. 67. Platt, R.: Severe hypertension in young persons. Quart. J. Med., 17:83, 1977. · 68. Popp, M. B., Friedberg, D. L., and MacMillan, B. G.: Clinical characteristics of hypertension in burned children. Ann. Surg., 191:473, 1980. 69. Potter, D. E., Schambelan, M., Salvatierra, 0., et a!.: Treatment of high renin hypertension with propranolol in children after renal transplantation. J. Pediatr., 90:307, 1977. 70. Powell, H. R., Rottenberg, E., Williams, A. L., eta!.: Plasma renin activity in acute poststreptococcal glomerulonephritis and the haemolytic-uraemic syndrome. Arch. Dis. Child., 49:802, 1974. 71. Propranolol in the treatment of essential hypertension. V.A. cooperative study group on antihypertensive agents. }.A.M.A., 237:2303, 1977. 72. Rahill, W. J., Molten, A., Hawking, K. M., eta!.: Hypertension and narrowing of the renal arteries in infancy. J. Pediatr., 84:39, 1974. 73. Remine, W. H., Chong, G. C., Van Heerden, J. A., eta!: Current management of pheochromocytoma. Ann. Surg., 179:740, 1973. 74. Repetto, H. A., Lewy, J. E., Braudo, J. L., eta!.: The renal functional response to furosemide in children with acute glomerulonephritis. J. Pediatr., 80:660, 1972. 75. Report of the task force on blood pressure control in children. Pedatrics, 59 (Suppl.): 797, 1977. 76. Sann, L., Revol, A., Zachman, M., eta!.: Unusual low plasma renin hypertension in a child. J. Clin. Endocrinol. Metab., 43:265, 1976. 77. Schwarten, D. E., Yune, H. Y., Klatte, E. C., eta!.: Clinical experience with percutaneous transluminal angioplasty (PTA) of stenotic renal arteries. Radiology, 135:601, 1980. 78. Sinaiko, A. R., and Mirkin, B. L.: Clinical pharmacology of antihypertensive drugs in children. PEDIAT. CLIN. NoRTH AM., 25:137, 1978. 79. Stackpole, R. H., Melicow, M. M., and Usen, A. C.: Pheochromocytoma in children. J. Pediatr., 63:325, 1963. 80. Stanley, P., Gyepes, M. T., Olson, D. L., eta!.: Renovascular hypertension in children and adolescents. Radiology, 129:123, 1978. 81. Still, J. L., and Cotton, D.: Severe hypertension in childhood. Arch. Dis. Child., 42:34, 1967. 82. Sutherland, D. J. A., Ruse, J. L., and Laidlaw, J. C.: Hypertension, increased aldosterone secretion and low plasma renin activity relieved by dexamethasone. Canad. Med. Assoc. J., 195:1109, 1966. 83. Tarazi, R. C.: Hemodynamic role of extracellular fluid in hypertension. Circ. Res., 38:73, 1976. 84. Tilford, D. L., and Kelsch, R. C.: Renal artery stenosis in childhood neurofibromatosis. Am. J. Dis. Child., 126:665, 1973. 85. Tourniaire, J., Audi-Parera, L., Loras, B., eta!.: Male pseudohermaphroditism with hypertension due to a 17-hydroxylation deficiency. Clin. Endocrinol., 5:53, 1973. 86. Vagnucci, A. H., and Shapiro, A. P.: Perspectives on the renin-angiotensin-aldosterone system in hypertension. Metabolism, 23:273, 1974. 87. Vazquez, A. M., and Kenny, F. H.: Hypertension secondary to excessive desoxycorticosterone implants or 9-alpha Huorocortisol in salt-losing congenital adrenal hyperplasia. J. Pediatr., 81 :549, 1972. 88. Vazquez, A. M.: Nephrocalcinosis and hypertension in juvenile primary hyperparathyroidism. Am. J. Dis. Child., 125:104, 1973. 89. V.A. Cooperative Study Group on Antihypertensive Agents. Effect of treatment on morbidity and mortality: Results in patients with diastolic blood pressures averaging 115 through 129 mm Hg. }.A.M.A., 202:1028, 1967. 90. Voors, A. W., Foster, M.S., Frerichs, R. R., eta!.: Studies of blood pressure in children ages 5 to 14 years, in a total biracial community. The Bogalusa Heart Study. Circulation, 54:319, 1976. 91. Warshaw, B. L., Anand, S. K., Olson, D. L., eta!.: Hypertension secondary to a renin-producing juxtaglomerular cell tumor. J. Pediatr., 94:247, 1979. 92. Whyte, R. K., Elseed, A.M., Fraser, C. B., eta!.: Assessment of Doppler ultrasound to measure systolic pressures in infants and young children. Arch. Dis. Child., 50:542, 1975. 93. Williams, R. H.: Textbook of Endocrinology. Edition 5. Phjiladelphia. W. B. Saunders Co., 1974. 94. Zahka, K. G., Neill, C. A., Kidd, L., eta!.: Cardiac involvement in adolescent hypertension. Echocardiographic determination of myocardial hypertrophy. Hypertension, 3:664, 1981. Children's Hospital 700 Children's Drive Columbus, Ohio 43205
Diagnosis and Treatment of Hypertension in Children
Mark Mentser, M.D.*
Within the past decade, awareness of and interest in the diagnosis and treatment of childhood hypertension has increased. 37• 43 • 46 Prior to 1970, most reported series emphasized the importance of a comprehensive diagnostic evaluation in hypertensive children, reporting that a secondary cause could be found in more than 80 per cent. 44 • 67 • 81 More recent studies indicate that primary (essential) hypertension does occur in children and that a thoroughly comprehensive, expensive, and invasive evaluation need not be performed in all. z, 38,47 With the recommendation of the Task Force on Blood Pressure Control in Children that blood pressure measurements be obtained annually in children three years of age and older, 75 an increasing number of asymptomatic children with blood pressure levels at or exceeding the 95th percentile will be identified. Over the coming decade efforts will need to be directed toward determination of the upper limit of "normotension," selection criteria for institution of antihypertensive therapy, and long-term consequences of prolonged pharmacologic treatments in growing children.
Measurement of Blood Pressure Accurate determination of blood pressure in children requires selection of the proper equipment and minimization of variables that may affect the measurements. Appropriate cuff selection is essential to accurate blood pressure recordings by indirect sphygmomanometry and one should not settle for the cuff that is readily available but not the most suitable. The inflatable bladder within the cuff should cover at least two thirds of the length of the upper arm, allowing room for comfortable placement of the stethoscope over the brachial artery. The length of the bladder should be sufficient to completely, or nearly completely, encircle the arm.1,75 Selection of the proper cuff depends on the size of the child's arm and not on the child's age. The child should be approached in a nonthreatening manner, and sufficient time should be allowed for recovery from recent noxious stimuli. The child should be in a comfortable sitting position (infants should be supine) with the arm fully exposed and at heart level. The observer should *Assistant Professor of Pediatrics, Ohio State University College of Medicine; Section of Nephrology, Children's Hospital, Columbus, Ohio
Pediatric Clinics of North America-Yo!. 29, No.4, August 1982
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have an unobstructed view of the manometer, which should be parallel to his eyesight to avoid effects of parallax. The cuff is inflated approximately 20 to 30 mm Hg above the point at which the palpable pulse disappears, and is then released at a rate of 2 to 3 mm Hg per second. As the pressure falls, the Korotkoff sounds become audible and pass through the five recognized phases. Phase 1 is marked by the onset of a clear tapping sound, slowly increasing in intensity as the cuff is slowly deflated. There is general agreement that phase 1 indicates the systolic pressure. Determination of the diastolic pressure is controversial as there is disagreement as to which phase (fourth or fifth) best correlates with direct intra-arterial measurement. The onset of muffiing is the fourth phase and is regarded by many as the best index of diastolic pressure in children. 1• 58• 75 The fifth phase is the point at which all sounds disappear and is regarded as the best index of diastolic pressure in adults.'· 27 • 89 Blood pressure measurements in newborn and small infants is difficult. Various techniques have been applied to this problem including the flush method, palpation, auscultation, and Doppler ultrasound. To measure blood pressure by the flush method, a suitable cuff is wrapped around the extremity (arm or leg) and that portion distal to the cuff is wrapped with an elastic bandage. The manometer is then inflated above the estimated systolic pressure, the bandage is removed, and the pressure is allowed to fall at 3 to 5 mm Hg per second. The point at which capillary filling occurs is noted as the flush pressure and most nearly reflects the mean arterial pressure. 59 The Doppler ultrasound provides a reliable and reproducible measurement of systolic blood pressure in infants.U· 29 By the Doppler method ultrasonic energy is beamed from and received by a transducer positioned over the underlying artery. The frequency of the reflected ultrasound waves is dependent upon the motion of the vessel walls produced by the velocity of blood flow. With deflation of the occluding cuff, the artery snaps open, causing a change in the frequency of reflected sound waves, and produces an amplified audible signal, the systolic pressure. As the diastolic pressure is approached the audible signal changes to a softer and fainter sound. Accurate determination of the diastolic pressure is difficult and comparisons with direct intraarterial measurements question the reliability of such determinations. 93 Sources of error in the measurement of blood pressure include cuff selection, 19· 60 deficiencies in the examiner's technique, and variations in the condition of the subject. 46 Blood pressure measurements taken in the thigh, lower leg, and forearm compare reasonably well to levels obtained in the upper arm provided appropriate equipment and techniques are employed. 65
Interpretation of Blood Pressure Levels Strict criteria for establishing the upper limit of "normotension" in children are not available at the present time. Blood pressure distribution curves by age demonstrate a gradual increase both in systolic and diastolic levels through adolescence, 38• 48 • 75• 90 but the absolute upper limit of normal for a given age remains arbitrary. In addition, lack of standardized techniques including patient position, use of single or multiple measurements, and identification of the diastolic pressure creates confusion when selecting a reference standard for clinical use. Nevertheless, physicians must select a
DIAGNOSIS AND TREATMENT OF HYPERTENSION IN CHILDREN
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set of reference standards and meticulously adhere to the techniques used for establishing them. The Task Force on Blood Pressure Control in Children has developed blood pressure charts similar to the height and weight curves familiar to pediatricians (Fig. 1). Blood pressures should be taken in a quiet environment with the correct size cuff and the fourth phase used as the diastolic pressure. Measurements exceeding the 95th percentile for age should be repeated on at least three separate occasions, and if persistently elevated, should be considered "abnormal." Hypertension is arbitrarily defined as a diastolic blood pressure greater than 90 mm Hg for children three to 12 years old and a diastolic pressure greater than 100 mm Hg for those over 12 years of age.
Causes of Hypertension Renal disease accounts for nearly 80 per cent of secondary hypertension in children. 49 Acute elevations in blood pressure are commonly seen in acute poststreptococcal glomerulonephritis, 39 in hemolytic-uremic syndrome, 40 and in vasculitic diseases such as systemic lupus erythematosus 3 or HenochSchonlein purpura. 56 In acute glomerulonephritis, salt and water retention with subsequent extracelluar fluid volume expansion contributes to the increase in systemic pressure. 74 Acute glomerulonephritis is generally a selflimited disease and chronic hypertension is an infrequent sequela.61 Mild to severe hypertension is often present in hemolytic-uremic syndrome and elevated blood pressure levels may persist even as renal function improves. 20 High peripheral renin activity has been found in some patients 70 and probably contributes to the hypertension by increased generation of the pressor compound angiotensin 11. 86 Hypertension may be seen in diffuse proliferative nephritis secondary to systemic lupus erythematosus3 or as a complication of intake of high dose corticosteroids even in the absence of significant renal involvement. Henoch-Schonlein purpura is a multisystem vasculitis characterized by a purpuric rash, arthralgia, crampy abdominal pain, and nephritis. Hypertension is usually present only in those children with severe nephritis and decreased renal function, but on occasion elevated blood pressure has been observed even in the absence of hematuria, proteinuria, or azotemia. 9 Renal parenchymal and renovascular diseases are most often associated with chronic hypertension. 5 2 Children with chronic pyelonephritis or obstructive uropathy commonly experience an increase in blood pressure associated with progressive deterioration of renal function. Normal blood pressure levels are maintained until the glomerular filtraton rate (GRF) is significantly reduced, at which point sodium retention leads to an expanded blood volume. The onset of hypertension in these patients often heralds the accelerated progression to end-stage renal disease. Children with chronic glomerulonephritis are often hypertensive at the onset of disease even when renal function is relatively well preserved. Focal glomerulosclerosis and membranoproliferative glomerulonephritis are commonly associated with moderate to severe hypertension which may be exacerbated by corticosteroid therapy. Renovascular hypertension is second only to coarctation of the aorta as a cause of surgically correctable high blood pressure in children. Renal artery stenosis has been diagnosed in very young children as in the case reported
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PERCENTILES OF BLOOD PRESSURE MEASUREMENT (RIGHT ARM, SEATED)
2
4
6
8
10
12
14
16
18
AGE Figure 1. Percentiles of blood pressure measurement in children. A, males; B, females. (From Report of the Task Force on Blood Pressure Control in Children. Pediatrics, 59(Suppl.):803, 1977, with permission.)
by Rahill et al. of a four month old infant whose blood pressure was 290 mm Hg systolic, 185 diastolic when referred for evaluation of a heart murmur; 72 Other reports of renovascular hypertension in infants stress signs and symptoms usually not thought to be caused by hypertension, including failure to thrive, anorexia, vomiting, irritability, convulsions, and congestive heart failure. 51 Older children often are discovered to be hypertensive on routine examination with the diagnosis being made by appropriate investigatory studies, including angiography. Fibromuscular dysplasia is the cause of the renovascular lesions in most children and is pathologically different from the medial dysplasia or arteriosclerotic lesions common to adults. 35 Radiologically, the lesions are most often focal, discrete areas of narrowing, distinctly different from the "string of beads" appearance typically found in adult females. 80 The lesions are often progressive 21 and multiple vessels, including the abdominal aorta, may be involved. 63
937
DIAGNOSIS AND TREATMENT OF HYPERTENSION IN CHILDREN
PERCENTILES OF BLOOD PRESSURE MEASUREMENT (RIGHT ARM, SEATED)
2
4
6
8
10
12
14
16
18
AGE Figure 1.
Continued.
Other renal conditions associated with hypertension include reninsecreting tumors, 91 renal transplantation, 5 3 radiation nephritis, 5° and genitourinary surgery.• Coarctation of the aorta is the most common surgically remediable cause of hypertension in children. In the newborn period, coarctation is often associated with other cardiac abnormalities and infants usually do well for the first few days or weeks of life until the development of congestive heart failure. Diagnosis is established by cardiac catheterization and at surgery the. "infantile" or preductal form of coarctation is found. 33 In spite of vigorous medical and/or surgical management the mortality in these infants is high. After the first year of life, most children with coarctation are asymptomatic. Hypertension is usually discovered on a routine physical examination in an otherwise healthy child. Diagnosis is made from the characteristic physical examination revealing a reduced blood pressure in the lower extremities with absent, diminished, or delayed femoral pulses, a systolic ejection murmur
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MARK MENTSER
heard best over the base of the heart, and sometimes a palpable thrill over the suprasternal notch. Children with this clinical presentation are usually found to have the "adult" or postductal type of coarctation consisting of a short narrowed aortic segment terminating distally to the ductus arteriosus. Abnormalities of the adrenal cortex or medulla are rare causes of secondary hypertension in the pediatric age group. The 21-hydroxylase deficiency is the most common of the adrenogenital syndromes, but children with this disorder are normotensive unless excessive mineralocorticoid has been administered.B" The ll- and 17-hydroxylase deficiencies are associated with hypertension. Females with the ll-hydroxylase deficiency present as virilized infants or adolescents, whereas males usually present within the first five years of life with precocious puberty and gynecomastia. 22 A deficiency in the 17-hydroxylase enzyme results in females with primary amenorrhea and genotypic males presenting as phenotypic females. 85 Both deficiencies are associated with elevated levels of desoxycorticosterone (DOC), which presumably produces hypertension secondary to its mineralocorticoid effects. Other adrenal causes of hypertension include Cushing's syndrome, primary hyperaldosteronism, and pheochromocytoma. Cushing's syndrome, secondary to either a tumor or adrenal hyperplasia, presents with growth retardation, obesity, hirsutism, and hypertension. Biochemical diagnosis is made by demonstrating loss of the diurnal variation of plasma cortisol, increased urinary metabolites, and variable suppression after administration of dexamethasone. 54 The pathogenesis of the hypertension is unknown but may be related to elevated levels of plasma renin substrate with subsequent generation of increased angiotensin. 32 Primary hyperaldosteronism in children is usually secondary to bilateral adrenal hyperplasia with prominent clinical features of severe hypertension and polyuria. 23 Elevated urinary aldosterone secretion, suppressed plasma renin activity, and potassium wasting constitute supportive diagnostic criteria. 14 Long-term administration of spironolactone is the recommended treatment. 15 Pheochromocytoma is a catecholaminesecreting tumor arising from the adrenal medulla and/or any location along the sympathetic chain. Children are likely to have sustained rather than paroxysmal hypertension along with episodes of sweating, palpitations, headache, and abdominal pain. 79 The diagnosis is confirmed by identifying elevated levels of urinary vanillylmandelic acid (VMA), norepinephrine, or epinephrine. 8 The tumor(s) may be localized preoperatively by excretory urogram, angiography, and CT scan,'8 but no investigatory procedures should be performed prior to pharmacologic treatment with alpha-blocking and in some cases beta-blocking agents. 73 Additional causes of secondary hypertension in children include Liddle's syndrome, 36 hyperthyroidism, 92 hyperparathyroidism, 88 dexamethasone-suppressible aldosteronism, 82 low renin hypertension/6 neurofibromatosis, 84 Guillain-Barre syndrome, 57 burns, 68 and leg traction. 41 Physicians caring for children should not be reluctant to make the diagnosis of primary hypertension. While it is generally true that the younger the child and the higher the blood pressure the more likely a secondary cause will be found, prepubertal children will be seen in whom extensive diagnostic evaluations are negative. The more common clinical situation is the asymptomatic adolescent with blood pressure levels at or just above the 95th percentile. Recent studies indicate that extensive evaluations of such
DIAGNOSIS AND TREATMENT OF HYPERTENSION IN CHILDREN
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individuals generally do not identify a significant number with abnormalities;45 therefore, as will be discussed in subsequent paragraphs, limited hypertensive workups are recommended. Epidemiologic studies reveal numerous factors associated with essential hypertension. A genetic influence has been established by finding a close correlation of blood pressure levels in twins, siblings, and between parents and their children. 73 The role of stress and diet (salt and obesity) remains unclear, but an increasing amount of data supports the influence of these environmental factors on the development of essential hypertension. 64 The etiology of essential hypertension is unknown. Arterial blood pressure is regulated by the simultaneous operation and interaction of the sympathetic nervous system, the renin angiotensin system, and body water composition (blood volume). Studies of these mechanisms in hypertensive adults are conflicting and little information in young people is available. Elevated urinary 12 or plasma catecholamines 13 in some adults suggest hyperactivity of the adrenergic nervous system. Renin profiling has been used to identify subgroups of adult hypertensives, 34 but the significance of these data with respect to mechanism and prognosis remains disputed. Measurements of extracellular fluid volume have generally been normal or decreased in the few published studies."'
Diagnostic Evaluation of Hypertensive Children The evaluation of hypertensive children should be individualized and a policy of establishing absolute indications for specific tests is to be discouraged. Proper use of equipment and blood pressure curves will identify children with blood pressure levels at or exceeding the 95th percentile for age and sex. Minimal evaluation should include a thorough family history with emphasis on the occurrence of essential hypertension and identification of immediate family members with evidence of target organ damage, e.g., stroke, heart attack, or renal failure. The child's history should be extensively reviewed for signs and symptoms associated with secondary causes of hypertension. Polyuria, dysuria, or enuresis may suggest an underlying renal disease; while palpitations, flushing, sweating, or abdominal pain may be secondary to excessive catecholamine production (pheochromocytoma). A history of drug use or abuse should be obtained in all adolescents, asking specifically about use of amphetamines and oral contraceptives. The physical examination should include blood pressure measurements in both arms and one leg, a diligent search for signs of secondary causes of hypertension, and detection of target organ damage by cardiac and funduscopic examination. Many endocrine causes of hypertension are distinguishable by characteristic stigmata, which, in their absence, will obviate the necessity of costly laboratory studies. Coarctation of the aorta is generally recognized by a discrepancy between upper and lower extremity blo~d pressures while the presence of an abdominal bruit is "suggestive" of renal artery stenosis. If the history and physical examination are not suggestive of a secondary cause for the hypertension, the "basic" laboratory tests should include urinalysis, hematocrit, and serum creatinine. Serum lipid and uric acid levels are often obtained in large prospective studies, but the value of these tests in individual patients remains unclear. M-mode echocardiography is probably the most sensitive indicator of early myocardial inv.olvement in the hyper-
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tensive process 94 and may eventually be shown to provide objective evaluation of the physiologic effects of "mildly" elevated blood pressure. However, until further standardized data are available for mild hypertensives, the clinical applicability of these studies is limited. Additional studies are generally indicated in children and adolescents with unequivocal hypertension, that is, prepubertal children with diastolic pressure greater than 90 mm Hg and postpubertal children with diastolic levels persistently equal to or greater than 100 mm Hg. If the urine contains red and white cells, protein, or casts, studies applicable to the diagnosis of glomerulonephritis (complement, ASO, etc.) or pyelonephritis (urine culture, specific gravity) should be performed. Since a renal condition is frequently the cause of secondary hypertension, an intravenous urogram is recommended in these children as part of the initial evaluation. Obstruction, renal scarring, or asymmetric kidney size, all readily apparent on intravenous urogram, may establish obstructive uropathy or chronic pyelonephritis as the cause of the hypertension. Although intravenous urography does not visualize the arterial vascular system, evidence suggesting unilateral renovascular disease may be obtained from a properly performed rapid sequence study. Differences in the appearance, concentration, and excretion of contrast material, discrepancy of at least 1.5 em between the two kidneys, hyperconcentration of contrast material in the affected kidney, and ureteral notching are useful signs of unilateral renal artery stenosis. In adults with angiographically proven renovascular disease, the rapid sequence intravenous urogram gives a 70 to 75 per cent positive detection rate, 6 while in children a 50 to 60 per cent incidence of positive studies is reported. 80 Since the visualized abnormalities depe~d on different blood flow rates to the two kidneys, this study will generally miss bilateral or segmental intrarenal vascular disease. Radionuclide studies cannot replace the intravenous urogram for evaluation of renal anatomy, but they may supplement the preliminary evaluation of suspected renovascular disease. The abdominal aorta and renal arteries may be visualized by rapid injection of technetium-labeled compounds followed by serial imaging. Renography using 1311-labeled Hippuran may provide presumptive evidence of unilateral renal artery stenosis if a discrepancy in the relative renal blood flow to the two kidneys is discovered. The incidence of positive studies in children with proven renovascular disease is similar to that with intravenous urography, about 50 per cent. 80 Renal angiography and sampling of renal venous blood for plasma renin activity are used to identify renovascular disease and to assist in the selection of patients for whom corrective surgery is indicated. Although the morbidity associated with these procedures when performed by experienced personnel is low, the decision whether to proceed is often difficult. While probably not indicated for individuals with mildly elevated blood pressure levels, in the absence of other secondary causes these studies should be obtained in prepubertal and postpubertal children with diastolic pressure levels exceeding 100 and llO mm Hg respectively. The study should include the abdominal aorta, origins of both renal arteries, and careful examination of small, intrarenal vessels. Hypertension secondary to renovascular disease is often curable, but assessment of the hemodynamic significance of a lesion should be included in the diagnostic evaluation prior to surgery. A physiologically significant
DIAGNOSIS AND TREATMENT OF HYPERTENSION IN CHILDREN
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lesion will cause increased release of renin from the affected kidney with suppression of renin production by the contralateral kidney. A preoperative prediction exceeding 80 per cent for surgical cure is possible in unilateral renal artery stenosis if the ratio of renal venous renin exceeds 1.5 : 1. 35• 80 With bilateral or segmental renal artery disease, selective renin sampling is less helpful in preoperative assessment but surgical cure or improvement of blood pressure control can be achieved in some cases.
Treatment Many therapeutic decisions must be made in the absence of supporting scientific or epidemiologic data. The VA cooperative study clearly established the effectiveness of antihypertensive treatment in reducing morbidity and mortality in adult males with diastolic blood pressure greater than 115 mm Hg, 13 and preliminary studies of the hypertension detection and follow-up program cooperative group suggest a reduced morbidity in treated adults with less severe diastolic hypertension. 27 Since the upper limits of "normotension" are yet to be defined in children and the incidence of cardiovascular disease in adults whose blood pressure levels tracked at the 95th percentile as youngsters is unknown, selection of the lowest "treatable" blood pressure remains arbitrary. Antihypertensive treatment of children less than 12 years of age with diastolic levels greater than 90 mm Hg and adolescents with levels greater than 100 mm Hg would appear justified at the present time, but future studies may prove these recommendations too conservative. For the asymptomatic child with mild essential hypertension, treatment begins with a nutritional and exercise program prior to the use of pharmacologic agents. Epidemiologic studies suggest a close correlation of salt intake and prevalence ofhypertension30 and blood pressure levels do fall in subjects adhering to a salt restricted diet."8 Recommendations to avoid adding salt during food preparation or at the table and limiting the intake of highly salty foods (pork products, canned or "fast" foods) are achievable goals in motivated patients. Controlled exercise programs in adults have produced a significant reduction in diastolic pressure 7 and there is no reason to believe that such activities should not be pursued in mildly hypertensive children. Isometric exercises and weight lifting should probably be discouraged since hypertensive adolescents attain a significant increase in diastolic blood pressure following isometric handgrip exertion. 16 Thiazide diuretics remain the agents of choice for the initiation of pharmacologic therapy in patients with mild hypertension. Chlorothiazide at 10 to 20 mg per kg per day or hydrochlorothiazide at 1 to 2 mg per kg per day lowers blood pressure initially through diuretic and natriuretic effects, but the sustained hypotensive action probably results from a reduction in peripheral vascular resistance. 10 Side effects are generally minimal but acute symptomatic volume depletion and decreased serum potassium within the first two weeks should be watched for. The more potent "loop" diuretics, furosemide and ethacrynic acid, should be reserved for patients with reduced renal function since urinary water and electrolyte losses are excessive. Following the stepped approach to antihypertensive therapy, a vasodilator or beta-blocker should be added if satisfactory blood pressure control is not achieved with the diuretic alone. Hydralazine and minoxidil lower blood pressure by reducing vascular resistance through direct relaxation of
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arteriolar smooth muscle. 31• 42 Hydralazine given at 1 to 5 mg per kg per day, administered in 2 to 4 divided doses, lowers blood pressure effectively in patients with mild to moderate hypertension. Side effects of tachycardia, flushing, headache, and palpitations limit its clinical usefulness and may necessitate reduction in dosage or withdrawal of the drug; however, addition of a beta-blocker may prevent the adverse cardiac effects and permit the use of higher doses. Minoxidil is an extremely potent vasodilator that should be reserved for patients with severe hypertension resistant to standard drug therapy. Succcessful reductions of blood pressure in children with chronic renal failure, systemic vasculitis, and after transplantation have been lifesaving;66 however, diuretic therapy or dialysis is required to control sodium retention. Hypertrichosis has led to discontinuation of treatment in many patients, but the dosage should be decreased gradually since severe rebound hypertension has been observed following abrupt withdrawal of the drug. 5 2 Propranolol, a nonselective beta-adrenergic blocking agent, has been used to treat mild essential and severe renal hypertension in adolescents and children.59· 71 Plasma renin activity is lowered in patients taking propranolol, but a direct effect on the central vasomotor center is also a postulated mode of action. 26 Bradycardia may be observed shortly after initiating treatment and all children should be tested for their ability to increase cardiac output on exertion. Insomnia, bad dreams, and hallucinations are occasionally observed and warrant prompt withdrawal of the drug. Propranolol is contraindicated in asthmatics and should be used with caution in diabetics. Metoprolol, a more cardioselective beta-blocker, and nadolol, a long-acting drug, are being evaluated in hypertensive adults but are not currently recommended for children. Methyldopa, guanethidine, clonidine, prazosin, and reserpine are additional antihypertensive agents with no established superiority over those drugs previously mentioned. 78 Captopril, the first orally active inhibitor of angiotensin I converting enzyme, offers specific pharmacologic therapy for hyperreninemic hypertension by blocking the conversion of angiotensin I to angiotensin II. The hypotensive action is secondary to reduction of this potent vasopressor compound, but elevation of bradykinin and suppression of aldosterone may also contribute to its effectiveness. 90 Leukopenia, hyperkalemia, proteinuria, rash, and taste disturbances are the major reported side effects. Captopril has been used effectively in children with severe hypertension, 17 but until further information is obtained regarding the potential effects of chronically elevated levels of renin and angiotensin I, as well as suppression of aldosterone, this agent should be reserved for treatment of severe resistant hypertension. Children with unilateral renal artery stenosis in whom selective renal venous renins lateralize to the affected kidney should be afforded the opportunity of a definitive curative procedure. Nonsurgical treatment with percutaneous transluminal angioplasty has been quite effective in hypertensive adults 24 • 77 and employed successfully in a 3V2 year old child. 55 Avoidance of surgery and the ability to repeat the procedure if hypertension recurs make this a promising therapeutic modality for renovascular disease in children.
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