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Evidence Summary

Other Supporting Document for Blood Pressure in Children and Adolescents (Hypertension): Screening

Preface

Release Date: February 2013


By Matthew Thompson, MD, MPH, DPhil, Tracy Dana, MLS, Christina Bougatsos, MPH, Ian Blazina, MPH, and Susan L. Norris, MD, MPH, MSc


The information in this article is intended to help clinicians, employers, policymakers, and others make informed decisions about the provision of health care services. This article is intended as a reference and not as a substitute for clinical judgment.

This article may be used, in whole or in part, as the basis for the development of clinical practice guidelines and other quality enhancement tools, or as a basis for reimbursement and coverage policies. AHRQ or U.S. Department of Health and Human Services endorsement of such derivative products may not be stated or implied.

This article was first published in Pediatrics on February 26, 2013 (Pediatrics 2013;131:490-525. www.pediatrics.org). Select for copyright and source information.

Abstract

Background: The prevalence of hypertension is increasing in children, and may persist into adulthood. This systematic review was conducted for the U.S. Preventive Services Task Force recommendation on the effectiveness of screening asymptomatic children and adolescents for hypertension in order to prevent cardiovascular disease.

Methods: Eligible studies were identified from Medline and the Cochrane Library (through July 2012). We included trials and controlled observational studies in asymptomatic children and adolescents on the effectiveness and harms of screening and treatment, as well as accuracy of blood pressure measurement. One author extracted study characteristics and results, which were checked for accuracy by a second author.

Results: No studies evaluated the effects of screening for hypertension on health outcomes. Two studies of screening tests for elevated blood pressure reported moderate sensitivities (0.65, 0.72) and specificities (0.75, 0.92). Sensitivities and specificities of child hypertension for the later presence of adult hypertension (7 studies) were wide ranging (0–0.63 and 0.77–1.0, respectively), and associations between child hypertension and carotid intima media thickening and proteinuria in young adults (3 studies) were inconsistent. Seven studies reported that drug interventions effectively lowered blood pressure in adolescents over short follow-up periods. No serious treatment-related adverse effects were reported.

Conclusions: There is no direct evidence that screening for hypertension in children and adolescents reduces adverse cardiovascular outcomes in adults. Additional studies are needed to improve diagnosis and risk stratification of children with elevated blood pressure and to quantify risks and benefits of interventions.

Introduction

Between 1% and 5% of children and adolescents have hypertension, and its prevalence has risen in the United States by 1% to 2% over recent decades1-4. Hypertension is usually asymptomatic, and a significant proportion of children with hypertension are undiagnosed5, 6. Screening children and adolescents for elevated blood pressure could identify hypertension at an early stage where interventions could be initiated, potentially decreasing the rate of progression of hypertension from childhood to adulthood and reducing the clinical consequences of hypertension in adulthood 7.

The strongest risk factor for primary hypertension in children of all ages and both genders is elevated BMI 8-14; children who are overweight or obese have a two- to threefold increased risk of hypertension8-10.This increased risk is particularly concerning given that ~17% of children and adolescents in the United States are now obese 15 and have higher risk of other cardiovascular risk factors such as an adverse lipid profile and insulin resistance 16. Other risk factors for primary hypertension include low birth weight, gender, ethnicity, and a positive family history 2,  3,  9,  10,  17-19.

Secondary hypertension is most commonly related to underlying renal parenchymal or renovascular disease; less common causes include aortic coarctation and endocrine disorders 20,  21. Elevated blood pressure is usually only 1 clinical manifestation of the underlying disorder, and treatment is typically directed at correcting the underlying cause.

For the majority of children and adolescents, the rationale for identifying elevated blood pressure lies in the potential to stratify risk of future cardiovascular disease. There is convincing evidence that structural and functional changes in the cardiovascular system, which indicate early atherosclerosis, can be detected in adolescents and young adults. What is less clear are the nature and magnitude of the relationship between elevated blood pressure and other cardiovascular risk factors in children or adolescents and cardiovascular risk in adults. Cohort studies that have followed children to young adulthood suggest that adiposity, insulin resistance, and an adverse lipid profile progress at an increased rate in prehypertensive and hypertensive children and adolescents compared with normotensive children 7,  22,  23.

 

Aims of This Review

The purpose of this systematic review is to provide the U.S. Preventive Services Task Force (USPSTF) with evidence to update their 2003 recommendation on screening for high blood pressure in children and adolescents 24. The larger review is available at www.uspreventiveservicestaskforce.org 25. With the input of members of the USPSTF, we developed an analytic framework (Figure 1) and key questions to guide our literature search and review.

  1. Is screening for hypertension in children/adolescents effective in delaying the onset or reducing adverse health outcomes related to hypertension?
  2. What is the diagnostic accuracy of screening tests for elevated blood pressure in children/adolescents?
  3. What is the association between hypertension in children/adolescents and hypertension and other intermediate outcomes in adults?
  4. What are the adverse effects of screening for hypertension in children/adolescents, including labeling and anxiety?
  5. What is the effectiveness of drug, nondrug, and combination interventions for treating primary hypertension in children/adolescents?
  6. What is the effectiveness of drug, nondrug, and combination interventions initiated for the treatment of primary hypertension in children/adolescents for reducing blood pressure and other intermediate outcomes in adults?
  7. What is the effectiveness of drug, nondrug, and combination interventions initiated for the treatment of primary hypertension in children/adolescents for reducing adverse health outcomes in adults related to primary hypertension?
  8. What are the adverse effects of drug, nondrug, and combination interventions for treating primary hypertension in children/adolescents?

Methods

This review was developed by the Oregon Evidence-based Practice Center under contract with the Agency for Healthcare Research and Quality (contract 290-2007-10057-I) and follows the systematic review methods of the USPSTF 26, 27.

Search Strategies

We searched the Cochrane Central Register of Controlled Trials and the Cochrane Database of Systematic Reviews (through July 2012) and Medline (1946 to July 9, 2012) for relevant studies and systematic reviews, and manually reviewed reference lists for relevant citations (Appendix 1).

Study Selection and Processes

Papers were selected for full review if they met predefined inclusion criteria (Appendix 2). Controlled studies of screening for hypertension in asymptomatic children and adolescents were included. For studies of diagnostic accuracy, eligible studies included a reference standard comparison and provided adequate data to reproduce contingency tables. Evidence from randomized placebo-controlled trials was used to assess the efficacy of treatments on multiple outcomes, including blood pressure, other intermediate health outcomes, and final health outcomes, in childhood, adolescence, and adulthood. Studies with <30 participants and studies of interventions for the treatment of obesity and lipid disorders in children were excluded, because these populations are considered in other USPSTF recommendations29.Toassess harms of treatment, studies without a comparison or a placebo group were included. Studies of secondary hypertension were excluded, although some studies included proportions of participants with secondary hypertension.

All citations identified through searches and other sources were independently reviewed by 2 authors for inclusion and exclusion. Discrepancies at the full-text level were resolved through consensus. One author extracted data on the patient population, study design, testing methods, analysis, follow-up, and results, and a second author checked data extraction for accuracy.

Quality Assessment and Synthesis

By using predefined criteria developed by the USPSTF,26 2 authors rated the quality of studies (good, fair, poor) and resolved discrepancies by consensus. Authors assessed the overall strength of the body of evidence for each key question as good, fair, or poor by using methods developed by the USPSTF on the basis of the number, quality, and sample size of studies, as well as the consistency of results among studies and directness of the evidence.26 The limited number of studies and the heterogeneity of study designs, interventions, and diagnostic tests precluded meta-analyses; results are therefore summarized qualitatively as means or as ranges, as appropriate.

Results

Our literature search identified a total of 6435 citations, of which we reviewed 1059 full-text publications and included 34 studies (Figure 2).

Key Question 1: Is Screening for Hypertension in Children/Adolescents Effective in Delaying the Onset or Reducing Adverse Health Outcomes Related to Hypertension?

No randomized trials compared health outcomes related to hypertension in screened versus nonscreened child or adolescent populations.

Key Question 2: What Is the Diagnostic Accuracy of Screening Tests for Elevated Blood Pressure in Children and Adolescents?

We identified 2 fair-quality studies that provided data on the diagnostic accuracy of screening tests (Appendix 3) 30, 31.Compared with a reference standard of 24-hour ambulatory measurement, office-based blood pressure measurement (3 measurements at each of 2 clinic visits) had a sensitivity of 0.65 (95% confidence interval [CI], 0.45–0.80) and a specificity of 0.75 (95% CI, 0.63–0.84) 31.The positive predictive value was 0.37 (95% CI, 0.28–0.47) and the negative predictive value was 0.63 (95% CI, 0.53–0.72). All 105 participants (mean age, 13 years) had been referred for evaluation at a specialty clinic, so they may not have been representative of screened populations of asymptomatic children. In addition, ambulatory measurement is not yet an internationally accepted reference standard in children and adolescents.

A second study examined a random sample of 9017 eighth graders, of whom about 10% (900/9017) had blood pressure >95th percentile on initial screening, whereas the remainder (8117/9017) were normotensive 30. At follow-up in 10th grade, the sensitivity and specificity of initial elevated blood pressure for persistent elevation of blood pressure were 0.72 (95% CI, 0.65–0.78) and 0.92 (95% CI, 0.91–0.92), respectively; however, the positive predictive value was low (0.17 [95% CI, 0.15–0.20]). This study primarily followed only the sample of children whose initial screening test was positive rather than the entire population, which may have biased the diagnostic accuracy in this study.

In addition, 12 studies compared ≥1 measurement of blood pressure with subsequent reference measurements but did not meet our inclusion criteria because either they failed to apply the reference tests to participants who initially screened negative or they did not use an acceptable reference standard 11, 32-42. Positive predictive values among these studies ranged from 0.04 to 0.53. The reasons for this heterogeneity were unclear but did not appear to be related to varying prevalence of hypertension, method or device used for testing, or thresholds used to define positive tests.

Key Question 3: What Is the Association Between Hypertension in Children/Adolescents and Hypertension and Other Intermediate Outcomes in Adults?

Ten longitudinal studies provided evidence on the association between elevated blood pressure or hypertension in childhood and elevated blood pressure, hypertension, or intermediate outcomes in adults (Appendix 4) 7, 43-51. These studies used different thresholds for defining elevated blood pressure and hypertension in childhood and different definitions of hypertension in adults. The sensitivities and specificities of elevated blood pressure or hypertension in childhood for predicting adult hypertension ranged from 0 to 0.63 and 0.77 to 1, respectively, depending on thresholds 45, 47, 51. Positive predictive values (i.e., the probability of adult hypertension given the presence of elevated blood pressure or hypertension in childhood) ranged from 0.19 to 0.65 45, 47. Five studies reported significant associations between elevated blood pressure in childhood and hypertension in adults, with odds ratios (ORs) ranging from 1.1 to 4.5 57, 47 and relative risks ranging from 1.5 to 9 43, 44, 48.

Two studies reported conflicting findings on the association between childhood hypertension and carotid intima media thickness in young adults. Systolic blood pressure (SBP) >80th percentile in adolescence was mildly associated with carotid intima media thickness in adulthood in 1 study (regression coefficient, 0.013; P < 0.001) 50. A second study, however, found no increased risk of carotid intima media thickness in adulthood related to elevated systolic blood pressure in childhood (highest quartile vs. lower 3 quartiles: OR, 1 [95% CI, 0.80–1.25]), although the level of SBP elevation is not defined in this study 49. Childhood hypertension was significantly associated with microalbuminuria in black but not white adults in a single study 46. We found no evidence for associations between diagnosed hypertension in childhood and other intermediate or final health outcomes.

Key Question 4: What Are the Adverse Effects of Screening for Hypertension in Children and Adolescents, Including Labeling and Anxiety?

One small good-quality study compared 85 children (10–18 years of age) with elevated blood pressure identified by screening to children matched by age and gender from the same community 52. The only outcome reported was rates of school absenteeism, which did not differ significantly between the 2 groups.

Key Question 5: What Is the Effectiveness of Drug, Nondrug, and Combination Interventions for Treating Primary Hypertension in Children and Adolescents?

Fourteen fair-quality randomized controlled trials (RCTs) 33, 53-66 (in 15 publications) of treatment of hypertension in children and adolescents met inclusion criteria (Table 1Appendix 5). The proportion of children with primary hypertension ranged from 31% 54 to 56% 55; however, most studies did not report the proportion of participants with secondary hypertension 53,   57-60, 62, 64-66.

Drug Interventions

All seven included trials of drug interventions examined different drugs 53-59. Most compared active drug (in different doses) to placebo, with follow-up of only 4 weeks. The magnitude of effects on SBP and diastolic blood pressure (DBP) varied and were not consistently different from changes in blood pressure in the placebo group (or these differences were not reported).

Five studies 53, 54, 57-59 reported the percentage of participants achieving target blood pressure at the end of the follow-up period, and all noted an increase in those who achieved target levels with the active drug (range, 15%–86% of subjects). However, 26% to 47% of children in the placebo groups also achieved normal blood pressure at the end of the study period 53-59. Most studies reported significant reductions in mean SBP (range, 1.9–10.2 mm Hg) and DBP (range, 0.4–8.1 mm Hg). Eplerenone (50 mg/day) produced a small increase in mean SBP and no change in DBP 55.

Most studies had limitations, most notably the failure to report the statistical significance of differences between treatment groups in addition to within-group treatment differences. Also, comparison among studies was difficult because of varying drug dosages.

Drug Plus Lifestyle Interventions

The school-based A Dietary/Exercise Alteration Program Trial (ADAPT) examined the effectiveness of a multicomponent, school-based intervention, including nutrition education for and promotion of diet modification to children and parents; expanded community availability of low-sodium foods in grocery stores, restaurants, and school lunches; a school-based exercise program; and propranolol and chlorthalidone compared with a no intervention group 60, 61. This complex intervention resulted in a significant decrease in both SBP and DBP at the 6-month follow-up (mean SBP change: −7.6 mm Hg [P < 0.0001]; mean DBP change: −6.9 mm Hg [P < 0.01]) compared with the control group. At 30 months, however, SBP increased from baseline in both the intervention (1.4 mm Hg) and control groups (3.5 mm Hg), although DBP remained below baseline levels (mean change: −4.2 mm Hg in the intervention group and −3.3 mm Hg in the control group).

Lifestyle Interventions

Most of the six trials examining lifestyle interventions included support related to the interventions (e.g., regular check-ins) in addition to diet, exercise, or meditation 33, 62-66. Only 1 study demonstrated statistically significant reductions in blood pressure compared with untreated controls 64. This small, school-based RCT compared the effects of 5 versus 3 weekly physical education classes in hypertensive children and reported that blood pressure decreased significantly more in participants receiving 5 weekly classes over the 8-month follow-up period (mean between-group difference in SBP: −4.9 mm Hg and DBP: −3.8 mm Hg; P < 0.05 for both outcomes) 64. In another trial, a low-sodium diet combined with personalized support from a nutritionist and/or potassium chloride supplementation was effective in reducing blood pressure compared with usual care plus placebo at 36 months among girls but not among boys66. Other studies of meditation 63, relaxation 33, and dietary changes 62, 65 reported no significant differences between intervention and control groups.

Key Question 6: What Is the Effectiveness of Drug, Nondrug, and Combination Interventions Initiated for the Treatment of Primary Hypertension in Children/Adolescents for Reducing Blood Pressure and Other Intermediate Outcomes in Adults?

No RCTs examined the effectiveness of interventions for hypertension in children or adolescents for reducing blood pressure or other intermediate outcomes in adults.

Key Question 7: What Is the Effectiveness of Drug, Nondrug, and Combination Interventions Initiated for the Treatment of Primary Hypertension in Children/Adolescents for Reducing Adverse Health Outcomes in Adults Related to Primary Hypertension?

No RCTs examined the effectiveness of interventions for hypertension in children or adolescents for reducing clinical outcomes in adults.

Key Question 8: What Are the Adverse Effects of Drug, Nondrug, and Combination Interventions for Treating Primary Hypertension in Children and Adolescents?

Drug Interventions

Twelve trials reported adverse events with drug therapy (Appendix 6) 53-59, 67-71. One study was rated good quality 67; the remainder were of fair quality 53-55, 57-59, 68-71. Four of the studies included children with primary hypertension 53, 57-59, whereas the remainder included children with primary or secondary hypertension 54, 55, 67-71. The number of children enrolled in the studies ranged from 76 to 304, the mean age ranged from 12 to 14 years, and the duration of follow-up for reporting adverse events ranged from 4 weeks to 1 year.

Serious adverse events were rarely reported, and there were no deaths in any of the studies. One study of metoprolol reported 1 case each of pneumonia and metometrorrhagia 53. Another study reported a case of near syncope and an elevated creatinine in a patient who received an incorrect dose of telmisartan. A third study reported 8 serious adverse events among 304 patients, although none were considered to be treatment related 55.

Adverse event data were often poorly reported, and most studies reported noncomparative data from open-label extensions of RCTs. Five studies of monotherapy reported similar rates of adverse events in the intervention (range, 27%–77%) and placebo groups (range, 25%–6%) 55, 57, 59, 67, 68. Children taking a combination of bisoprolol plus hydrochlorothiazide had lower overall rates of adverse events compared with placebo (53%–75%; P = 0.05) after 12 weeks of follow-up 56. Withdrawals caused by adverse events ranged from 0% to 7% in children receiving active treatments 53, 54, 56-59, 67-71 and 0% to 6.2% in placebo groups53, 56, 58, 59, 67, 68.

Headache was the most common specific adverse event in most studies: rates ranged from 2% to 33% in children receiving active treatments53, 56, 57, 59, 68, 71, but only 2 studies reported rates for the placebo group. One study reported that no headaches occurred in the placebo group compared with 11% of active treatment patients 59, whereas in a second study, headache was reported in 31% versus 26% (placebo vs. combination treatment; significance not reported) 56. Other commonly reported adverse events associated with active treatments were cough, upper respiratory infections, and gastrointestinal events, including nausea and diarrhea, although specific rates were not always reported 53, 54, 56-59, 68-71.

Two studies pooled adverse event data from selected drug trials submitted to the Food and Drug Administration over a 7-year period; however, neither study used standard systematic review methods 72, 73. Pooled patient-level data from 1707 children from 10 placebo-controlled RCTs of 10 different active agents 72 revealed similar rates of adverse events between active treatment (0.83 events per patient) and placebo groups (0.76 per patient) after 2 to 4 weeks of follow-up (between-group P = 0.37). Pooled data from 8 RCTs of hypertensive children revealed no difference in the incidence of cough between active treatment and placebo groups (3% in both groups; P = 0.86) 73.

Other Interventions

The fair-quality ADAPT of a propranolol and chlorthalidone/lifestyle intervention described in key question 5 reported no adverse events 60, 61. No studies of lifestyle modification alone reported adverse events.

 

Discussion

Direct evidence linking screening of children and adolescents for hypertension and delaying the onset or reducing the risk of cardiovascular outcomes in adults is not available, and indirect evidence is sparse and of variable quality. We did not identify evidence for the effectiveness of interventions used to treat primary hypertension in children on lowering blood pressure levels or reducing adverse health outcomes in adults. A summary of the evidence is provided in Table 2.

High-quality data on the diagnostic accuracy of blood pressure measurement to detect hypertension were also sparse and suggest moderate sensitivities (0.65 and 0.72), with somewhat higher specificities (0.75 and 0.92). These data suggest that many children who have elevated blood pressure on screening will not have hypertension. There are also some data to suggest that hypertension in childhood is associated with hypertension in young adults (OR range, 1.1–4.5; relative risk range, 1.5–9) or has low to moderate sensitivities (0 and 0.63) and specificities (0.77 and 1) for predicting adult hypertension. Moreover, the association between childhood hypertension and carotid intima media thickness and microalbuminura in young adults was also inconclusive, and direct evidence on other intermediate or final health outcomes was lacking.

The effectiveness of antihypertensive medications in children and adolescents has been examined in 7 trials, all of which were small and of short duration, and each examined a different agent. Most importantly, their antihypertensive effects varied in magnitude, were not consistently present for a given agent for both SBP and DBP, and were not consistently different from placebo or from baseline. Blood pressures in placebo groups often improved along with those of the intervention group, suggesting regression to the mean. From the limited data we identified, medications appeared to be well tolerated, with no serious adverse effects.

Interventions for treating elevated blood pressure that involve lifestyle interventions alone or in combination with an antihypertensive medication found inconsistent results. Of the 3 studies that had positive results, increased physical education at school was effective at reducing blood pressure in 1 study 64, whereas in a second longer-term school-based study, the effects of an antihypertensive combined with a complex lifestyle program (the ADAPT program) were not sustained 60, 61, and finally, a low sodium diet combined with personalized support was only effective in girls 66.

The most important potential limitation of this review was the absence of any evidence to address several of the key questions and the limited quantity and quality of evidence for others. This lack of evidence inevitably limits the conclusions that can be drawn from this review. Second, our search strategy, although rigorous, may have failed to identify relevant studies. We used citation searching of included articles and reviewed all articles identified by the expert reviewers to augment our search strategy. We limited our search to English language publications, which could have limited eligible studies. We cannot exclude the possibility of publication and selective reporting biases, but we were not able to formally test for this. In addition, by including only studies where the interventions were directed against treatment of hypertension (e.g., rather than obesity), indirect evidence was excluded. Finally, identified studies had multiple deficiencies in reporting and methodology, which limited the data available for analysis and interpretation. Limitations included the lack of studies that examined 1 intervention in >1 trial or obvious clinical heterogeneity, precluding the use of meta-analyses.

Future research in this area needs to address the following major gaps in the current state of evidence.

  • Diagnostic accuracy of blood pressure measurement in primary care and community settings for screening children of varying ages and characteristics. This includes identifying the number, frequency, and timing of readings needed to confirm or rule out hypertension 74.
  • Adverse effects of screening, including health care utilization, burden on the family, and discomfort and anxiety for the child and family.
  • Epidemiologic studies to describe the natural history of elevated blood pressure and hypertension in children and adolescents, identifying factors that predict persistence into adulthood, and regression to normal based on baseline characteristics such as age, BMI, and pattern of blood pressure. Such studies need to use current definitions of hypertension and be of sufficient duration to draw clinically useful conclusions 74, 75.
  • Epidemiologic studies to better define thresholds used to define hypertension in children and adolescents and their association with both structural (e.g., carotid intima media thickening, left ventricular mass) and functional (e.g., arterial stiffening) markers of target end organ damage related to hypertension.
  • Longer-term trials of benefits and risks of all antihypertensive agents (as monotherapy and in combination) and evidence for both short- and long-term safety. Given the expected duration of antihypertensive therapy, the absence of long-term safety data is a significant limitation.
  • Large, controlled, good-quality trials of feasible nondrug interventions for children and adolescents using more sophisticated approaches to complex interventions to identify components that provide the greatest benefit over prolonged periods.

Conclusions

The prevalence of hypertension in children and adolescents is increasing in the United States, largely driven by increased BMI. Screening children for elevated blood pressure or hypertension has the potential to shift the management of hypertension to younger age groups and potentially reduce future cardiovascular disease risk in adults. However, at present, the evidence needed to support these practices is limited. Although it would be logistically (and ethically) very challenging to demonstrate the effects of interventions in children and adolescents with elevated blood pressure on cardiovascular outcomes occurring many decades later in adults, there are clearly a number of outstanding research gaps that can be addressed by feasible research designs in a much shorter time frame. Increasingly, blood pressure is being viewed within a paradigm of overall cardiovascular risk stratification, along with other risk factors, such as lipid profiles, insulin resistance, and BMI16.We anticipate that addressing these current gaps in the evidence for blood pressure will be critical to add to clinicians' ability to identify children and adolescents with increased cardiovascular risk and also to offer a balanced assessment of the overall benefit of interventions to reduce this risk and prevent future cardiovascular disease.

 

Copyright and Source Information

Source: This article was first published in Pediatrics (Pediatrics 2013;131:490-525).

Acknowledgments: The authors thank the responsible Medical Officer at the Agency of Healthcare Research and Quality, Iris Mabry-Hernandez, MD, MPH, and U.S. Preventive Services Task Force members Kirsten Bibbins-Domingo, PhD, MD, David Grossman, MD, MPH, Bernadette Melnyk, PhD, RN, CPNP/NPP, and Wanda Nicholson, MD, MPH. We also thank Matthew Gillman, MD, for providing clinical expertise.

Disclaimer: The staff at the Agency for Healthcare Research and Quality and members of the U.S. Preventive Services Task Force developed the scope of the work and reviewed draft manuscripts. Approval from the Agency for Healthcare Research and Quality was required before the manuscript was submitted for publication, but the authors are solely responsible for the content and the decision to submit it for publication.

Funding: This review was supported by the Agency for Healthcare Research and Quality for the U.S. Preventive Services Task Force under contract 290-2007-10057-I to support the work of the U.S. Preventive Services Task Force.

Financial Disclosure: The authors have indicated they have no financial relationships relevant to this article to disclose.

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  78. Frank GC, Farris RP, Ditmarsen P, Voors AW, Berenson GS. An approach to primary preventive treatment for children with high blood pressure in a total community. J Am Coll Nutr. 1982;1(4):357-74.

Figure 1. Analytic framework and key questions

a The assessment and treatment of secondary hypertension is beyond the scope of this review.
b Includes left ventricular hypertrophy, urinary albumin excretion (microalbuminuria), intima media thickness (measured at carotid and/or femoral arteries), and retinal vascular changes.
KQ = key question.

Text Description.

Figure 1 depicts the analytic framework, which outlines the evidence areas covered in the review, including the populations, screening, interventions, and outcomes. The population is children and adolescents who have no symptoms for hypertension, in primary care generalizable settings. An arrow represents screening for hypertension and diagnostic accuracy of the screening test (Key Question 2), and a subsequent arrow represents adverse effects from screening (Key Question 4). Those with high blood pressure are then diagnosed as having either primary or secondary hypertension. The assessment and treatment of secondary hypertension is beyond the scope of this review. For those with primary hypertension, interventions include drug, lifestyle, and combination drug and lifestyle interventions, which are depicted in the middle of the framework. A subsequent arrow assesses the effectiveness of interventions on blood pressure and other intermediate markers in childhood and during adolescence (Key Question 5), and a dotted line represents the effectiveness of these same outcomes in adulthood (Key Question 6). Intermediate outcomes include left ventricular hypertrophy, urinary albumin excretion (microalbuminuria), intima media thickness (measured at carotid and/or femoral arteries), and retinal vascular changes. Key Question 7 assesses the effectiveness of interventions on final health outcomes in adulthood represented at the end of the framework, and an arrow for Key Question 8 examines adverse effects from interventions. In addition, an overarching arrow directly assesses the impact of screening on final health outcomes in adulthood (Key Question 1), and a dotted line examines the association between hypertension in childhood with hypertension and other intermediate outcomes in adulthood (Key Question 3).

Figure 2. Literature search flow diagram.

a Cochrane databases include the Cochrane Central Register of Controlled Trials and the Cochrane Database of Systematic Reviews.
b Other sources include reference lists, suggested by peer reviewers, etc.
c Some articles are included for >1 key question.
d Twelve of these studies did not provide enough data to recreate 2 X 2 tables or calculate sensitivity and specificity.

Text Description.

Figure 2 is a flow chart that summarizes the search and selection of articles. Abstracts of potentially relevant articles were identified through bibliographic databases, including MEDLINE, the Cochrane Central Register of Controlled Trials, and the Cochrane Database of Systematic Reviews, as well as through other sources, including expert reviewers and reference lists. There were 6,435 abstracts of potentially relevant articles reviewed. After excluding 5,376 abstracts and articles that were not relevant to the key questions, 1,059 full-text articles were retrieved for further review. A total of 1,024 full-text articles were excluded for the following reasons: wrong population, including secondary hypertension, adults only, etc. (550 articles); wrong intervention (22 articles); wrong outcome (122 articles); wrong study design for key question (38 articles); systematic review, not directly used (3 articles); no original data (215 articles); not English language (2 articles); inadequate duration (23 articles); sample size too small, N<30 (19 articles); and no or inadequate reference standard (30 articles). For the last category, 12 of these studies did not provide enough data to recreate 2 by 2 tables or calculate sensitivity and specificity. Thirty-four unique studies, in 35 publications, were included in the review. Note that some articles were included for more than one key question. For Key Question 1, no studies were included. For Key Question 2, two trials were included. For Key Question 3, 10 cohort studies were included. For Key Question 4, one study was included. For Key Question 5, 14 randomized controlled trials in 15 publications were included. For Key Question 6, no studies were included. For Key Question 7, no studies were included. For Key Question 8, 13 trials and two FDA analyses were included.

Table 1. Effect of Interventions on Blood Pressure: Reported Mean Differences From Baseline and/or Placebo

Author, Year, Duration Interventions Baseline
(mm Hg)
Follow-up
(mm Hg)
Mean Difference:
Follow-up Versus
Baseline (mm Hg)
Mean Difference
at Follow-up:
Intervention Versus
Placebo (mm Hg)
SBP DBP SBP DBP SBP DBP SBP DBP
Drug interventions
Batisky et al 200776 (4 wk) Metoprolol 0.2 mg/kg
Metoprolol 1.0 mg/kg
Metoprolol 2.0 mg/kg
Placebo
131.4
135.0
130.6
132.7
76.3
81.0
76.7
81.4
126.2
127.3
124.3
130.8
73.2
76.1
69.2
79.3
−5.2
−7.7
−6.3
−1.9
−3.1
−4.9
−7.5
−2.1
−4.6
−3.5
−0.2
−6.1
−3.2
−10.1
Flynn et al 200454 (4 wk) Amlodipine 2.5 mg
Amlodipine 5 mg
Placebo
137.9a 74.2a NR −6.9
−8.7
−3.6
−4.2
−4.4
−0.4
NR

NR

Li et al 201055 (4 wk) Eplerenone 25 mg
Eplerenone 50 mg
Eplerenone 100 mg
Placebo (mean, all arms)
125.0
125.7
128.1
128.7
71.3
70.9
70.3
70.4
124.1
126.2
127.0
129.5
70.7
70.9
69.4
69.9
−0.9
0.5
−1.1
0.8
−0.6
0.0
−0.9
−0.5
−5.4
−3.3
−2.5
0.8
1.0
−0.5
Sorof et al 200256 (4 wk) Bisoprolol + hydrochlorothiazide (all doses)
Placebo
133.8
133.8
83.0
81.8
124.0
128.5
76.0
79.5
−9.8
−5.3
−7.0
−2.3
−4.5
−3.5
Trachtman et al 200357 (3 wk) Felodipine 2.5 mg
Felodipine 5 mg
Felodipine 10 mg
Placebo
NR NR
NR
NR
83.1
NR NR
NR
NR
81.0
NR NR
NR
NR
−2.1
−0.7
−0.1
−1.1
−2.1
−4.6
1.3
Trachtman et al 200858 (4 wk) Candesartan (all doses)
Placebo
Not reported −10.2
−3.7
−6.6
−1.8
NR
NR
Wells et al 201059 (4 wk) Telmisartan, low-dose
Telmisartan, high-dose
Placebo
132.0
131.0
130.0
79.0
78.4
78.4
123.0
117.0
126.0
71.3
70.6
75.5
−9.7
−14
−6
−8.1
−7.8
−3.5
−3.6
−8.5
−4.2
−4.9
Drug plus lifestyle interventions
Berenson et al 198360 (6 mo) ADAPT program
Control
116.6
118.5
77.7
78.3
109.0
115.5
70.8
74.4
−7.6
−3.0
−6.9
−3.9
−6.5
−3.6
Berenson et al 199061 (30 mo)b ADAPT program
Control
116.6
118.5
77.7
78.5
118.0
122.0
73.5
75.2
1.4
3.5
−4.2
−3.3
−3.6
−1.7
Lifestyle interventions
Couch et al 200862 (6 mo) DASH diet
Routine care
129.4
124.3
80.4
81.7
120.1
120.0
75.2
76.4
−9.3
−4.3
−5.2
−5.3
0.1
−1.2
Ewart et al 198733 (9 mo) Relaxation training
No intervention
127.0
126.5
79.1
80.4
118.6
120.9
72.9
76.0
−8.4
−5.6
−6.2
−4.4
−2.3
−3.1
Gregoski et al 201163 (3 mo) Meditation
LifeSkills training
Regular health education
119.4
119.6
121.4
68.1
68.0
69.
116.6
119.8
121.0
66.3
68.2
68.7
−2.8
0.2
−0.4
−1.8
0.2
−0.6
−4.4
−1.2
−2.4
−0.5
Hansen et al 199164 (3 mo) Extra physical education classes
No extra classes
Not reported −4.9
−3.8
Howe et al 199165 (4 wk) Low sodium diet
High sodium diet
115.0a 60.1a 112.6
113.8
59.1
60
NR
NR
NR
NR
−1.2
−0.9

DASH = Dietary Approaches to Stop Hypertension; — indicates that data is not available; NR = Not reported.
a Values for total cohort; data not stratified according to treatment group.
b Continuation of Berenson et al 1983 study.

Table 2. Summary of Evidence

Number of Studies
(Overall Quality)
Limitations Consistency Applicability to Primary Care Summary of Findings
Key question 1: Is screening for hypertension in children/adolescents effective in delaying the onset or reducing adverse health outcomes related to hypertension?
No studies NA NA NA NA
Key question 2: What is the diagnostic accuracy of screening tests for elevated blood pressure in children/adolescents?
2 trials (poor) Studies were flawed or not directly applicable to an asymptomatic US population. Only 1 included a comparison with a gold standard of ambulatory monitoring. Consistent Low Sensitivity and specificity of office-based screening for hypertension was 0.65 and 0.75 (positive predictive value, 0.37) compared with ambulatory screening in 1 study of a referred population.

A second, school-based study comparing an initial positive screen to subsequent diagnosis of hypertension had sensitivity (0.72) and specificity (0.92), but the positive predictive value was lower (0.17).

Key question 3: What is the association between hypertension in children/adolescents and hypertension and other intermediate outcomes in adults?
10 cohort studies (poor) Studies used different thresholds for defining elevated blood pressure and hypertension in children and different definitions of hypertension in adults. Studies had methodologic shortcomings. Inconsistent Moderate Sensitivities and specificities of elevated blood pressure or hypertension from childhood to adult hypertension ranged from 0 to 0.66 and 0.77 to 1, respectively. PPVs ranged from 0.19 to 0.65. Five studies reported significant associations between elevated blood pressure in childhood and hypertension in adults, with ORs ranging from 1.1 to 4.5 and RRs from 1.5 to 9. Two studies reported associations between childhood hypertension and carotid intima media thickness in young adults, with conflicting findings. One study reported a significant association between childhood hypertension and microalbuminuria only in black individuals.
Key question 4: What are the adverse effects of screening for hypertension in children/adolescents, including labeling and anxiety?
1 study (poor) Evidence limited to results from 1, good-quality study. NA (1 study) High Children labeled as hypertensive did not miss more days of school in the year after diagnosis compared with prelabeling or compared with nonhypertensive children. Other harms associated with screening were not reported.
Key question 5: What is the effectiveness of drug, nondrug, and combination therapies for treating primary hypertension in children/adolescents?
14 RCTs (poor) Longest drug study duration was only 4 wk.

For many studies, the proportion of children with secondary hypertension was unclear.

Consistent Moderate Children achieving normotensive status (on the basis of varying definitions) ranged from 15% to 86% in patients taking drug treatments and 11% to 48% in patients taking placebo.

There were significant reductions of mean SBP (range 2–10 mm Hg), and mean DBP (range 0.4–8 mm Hg) with some drugs and dosages. The difference between intervention and placebo groups ranged from 0 to 9 mm Hg for SBP and 0.5 to 10 mm Hg for DBP. However, reductions were often only at higher doses of active treatments, and studies only lasted for 4 wk.

One school-based study of a drug plus lifestyle intervention reported a significant, sustained reduction in blood pressure in the combination group versus the control group.

Studies of nondrug therapies were limited, and only 1 study examining the effect of additional physical education classes in school reported a sustained mean reduction in blood pressure in for both boys and girls.

Key question 6: What is the effectiveness of drug, nondrug, and combination therapies initiated for the treatment of primary hypertension in children/adolescents for reducing blood pressure and other intermediate outcomes in adults?
No studies NA NA NA NA
Key question 7: What is the effectiveness of drug, nondrug, and combination therapies initiated for the treatment of primary hypertension in children/adolescents for reducing adverse health outcomes in adults related to primary hypertension?
No studies NA NA NA NA
Key question 8: What are the adverse effects of drug, nondrug, and combination therapies for treating primary hypertension in children/adolescents?
15 studies (13 RCTs, 2 FDA analyses) (fair) Numerous trials from key question 5 did not report comparative events rates between active treatment and placebo arms, and adverse event rates overall were not well-reported in most studies. Consistent Moderate Studies of antihypertensive drugs in children and adolescents generally reported no significant difference between active treatments and placebo in adverse event rates or in withdrawals due to adverse events. In one study, a combination of bisoprolol and hydrochlorothiazide was associated with lower adverse event rates than placebo.

Four studies reported serious adverse events, although with the exception of 1 case of syncope due to a dosing error, serious adverse events were generally not deemed treatment related. Analysis of FDA data revealed no significant difference between drug treatments and placebo in the incidence of specific adverse events, including headache (the most commonly reported adverse event), cardiac events, gastrointestinal events, and cough.

No studies reported on harms associated with nondrug treatments.

FDA, Food and Drug Administration; NA, not applicable; PPV, positive predictive value; RR, relative risk.

Appendix 1. Search Strategies.

Screening

Database: Ovid Medline(R) and Ovid OLDMEDLINE(R)
1 Hypertension or hypertension.mp.
2 prehypertension.mp.
3 pre-hypertension.mp.
4 2 or 3
5 high blood pressure.mp.
6 or/1–5
7 Mass screening
8 6 and 7
9 Limit 8 to (English language and humans)
10 Limit 9 to “all child (0 to 18 years)”
11 9 and (child$ or pediatri$ or adolescen$ or school-age).mp.
12 10 or 11

Database: EBM Reviews: Cochrane Central Register of Controlled Trials
1 Hypertension/ or hypertension.mp.
2 prehypertension.mp.
3 pre-hypertension.mp.
4 2 or 3
5 high blood pressure.mp.
6 or/1–5
7 Mass screening/
8 6 and 7
9 8 and (child$ or pediatri$ or school or adolescen$ or teen$).mp.

Diagnostic accuracy

Database: Ovid Medline(R) and Ovid OLDMEDLINE(R)
1 Hypertension/
2 prehypertension.mp. or Prehypertension/
3 1 or 2
4 Blood pressure determination/
5 sensitivity.mp.
6 specificity.mp.
7 5 and 6
8 “Sensitivity and specificity”/
9 7 or 8
10 3 and 9
11 4 and 9
12 10 or 11
13 Limit 12 to “all child (0 to 18 years)”

Database: EBM Reviews: Cochrane Central Register of Controlled Trials
1 Hypertension/
2 prehypertension.mp. or Prehypertension/
3 1 or 2
4 Blood pressure determination/
5 sensitivity.mp.
6 specificity.mp.
7 5 and 6
8 “Sensitivity and specificity”/
9 7 or 8
10 3 and 9
11 4 and 9
12 10 or 11
13 12 and (child$ or pediatr$ or school or adolescen$ or teen$).mp.

Tracking

Database: Ovid Medline(R) and Ovid OLDMEDLINE
1 “cardiovascular risk in young finns”.mp.
2 “bogalusa heart”.mp.
3 muscatine.mp.
4 (“childhood determinants of adult health” or cdah).mp. [mp=title, abstract, original title, name of substance word, subject heading word, protocol
supplementary concept, rare disease supplementary concept, unique identifier]
5 or/1–4
6 5 and (child$ or pediatric$ or adolescen$).mp. [mp=title, abstract, original title, name of substance word, subject heading word, protocol supplementary
concept, rare disease supplementary concept, unique identifier]
Screening
7 blood pressure.mp. or Blood Pressure/
8 Hypertension/ or hypertension.mp.
9 7 or 8
10 9 and (child$ or pediatric$ or adolescen$).mp.
11 10 and adult$.mp. [mp=title, abstract, original title, name of substance word, subject heading word, protocol supplementary concept, rare disease
supplementary concept, unique identifier]
12 Longitudinal studies/
13 11 and 12
14 6 or 13
15 “Amsterdam Growth and Health Longitudinal Study”.mp.
16 15 and (child$ or pediatric$ or adolescen$).mp.
17 14 or 16
18 17 not pregnancy.mp. [mp=title, abstract, original title, name of substance word, subject heading word, protocol supplementary concept, rare disease
supplementary concept, unique identifier]
19 17 not infan$.mp. [mp=title, abstract, original title, name of substance word, subject heading word, protocol supplementary concept, rare disease
supplementary concept, unique identifier]
20 18 or 19
21 Limit 20 to (English language and humans)
22 Atherosclerosis/
23 Vascular diseases/
24 Albuminuria/
25 Cerebrovascular disorders/
26 Hypertrophy, Left ventricular/
27 Hypertension/
28 or/22–27
29 21 and 28

Interventions

Database: Ovid Medline(R) and Ovid OLDMEDLINE(R)
1 Hypertension/dh, de, dt, pc, rt, rh, su, th [Diet Therapy, Drug Effects, Drug Therapy, Prevention & Control, Radiotherapy, Rehabilitation, Surgery, Therapy]
2 Wt Loss/
3 Exercise/
4 dietary modification.mp. or Food Habits/
5 Diet, sodium-restricted/
6 Angiotensin-Converting Enzyme Inhibitors/ad, ae, po, tu, to [Administration & Dosage, Adverse Effects, Poisoning, Therapeutic Use, Toxicity]
7 Angiotensin II Type 1 Receptor Blockers/ad, ae, po, tu, to [Administration & Dosage, Adverse Effects, Poisoning, Therapeutic Use, Toxicity]
8 Labetalol/ad, ae, po, tu, to [Administration & Dosage, Adverse Effects, Poisoning, Therapeutic Use, Toxicity]
9 Adrenergic β-Antagonists/ad, ae, po, tu, to [Administration & Dosage, Adverse Effects, Poisoning, Therapeutic Use, Toxicity]
10 Atenolol/ad, ae, po, tu, to [Administration & Dosage, Adverse Effects, Poisoning, Therapeutic Use, Toxicity]
11 Bisoprolol/ad, ae, tu [Administration & Dosage, Adverse Effects, Therapeutic Use]
12 Metoprolol/ad, ae, po, tu, to [Administration & Dosage, Adverse Effects, Poisoning, Therapeutic Use, Toxicity]
13 Propranolol/ad, ae, po, tu, to [Administration & Dosage, Adverse Effects, Poisoning, Therapeutic Use, Toxicity]
14 Calcium Channel Blockers/ad, ae, po, tu, to [Administration & Dosage, Adverse Effects, Poisoning, Therapeutic Use, Toxicity]
15 Amlodipine/ad, ae, po, tu, to [Administration & Dosage, Adverse Effects, Poisoning, Therapeutic Use, Toxicity]
16 Felodipine/ad, ae, tu, to [Administration & Dosage, Adverse Effects, Therapeutic Use, Toxicity]
17 Isradipine/ad, ae, po, tu, to [Administration & Dosage, Adverse Effects, Poisoning, Therapeutic Use, Toxicity]
18 Nifedipine/ad, ae, po, tu, to [Administration & Dosage, Adverse Effects, Poisoning, Therapeutic Use, Toxicity]
19 Clonidine/ad, ae, po, tu, to [Administration & Dosage, Adverse Effects, Poisoning, Therapeutic Use, Toxicity]
20 Diuretics/ad, ae, po, tu, to [Administration & Dosage, Adverse Effects, Poisoning, Therapeutic Use, Toxicity]
21 Hydrochlorothiazide/ad, ae, po, tu, to [Administration & Dosage, Adverse Effects, Poisoning, Therapeutic Use, Toxicity]
22 Chlorthalidone/ad, ae, tu, to [Administration & Dosage, Adverse Effects, Therapeutic Use, Toxicity]
23 Furosemide/ad, ae, po, tu, to [Administration & Dosage, Adverse Effects, Poisoning, Therapeutic Use, Toxicity]
24 Spironolactone/ad, ae, tu, to [Administration & Dosage, Adverse Effects, Therapeutic Use, Toxicity]
25 Triamterene/ad, ae, po, tu, to [Administration & Dosage, Adverse Effects, Poisoning, Therapeutic Use, Toxicity] (
26 Amiloride/ad, ae, tu, to [Administration & Dosage, Adverse Effects, Therapeutic Use, Toxicity]
27 Adrenergic α-Antagonists/ad, ae, po, tu, to [Administration & Dosage, Adverse Effects, Poisoning, Therapeutic Use, Toxicity]
28 Doxazosin/ad, ae, po, tu, to [Administration & Dosage, Adverse Effects, Poisoning, Therapeutic Use, Toxicity]
29 Prazosin/ad, ae, po, tu, to [Administration & Dosage, Adverse Effects, Poisoning, Therapeutic Use, Toxicity]
30 Vasodilator Agents/ad, ae, po, tu, to [Administration & Dosage, Adverse Effects, Poisoning, Therapeutic Use, Toxicity]
31 Hydralazine/ad, ae, po, tu, to [Administration & Dosage, Adverse Effects, Poisoning, Therapeutic Use, Toxicity]
32 Minoxidil/ad, ae, po, tu [Administration & Dosage, Adverse Effects, Poisoning, Therapeutic Use]
33 Captopril/ad, ae, po, tu, to [Administration & Dosage, Adverse Effects, Poisoning, Therapeutic Use, Toxicity]
34 Enalapril/ad, ae, po, tu, to [Administration & Dosage, Adverse Effects, Poisoning, Therapeutic Use, Toxicity]
35 Fosinopril/ad, ae, tu, to [Administration & Dosage, Adverse Effects, Therapeutic Use, Toxicity]
36 Lisinopril/ad, ae, po, tu, to [Administration & Dosage, Adverse Effects, Poisoning, Therapeutic Use, Toxicity]
37 Losartan/ad, ae, po, tu, to [Administration & Dosage, Adverse Effects, Poisoning, Therapeutic Use, Toxicity]
38 (benazepril or quinapril or irbesartan or terazosin).mp.
39 or/2–38
40 Hypertension/
41 39 and 40
42 1 or 41
43 Limit 42 to (English language and humans)
44 Limit 43 to “all child (0 to 18 years)”

Database: EBM Reviews: Cochrane Central Register of Controlled Trials
1 Wt Loss/
2 Exercise/
3 dietary modification.mp. or Food Habits/
4 Diet, Sodium-Restricted/
5 Angiotensin-Converting Enzyme Inhibitors/ad, ae, po, tu, to [Administration & Dosage, Adverse Effects, Poisoning, Therapeutic Use, Toxicity]
6 Angiotensin II Type 1 Receptor Blockers/ad, ae, po, tu, to [Administration & Dosage, Adverse Effects, Poisoning, Therapeutic Use, Toxicity]
7 Labetalol/ad, ae, po, tu, to [Administration & Dosage, Adverse Effects, Poisoning, Therapeutic Use, Toxicity]
8 Adrenergic β-Antagonists/ad, ae, po, tu, to [Administration & Dosage, Adverse Effects, Poisoning, Therapeutic Use, Toxicity]
9 Atenolol/ad, ae, po, tu, to [Administration & Dosage, Adverse Effects, Poisoning, Therapeutic Use, Toxicity]
10 Bisoprolol/ad, ae, tu [Administration & Dosage, Adverse Effects, Therapeutic Use]
11 Metoprolol/ad, ae, po, tu, to [Administration & Dosage, Adverse Effects, Poisoning, Therapeutic Use, Toxicity]
12 Propranolol/ad, ae, po, tu, to [Administration & Dosage, Adverse Effects, Poisoning, Therapeutic Use, Toxicity]
13 Calcium Channel Blockers/ad, ae, po, tu, to [Administration & Dosage, Adverse Effects, Poisoning, Therapeutic Use, Toxicity]
14 Amlodipine/ad, ae, po, tu, to [Administration & Dosage, Adverse Effects, Poisoning, Therapeutic Use, Toxicity]
15 Felodipine/ad, ae, tu, to [Administration & Dosage, Adverse Effects, Therapeutic Use, Toxicity]
16 Isradipine/ad, ae, po, tu, to [Administration & Dosage, Adverse Effects, Poisoning, Therapeutic Use, Toxicity]
17 Nifedipine/ad, ae, po, tu, to [Administration & Dosage, Adverse Effects, Poisoning, Therapeutic Use, Toxicity]
18 Clonidine/ad, ae, po, tu, to [Administration & Dosage, Adverse Effects, Poisoning, Therapeutic Use, Toxicity]
19 Diuretics/ad, ae, po, tu, to [Administration & Dosage, Adverse Effects, Poisoning, Therapeutic Use, Toxicity]
20 Hydrochlorothiazide/ad, ae, po, tu, to [Administration & Dosage, Adverse Effects, Poisoning, Therapeutic Use, Toxicity]
21 Chlorthalidone/ad, ae, tu, to [Administration & Dosage, Adverse Effects, Therapeutic Use, Toxicity]
22 Furosemide/ad, ae, po, tu, to [Administration & Dosage, Adverse Effects, Poisoning, Therapeutic Use, Toxicity]
23 Spironolactone/ad, ae, tu, to [Administration & Dosage, Adverse Effects, Therapeutic Use, Toxicity]
24 Triamterene/ad, ae, po, tu, to [Administration & Dosage, Adverse Effects, Poisoning, Therapeutic Use, Toxicity]
25 Amiloride/ad, ae, tu, to [Administration & Dosage, Adverse Effects, Therapeutic Use, Toxicity]
26 Adrenergic α-Antagonists/ad, ae, po, tu, to [Administration & Dosage, Adverse Effects, Poisoning, Therapeutic Use, Toxicity]
27 Doxazosin/ad, ae, po, tu, to [Administration & Dosage, Adverse Effects, Poisoning, Therapeutic Use, Toxicity]
28 Prazosin/ad, ae, po, tu, to [Administration & Dosage, Adverse Effects, Poisoning, Therapeutic Use, Toxicity]
29 Vasodilator Agents/ad, ae, po, tu, to [Administration & Dosage, Adverse Effects, Poisoning, Therapeutic Use, Toxicity]
30 Hydralazine/ad, ae, po, tu, to [Administration & Dosage, Adverse Effects, Poisoning, Therapeutic Use, Toxicity]
31 Minoxidil/ad, ae, po, tu [Administration & Dosage, Adverse Effects, Poisoning, Therapeutic Use]
32 Captopril/ad, ae, po, tu, to [Administration & Dosage, Adverse Effects, Poisoning, Therapeutic Use, Toxicity]
33 Enalapril/ad, ae, po, tu, to [Administration & Dosage, Adverse Effects, Poisoning, Therapeutic Use, Toxicity]
34 Fosinopril/ad, ae, tu, to [Administration & Dosage, Adverse Effects, Therapeutic Use, Toxicity]
35 Lisinopril/ad, ae, po, tu, to [Administration & Dosage, Adverse Effects, Poisoning, Therapeutic Use, Toxicity]
36 Losartan/ad, ae, po, tu, to [Administration & Dosage, Adverse Effects, Poisoning, Therapeutic Use, Toxicity]
37 (benazepril or quinapril or irbesartan or terazosin).mp.
38 or/1–37
39 Blood Pressure/
40 38 and 39

Systematic reviews

Database: EBM Reviews: Cochrane Database of Systematic Reviews
1 hypertension.ti.
2 blood pressure.ti.
3 1 or 2
4 3 and (child$ or pediatri$ or school or adolescen$ or teen$).mp.
5 4 not (neonat$ or newborn or infan$).ti.
6 5 not (pregnan$ or postpartum).ti.

Appendix 2. Inclusion and Exclusion Criteria

  Key Questions Inclusion Criteria Exclusion Criteria
Settings All Primary care clinics, well-child/adolescent visits, school or community-based screening Pediatric specialty/subspecialty clinics, inpatient, or long-term care settings, emergency or urgent care facilities
Populations 1, 2, and 4 Asymptomatic, otherwise healthy children and adolescents, 0–18 y of age, with no known diagnosis of hypertension Pregnant adolescents
3 and 5–8: Primary hypertension defined as average blood pressure between 95th percentile and 5 mm Hg above the 99th percentile Majority of study population included secondary hypertension
Interventions: 1–4 Blood pressure measurements using auscultatory or oscillometric devices that can be performed in a primary care clinic 24-h, ambulatory, or home-based blood pressure measurements. Diagnostic tests or investigations used to identify or confirm possible causes of secondary hypertension
5–8: Drug: Antihypertensive medications which are currently FDA-approved for use in children/adolescents
Lifestyle: Diet, exercise, etc.
Interventions for treatment of secondary hypertension

Interventions where reduction in blood pressure was not a primary objective of the study (eg, weight loss studies)

Outcomes 4, 5, and 6: Blood pressure
Left ventricular hypertrophy (defined using left ventricular mass index and/or measures of left ventricular geometry)
Urinary albumin excretion (microalbuminuria)
Intima-medial thickness (measured at carotid and/or femoral arteries)
Retinal vascular changes
Measures of cognitive function
Blood pressure variability, such as diurnal variations or nocturnal blood pressure dipping
Arterial wall dysfunction, including measures of arterial stiffness, pulse wave velocity, or augmentation index
Metabolic measures, eg, measures of impaired glucose tolerance, levels of insulin, lipid profiles, homocysteine levels, uric acid levels
Inflammatory markers including C-reactive protein
Body changes in weight or BMI
1 and 7: Severe visual impairment
Stage IV or V chronic kidney disease
Cardiovascular events, including ischemic heart disease, heart failure
Cerebrovascular events, including hemorrhagic and thrombotic stroke, hypertensive encephalopathy
Mortality (all-cause and disease-specific)
Studies reporting intermediate outcomes
2 Measures of predictive validity of screening tests (eg, predictive value, likelihood ratios, sensitivity, specificity) Studies that do not provide enough data to recreate 2 X 2 tables or calculate sensitivity and specificity
Studies that do not use a true reference standard for comparison
3 Measures of association (eg, odds ratio; risk ratio, sensitivity, specificity, correlation or regression coefficients) Studies not reporting measures of association
8 Side effects of hypertension treatments or interventions
Study designs 1 Randomized controlled trials, controlled clinical trials, observational studies with a comparison group (eg, comparative cohort and case-control studies), and systematic reviews Study designs other than those specified
2 Studies of predictive validity that compare with a reference standard (eg, ambulatory monitoring) Study designs other than those specified
3 Longitudinal cohort and epidemiology studies Study designs other than those specified
4 and 8 Randomized controlled trials, controlled clinical trials, observational studies with a comparison group (eg, large cohort and case-control studies), and systematic reviews. If none were identified, uncontrolled before-after studies were examined Study designs other than those specified
5–7 Randomized controlled trials, controlled clinical trials, observational studies with a comparison group (eg, large cohort and case-control studies), and systematic reviews Study designs other than those specified

Appendix 3. Diagnostic Accuracy of Screening for Elevated Blood Pressure in Children and Adolescents

Study, Year Screening Test Reference Standard Definition of a Positive
Screening Examination
Population Sensitivity Specificity Positive Predictive
Value
Negative Predictive
Value
Quality Rating
Fixler and Laird 198330 Three measures with mercury sphygmomanometer measured at least 4 wk apart Initial screening results compared with subsequent measures SBP or DBP ≥95th percentile based on normative levels for the study population n = 9017; eighth graders with followup at 10th grade; mean age not reported; all were in eighth grade at time of initial screening: 53% male, 44% black, 42% white, 14% Hispanic Initial positive screen versus subsequent screens: 0.72 (95% CI, 0.65–0.78) Initial positive screen versus subsequent positive screening test: 0.92 (95% CI, 0.91–0.92) Initial positive screen versus subsequent positive screening test: 0.17 (95% CI, 0.15–0.2) Initial positive screen versus subsequent positive screening test: 0.993 (95% CI, 0.991–0.994) Fair
Stergiou et al 200831 Three averaged measurements with mercury sphygmomanometer, measured in nondominant arm in sitting position after 5 min at rest 24-h ambulatory blood pressure measurements SBP or DBP ≥95th percentile based on US normative blood pressure tables N = 102; 100% referred for screening; mean age 13 y (SD, 3; range, 6–18); 63% male; race not reported Positive ambulatory result versus positive clinic result: 0.65 (95% CI, 0.45–0.80) Positive ambulatory result versus positive clinic result: 0.75 (95% CI, 0.63–0.84) Positive ambulatory result versus positive clinic result: 0.37 (95% CI, 0.28–0.47) Positive ambulatory result versus positive clinic result: 0.63 (95% CI, 0.53–0.72) Fair

Appendix 4. Studies Tracking Hypertension From Childhood to Adulthood

Author, Year, and Study Name
(Follow-up)
Definition of HTN
in Childhood
Definition of HTN
in Adulthood
Outcomes Quality Considerations
Recruitment Attrition: % With Complete Data, % of Original N at Follow-up Measurement Method Stated for Both Time Periods? Statistical Analysis and Adjusted Variables
Blood pressure outcomes
Bao et al 199543; Bogalusa Heart Study (15 y) >80th percentile SBP >140 mm Hg or DBP >90 mm Hg or ever treated for hypertension Hypertension at follow-up, baseline highest SBP quintile versus other SBP quintiles:

18% (54/301) vs. 5% (60/1204); risk ratio 3.6; 95% CI, 2.5–5.1

Hypertension at follow-up, baseline highest DBP quintile versus other DBP quintiles:

15% (45/301) vs. 6% (72/1204); risk ratio 2.5; 95% CI, 1.8–3.6

Unclear; data from 1505 subjects who completed baseline and follow-up surveys (of 3865 at baseline) No loss (Cohort selected based on availability of data; 39% of original cohort completed both surveys) Yes Logistic regression; age, race, sex, SBP, DBP, BMI, change in BMI
Beckett et al 199244; Longitudinal Study (20 y) SBP not defined DBP >90 mm Hg DBP 80 vs. 60 mm Hg at age 15 and presence of hypertension at age 35:

Males: risk ratio 3.0; females: risk ratio 4.5

DBP 85 vs. 60 mm Hg at age 15 and presence of hypertension at age 35:

Males: risk ratio 3>9; females: risk ratio 6.6

DBP 90 vs. 60 mm Hg at age 15 and presence of hypertension at age 35:

Males: risk ratio 4.9; females: risk ratio 9.0

Unclear; data from 523 subjects who completed baseline and follow-up surveys (of 976 at baseline) No loss (Cohort selected based on availability of data; 54% of original cohort completed both surveys) No Not applicable
Gillman et al 199345; Study not named (12 y)

 
>90th percentile (SBP: 113 mm Hg, within study) >90th percentile (SBP: 139 mm Hg, within study) Positive predictive value, sensitivity, and specificity of BP at age 10 predicting BP >90th percentile at age 20:

SBP, males:
>75th percentile (108 mm Hg): 0.26, 0.59, 0.80
>90th percentile (113 mm Hg): 0.35, 0.33, 0.93
>95th percentile (117 mm Hg): 0.44, 0.17, 0.97
>99th percentile (123 mm Hg): 0.58, 0.04, >0.99

SBP, females:
>75th percentile (108 mm Hg): 0.27, 0.66, 0.79
>90th percentile (114 mm Hg): 0.39, 0.36, 0.94
>95th percentile (118 mm Hg): 0.48, 0.20, 0.98
>99th percentile (125 mm Hg): 0.65, 0.04, >0.99

DBP, males:
>75th percentile (68 mm Hg): 0.21, 0.34, 0.82
>90th percentile (71 mm Hg): 0.24, 0.16, 0.93
>95th percentile (73 mm Hg): 0.27, 0.08, 0.97
>99th percentile (77 mm Hg): 0.34, 0.01, >0.99

DBP, females:
>75th percentile (67 mm Hg): 0.19, 0.49, 0.77
>90th percentile (71 mm Hg): 0.24, 0.23, 0.92
>95th percentile (74 mm Hg): 0.30, 0.10, 0.98
>99th percentile (78 mm Hg): 0.38, 0.02, >0.99

Children from a single school in East Boston MA; sampling method unclear 6% (20/337) attrition Yes Not applicable
Juhola et al 201147; Cardiovascular Risk in Young Finns Study (27 y)

Other publication: Juonala et al 200477

≥95th percentile Unclear Prehypertension or hypertension in adulthood and BP ≥95th percentile in childhood:

Female, ages 6 and 9: OR 2.4 (95% CI, 1.1–5.2)

Female, ages 12, 15, and 18: OR 2.3 (95% CI, 1.6–3.5)

Males, ages 6 and 9: OR 2.8 (95% CI, 1.5–5.1)

Males, ages 12, 15, and 18: OR 2.1 (95% CI, 1.5–3.1)

PPV, sensitivity, specificity of BP >95th percentile in childhood and hypertension in adulthood:

All ages (6–18): 0.44; 0.1; 0.97

Finnish children and adolescents aged 3, 6, 9, 12, and 15 y randomly sampled from 5 cities 38.7% (1392/3596) lost to follow-up at 27 y Yes Logistic regression; age, sex, race, study year
Lauer et al 199348; Muscatine Study (unclear) Unclear; results reported for >90th percentile SBP or DBP >90th percentile (cohort specific) 24% of children with BP >90th percentile had BP >90th percentile in adulthood; risk ratio 2.4 (P < 0.001)

39% of children with SBP >90th percentile had SBP >80th percentile in adulthood; risk ratio 1.9 (P < 0.001)

17% of children with DBP >90th percentile had DBP >90th percentile in adulthood; risk ratio 1.7 (P < 0.001)

32% of children with DBP >90th percentile had DBP >80th percentile in adulthood; risk ratio 1.5 (P < 0.001)

Unclear; data from 2445 subjects who completed baseline and follow-up surveys (number at baseline not reported) No loss (Cohort selected based on availability of data) Yes Not applicable
Shear et al 198751; Bogalusa Heart Study (8 y) Not reported ≥140/90 mm Hg SBP ≥80th percentile at years 1, 4, and 6 and hypertensive at followup:

Sensitivity: 0.27; Specificity: 0.95

DBP ≥80th percentile at years 1, 4, and 6 and hypertensive at followup:

Sensitivity: 0.33; Specificity: 0.96

SBP ≥90th percentile at years 1, 4, and 6 and hypertensive at followup:

Sensitivity: 0.13; Specificity: 0.99

DBP ≥90th percentile at years 1, 4, and 6 and hypertensive at followup:

Sensitivity: 0.07; Specificity: 0.99

SBP ≥95th percentile at years 1, 4, and 6 and hypertensive at followup:

Sensitivity: 0.07; Specificity: 1.0

DBP ≥95th percentile at years 1, 4, and 6 and hypertensive at followup:

Sensitivity: 0.0; Specificity: 1.0

Data from 1501 subjects who completed baseline and follow-up surveys (of 4238 subjects at baseline) No loss (cohort selected based on availability of data; 35% of original subjects completed both surveys) Yes Not applicable
Sun et al 20077; Fels Longitudinal Study (unclear) Least-squares means determined according to age and gender (absolute values not reported) SBP >130 mm Hg and/or DBP >85 mm Hg Odds of hypertension at >30 y of age given SBP exceeding criterion values at single examination in childhood:

Males
5–7 y old males: 3.8 (95% CI, 1.5–9.7)
8–13 y old males: 3.5 (95% CI, 1.5–8.3)
14–18 y old males: 1.1 (95% CI, 0.5–2.4)

Females
5–7 y old females: 4.5 (95% CI, 1.1–17.7)
8–13 y old females: 2.7 (95% CI, 1.0–7.1)
14–18 y old females: 3.8 (95% CI, 1.2–12.7)

Unclear; data from 493 subjects who completed baseline and follow-up surveys (of 976 at baseline) 8% loss to follow-up in Fels Longitudinal Study overall; data from 51% of original subjects Yes Not applicable
Other outcomes
Hoq et al 200246; Bogalusa Heart Study (16 y) ≥90th percentile for age, ethnicity, and gender ≥90th percentile for age, ethnicity, and gender Annual change in BP on adulthood urinary albumin/creatinine ratio by ethnicity

Childhood SBP by ethnicity:

Blacks: regression coefficient 0.016 (P = 0.05)

Whites: regression coefficient −0.002 (P = 0.78)

Annual change in SBP from childhood to adulthood by ethnicity:

Blacks: regression coefficient 0.315 (P = 0.002)

Whites: regression coefficient −0.045 (P = 0.55)

Childhood DBP by ethnicity:

Blacks: regression coefficient 0.026 (P = 0.012)

Whites: regression coefficient −0.002 (P = 0.761)

Annual change in DBP from childhood to adulthood by ethnicity:

Blacks: regression coefficient 0.292 (P = 0.016)

Whites: regression coefficient 0.063 (P = 0.5)

Unclear; data from 2122 subjects who completed baseline and follow-up surveys (of 3865 at baseline) No loss (cohort selected based on availability of data; data from 55% of original subjects) Yes Logistic regression; sex, childhood age, BMI, BP, annual change in BP
Li et al 200349; Bogalusa Heart Study (22 y)


 
Not reported Not reported Odds of carotid intima media thickness in upper quartile given SBP risk factor (not defined): childhood (14–17 y): 1.00 (95% CI, 0.80–1.25) Unclear; data from 486 subjects who completed baseline and follow-up surveys and carotid artery ultrasound (of 3865 at baseline) NR (94% [486/516] had data available); data from 13% of original subjects Yes Logistic regression; age, race, sex
Raitakari et al 200350; Cardiovascular Risk in Young Finns Study (21 y) ≥80th percentile ≥80th percentile Relationship between SBP >80th percentile at age 12–18 (mean age 14.9 y) and carotid intima media thickness 21 y later: regression coefficient 0.013 (SE 0.003); P = 0.001 Finnish children and adolescents aged 3, 6, 9, 12, and 15 y randomly sampled from 5 cities 38% (1367/3596) lost to follow-up at 21 y Yes Logistic regression; age, race, sex

BMI, body mass index; BP, blood pressure; DBP, diastolic blood pressure; NR, not reported; PPV, positive predictive value; SBP, systolic blood pressure.

Appendix 5. Interventions for Hypertension in Children and Adolescents

Author, Year (Quality Rating) Study Design, Setting, and Duration N Demographic Characteristics Intervention Proportion of Patients Achieving
≤95th Percentile of Blood Pressure
for Age, Gender, and Height
Blood Pressure
(mm Hg)
Drug interventions
Batisky et al 200753 (fair) RCT
28 sites
United States
4 wk
140 Mean age 13 y (SD 2.8)
70% male
26% black
Mean SBP: 132 mm Hg
Mean DBP: 78 mm Hg
74% BMI ≥95th percentile
Group A: Metoprolol ER 0.2 mg/kg
Group B: Metoprolol ER 1.0 mg/kg
Group C: Metoprolol ER 2.0 mg/kg
Group D: Placebo
Groups A–C pooled: 46% (95% CI, 37–55)
Group B: 26% (95% CI, 8–44)
Mean change from baseline, SBP:
Group A: −5.2 (95% CI, −7.7 to −2.6)
Group B: −7.7 (95% CI, −11.3 to −4.0)
Group C: −6.3 (95% CI, −8.7 to −3.8)
Group D: −1.9 (95% CI, −5.5 to 1.8)
Flynn et al 200454 (fair) RCT crossover
49 sites in North and South America
4 wk
268 Mean age 12 y (SD 3.3)
Mean SBP: 137.9 mm Hg (SD 12.7)
Mean DBP: 74.2 mm Hg (SD 11.6)
31.3% (84/268) primary hypertension
Study Phase 2 (included placebo comparison)
Group A: Amlodipine 2.5 mg/day
Group B: Amlodipine 5.0 mg/day
Group C: Placebo
SBP
Group A: 40%
Group B: 35%
Group C: 30%
DBP
Group A: 42%
Group B: 75%
Group C: 48%
Phase 2 results
Mean change from baseline, SBP:
Group A: −6.9 ± 12.5 (P = NS) (P = 0.05 versus placebo)
Group B: −8.7 ± 13.3 (P = NS) (23.6 ± 12.7, P = 0.01 versus placebo)
Group C: −3.6 ± 12.7 (P = NS)
Mean change from baseline, DBP:
Group A: −4.2 ± 10.7 (P = NS)
Group B: −4.4 ± 10.2 (P = NS)
Group C: −0.4 ± 11.0 (P = NS)
Li et al 201055; (fair) RCT
43 sites in the United States, India, South Africa, Russia, and Dominican Republic
4 wk
304 Mean age not reported (53% <12 y)
63% male
35% black
57% white
11% Hispanic
8% Asian
56% primary hypertension
Study Phase B (included placebo comparison)
Group A: Eplerenone 25 mg once daily
Group B: Eplerenone 25 mg twice daily
Group C: Eplerenone 25 mg bid for 2 wk followed by 50 mg bid for 4 wk
Group D: Placebo
NR Phase B results
Least-squares mean change from baseline, SBP:
Group A: P = NS
Group B: 2.76 (95% CI, −5.5 to 0; P = 0.048 versus placebo)
Group C: P = NS
Least-squares mean change from baseline (any group), DBP: P = NS
Sorof et al 200256 (fair) RCT
Clinical trial from 22 sites in United States and Brazil
4 wk
94 Mean age 14 y
57% male
43% white
41% black
14% Hispanic
1% Asian
1% multiracial
Mean BMI = 28 kg/m2
Group A: Bisoprolol fumarate 2.5+ hydrochlorothiazide 6.25
Group B: Bisoprolol 5 mg + hydrochlorothiazide 6.25 mg
Group C: Bisoprolol fumarate 10 mg + hydrochlorothiazide 6.25 mg
Group D: Placebo
NR Least squares mean change from baseline, SBP:
Groups A–C pooled: −9.3 (P < 0.05 versus placebo)
Group D: −4.9
Least-squares mean change from baseline, DBP:
Groups A–C pooled: −7.2 (P < 0.05 versus placebo)
Group D: −2.7
Trachtman et al 200357 (fair) RCT
Clinical trial from 30 sites in the United States
3 wk
133 Mean age 12 y (SD 3)
60% male
39% black
Group A: 2.5 mg felodipine ER
Group B: 5 mg felodipine ER
Group C: 10 mg felodipine ER, titrated to target dose
Group D: Placebo
BP ≤90th percentile
Group A: 15%
Group B: 18%
Group C: 19%
Group D: 11%
Mean difference SBP at follow-up versus placebo (95% CI):
Group A: −0.71 (−4.8 to 3.38; P = NS)
Group B: −0.06 (−4.6 to 3.3; P = NS)
Group C: −1.73 (−6.58 to 3.13; P = NS)
Mean difference DBP at follow-up versus placebo (95% CI):
Group A: −2.07 (−6.82 to 2.69; P = NS)
Group B: −4.64 (−9.18 to 0.09; P <0.05)
Group C: 1.31 (−3.56 to 6.11; P = NS)
Trachtman et al 200858 (fair) RCT
Clinical trial from 42 sites in United States and Europe
4 wk
240 Mean age not reported (29% <12 y; 71% >12 y)
71% male
69% BMI ≥ 95th percentile
47% black
45% white
Group A: Candesartan 2/4 mg

Group B: Candesartan 8/16 mg
Group C: Candesartan 16/32 mg
Group D: Placebo

Group A: 54%
Group B: 62%
Group C: 65%
Group D: 31%
Least-squares mean change from baseline, SBP:
Groups A–C: −10.22 (P < 0.0001 versus placebo)
Group D: −3.66
Least squares mean change from baseline, DBP:
Groups A–C: −6.56 (P = 0.0029 versus placebo)
Group D: −1.8
Wells et al 201059 (fair) RCT
Clinical trial at 16 sites in United States, Brazil, and Mexico
4 wk
77

 

Mean age: 14 y (SD 3)
57% male
51% white
37% black
Group A: Telmisartan 1 mg/kg/day(low-dose group)
Group B: Telmisartan 1 mg/kg/day, titrated up to 2 mg/kg/day after 1 wk (high-dose group)
Group C: Placebo
Group A: 50% (6–<12 y); 68% (12–<18 y)
Group B: 86% (6–<12 y); 79% (12–<18 y)
Group C: 33% (6–<12 y); 27% (12–<18 y)
Adjusted mean difference SBP at follow-up versus placebo (95% CI):
Group A: −3.6 (−9.2 to 1.9, P = NS)
Group B: −8.5 (−14 to −3.0, P = 0.0027)
Adjusted mean difference DBP at follow-up versus placebo (95% CI):
Group A: −4.5 (−9.5 to 0.4, P = NS)
Group B: −4.8 (−9.7 to 0, P = 0.051)
Drug plus lifestyle interventions
Berenson et al 198360 fair)

Other publication:
Frank et al 198278

RCT
School-based in United States
6 mo
150 NR ADAPT Program
Group A: Propranolol 20–40 mg + chlorthalidone 6.25–12.5 mg + nutrition education and promotion of dietary modification
Group B: Hypertensive control group with no treatment
NR Mean change from baseline, SBP:
Group A: −7.6
Group B: −3.0
Mean change from baseline, DBP:
Group A: −6.9
Group B: −3.9
Berenson et al 199061 (fair)

Continuation of Berenson et al 198360

RCT

School-based in United States

30 mo
150 Mean age 12 y
55% male
47% white
Mean SBP 117.7 mm Hg
Mean DBP 78.1 mm Hg
Same as above NR Adjusted mean difference, SBP:
Group A versus Group B: −3.6 (SD 1.12; P < 0.01)
Adjusted mean difference DBP:
Group A versus Group B: −1.7 (SD 0.82; P < 0.05)
Lifestyle interventions
    Diet
Couch et al 200862 (fair) RCT
Cincinnati Children's Hospital Medical Center, United States
6 mo
57 Mean age 14 y
63% male
Mean SBP 128.7 mm Hg
Mean DBP 80.5 mm Hg
Group A: DASH-type diet modified for adolescent population + counseling
Group B: Counseling alone
NR Mean difference at follow-up, SBP:
Group A versus Group B: 0.1
Mean difference at follow-up, DBP:
Group A versus Group B: −1.2
Proportion achieving normotensive status:
Group A 61% versus Group B 44%; P = NS
Howe et al 199165 (fair) RCT crossover
School-based
Adelaide, Australia
2 phases of 4 wk each
103 Mean age 13 y (range 11–14)
Mean SBP 115.0 mm Hg
Mean DBP 60.1 mm Hg
Group A: Low-sodium diet (<75 mmol/day) + counseling
Group B: High-sodium diet (>150 mmol/day) + counseling
NR No significant differences in SBP or DBP between diets; baseline values not reported
Sinaiko et al 199366 (fair) RCT
St. Paul and Minneapolis public schools, United States
3 y
210 Mean age 13 y
50% male
Mean SBP 113.8 mm Hg
Mean DBP 65.1 mm Hg
Group A: Low sodium diet (<70 mmol/day)
Group B: Potassium chloride supplementation
Group C: Participant's usual diet + placebo
NR Changes in SBP:
Boys: No significant differences in rates of increase in SBP between low sodium, potassium supplement, and placebo groups.
Girls: Significant difference in SBP between low sodium group (slight overall decrease) and the placebo group (significant increase from baseline). No other differences between groups.
Changes in DBP:
Boys: No significant differences in rates of increase in BP between low sodium, potassium supplement, and placebo groups
Girls: The low sodium group was the only group that had rates of increase in DBP compared with placebo that were significantly greater than zero
   Exercise
Hansen et al 199164 (fair) RCT
Odense, Denmark
School-based
8 mo
137 Age range 9–11 y
Other demographic characteristics: NR
Group A: 3 extra lessons per week of an ordinary school physical education program
Group B: No extra physical education lessons
NR Mean difference at follow-up, SBP
Group A versus Group B: −4.9; P < 0.05
Mean difference at follow-up, DBP:
Group A versus Group B: −3.8; P < 0.05
   Meditation
Gregoski et al 201163 (fair) RCT
School-based in United States
3 mo
166 Mean age 15 y
59% female
100% black
Mean SBP 118.9 mm Hg
Mean DBP 63.6 mm Hg
Group A: Breathing awareness meditation
Group B: LifeSkills training (weekly 50-min sessions focusing on training in problem-solving skills, reflective listening, conflict resolution, anger management to enhance social skills and assertiveness)
Group C: Health education control
NR Mean 24-h SBP at 3-mo follow-up:
Group A versus Group B versus Group C:
116.6 vs 119.8 vs 121.0
Group A versus Group B: P = NS
Group A versus Group C: P = 0.05
Mean 24-h DBP at 3-mo follow-up:
Group A versus Group B versus Group C:
66.3 vs 68.2 vs 68.7; P = NS for all comparisons
   Progressive muscle relaxation
Ewart et al 198733 (fair) RCT
2 large Baltimore City public high schools
9 mo
159 BMI range: 19.0–31.2 kg/m2
Mean age 15 y (range 13–17)
60% male
55% black
Group A: Progressive muscle relaxation (12 wk, 15–20 min, 4 d/wk) provided in school NR No significant differences in SBP and DBP between treatment and control groups

BP, blood pressure; DASH, Dietary Approaches to Stop Hypertension; ER, extended release; NR, not reported; NS, not significant.

Appendix 6. Harms of Interventions for Hypertension in Children and Adolescents

Author, Year (Quality Rating) Relevance Type of Study, Setting, and
Duration
Mean Age
(SD) (y)
Number Randomized
or Analyzed
Intervention Adverse Events
Drug interventions
Batisky et al 200753 (fair) All participants had primary hypertension RCT
28 centers
United States
4-wk dose-ranging study
52-wk safety study
12.5 (2.8) 144 randomized in dosing study
100 analyzed in safety study
4-wk dose ranging study:
ER metoprolol succinate 0.2–2.0 mg/kg
Placebo
52-wk open-label study:
25 mg or 12.5 mg once daily at investigator discretion; increase every 2 wk until maximum of 200 mg once daily
4-wk dose-ranging study:
1 withdrawal due to AEs
Heart rate decreased by 6.5 bpm in 1.0 mg/kg group (compared with increase of 5.4 bpm in placebo group)
Fatigue noted by 1 patient each in the 0.2, 1.0, and 2.0 mg/kg groups
52-wk safety study:
5 withdrawals due to AEs (1 each of fatigue, nightmares, anxiety, dizziness, asthma)
Serious AEs: 2/100 (2%; 1 pneumonia and 1 menometrorrhagia)
Other AEs:
Headache: 30%
Upper respiratory tract infection: 20%
Cough: 19%
Nasopharyngitis: 13%
Pharyngolaryngeal pain: 12%
Fatigue: 9%
Diarrhea: 7%
Dizziness: 6%
Flynn et al 200454 (fair) 31% with primary hypertension RCT crossover
Clinical trial from 49 centers in North and South America
2 4-wk phases
12.1 (3.3) 268 randomized; 84 with primary hypertension Amlodipine 2.5–5.0 mg/day
Placebo
Withdrawals due to AEs: 12/268, of which 6 considered by study investigators to be study drug related (3 worsening hypertension, 1 facial edema, 1 finger edema and rash, 1 premature ventricular contractions)
Serious AEs:
5/268 (2%; 1 each: urinary tract infection, gastroenteritis and hypovolemia, pulmonary edema, pneumonia, pancreatitis)
Hazan et al 201067 (good) Primary hypertension 75% (225/302); Patients with clinically significant medical condition or chronic disease, malignant or severe hypertension excluded RCT
Clinical trial at 61 sites; 2 cohorts stratified by race
2-wk washout period
Phase 1: 3-wk dosing study
Phase 2: 2-wk withdrawal study
12.2 (2.97) 422 screened; 302 randomized Olmesartan medoxomil Any adverse event: olmesartan 33/93 (36%) versus placebo 27/89 (30%)
Incidence of specific AEs not reported; headache most common
Li et al 201068 (fair) Hypertensive (20.9% with renal etiology, otherwise not reported), or high-normal blood pressure in the presence of associated clinical condition such as diabetes mellitus Dose-ranging RCT; 78 clinical centers in United States, Russia, Israel
Phase A: 10-day run-in

Phase B: 4-wk dose-ranging
Phase C: 2-wk withdrawal versus placebo
Phase D: 1-y open-label safety phase

12.1 (2.6) 376 screened
255 eligible
253 randomized
Fosinopril Overall study withdrawals across all 4 phases of study due to AEs: 5/253 (2%)
Phase C: Incidence of AEs similar between placebo (33.9%) and combined fosinopril treatment groups (34.3%)
Phase D: Specific AEs:
Headache: 51/253 (20%)
Nasopharyngitis: 24/253 (10%)
Cough: 23/253 (9%)
Pharyngitis: 22/253 (9%)
Abdominal pain: 16/253 (6%)
Li et al 201055 (fair) 56% primary hypertension
22% obesity-related hypertension
17% renal-related hypertension
RCT
Clinical trial in 43 centers in the United States, India, South Africa, Russia, and Dominican
Republic
Phase A: 6-wk dosing study (no placebo)
Phase B: 4-wk placebo-controlled study
Age <12 y: 52.6% 304 randomized Eplerenone 25 mg once daily, 25 mg twice daily, or 25 mg twice daily for 2 wk then 50 mg twice daily for 4 wk
Placebo
Phase A:
Any AE: low dose 38% versus middle dose 31% versus high dose 40%:
274 reports of mild AEs, mainly headache and upper respiratory tract infections
106 reports of moderate AEs
18 reports of severe AEs (4 possibly or definitely related to treatment: migraine, fatigue, bronchitis, headache)
4 permanent discontinuations, 3 of which were considered treatment-related: hypotension, hypertension, fatigue
Phase B:
No significant differences in AE frequencies between active therapy and placebo; 8 patients had worsening hypertension during this phase, including 2 in the high dose group that were withdrawn from the study
Shahinfar et al 200569 (fair) Hypertension; “more than 50% had underlying kidney disease” (secondary hypertension) but no additional details reported Dose-ranging RCT: phase 1 randomized to 3 different doses, phase 2 randomized washout; 43 clinical centers in North and South America (including United States), Europe, Africa, 36 days 12 (3.1) 175 randomized Losartan Withdrawals due to AEs: 1/175 (<1%)
Drug-related AEs: 14/175 (8%), of which headache (5) was most common event
Comparison of AEs in Phase 2 between active drug and control not reported
Soffer et al 200370 (fair) Hypertension; unclear severity of underlying kidney disease (study entry required glomerural filtration rate ≥30 mL/min/1.73 m2) Dose-ranging RCT
Phase 1 randomized to 3 different doses, phase 2 randomized washout
Multisite (number and location not reported); 29 days
Mean not reported 47%
<6–12 y, 53% 13–16 y
115 randomized Lisinopril Withdrawals due to AEs: 1/115 (<1%)
Drug-related AEs: 14/115 (12%)
Headache: 4/115 (4%)
Gastrointestinal (abdominal pain, diarrhea, nausea and/or vomiting): 2/115 (2%)
Dizziness: 2/115 (2%)
Cough: 1/115 (<1%)
Sorof et al 200256 (fair) Excluded severe hypertension and correctable secondary hypertension RCT
Clinical trial from 22 sites in United States and Brazil
2-wk run-in, 8-wk titration period, 2-wk dose maintenance period, 2-wk tapering period
13.8 (3.1) 94 randomized (62 treatment+32 placebo B/HT (n = 62):
B 2.5 mg/HT 6.25 mg
B 5 mg/HT 6.25 mg
B 10 mg/HT 6.25 mg
Placebo (n = 32)
B/HT group had fewer overall AEs than placebo group, 33/62 (53%) vs 24/32 (75%) (P = 0.047) and fewer serious AEs, 1/62 (2%) vs 5/32 (16%) (P = 0.016)
B/HT group:
Most common AE was headache (26%)
1 patient had severe hypertension, and discontinued the study.
Placebo group:
Most common AE was headache (31%)
2 patients had severe hypertension, and discontinued the study
Trachtman et al 200357 (fair) Excluded secondary hypertension RCT
Clinical trial at 30 sites in the United States
1- to 3-wk screening period, 2- to 3-wk dose titration period, 3-wk maintenance study
12.1 (2.7) 133 randomized ER felodipine
2.5 mg (n = 33), 5 mg (n = 340), or 10 mg (n = 31), titrated to target dose over 2–3 wk, depending on dosage
Placebo (n = 35)
1 withdrawal due to “heart racing”; heart rate was 96 bpm and ECG normal; and 1 withdrawal due to vomiting the first dose (5 mg)
% reporting AEs: placebo 66% and 64%, 56%, and 77% in the felodine ER 2.5 mg, 5.0 mg, and 10 mg groups, respectively
Most common AEs were headaches (33%), respiratory infections (12%), and nausea (10%)
Pedal edema was noted in 2 (2%) of patients
Trachtman et al 200858 (fair) Excluded secondary hypertension
Other hypertensives, except for other angiotension receptor blockers, were permitted
RCT
Clinical trial from 42 sites in United States and Europe
4-wk trial and 1-y open-label study
% Age >12 y: 70.8% 240 randomized 4 wk trial:
Candesartan doses 2, 8, and 16 mg/day for those <50 kg, and 4, 16, and 32 mg/day for those ≥50 kg
3/240 patients in the 4 wk trial and 5/233 patients in the 52 wk study discontinued due to AEs, specifically hypotension, arm fracture, dizziness, headache, low white blood cell count, and progression of underlying renal disease (2 patients)
Most common AEs: headache, upper respiratory infection, dizziness, cough, and sore throat
Wells et al 200271 (fair) Severe or symptomatic hypertension excluded Dose-ranging RCT
2-wk dose ranging phase and 2-wk placebo controlled washout phase
Median 12 y 110 enrolled Enalapril
Drug-related AEs: 12/110 (11%)
Dizziness: 4/110 (4%)
Headache: 2/110 (2%)
Cough: 3/110 (3%)
No incidence of renal failure, angioedema or hyperkalemia
5 laboratory AEs possibly, probably or definitely related to study drug
Wells et al 201059 (fair) Excluded secondary hypertension RCT
Clinical trial at 16 centers in United States, Brazil, and Mexico
4 wk, after 2-wk washout period
14 (2.5) 115 enrolled
77 randomized
Telmisartan low dose (1 mg/kg/day) (n = 30) and high dose (1 mg/kg/day titrated up to 2 mg/kg/day after 1 wk) (n = 31)
Placebo (n = 16)
Any AE:
High-dose patients: 41.9%
Low dose patients: 41.7%
Placebo patients: 31.3%
Significance not reported
2 patients discontinued due to AEs, both in the high dose group: 1 patient who experienced a serious AE (near syncope and moderate increase in blood urea nitrogen and serum creatinine) who received an excessive dose in error; and 1 patient due to moderate-intensity dizziness, weakness, and headache
Drug plus lifestyle interventions
Berenson et al 198360 (fair) BP >90th percentile for height, control group with blood pressure <80th percentiles and the 50–60th percentile for comparison (based on centiles derived from study)
Excluded children with evidence of secondary hypertension
“Close to clinical trial”
School-based
6 mo
12 150 (50 high blood pressure treatment group, 50 high blood pressure comparison group, 50 medium blood pressure comparison group) Group A:
Propranolol
20 mg/day for children <40 kg, 40 mg/day for those >40 kg + chlorthalidone
6.25 mg per day for children <40 kg, 12.5 mg/day for those >40 kg + nutrition education and promotion of dietary modification to children and parents
Group B (high BP elevation at baseline):
No treatment
Group C (medium BP elevation at baseline):
No treatment
AEs reported as very low incidence with no major complications
1 temporary withdrawal from active treatment due to nightmares
Other clinical studies (FDA analyses)
Baker-Smith et al 201073 (not rated) Mild to moderate hypertension Nonsystematic review and meta-analysis of data from 8 trials submitted to FDA between 1998 and 2005 (original studies not cited)
2 wk (median)
13 1299 analyzed (42% placebo + 58% active drug) ACEs (6 datasets) and ARBs (2 datasets), including benazepril (n = 85), enalapril (n = 101), fosinopril (n = 222), lisinopril (n = 104), quinapril (n = 112), ramipril (n = 217), irbesartan (n = 293), losartan (n = 165)
Dosages not reported
Subjects who reported cough in the cohort receiving active drugs (21/748, 2.8%) vs placebo (14/551, 2.5%), P = 0.86
Subjects who reported cough in the ACE group: (17/524, 3.2%); ARB group (4/224, 1.8%), P = 0.34
Smith et al 200872 (not rated) Unclear; severe hypertension and significant renal disease excluded Nonsystematic review and meta-analysis of data from 10 RCTs submitted to FDA between 1998 and 2005 (original studies not cited)
2 to 4 wk (varied by trial)
12.1 1707 analyzed (685 placebo, 1022 active treatments) Active treatments (n = 1022; mean doses not reported): amlodipine (n = 258), benazepril (n = 85), enalapril (n = 101), felodipine (n = 133), fosinopril (n = 235), irbesartan (n = 295), lisinopril (n = 104), losartan (n = 165), quinapril (n = 112), ramilpril (n = 219), placebo (n = 685) Placebo versus active treatment:
No significant difference between groups for any AEs
Any AE: 235/685 (34%) vs 382/1022 (37%)
Hypertension: 3/685 (4%) vs 1/1022 (>1%)
Hypotension: 0/235 (0%) vs 3/1022 (>1%)
Cardiac: 8/685 (1%) vs 16/1022 (2%)
Neuropsychological: 13/685 (2%) vs 26/1022 (3%)
Headache: 113/685 (17%) vs 179/1022 (18%)
Syncope: 15/685 (2%) vs 31/1022 (3%)
Gastrointestinal: 54/685 (8%) vs 90/1022 (9%)
Asthma: 11/685 (2%) vs 12/1022 (1%)
Elevated LFT: 7/685 (1%) vs 7/1022 (>1%)
Muscle aches: 11/685 (2%) vs 17/1022 (2%)

ACE, angiotensin-converting enzyme inhibitors; AE, adverse event; ARB, angiotensin receptor blockers; bpm, beats per minute; B/HT, bisoprolol fumarate/hydrochlorothiazide; ECG, electrocardiograph; ER, extended release; FDA, Food and Drug Administration; LFT, liver function test.

Current as of: February 2013

Internet Citation: Evidence Summary: Blood Pressure in Children and Adolescents (Hypertension): Screening. U.S. Preventive Services Task Force. February 2013.
https://www.uspreventiveservicestaskforce.org/Page/Document/evidence-summary16/blood-pressure-in-children-and-adolescents-hypertension-screening

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