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NDT Advance Access published online on November 7, 2008
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfn597
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© The Author [2008]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org


Hypertension in the young: epidemiology, sequelae and therapy

Joseph T. Flynn

Division of Nephrology, Seattle Children's Hospital, University of Washington School of Medicine, Seattle, WA, USA

Correspondence and offprint requests to: Joseph T. Flynn, Division of Nephrology, A-7931, Seattle Children's Hospital, 4800 Sand Point Way NE, Seattle, WA 98105, USA. Tel: +1-206-987-2524; Fax: +1-206-987-2636; E-mail: joseph.flynn{at}seattlechildrens.org

Keywords: antihypertensive medications; cardiovascular disease; children; epidemiology; hypertension



   Epidemiology
Top
 Epidemiology
Adverse effects of elevated...
 Advances in treatment
 Conclusions
 References
 
The first hint of a shift in the epidemiology of childhood hypertension was seen in a 2004 analysis [1] of National Health and Nutrition Examination Survey (NHANES) data in the United States (US) that demonstrated that overall blood pressure (BP) levels in US children and adolescents have increased over the past decade: Systolic blood pressure (SBP) was found to be 1.4 mmHg higher in 1999–2000 compared to 1988–1994 and diastolic blood pressure (DBP) was found to be 3.3 mmHg higher. This increase in overall BP levels was more pronounced in non-Hispanic black and Mexican-American children, particularly in girls. The difference for black children has previously been described [2], but prior studies had generally shown similar blood pressures for Mexican-American children compared to other ethnic groups [3]. While some of the increase in childhood BP levels was attributed to obesity, particularly among the Mexican-American children [1], much of it could not, implying that other, as yet unidentified, forces were at work among American children resulting in the increased BP levels.

A more recent review of BP data in 8- to 17-year-old children from the NHANES and other related population-based studies conducted in the United States from 1963 to 2002 clearly demonstrates an increase in the prevalence of high BP in children (Figure 1) [4], countering earlier suggestions that the prevalence of childhood hypertension has remained stable over time [5]. A significant strength of this analysis was the application of current BP criteria for hypertension and pre-hypertension in childhood to all of the data in the various surveys included, thereby eliminating one of the problems affecting prior analyses. As illustrated in Figure 1, the prevalence of pre-hypertension has now reached 10%, and the prevalence of hypertension nearly 4%. Consistent with the earlier analysis by Munter [1], Din-Dzietham demonstrated that the recent trends in high BP have had a much greater effect on non-Hispanic blacks and Mexican Americans than on whites [4] (Figure 1).


Figure 1
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  		Fig. 1 Prevalence of pre-hypertension (left-hand bars) and hypertension (right-hand bars) among American children in 1999–2002 compared to 1988–1994 [4].

 
A key aspect of both of the population studies discussed above is the impact of childhood obesity. As seen in Figure 2, the prevalence of obesity among American children has more than trebled over the past 30 years, and now approaches 20% in children aged 6–11 years [6,7]. A similar picture is emerging among younger children as well: in New York City, among 16 000 children (mean age 3.5 years) enrolled in the Head Start Program in 2004, 27% were obese and 15% were overweight [8]. In a recent study, it was projected that the increase in childhood obesity in the United States will result in a significant increase in obesity among 35-year-olds by 2020, which could then translate into a significant increase in adult cardiovascular disease [9].


Figure 2
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  		Fig. 2 Percent of children and adolescents with BMI ≥95th percentile for age and gender in NHANES surveys since 1963 [6].

 
The increase in childhood obesity is not limited to the United States. Significant increases in childhood body mass index (BMI) have been documented in several European countries, including Poland [10] and Italy. Among a randomly selected sample of children and adolescents in Catanzaro, Italy, 18% of children were classified as being at risk for overweight (BMI percentile 85–94%) and another 11% were classified as obese (BMI percentile ≥95%) [11]. Obese children in this sample were more likely to have elevated systolic or diastolic BP than non-obese children, and BMI was a significant predictor of elevated BP. Lesser developed countries are experiencing significant increases in childhood obesity as well. Anthropometric data obtained in 23 459 children in the Seychelles demonstrate an increase in the prevalence of obesity from 2.1 to 5.2% in boys and from 3.1 to 6.2% in girls between 1998 and 2004, with analogous increases in the percentage of children at risk of overweight [12]. Decreased physical activity, which has been closely linked to the childhood obesity epidemic in North America, was present even in this developing country and was associated with excess weight.

Childhood obesity has many significant health consequences, among them impaired glucose tolerance, dyslipidaemia, elevated BP, hepatic disease, orthopaedic problems and psychosocial disorders [13]. From a cardiovascular standpoint, numerous studies over the years have firmly established the link between increased BMI in childhood and the development of elevated BP. Recent school screening studies conducted in the United States over the past several years provide ample evidence of this effect, most notably in Houston, TX, where the prevalence of hypertension in adolescents has been shown to be as high as 10% among those with BMI ≥95th percentile [14]. Strong associations between overweight and elevated BP have also recently been reported in sixth-graders in Seminole County, FL [15] and in even younger children in Anadarko, OK [16]. An additional finding in all of these recent studies is a higher prevalence of both overweight and elevated BP among minority children (including Native Americans, African Americans and those of Hispanic ethnicity) compared to white children. This has significant public health implications given the excess prevalence of hypertension-related sequelae such as kidney disease in minority adults [17,18].



   Adverse effects of elevated BP in the young
Top
 Epidemiology
 Adverse effects of elevated...
Advances in treatment
 Conclusions
 References
 
In adults, long-standing hypertension has significant sequelae, including coronary artery disease, stroke and kidney damage [19]. Unfortunately, however, the natural history of primary hypertension in children has never been studied; therefore, the long-term outcome of a hypertensive adolescent or school-aged child cannot be predicted. Nevertheless, some insights into the effects of long-standing hypertension can be gleaned from paediatric populations with secondary hypertension, including aortic coarctation and chronic kidney disease, and from examination of hypertensive target-organ damage in the young.

There is a substantial literature on the late cardiovascular effects of repaired coarctation of the aorta that can provide clues as to the long-term prognosis of persistent childhood hypertension. Recent studies have focused on the high incidence of hypertension despite successful surgical repair [20], suggesting that even a brief period of hypertension early in life can increase the risk of hypertension in adulthood. A plausible mechanism for persistent or late hypertension in such patients may be the effects of hypertension on resistance vessels, the so-called Folkow hypothesis [21]. Earlier studies of patients post-coarctation repair have documented a high incidence of left ventricular hypertrophy (LVH) and sudden cardiac death [22,23].

Children with chronic kidney disease are another group of patients in which persistent hypertension has significant late sequelae. The majority of children with chronic kidney disease are hypertensive [24], and many have associated immediate consequences of their hypertension such as LVH [25]. Additionally, cardiovascular disease is now recognized as the leading cause of late morbidity and mortality in adults with childhood-onset chronic kidney disease [26]. However, it must also be recognized that other risk factors for the development of cardiovascular disease other than elevated BP such as inflammation, dyslipidaemia and disordered calcium-phosphorous metabolism are almost always present in children with chronic kidney disease [27], making it difficult to determine the specific contribution of hypertension in their long-term outcome.

Better information on the significance of persistent hypertension in the young is provided by the many studies documenting several types of hypertensive target-organ damage in children and adolescents. Recent publications have focused on LVH, increased carotid intima-media thickness (cIMT) and even impaired cognitive function as consequences of elevated BP in childhood. Furthermore, several reports have also demonstrated that target-organ changes may even occur in young people with white coat hypertension (WCH), implying that any level of BP elevation at an early age may be detrimental.

LVH was first demonstrated to occur in hypertensive youth by Laird and Fixler [28], who also demonstrated the superiority of echocardiography over other diagnostic methods. Since then, LVH has been repeatedly shown to occur in a significant proportion of hypertensive children and adolescents, with reported prevalences ranging between 20 and 41% depending upon the diagnostic criteria utilized [29–31]. It is especially interesting that the development of LVH in the young may not be related to the severity of BP elevation. While single-center data have demonstrated a correlation between the severity of BP elevation and the likelihood of developing LVH [29,30], a recent large multi-centre study failed to demonstrate any relationship between LVH and specific parameters of BP elevation [31]. This conflicting data underscores the need to perform echocardiography at the diagnosis of hypertension and periodically thereafter in children and adolescents, as recommended in 2004 by the National High Blood Pressure Education Program Working Group [32]. Emerging data on LVH in children with WCH [33] adds further weight to this recommendation.

Several other target-organ effects of hypertension in the young have been recently documented. Increased cIMT, which is well established as a surrogate marker for atherosclerosis in adults [34] has also been found in children and adolescents with primary hypertension in single-center reports [35,36]. Although early studies of cIMT in hypertensive youth were complicated by the effects of obesity [35], a more recent study that controlled for BMI demonstrated a definitive relationship between elevated BP itself and increased cIMT in young patients [36]. While this supports a generalized effect of increased BP on vascular structure in the young, more data are still needed to prove that increased cIMT in the paediatric age group truly represents subclinical atherosclerosis [37].

An additional target-organ effect of elevated BP recently demonstrated in the young is impaired cognitive function [38]. While long-standing hypertension has long been recognized as a risk factor for the development of cognitive impairment and even dementia in the elderly [39], this study demonstrated that children and adolescents with elevated BP (>90th percentile) had poorer performance on selected cognitive tests compared to normotensive children. This provocative finding, while requiring confirmation, adds impetus to consensus recommendations for instituting antihypertensive drug therapy in children and adolescents with persistently elevated BP [32].

Fewer paediatric data are available on the other major target-organ effect of hypertension, namely renal damage. As noted above, although hypertension commonly accompanies chronic kidney disease in children, and although changes consistent with hypertensive nephrosclerosis have been described in autopsy specimens from persons aged 14–21 years [40], hypertension alone is rarely if ever the cause of kidney disease in the young. Even microalbuminuria (MA), which is commonly seen in hypertensive adults, is infrequently seen in children with isolated hypertension. One study comparing hypertensive children in a referral clinic to another group identified by school-based screening did not show significant MA despite a significant prevalence of LVH [41]. However, a more recent study demonstrated that approximately 58% of hypertensive adolescents had MA, with an increased prevalence in Stage 2 hypertension compared to Stage 1 [42]. The reduction of BP in the latter study with an ACE inhibitor was accompanied by a reduction in both microalbuminuria and LVH. However, since both of these are relatively small single-center studies with many limitations, further study is clearly needed to define the role of hypertension in producing kidney damage in the young.



   Advances in treatment
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 Epidemiology
 Adverse effects of elevated...
 Advances in treatment
Conclusions
 References
 
Non-pharmacologic measures—dietary changes, exercise and weight loss—have long been recommended as primary therapy for childhood hypertension, especially in obese children [32]. The efficacy of these measures, however, has been subject to question, primarily because of high rates of non-adherence with prescribed lifestyle changes [43]. However, while traditional approaches that involve periodic visits to paediatric specialty clinics may have limited success [44], new data is emerging that comprehensive programs including nutritional education, counselling and physical training can not only lead to sustained weight loss [43] but can also produce improvements in cardiovascular risk factors including BP [45]. Successful BP reduction was also recently demonstrated in a study of the DASH eating plan in adolescents [46].

However, given the intensive nature of the above non-pharmacologic approaches, and since some hypertensive children may have hypertensive target-organ damage that could be reversed with effective treatment, antihypertensive medications may be needed. As has already been noted, the long-term consequences of untreated hypertension in an asymptomatic, otherwise healthy child or adolescent remain unknown [47]. Additionally, there is an almost complete lack of data on the long-term effects of antihypertensive medications on the growth and development of children. Therefore, use of pharmacologic therapy is usually limited to children and adolescents with one of the following indications [32]:

  • Symptomatic hypertension
  • Secondary hypertension
  • Hypertensive target-organ damage
  • Diabetes (Types I and II)
  • Persistent hypertension despite non-pharmacologic measures.

Historically, few drug trials were conducted in children, with the consequence that many drugs had to be used empirically, without the benefit of specific paediatric efficacy, safety or dosing information. Given the relatively low incidence of hypertension in childhood, it is not surprising that this situation was especially true for antihypertensive medications [48]. While Food and Drug Administration (FDA) initiatives to increase data on paediatric drug use date to as early as 1979, these had little or no impact until passage of the FDA Modernization Act (FDAMA) in 1997 [49]. This legislation contained a provision that granted 6 additional months of patent protection to drug manufacturers if they conducted paediatric trials. Subsequent legislation (Best Pharmaceuticals for Children Act, Paediatric Research Equity Act, FDA Amendments Act of 2007) has extended this provision and also has led to other initiatives, including public posting of internal FDA pharmacology and efficacy reviews on the Internet, and mechanisms to promote studies of medications with lapsed patent protection. These initiatives have led to a significant number of paediatric clinical trials of antihypertensive medications and have also increased the number of such medications with specific paediatric labelling (Table 1), correcting a significant deficiency for antihypertensive medications, and perhaps most importantly, increasing the amount of clinically useful information for practitioners. More recently, the European Medicines Agency has enacted the so-called paediatric rule that requires manufacturers to study medications in children in order to be able to market them in Europe [50].


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  		Table 1 Paediatric labelling of antihypertensive medications: impact of the Food and Drug Administration Modernization Act (FDAMA) and successor legislation

 
In addition to information on efficacy and safety, some of the paediatric trials of antihypertensive medications have yielded unexpected information. For example, the paediatric amlodipine pharmacokinetic study [51] confirmed observations in earlier single-centre case series that younger children appear to metabolize calcium channel blockers more rapidly than older patients, providing a rationale for the finding from the case series that younger children appear to require higher doses on a mg/kg basis than older children [52,53]. However, it was also learned in the same study that plasma amlodipine concentrations were similar no matter whether the drug was dosed once daily or twice daily, contradicting the widespread clinical practice of dosing amlodipine twice daily in children. Racial differences in response to antihypertensive medications, a common finding in adult clinical trials [54], has not been observed in paediatric trials of calcium channel blockers or beta blockers [55,56]. However, fosinopril, which was found to be effective overall in hypertensive children and adolescents [57], was noted to be less effective in black children than in white children at comparable doses in a post hoc analysis of the trial data [58]. This appears to justify FDA requirements for enhanced enrolment of black children and adolescents in trials of antihypertensive medications.

Since many children cannot swallow standard pills and capsules, drug formulation is an important issue for paediatricians and others who care for children [59]. Unfortunately, the FDAMA and related legislation do not contain provisions to stimulate marketing of liquid preparations of medications studied in children [48], leaving this need unfulfilled. However, several of the paediatric drug trials (notably several ACE inhibitors and at least one angiotensin receptor blocker) have incorporated an extemporaneous suspension into the study design, and the suspensions utilized have subsequently been incorporated into the FDA-approved label information for these compounds. While this does provide some useful information for these medications, there are many unresolved questions with respect to stability of extemporaneously prepared suspensions [60] that highlight the problems faced in prescribing most antihypertensive medications to children.

Other recent topics of interest related to the pharmacologic therapy of childhood hypertension include how to best improve the trial design to improve efficacy results [61], and the potential impact of the EMEA's paediatric rule [62]. Many studies of antihypertensive medications conducted in children have failed to demonstrate a dose–response despite ample data confirming efficacy in adults [63,64]. Some of these failures may be related to the FDA-mandated trial designs for paediatric antihypertensive trials, while others have likely been related to the dose ranges chosen for study in children [61]. Future trials should benefit from these early lessons, thereby leading to improved information on the efficacy of these compounds in the young. Similarly, the anticipated effects of the EMEA's paediatric rule on the number and type of trials conducted in children should result in improved clinical recommendations for use of these agents in hypertensive children and adolescents. What remains for future study is whether use of antihypertensive drugs in the young will result in prevention or amelioration of the long-term cardiovascular sequelae of hypertension.



   Conclusions
Top
 Epidemiology
 Adverse effects of elevated...
 Advances in treatment
 Conclusions
References
 
Elevated BP in children and adolescents is increasing in frequency and is increasingly recognized as having significant short- and long-term health consequences. While efforts to address the childhood obesity epidemic may ultimately reduce the number of young patients with hypertension, improved pharmacologic and non-pharmacologic therapies for childhood hypertension also offer the potential for preventing or at least ameliorating early cardiovascular disease.

Conflict of interest statement. The author is a paid consultant to Boehringer-Ingelheim Pharmaceuticals, Novartis Pharmaceuticals and Pfizer, Inc., and is currently participating in a clinical trial sponsored by Merck, Inc. The contents of this paper have not been previously published.



   References
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 Epidemiology
 Adverse effects of elevated...
 Advances in treatment
 Conclusions
 References
 

  1. Muntner P, He J, Cutler JA, et al. Trends in blood pressure among children and adolescents. JAMA (2004) 291:2107–2113.[Abstract/Free Full Text]
  2. Daniels SR, Obarzanek E, Barton BA, et al. Sexual maturation and racial differences in blood pressure in girls: the National Heart, Lung, and Blood Institute Growth and Health Study. J Pediatr (1996) 129:208–213.[CrossRef][Web of Science][Medline]
  3. Berenson GS, Wattigney WA, Webber LS. Epidemiology of hypertension from childhood to young adulthood in black, white, and Hispanic population samples. Public Health Rep (1996) 111(Suppl_2):3–6.
  4. Din-Dzietham R, Liu Y, Bielo MV, et al. High blood pressure trends in children and adolescents in national surveys, 1963 to 2002. Circulation (2007) 116:1488–1496.[Abstract/Free Full Text]
  5. Chiolero A, Bovet P, Paradis G, et al. Has blood pressure increased in children in response to the obesity epidemic? Pediatrics (2007) 119:544–553.[Abstract/Free Full Text]
  6. Trends in child and adolescent overweight. 2006. Available at http://www.cdc.gov/nchs/products/pubs/pubd/hestats/overweight/overwght_child_03.htm (accessed 29 August 2008).
  7. Ogden CL, Carroll MD, Curtin LR, et al. Prevalence of overweight and obesity in the United States, 1999–2004. JAMA (2006) 295:1549–1555.[Abstract/Free Full Text]
  8. Young C, Peretz P, Jaslow R, et al. Obesity in early childhood: more than 40% of head start children in NYC are overweight or obese. (2006) 1–2. NYC Vital Signs, New York City Department of Health and Mental Hygiene.
  9. Bibbins-Domingo K, Coxson P, Pletcher MJ, et al. Adolescent overweight and future adult coronary heart disease. N Engl J Med (2007) 357:2371–2379.[Abstract/Free Full Text]
  10. Chrzanowska M, Koziel S, Ulijaszek SJ. Changes in BMI and the prevalence of overweight and obesity in children and adolescents in Cracow, Poland, 1971–2000. Econ Hum Biol (2007) 5:370–378.[CrossRef][Web of Science][Medline]
  11. Pileggi C, Carbone V, Nobile CG, et al. Blood pressure and related cardiovascular disease risk factors in 6–18 year-old students in Italy. J Paediatr Child Health (2005) 41:347–352.[CrossRef][Web of Science][Medline]
  12. Bovet P, Chiolero A, Madeleine G, et al. Marked increase in the prevalence of obesity in children of the Seychelles, a rapidly developing country, between 1998 and 2004. Int J Pediatr Obes (2006) 1:120–128.[CrossRef][Medline]
  13. Daniels SR, Arnett DK, Eckel RH, et al. Overweight in children and adolescents: pathophysiology, consequences, prevention, and treatment. Circulation (2005) 111:1999–2012.[Abstract/Free Full Text]
  14. Sorof JM, Lai D, Turner J, et al. Overweight, ethnicity, and the prevalence of hypertension in school-aged children. Pediatrics (2004) 113:475–482.[Abstract/Free Full Text]
  15. Tarlton PA. Prevalence of elevated blood pressure in Hispanic versus non-Hispanic 6th graders. J Sch Nurs (2007) 23:47–52.[Abstract/Free Full Text]
  16. Moore WE, Stephens A, Wilson T, et al. Body mass index and blood pressure screening in a rural public school system: the Healthy Kids Project. Prev Chronic Dis (2006) 3:A114.[Medline]
  17. Martins D, Tareen N, Norris KC. The epidemiology of end-stage renal disease among African Americans. Am J Med Sci (2002) 323:65–71.[CrossRef][Web of Science][Medline]
  18. Benabe JE, Rios EV. Kidney disease in the Hispanic population: facing the growing challenge. J Natl Med Assoc (2004) 96:789–798.[Medline]
  19. Kaplan NM. Primary hypertension: natural history and evaluation. In: Kaplan's Clinical Hypertension—Kaplan NM, ed. (2006) Philadelphia, PA: Lippincott Williams and Wilkins. 122–160.
  20. O’Sullivan JJ, Derrick G, Darnell R. Prevalence of hypertension in children after early repair of coarctation of the aorta: a cohort study using casual and 24 hour blood pressure measurement. Heart (2002) 88:163–166.[Abstract/Free Full Text]
  21. Folkow B. Structure and function of the arteries in hypertension. Am Heart J (1987) 114:938–948.[CrossRef][Web of Science][Medline]
  22. Maron BJ, Humphries JO, Rowe RD, et al. Prognosis of surgically corrected coarctation of the aorta. A 20-year postoperative appraisal. Circulation (1973) 47:119–126.[Abstract/Free Full Text]
  23. Simon AB, Zloto AE. Coarctation of the aorta. Longitudinal assessment of operated patients. Circulation (1974) 50:456–464.[Abstract/Free Full Text]
  24. Flynn JT, Mitsnefes M, Pierce C, et al. Blood pressure in children with chronic kidney disease. A report from the chronic kidney disease in children study. Hypertension (2008) 52:631–637.[Abstract/Free Full Text]
  25. Mitsnefes MM, Kimball TR, Kartal J, et al. Progression of left ventricular hypertrophy in children with early chronic kidney disease: 2-year follow-up study. J Pediatr (2006) 149:671–675.[CrossRef][Web of Science][Medline]
  26. Groothoff JW. Long-term outcomes of children with end-stage renal disease. Pediatr Nephrol (2005) 20:849–853.[CrossRef][Web of Science][Medline]
  27. Flynn JT. Cardiovascular disease in children with chronic renal failure. Growth Horm IGF Res (2006) 16(Suppl A):S84–S90.[CrossRef][Web of Science][Medline]
  28. Laird WP, Fixler DE. Left ventricular hypertrophy in adolescents with elevated blood pressure: assessment by chest roentgenography, electrocardiography, and echocardiography. Pediatrics (1981) 67:255–259.[Abstract/Free Full Text]
  29. Hanevold C, Waller J, Daniels S, et al. The effects of obesity, gender, and ethnic group on left ventricular hypertrophy and geometry in hypertensive children: a collaborative study of the International Pediatric Hypertension Association. Pediatrics (2004) 113:328–333.[Abstract/Free Full Text]
  30. McNiece KL, Gupta-Malhotra M, Samuels J, et al. Left ventricular hypertrophy in hypertensive adolescents: analysis of risk by 2004 National High Blood Pressure Education Program Working Group staging criteria. Hypertension (2007) 50:392–395.[Abstract/Free Full Text]
  31. Brady TM, Fivush B, Flynn JT, et al. Ability of blood pressure to predict left ventricular hypertrophy in children with primary hypertension. J Pediatr (2008) 152:73–78. 8 e1.[CrossRef][Web of Science][Medline]
  32. National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and Adolescents. The fourth report on the diagnosis, evaluation, and treatment of high blood pressure in children and adolescents. Pediatrics (2004) 114:555–576.[Free Full Text]
  33. Kavey RE, Kveselis DA, Atallah N, et al. White coat hypertension in childhood: evidence for end-organ effect. J Pediatr (2007) 150:491–497.[CrossRef][Web of Science][Medline]
  34. Poredos P. Intima-media thickness: indicator of cardiovascular risk and measure of the extent of atherosclerosis. Vasc Med (2004) 9:46–54.[Abstract/Free Full Text]
  35. Sorof JM, Alexandrov AV, Cardwell G, et al. Carotid artery intimal-medial thickness and left ventricular hypertrophy in children with elevated blood pressure. Pediatrics (2003) 111:61–66.[Abstract/Free Full Text]
  36. Lande MB, Carson NL, Roy J, et al. Effects of childhood primary hypertension on carotid intima media thickness: a matched controlled study. Hypertension (2006) 48:40–44.[Abstract/Free Full Text]
  37. Flynn JT. What is the significance of increased carotid intima media thickness in hypertensive adolescents? Hypertension (2006) 48:23–24.[Free Full Text]
  38. Lande MB, Kaczorowski JM, Auinger P, et al. Elevated blood pressure and decreased cognitive function among school-age children and adolescents in the United States. J Pediatr (2003) 143:720–724.[CrossRef][Web of Science][Medline]
  39. Paglieri C, Bisbocci D, Di Tullio MA, et al. Arterial hypertension: a cause of cognitive impairment and of vascular dementia. Clin Exp Hypertens (2004) 26:277–285.[CrossRef][Web of Science][Medline]
  40. Tracy RE, Mercante DE, Moncada A, et al. Quantitation of hypertensive nephrosclerosis on an objective rational scale of measure in adults and children. Am J Clin Pathol (1986) 85:312–318.[Web of Science][Medline]
  41. Sorof JM, Turner J, Franco K, et al. Characteristics of hypertensive children identified by primary care referral compared with school-based screening. J Pediatr (2004) 144:485–489.[CrossRef][Web of Science][Medline]
  42. Assadi F. Effect of microalbuminuria lowering on regression of left ventricular hypertrophy in children and adolescents with essential hypertension. Pediatr Cardiol (2007) 28:27–33.[CrossRef][Web of Science][Medline]
  43. Denzer C, Reithofer E, Wabitsch M, et al. The outcome of childhood obesity management depends highly upon patient compliance. Eur J Pediatr (2004) 163:99–104.[CrossRef][Web of Science][Medline]
  44. Quattrin T, Liu E, Shaw N, et al. Obese children who are referred to the pediatric endocrinologist: characteristics and outcome. Pediatrics (2005) 115:348–351.[Abstract/Free Full Text]
  45. Reinehr T, de Sousa G, Toschke AM, et al. Long-term follow-up of cardiovascular disease risk factors in children after an obesity intervention. Am J Clin Nutr (2006) 84:490–496.[Abstract/Free Full Text]
  46. Couch SC, Saelens BE, Levin L, et al. The efficacy of a clinic-based behavioral nutrition intervention emphasizing a DASH-type diet for adolescents with elevated blood pressure. J Pediatr (2008) 152:494–501.[Web of Science][Medline]
  47. Kay JD, Sinaiko AR, Daniels SR. Pediatric hypertension. Am Heart J (2001) 142:422–432.[CrossRef][Medline]
  48. Flynn JT. Pediatric use of antihypertensive medications: much more to learn. Curr Ther Res Clin Exp (2001) 62:314–328.[CrossRef][Web of Science]
  49. Flynn JT, Daniels SR. Pharmacologic treatment of hypertension in children and adolescents. J Pediatr (2006) 149:746–754.[CrossRef][Web of Science][Medline]
  50. Dunne J. The European regulation on medicines for paediatric use. Paediatr Respir Rev (2007) 8:177–183.[CrossRef][Web of Science][Medline]
  51. Flynn JT, Nahata MC, Mahan JD Jr, et al. Population pharmacokinetics of amlodipine in hypertensive children and adolescents. J Clin Pharmacol (2006) 46:905–916.[Abstract/Free Full Text]
  52. Flynn JT, Smoyer WE, Bunchman TE. Treatment of hypertensive children with amlodipine. Am J Hypertens (2000) 13:1061–1066.[CrossRef][Web of Science][Medline]
  53. Parker ML, Robinson RF, Nahata MC. Amlodipine therapy in pediatric patients with hypertension. J Am Pharm Assoc (Wash) (2002) 42:114–117.[CrossRef][Medline]
  54. Brewster LM, van Montfrans GA, Kleijnen J. Systematic review: antihypertensive drug therapy in black patients. Ann Intern Med (2004) 141:614–627.[Abstract/Free Full Text]
  55. Flynn JT, Newburger JW, Daniels SR, et al. A randomized, placebo-controlled trial of amlodipine in children with hypertension. J Pediatr (2004) 145:353–359.[CrossRef][Web of Science][Medline]
  56. Batisky DL, Sorof JM, Sugg J, et al. Efficacy and safety of extended release metoprolol succinate in hypertensive children 6 to 16 years of age: a clinical trial experience. J Pediatr (2007) 150:134–139. 9 e1.[CrossRef][Web of Science][Medline]
  57. Li JS, Berezny K, Kilaru R, et al. Is the extrapolated adult dose of fosinopril safe and effective in treating hypertensive children? Hypertension (2004) 44:289–293.[Abstract/Free Full Text]
  58. Menon S, Berezny KY, Kilaru R, et al. Racial differences are seen in blood pressure response to fosinopril in hypertensive children. Am Heart J (2006) 152:394–399.[CrossRef][Web of Science][Medline]
  59. Nahata MC. Lack of pediatric drug formulations. Pediatrics (1999) 104:607–609.[Abstract/Free Full Text]
  60. Ghulam A, Keen K, Tuleu C, et al. Poor preservation efficacy versus quality and safety of pediatric extemporaneous liquids. Ann Pharmacother (2007) 41:857–860.[Abstract/Free Full Text]
  61. Benjamin DK Jr, Smith PB, Jadhav P, et al. Pediatric antihypertensive trial failures: analysis of end points and dose range. Hypertension (2008) 51:834–840.[Abstract/Free Full Text]
  62. Hoppu K. Paediatric clinical pharmacology: at the beginning of a new era. Eur J Clin Pharmacol (2008) 64:201–205.[CrossRef][Web of Science][Medline]
  63. Trachtman H, Frank R, Mahan JD, et al. Clinical trial of extended-release felodipine in pediatric essential hypertension. Pediatr Nephrol (2003) 18:548–553.[Web of Science][Medline]
  64. Flynn JT, Meyers KE, Neto JP, et al. Efficacy and safety of the Angiotensin receptor blocker valsartan in children with hypertension aged 1 to 5 years. Hypertension (2008) 52:222–228.[Abstract/Free Full Text]
Received for publication: 4. 9.08
Accepted in revised form: 29. 9.08


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