Abbreviations AAP: american Academy of Pediatrics; ABPM: ambulatory blood pressure measurement; ACE: angiotensin-converting enzyme; ACEI: angiotensin-converting enzyme inhibitor; alloTHF: allotetrahydrocortisol; ARB: angiotensin receptor blocker; b.i.d.: twice daily; BP: blood pressure; CKD: chronic kidney disease; CO2: CO2 angiography; CT: computed tomography; CTA: CT angiography; DSA: digital subtraction angiography; EMEA: European Medicines Agency; ER: extended release; ESC: European Society of Cardiology; ESCAPE: Effect of Strict Blood Pressure Control and ACE Inhibition on Progression of Chronic Renal Failure in Pediatric Patients; ESH: The European Society of Hypertension; EU: European Union; FDA: Food and Drug Administration; GFR: glomerular filtration rate; HDL-C: high-density lipoprotein cholesterol; IGT: impaired glucose tolerance; IMT: intima-media thickening; LDL-C: low-density lipoprotein cholesterol; LVH: left ventricular hypertrophy; LVM: left ventricular mass; MRA: MR angiography; ONTARGET: Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial; OSA: obstructive sleep apnea; PRA: plasma renin activity; PUMA: Paediatric Use Marketing Authorization; q.d.: once daily; SDB: sleep-disordered breathing; t.i.d.: three times daily; TH18oxoF: 18-oxo-tetrathydrocortisol; THAD: tetrahydroaldosterone; THE: tetrahydrocortisone; THF: tetrahydrocortisol; UAE: Urinary albumin excretion.
Introduction and purpose
The European Society of Hypertension (ESH) and European Society of Cardiology (ESC) guidelines on the management of arterial hypertension, first published in 2003  and subsequently updated in 2007 , regrettably did not contain any section devoted to hypertension in childhood and adolescence. This was not due to lack of awareness of the importance of this problem. Indeed, there is growing evidence that children and adolescents with mild blood pressure (BP) elevations are much more common than it was thought in the past. Longitudinal studies have now made it clear that BP abnormalities in those age ranges do not infrequently translate into adult hypertension, thereby emphasizing the importance of the tracking phenomenon not just epidemiologically but also clinically. Furthermore, hypertension in children and adolescents has gained ground in cardiovascular medicine, thanks to the progress made in several areas of pathophysiological and clinical research. For example, it has been possible to look at BP values of children and adolescents not just in the artificial environment of the physician's office but in the more meaningful context of daily life conditions. It has also become possible to look at the presence of subclinical organ damage through measures and markers much more sensitive than those available years ago, with the opportunity of detecting incipient modifications of organ function and structure previously impossible to discover, thus gaining a more precise assessment of the clinical significance of the existing BP abnormalities. It has lastly been possible to relate adult hypertension and organ damage to several abnormalities of the younger age, for example overweight and tachycardia, thus adding to the rationale of extending at least some of the cardiovascular prevention strategies previously derived for adults to pre-adult individuals.
However, there are at least two reasons justifying omission of children's hypertension in previous guidelines. The first is that clinical cares of children and adolescent, on one side, and of adults, on the other side, are entrusted to different sets of physician, and therefore a task force charged to formulate recommendations for high BP in children should have been opened to the fundamental contributions of experts in this area, what has been done for the preparation of the present document specifically related to pediatric hypertension.
The second, but not minor, reason is the different nature of data and arguments on which recommendations for high BP in adults and, respectively, children are based. In adults, most of the recommendations of guidelines can be on evidence provided by observational and interventional trials, although admittedly some are only based on wisdom or experts' opinion [2,3]. For instance, the definition of hypertension in adults is founded on observational data in more than 1 million people showing a continuous relation between increasing SBP and DBP values with cardiovascular events such as stroke and myocardial infarction ; arbitrary cutoffs subdividing normotension from hypertension, and different grades of hypertension are indicated (although with various weights of evidence) by the results of intervention trials; and, finally, intervention trials on more than 250 000 patients provide comparative information on the effects of BP lowering per se and with different agents.
Nothing of the like is available in children and adolescents. The remoteness of incident cardiovascular events from BP values many years beforehand makes the relationship of BP values with events hardly feasible. Large intervention studies are lacking and, therefore, cannot provide hints about cutoffs for evidence-based recommendations about initiation of treatment and goal BP values, or the preferential use of one or other classes of drugs in various conditions. Many of the classifications and recommendations in children are based on statistical considerations, and result from assumptions rather than the results of experiments or from extrapolations from evidence obtained in adults. Despite the fact that guidelines on pediatric hypertension is only based on wisdom, it would be unethical to neglect giving due attention to this medically and socially important problem. Accompanying recommendations with the awareness that a lot of information is still missing may help devising observational and interventional studies filling some of the existing gaps of knowledge. This is not the least aim of the present guidelines, and a special section at the end of this document is devoted to the planning of future studies.
Definition and classification of hypertension
The incorporation of BP measurement into routine pediatric healthcare and the publication of norms for BP in children [5–7] has not only enabled detection of significant asymptomatic hypertension secondary to a previously undetected disorder, but it has also confirmed that mild elevations in BP during childhood are more common than was previously recognized, particularly in adolescents.
The roots of hypertension in adulthood extend back to childhood. Indeed, childhood BP has been shown to track into adulthood. That is to say, children with elevated BP are more likely to become hypertensive adults [8–12], an observation emphasizing the importance of BP control in children and adolescents. Importantly, both the use of repeated measurements (aiming at the reduction of measurement error) in the identification of those children with elevated BP , as well as the assessment of co-morbidities (in particular, obesity) and family history of cardiovascular disease , critically improve accuracy of the prediction of hypertension later in life .
As mentioned in the introduction, one limit to the attempt to create recommendations is that there are no prospective studies with sufficiently long follow-up to directly link childhood BP levels to the occurrence of cardiovascular disease or mortality. Therefore, surrogate markers of hypertensive end-organ damage (heart, blood vessels and kidney) have been used instead, although the body of available data is substantially smaller than in adults [14,15]. Left ventricular hypertrophy (LVH) [16,17], thickening and stiffening of large arteries [18–22] and urinary albumin excretion (UAE)  are among the most valuable markers.
Diagnostic criteria for elevated BP in children are based on the concept that BP in children increases with age and body size, making it impossible to utilize a single BP level to define hypertension, as done in adults.
Extensive pediatric normative data on auscultatory clinic measurements have been provided for the United States, based on more than 70 000 children . BP percentiles have been calculated for each sex, age group and for seven height percentile categories (www.pediatrics.org/cgi/content/full/114/2/S2/555). Height percentiles are based on the growth charts of the Center for Disease Control and Prevention (www.cdc.gov/growthcharts). In Europe, reference values were obtained in 1991 by pooling data from 28 043 individuals using the auscultatory method , but unfortunately, tables do not include age, sex and height together. However, normative values have been calculated for Italy in 1999 from auscultatory data in 11 519 school children aged 5–17 years and reported for age, sex and height . Two more recent studies [27,28] provide normative data for the oscillometric method with the Dinamap model 8100, the accuracy of which has known limitations. Oscillometric data with a validated equipment have quite recently been reported from the Nord-Trondelag Health Study II , but these are limited to adolescents (age 13–18 years); furthermore, 95th percentile values are rather high even after exclusion of overweight and obese individuals. Validated oscillometric data have also become available from a large cohort of Hong Kong Chinese schoolchildren , but these can hardly be extrapolated to the European population.
In conclusion, because of the large amount of data available, the Task Force for Blood Pressure in Children  is still the study of reference. It should be considered, however, that the data of the US Task Force do not refer to a European population and that at all ages they are several mmHg lower than those measured by the same auscultatory method in the Italian normative study  and about 10 mmHg lower than the oscillometric data of the Norwegian study . Further problems concerning the use of oscillometric devices versus the auscultatory method are discussed in the section entitled ‘Office and clinic blood pressure’.
According to the criteria of the Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in Children and Adolescents , criteria shared by this report, normal BP in children is defined as SBP and DBP less than 90th percentile for age, sex and height, whereas hypertension is defined as SBP and/or DBP persistently 95th percentile or more, measured on at least three separate occasions with the auscultatory method. Children with average SBP or DBP 90th percentile or more but less than 95th percentile are classified as having high-normal BP. Adolescents with BP 120/80 mmHg or more even if less than 90th percentile are also considered as having high-normal BP (Table 1). Tables 2 and 3 report the BP percentiles for boys and girls aged 1–18 years, as provided by the Fourth Report .
Additionally, the Fourth Report provides criteria for staging the severity of hypertension in children and adolescents, which can then be used clinically to guide evaluation and management. Stage 1 hypertension is defined as BPs from the 95th percentile to the 99th percentile plus 5 mmHg. Stage 2 hypertension denotes any BP above the 99th percentile plus 5 mmHg. Children or adolescents with stage 2 hypertension should be evaluated and treated more quickly and/or intensively than those with a lower degree of BP elevation.
Blood pressure measurement
The diagnosis of hypertension should be based on multiple office BP measurements, taken on separate occasions over a period. Although office BP should be used as reference, BP values obtained out of office may improve the evaluation in untreated and treated individuals.
Office or clinic blood pressure
Office BP measurement has provided the basis for the present knowledge of the potential risk associated with hypertension  and has guided patient management for many years. There are certain issues in the measurement of BP that apply to both children and adults, and they have been discussed in the ESH/ESC Guidelines .
In children and adolescents, one aspect to be taken into consideration is whether to use auscultatory or oscillometric methods. Korotkoff sounds-based measurement has been the most frequently used to assess SBP (K1) and DBP (K4 or K5). Although initially K4 was officially accepted as the measure of DBP for children under 13 years of age, today K5 is recommended . Oscillometric devices, which calculate BP from pressure oscillations detected in the arm cuff, have been introduced more recently. This method determines mean BP directly from the point of maximum oscillation. Neither SBP nor DBP is measured directly, but is calculated using an algorithm based on a putative relationship between the oscillations. Then, in cases in which the oscillation is shorter than usual, as is common in children, the potential for erroneous measurement increases . If an oscillometric method is applied, the monitor should have passed the validation procedure recommended by the British Hypertension Society , the American Association for the Advancement of Medical Instrumentation  or the European Society of Hypertension International Protocol . Few oscillometric devices for office, home or ambulatory BP monitoring have been successfully validated using an established protocol. The continuously updated data available on monitor validation for children is found at www.dableducational.org. It should, however, be noticed that available reference values for defining BP classes (such as those of Tables 2 and 3) have been obtained by the auscultatory method, and that values obtained with oscillometric equipments are considerably higher [29,36,37]. Therefore, if hypertension is detected by the oscillometric methods, it must be confirmed by the auscultatory method. The recent banning of mercury devices in the European Community will undoubtedly favor the development of oscillometric devices, but it is also true that the auscultatory method can continue to be used with manometers other than the mercury one. It would be convenient, however, to start assembling reference BP data using oscillometric devices.
The specific recommendations for office BP measurement in children and adolescents are shown in Box 1[24,38,39].
Ambulatory blood pressure
Ambulatory BP measurement (ABPM) is now increasingly recognized as being indispensable to the diagnosis and management of hypertension [40,41], and it has contributed significantly to our understanding of hypertension by ‘unmasking’ BP phenomena that were not readily apparent using office BP. These have included the dipping and nondipping patterns of nocturnal BP , white coat  and masked hypertension .
The clinical use of 24-h ABPM depends on the use of normal BP ranges as reference values. Preliminary reference values have been obtained in some European populations [45,46]. Although the relatively small number of individuals limits the normative usefulness of the data, the information represents an important starting point for the future development of stronger normative data (Tables 4 and 5).
Recommendations for the use of 24-h ABPM are given in Box 2. Use of ABPM in clinical trials may play an even more important role in children than it does in adults  because of the smaller number of children who have hypertension.
Home blood pressure
Concerning home BP measurements, evidence in children and adolescents is limited. In children, home BP has superior reproducibility than office BP has and is similar to that for ABPM . One study suggests that home monitoring for 3 days, with duplicate morning and evening measurements, is the minimum schedule required, though 6–7 days of monitoring is recommended . Home BP in children is lower than daytime ambulatory BP, probably due to a high level of physical activity during the day [50–52]. It is likely that home BP has a slightly better correlation than does casual BP with ABPM for daytime BP, although not for night-time BP . One school-based study in 778 children and adolescents has provided an initial approach to normalcy data for home BP (Table 6) .
White-coat (or isolated office) and masked (or isolated ambulatory) hypertensions
In adults, ambulatory and, less frequently, home BP monitorings are also used to define those patients whose BP values are in the hypertensive range in the office but not out-of-office (white-coat) or, vice versa, are in the normotensive range in the office but not out-of-office (masked) . Definition of these conditions is more difficult in children and adolescents, however, because of the above-mentioned uncertainties in reference values of office and, particularly, ambulatory and home BP. Furthermore, although in adults, ambulatory and home BP values and their cutoffs for definition of hypertension are normally lower than those measured in the office, in children and adolescents, daytime ambulatory BP and often home BP are reported to be no lower and perhaps slightly higher than office BP (compare Tables 2 and 3 with Tables 4–6). This may be due to a marked level of physical activity in children or, alternatively, to the paucity and, consequently, the imprecision of the available reference values.
It is no surprise, therefore, that the reported prevalence of white-coat hypertension in various studies on children and adolescents has ranged from 1 to 44% [55–57]. Only two studies have investigated masked hypertension [56,57] and report it in approximately 10% of cases. In children as in adults, both white-coat [55,56] and masked hypertensions  have been found to be associated with higher left ventricular mass (LVM) than confirmed in normotensive individuals.
Diagnosis and evaluation
Several steps should be followed, from screening to confirmation, to rule out secondary causes of hypertension, if indicated. The proposed diagnostic algorithm is found in Fig. 1. Once hypertension is confirmed, organ damage evaluation should include heart, great vessels, kidney, central nervous system and retina if possible, due to the importance of subclinical organ damage as an intermediate stage in the continuum of vascular disease. Subsequently, evaluation of organ damage is also useful as an intermediate endpoint for monitoring treatment-induced protection. Boxes 3–5 contain the most relevant aspects of the family and clinical history, examination, laboratory and other investigations recommended at the time of evaluation of hypertension in children and adolescents [58–62].
Evaluation of target organ damage
LVH remains to date the most thoroughly documented form of end-organ damage caused by hypertension in children and adolescents. LVH is known to be an independent risk factor for cardiovascular events in adults, although no such evidence is available from prospective studies in children, it appears prudent to identify LVH in children at any early time, as this may facilitate primary prevention of cardiovascular disease. Echocardiography is a tool sensitive enough to assess LVM in children. LVM is calculated using the Devereux equation  and should be standardized to height (m2.7) to minimize the effect of changes in body size during childhood . If LVH is defined when LVM g/m2.7 is 95th percentile or more (the same cutoff percentile used for defining hypertension) a value of 38.6 g/m2.7 has been reported . However, the cutoff value used in adults (51 g/m2.7) corresponds to the 97.5th percentile. Furthermore, reference data have been calculated from relatively small cohorts, prospective data are missing, and the few available studies have used different criteria. Therefore, it is no surprise if LVH prevalences ranging from 14 to 42% have been reported [66–68].
The first morphological changes of the arterial wall, thickening of the intima-media complex, can be identified by high-resolution ultrasound. Investigators have used intima-media thickening (IMT) to study children at high risk for development of atherosclerosis later in life. Children with familial hypercholesterolemia have higher IMT than age-matched healthy children . Overweight and obesity are associated with increased IMT in children with or without essential hypertension [70,71]. Jourdan et al. proposed normative values for carotid and femoral IMT and large vessel distensibility in the cross-sectional study of 247 healthy adolescents. They found that 38.8% of hypertensive children had a carotid IMT greater than 2 SDs above normal .
Increased arterial stiffness has also been reported to be more common in hypertensive children than in normotensive ones , but a large body of data for establishing normal ranges of arterial distensibility, or its inverse arterial stiffness in children is desirable before safer conclusions can be reached.
Diagnosis of hypertension-related renal damage is based on a reduced renal function or an elevated UAE. Renal insufficiency is classified according to the glomerular filtration rate (GFR) calculated by the Schwartz formula, which is based on age, body height and serum creatinine, in which GFR (ml/min per 1.73 m2) = K × (body height in cm/serum creatinine in mg/dl). K is an age-dependent coefficient (preterm neonates 0.33; term neonates 0.45; children 2–12 years 0.55; girls 13–18 years; 0.55; boys 13–18 years; 0.70). Permanently reduced estimated GFR indicates renal damage. Although a temporary increase in serum creatinine (up to 20%) may occur when antihypertensive therapy is initiated or potentiated, mainly with the use of angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), this should not be taken as a sign of progressive renal deterioration.
In adults, an increase in UAE is a marker of hypertension-induced renal damage. Proteinuria is a marker of glomerular damage in primary and secondary glomerulopathies. It can increase as a consequence of elevated BP, so it is an indication for BP-lowering interventions. Even small amounts of UAE are correlated with progression of nephropathy and to a higher cardiovascular risk. An increased rate of urinary albumin or protein excretion indicates a deranged glomerular filtration barrier. Microalbuminuria (20–300 μg/g creatinine, 2–30 mg/mmol creatinine, 30–300 mg/day, 20–200 μg/min) has been shown to predict the development of diabetic nephropathy, whereas the presence of overt proteinuria (>300 mg/day) indicates the existence of established renal parenchymal damage. The role of microalbuminuria assessment in pediatric essential hypertension, however, has yet to be fully established except for the observation that LVH and microalbuminuria are often associated in children with essential hypertension .
Cerebral seizures, stroke, visual impairment and retinal vascular changes are complications associated with severe hypertension in children and even in infants. Nowadays, these complications seldom occur in infants and children due to early diagnosis and efficient antihypertensive treatment. Diagnostic procedures, other than a neurologic and ophthalmologic clinical evaluation, include electroencephalography and in emergency cases, cranial computed tomography (CT), to exclude intracranial hemorrhage. MRI techniques have replaced the routine CT scan, in the rare cases when small silent brain infarcts, microbleeds and white matter lesions have to be identified.
Vascular injuries to small arteries (narrowing of arterioles) may occur early in the development of hypertension. Few studies of retinal abnormalities have been conducted in children with hypertension so far. In a study of 97 children and adolescents with essential hypertension, Daniels et al. found that 51% displayed retinal abnormalities, as detected from direct ophthalmoscopy. Recently Mitchell et al. showed that even in young children aged 6–8 years, each 10 mmHg increase in SBP was associated with 1.43–2.08 μm narrowing of retinal arterioles detected from quantitative analysis of digital retinal photographs. The routine application of fundoscopy should be restricted to assessing the presence of hypertensive encephalopathy or malignant hypertension.
Genetic analysis merits a specific comment even if it has not yet been demonstrated to have a clear role to play in the routine assessment of children with hypertension. Monogenic causes of hypertension are rare, but they should be detected during the pediatric age, for successful treatment and avoidance of the hypertension-associated morbidity and mortality [76,77]. All presently known monogenic causes of hypertension are characterized by abnormal sodium transport in the kidney, volume expansion and low renin. Among them, Liddle's syndrome , glucocorticoid-remediable aldosteronism , apparent mineralocorticoid excess , Gordon's syndrome , mineralocorticoid receptor hypersensitivity syndrome  and hypertensive forms of congenital adrenal hyperplasia  have been identified. Monogenic diseases should be suspected in children with low renin hypertension and a family history of early-onset severe hypertension, death from cerebral vascular accidents and heart failure or refractory hypertension. Hypokalemia is a common feature of the majority of low renin hypertension stated with the exception of Gordon's syndrome. Figure 2 outlines a rational approach for performing a genetic test.
Correlates of high blood pressure
As most cases of high-normal BP and hypertension in childhood are now known not to be cases of secondary hypertension to be detected and specifically treated, efforts should be made to understand conditions associated in order to return BP within the normal range or to avoid high-normal BP in youth developing into full hypertension in adulthood.
Considerable advances have been made in recent years in identifying conditions often associated with and considered responsible for high BP in children and adolescents, whereas more limited evidence has been accumulated on the results of corrective interventions.
Overweight is probably the most important of the conditions associated with elevated BP in childhood  and accounts for more than half the risk for developing hypertension [84–87]. Fatter children are known to be more likely to remain fat, and adiposity is the most powerful risk factor for higher BP. Unfortunately, from 1970 to 1990, the prevalence of overweight in US children and adolescents increased from 5 to 11% , and a similar trend was observed in British children . A recent survey of school-aged (6–11 years) children in Milan, Italy, has reported a prevalence of overweight ranging from 17.0 to 38.6% according to the different definitions used . In addition to body mass index, waist circumference (abdominal obesity) has been shown to play a role . Birth size and postnatal growth have also been recently implicated in the development of high BP and adult cardiovascular disease [92–97]. Finally, dietary habits early in life, and particularly high salt intake, have been implicated as factors favoring higher BP values [98,99].
Life style measures
Data about BP reduction from randomized intervention trials for reducing weight are limited. Lifestyle trials are currently under way in many settings [100,101], but until these are finished, evidence-based recommendations are limited. Most, however, are obvious and common sense. From reviews, it appears that ‘40 min of moderate to vigorous aerobic-based physical activity 3–5 days/week is required to improve vascular function and reduce BP in obese children’ .
Thus, any intervention that not only reduces energy intake but also increases physical activity in these children is likely to be helpful in keeping BP lower. In general, such interventions should be global policy in schools and as ‘advice’ to parents, not just advice directed at individual children. Group activities, a whole new ethos of outdoor lifestyle promotion, wherever and whenever possible, as part of school curricula, and regular vigorous activity sessions for boys and girls are regarded as essential components in helping children and parents (re-)learn that these are the foundation of what we currently know of how to keep BPs low through childhood and adolescence. Specific dietary measures, again, are only partially evidence based, but guidelines are available [100–102]. These include proposals for salt reduction and increased potassium at young ages [103–105]. As above, dietary trials are underway [100,101,104]. Recommendations are outlined in Box 6.
The accumulating evidence on the importance of fetal and early life factors in determining cardiovascular risk should call attention to a very early onset of preventive measures, such as discouraging maternal smoking and encouraging breast feeding for 6–9 months . Sodium restriction in bottle feeds may also be important, as shown in the Dutch trial followed to age 15 years for effects on BP .
Evidence for therapeutic management
Cardiovascular endpoints such as myocardial infarction, stroke, renal insufficiency or heart failure are extremely uncommon in childhood, and their rarity has so far prevented event-based randomized therapeutic trials. Despite this, clinical experience shows that reduction of high BP in life-threatening conditions, such as acute heart failure, hypertensive encephalopathy and malignant hypertension, improves survival and reduces sequelae in children. Because of the rarity of events, most of the limited evidence available so far is based on the use of organ damage markers including LVH and increased UAE as study endpoints.
Trials based on intermediate endpoints
Pediatric research about the effects of antihypertensive treatment on cardiac end-organ damage are limited to small, uncontrolled studies in heterogeneous populations with primary and secondary hypertension. Some data, nevertheless, suggest that effective antihypertensive treatment may ameliorate cardiac geometry in children. Regression of LVH was reported in three children with essential hypertension receiving enalapril, in 19 children with primary and secondary hypertension treated with ramipril for 6 months, and in 65 children with chronic kidney disease (CKD) stage 2–4 receiving ramipril for up to 2 years [107–109]. All published studies in children refer to ACE inhibitors, and comparative data with other classes of antihypertensive agents are available.
Renal function and disease
Data in adults have shown that, among antihypertensive agents, blockers of the renin–angiotensin system are particularly effective in reducing proteinuria and CKD progression (see section entitled ‘Pharmacological therapy’). This evidence has prompted a large pediatric intervention study; the Effect of Strict Blood Pressure Control and ACE Inhibition on Progression of Chronic Renal Failure in Pediatric Patients (ESCAPE) trial, which has shown efficient BP and proteinuria reduction for the ACE inhibitor ramipril in 352 children with CKD . Still, a gradual rebound of proteinuria despite persistently good BP control was observed on extended treatment, questioning the long-term nephroprotective advantage of ACE inhibition in children .
When to initiate antihypertensive treatment
As in adults, also in children, the decision to initiate antihypertensive treatment should not be taken on BP levels alone, but should also consider the presence or absence of target organ damage, other risk factors or diseases such as obesity, renal diseases or diabetes. In children with proven secondary hypertension, specific treatment of the underlying disease must be initiated immediately after detection. In children with primary hypertension, antihypertensive therapy should first target the risk factors for BP elevation (i.e. overweight, increased salt intake, low physical activity) in the same way as described in the section entitled ‘Preventive measures’.
Nonpharmacological therapy should be continued even after starting pharmacological therapy, as it can improve the overall cardiovascular risk profile in hypertensive children. Pharmacological therapy should be started as stated in Box 7. Unfortunately, the decision about when to initiate pharmacological therapy cannot be supported by trial evidence, which is totally missing. Consequently, the suggestions indicated in the decision-making tree of Fig. 3 are formulated in analogies with what has been shown in adults, and are based on wisdom. Particularly in small children, closer attention should be paid to the benefit-to-risk ratio of prolonged drug administration.
Goal of treatment
Blood pressure target in the general hypertensive population
In adults, the recommendation of reducing BP to below 140/90 mmHg is sufficiently evidence based [2,3]. In the absence of prospective long-term studies linking children BP levels to cardiovascular outcomes, pediatric BP targets are commonly defined in relation to the distribution of BP in the normal population. The 95th percentile is commonly used as a cutoff for defining hypertension in children and adolescents. This provides a rationale for targeting children and adolescents with essential hypertension to a BP below the 95th age, sex and height specific percentiles, but it is probably wiser and safer to aim at a BP below the 90th percentile.
Blood pressure target in renal and diabetic disease
Current guidelines recommend reducing casual BP in adults with hypertension and additional diseases such as diabetes, cardiovascular and renal disease to below 130/80 mmHg with a BP target below 120/75 mmHg suggested in proteinuric adults . It has recently been recognized, however, that recommendations in favor of these very low targets may deserve additional evidence .
In children with CKD, there is preliminary evidence from the prospective randomized ESCAPE trial that strict BP control aiming for a 24-h target below the 50th percentile of mean arterial pressure by the addition of other antihypertensive agents to ACEI therapy results in a better 5-year renal survival, despite a return of proteinuria toward pretreatment values . Peer-reviewed publication of the results of this important trial is required for more precise recommendations. Nonetheless, some further preliminary information can be reported from still unpublished analyses of ESCAPE by courtesy of the authors. Analysis by achieved BP levels shows similar renal outcomes with any 24-h BP below the 75th percentile, contrasting with significantly reduced 5-year renal survival in patients exceeding this cutoff level. A poorer renal survival is associated with an attained 24-h BP above the 90th percentile. Proteinuria appears to be an important modifier of the renoprotective efficacy of intensified BP control. Despite the dissociation in time of the renoprotective and antiproteinuric effects, an improved renal survival is associated with targeting BP to lower levels only in children with even mild baseline proteinuria, whereas no benefit of more intense BP lowering is found in children with nonproteinuric disease. Apart from the renoprotective effect, unpublished data from the ESCAPE trial suggest that intensified BP control, adding to ramipril other antihypertensive drugs, may be associated with regression of the LVH previously reported in these children at baseline .
Although overt diabetic nephropathy is rarely observed in children with diabetes, these patients are considered to be at increased long-term risk for hypertension and renal damage [114,115]. Subtle alterations such as slight increases of SBP and/or a blunted circadian BP variation are commonly found by ABPM early in the course of the disease [115,116] when casual BP is still normal. Impaired nocturnal dipping often precedes microalbuminuria, the earliest marker of diabetic nephropathy . Although pediatric evidence of the efficacy of preventive antihypertensive and antiproteinuric treatment strategies in juvenile diabetes is still lacking, evidence established in adults reinforces the recommendation of aiming at a strict control in children with diabetes.
Home and ambulatory blood pressure targets
Ambulatory BP monitoring is regarded as the gold standard for the diagnosis and monitoring of hypertension, and detecting both white-coat and masked hypertensions. In children, data of the ESCAPE study show a less variable BP response to antihypertensive treatment with ABPM as compared with office BP measurement . Therefore, it seems wise to recommend the use of ABPM to monitor attainment and maintenance of BP targets in children with renal disease. As ABPM cannot be done frequently, both office and home BP monitorings should be utilized as supplementary information. BP values obtained by home monitoring correlate more closely than do office BP values to ABPM-derived mean daytime BP and should be considered superior information.
These have been reported in the section entitled ‘Preventive measures’, but it should be reiterated here that lifestyle measures should not only precede but also accompany pharmacological treatment.
Until recently, no antihypertensive drug was licensed for use in children and adolescents. The US effort (Best Pharmaceuticals for Children Act, Pediatric Research Equity Act) has stimulated European authorities to realize that children also have the right to be treated with drugs that have been studied in and authorized for children. The goal of the Regulation of Medicinal Products for Pediatric Use (EU Regulation 1901/2006/EC)  is to increase the availability of medicines authorized for children, as well as to improve the information on the use of medicinal products in the pediatric population defined in the above EU regulation as aged 0–18 years. Cardiovascular drugs in particular are not licensed for use in children and the inventory list for pediatric needs (Assessment of pediatric needs – Cardiovascular products, EMEA 436949/2006) – contains all antihypertensive agents that need to be studied in this age group. Pharmaceutical companies will receive an incentive of a 6-month prolongation of market exclusivity for adequately performed pediatric studies. Furthermore, studies on the pediatric population with drugs that are off-patent will get a new exclusivity according to the Paediatric Use Marketing Authorization (Art. 40, EU regulation). With this procedure, ACEIs, beta-blockers, calcium channel blockers, dihydralazine, prazosin and diuretics can be licensed for infants, children and adolescents.
The legislation changes in the United States (Food and Drug Administration Modernization Act, 1997, Best Pharmaceuticals for Children Act, 2002)  have led to the study and approval of new antihypertensive medications for use in children and adolescents. The recent Regulation of Medicinal Products for Paediatric Use (EU Regulation 1901/2006/EC) in Europe will lead to further approval of antihypertensive agents for children and even infants. Several antihypertensive drugs are commercially available in liquid form or can be extemporaneously compounded for flexible dosing and ease of administration. Recent clinical trials have expanded the number of drugs that have pediatric dosing information based on dose finding studies. For new drugs and lower administration ages, more information will be provided in the near future. One negative consequence of the new regulation is that for older compounds with expired patent protection, reliable pediatric data obtained from controlled studies (dose finding and efficacy) are lacking. Probably, the Paediatric Use Marketing Authorization (PUMA) will help resolve this problem, at least in part. For the time being, the present recommendations are based on few industry-sponsored studies, and mostly on single-center case series, collective clinical experience, expert opinion and extrapolation from data obtained in adults.
It is reasonable that in children, treatment should be started with a single drug administered at a low dose in order to avoid rapid fall in BP. If BP does not decrease sufficiently after a few weeks, usually 4–8, an increase to the full dose should be initiated. When BP does not respond adequately or significant side effects occur, the switching to another antihypertensive drug of a different class is recommended. This procedure allows finding the patient's best individual response to the drug in terms of efficacy and tolerability. As the response rate is often not sufficient in single-drug treatment, particularly in moderate or severe hypertension, combination therapy is often necessary.
Like in adults, choice of antihypertensive agents can include ACEIs, angiotensin receptor antagonists (ARBs), calcium antagonists, beta-blockers and diuretics. A few placebo-controlled studies are available, but almost no head-to-head study directly comparing the efficacy and safety of different antihypertensive drugs in children or adolescents. A recent review  of 27 pediatric studies reports comparable BP reductions with ACEIs (10.7/8.1 mmHg), ARBs (10.5/6.9 mmHg) and calcium antagonists (9.3/7.2 mmHg).
Propranolol has been included in treatment recommendations for pediatric hypertension for many years, but it has only been studied specifically as an antihypertensive agent in few trials on very few children [121,122]. Most of the information about the safety and efficacy of this drug comes from studies of nonhypertensive children with cardiac disease or portal hypertension . The situation is similar for atenolol and metoprolol . The only study specifically directed to hypertension is a recent 52-week trial  on 140 children (aged 6–11 years) reporting that an extended-release preparation of metoprolol produced significant reductions in SBP and DBP at 1.0 and 2.0 mg/kg when compared with placebo. The drug was well tolerated, and only 5% of participants had to drop out due to adverse events.
The efficacy and safety data for diltiazem, verapamil, nifedipine, felodipine and isradipine  are limited. There have been, however, several trials for amlodipine , which is extensively used in the treatment of hypertension in children . Amlodipine decreased SBP compared with placebo in a large multicenter trial  that included 268 children aged from 6 to 16 years. A significant dose–response relationship was established with doses from 0.06 to 0.34 mg/kg per day. A pharmacokinetic study  indicated that amlodipine pharmacokinetic parameters for children younger than 6 years with low body weight were significantly different than were those for older/larger individuals. This suggests the need for higher doses (on a mg/kg basis) when treating young children with amlodipine.
Angiotensin-converting enzyme inhibitors
The oldest ACEI, captopril, has been extensively studied in children. Its efficacy and safety appear to be well established, but the drug has a short duration of action. As it must be administered two or three times a day, it has been replaced by the longer-acting ACEIs . Some of these have been studied recently in children . Placebo-controlled efficacy results are available for enalapril , fosinopril  and lisinopril , whereas pharmacokinetic studies have been carried out for enalapril , lisinopril  and quinapril . The enalapril  and lisinopril  trials have established minimum effective doses of 0.08 mg/kg per day, but doses of 0.6 mg/kg per day were well tolerated. These drugs were studied in an extemporaneous suspension formulation. The fosinopril study  failed to establish a dose–response effect on BP reduction. The authors suggested that probably all the doses used were too high (0.1, 0.3 and 0.6 mg/kg per day; the maximum dose permitted was 40 mg/day). Fosinopril , however, did produce greater SBP reduction than did placebo, and the drug was well tolerated. The study included a 52-week open-label extension that provided more information about safety and tolerability than did other trials. Ramipril has been studied mostly in children with chronic renal disease. At a dose of 6 mg/m2 daily, it reliably reduced 24-h mean BP, especially in severely hypertensive or proteinuric children . Ramipril at a lower dose of 2.5 mg/m2 per day reduced BP and proteinuria also in children with primary hypertension and renal hypertension with chronic renal failure .
Angiotensin receptor blockers
Data on the effects of ARBs in hypertensive children have accumulated recently . Short-term treatment with losartan in children with estimated GFRs 30 ml/min per 1.73 m2 or more produced significant dose-dependent reductions in DBP . The effective starting dose was 0.75 mg/kg per day, but doses as high as 1.44 mg/kg per day were well tolerated. For irbesartan, a small pharmacokinetic study indicated that doses of 75–150 mg/day were effective in children with hypertension . Another small trial  in hypertensive children with proteinuria showed that irbesartan at doses from 3.8 to 5.9 mg/kg per day significantly reduced BP and proteinuria. Data for candesartan come from a small study conducted in 17 children 1–6 years old. Candesartan  was used at a once-a-day dose of 0.16–0.47 mg/kg body weight. BP significantly decreased, and the effect on BP was similar in individuals with or without overt proteinuria, which also decreased in a similar way. Recently, valsartan has effectively lowered SBP and DBP compared with placebo in children 1–5 years old .
Other antihypertensive agents
No pediatric studies have been conducted for diuretics, except for a very small old study on chlorthalidone , direct vasodilators, centrally acting agents, or alpha-1 receptor antagonists, despite their having a long history of clinical use in the pharmacological management of hypertension in children . Pediatric experience has been reported with hydrochlorothiazide and chlorthalidone. The latter has a longer half-life, and the dose interval is 24 or 48 h. Very high doses of thiazides affect BP only marginally, but may be associated with increased incidence and severity of side effects.
Therefore, the selection of the drug used to initiate the lowering of BP depends on extrapolations from pathophysiological aspects and clinical experience. As many of children and adolescents requiring antihypertensive drug therapy have some degree of renal disease, the most widely used drugs are agents inhibiting the renin–angiotensin system, mainly ACEIs, or ARBs if intolerance to ACEIs exists. Loop diuretics such as furosemide are essential in children with advanced chronic renal failure or with heart failure. The recommended doses for antihypertensive drugs in children are shown in Table 7, and the specific recommendations and contraindications are shown in Table 8.
In children with renal disease, monotherapy is often not sufficient to achieve adequate BP control. Therefore, early combination therapy is required. Early dose combination of antihypertensive agents is more efficient and has a lower rate of adverse drug reaction compared with that of high-dose monotherapy. Antihypertensive drugs of different classes have complementary effects, resulting in a higher degree of BP reduction and a lower rate of adverse drug reaction. The best choices of antihypertensive drug combinations are those recommended in the ESH/ESC 2007 Guidelines . Fixed-dose combinations of two drugs are rarely used in children, as individual-based contributions are preferred, but fixed combinations may have a place in treating adolescents to improve compliance .
Therapeutic approaches under special conditions
Hypertension requires specific therapeutic approaches in several situations not only out of the necessity to reach lower goals than are usually recommended, but also because of the presence of characteristic mechanisms that can benefit from particular antihypertensive agents. CKD, diabetes mellitus and metabolic syndrome, heart failure and sleep apnea are among the most common.
Chronic kidney disease
In the section entitled ‘Goal of treatment’, we have summarized recent preliminary evidence from the ESCAPE trial, suggesting that hypertension in children with CKD, especially if accompanied by proteinuria, requires more intensive management in order to reduce proteinuria and prevent progressive deterioration of renal function. Although nonpharmacological options should be considered, pharmacological treatment remains the mainstay of antihypertensive management in all stages of CKD. The different classes of antihypertensive agents are comparable with respect to their BP-lowering efficacy in children with CKD [120,145], but most of the available clinical evidence has been obtained with drugs blocking the renin–angiotensin system, [110,120,146]. They have a powerful antiproteinuric action in pediatric nephropathies and display a favorable safety profile. Furthermore, the only study so far comparing the effects of an ARB, irbesartan, and a calcium antagonist, amlodipine, in children with proteinuric nondiabetic CKD has shown a significant reduction of proteinuria only with ARB treatment, despite similar effects of the two randomized treatments on BP .
At this time, therefore, it appears reasonable to recommend agents blocking the renin–angiotensin system as first choice in proteinuric, and also in nonproteinuric patients with CKD.
In three-quarters of hypertensive children with CKD stage 2–4, BP control can be achieved by antihypertensive monotherapy, but at least 50% of children require more than one drug to achieve a sufficiently low BP target. If multiple drug therapy is required, diuretics and calcium channel blockers are the most suitable options. ARBs in combination with ACEIs have been suggested to have additional antiproteinuric and renoprotective effects , and a very small short-term study has also been done in children . However, the negative results recently reported in the high-risk adult patients of ONTARGET  for the combination of the blockers of the renin–angiotensin system call for caution in the use of this combination at all ages. Clearly, more evidence is required.
Diabetic nephropathy, albeit uncommon in this age group, requires a similar approach to other CKD. Extrapolating from findings on adults, it appears appropriate to consider the microalbuminuric stage as a signal to begin BP lowering in order to reduce the risk of progression to the proteinuric stage. In this case, nocturnal BP control can play a key role. ABPM is useful in order to assess the BP goal. In the absence of hypertension or microalbuminuria, treatment with ACEIs or ARBs can be considered if circadian BP variability is persistently blunted .
Diabetes mellitus and metabolic syndrome
In type 2 diabetes or insulin resistance, the underlying mechanisms of metabolic syndrome , treatment of high BP should be based on lifestyle changes, diet and physical exercise, which allows for weight reduction and improves muscular blood flow. If recourse to drugs is decided, the preferred drugs should be those that might induce reduction of insulin resistance and subsequent changes in the lipid profile and in glucose levels. Therefore, ACEIs, ARBs or calcium antagonists are preferable over diuretics and beta-blockers if no compelling contraindications are present. If a combination of drugs is required, low-dose diuretics can be used, but a combination of thiazide diuretics and beta-blockers should better be avoided .
Hypertension is a major risk factor for the development of heart failure. As in adults, the treatment of heart failure in children includes diuretics, beta-blockers and drugs blocking the renin–angiotensin system . No outcome trials have been done in children, but evidence from many studies in adult heart failure suggests that ACEIs (and alternatively ARBs) together with beta-blockers may not only reduce symptoms but increase survival in children with heart failure . Diuretics (loop and aldosterone antagonists) are indicated in children with heart failure and fluid overload. Diuretics should not be administered alone, but in combination with drugs blocking the renin–angiotensin and cardiac sympathetic system, although all drugs should be administered in slowly increasing doses. In case of acute heart failure from a hypertensive emergency, intravenous loop diuretics and vasodilatory drugs are preferred.
Sleep apnea syndrome
The sleep apnea syndrome is frequently associated with hypertension, particularly among overweight children. During the last few years, the potential relationship between childhood sleep-disordered breathing (SDB)/obstructive sleep apnea (OSA) and cardiovascular diseases in children has been underlined. The evidence linking moderate to severe SDB in childhood and elevated risk of hypertension is controversial. A meta-analysis of studies investigating the relation between high apnea–hypopnea index and hypertension in children reported, an increased risk of hypertension [odds ratio of 2.93; 95% confidence interval (CI) = 1.18–7.29] , whereas a more recent one failed to find a statistically significant association (random-effect odds ratio of 1.87; 95% CI = 0.73–4.80) . The impact of overweight and obesity on both hypertension and SDB can be a confounding factor. For the time being, it appears wise to address treatment to reducing overweight. In extreme cases with severe OSA, positive pressure breathing equipment or surgery might become necessary .
A hypertensive crisis (emergency or urgency) is a life-threatening condition associated with severe hypertension. Hypertensive emergency is defined as severe hypertension complicated with acute target organ dysfunction (mainly neurological, renal or cardiac). Hypertensive urgency is defined as severe hypertension without acute target organ dysfunction. Children with hypertensive emergencies should be treated in an intensive care unit to ensure monitoring and support of the vital organs.
The treatment strategy must be directed toward the immediate reduction of BP to reduce the hypertensive damage to the target organs, but not at a rate likely to cause hypoperfusion of vital organs by an excessively rapid reduction of BP (mainly cerebral hypoperfusion with neurological sequelae). Then, careful neurological and cardiovascular assessment should be undertaken throughout the initial treatment. There is no experimental evidence upon which recommendations on the optimal rate of BP reduction in hypertensive emergencies could be based. From clinical experience, BP should be lowered by no more than 25–30% over the first 6–8 h, followed by a further gradual reduction over the next 24–48 h [157,158]. Faster normalization of severe hypertension must be strictly avoided, as it may cause more harm than severe hypertension itself. Children with a hypertensive emergency should always be treated with intravenous drugs. Continuous infusion is safer than is bolus injection with regard to complications (unexpected hypotension with vital organ hypoperfusion). Sodium nitroprusside and labetalol are the most commonly used drugs for hypertensive emergencies in children. Hypertensive urgencies can be treated with orally administered drugs. Table 9 indicates drugs and doses used for pediatric hypertensive crises.
Resistant hypertension is defined as hypertension in which a therapeutic plan including lifestyle measures and prescription of at least three drugs, including a diuretic in adequate doses, has failed to lower SBP and DBP to goal. Resistant hypertension in children and adolescents, once verified with ABPM and having excluded the conditions outlined in Box 8, almost invariably indicates presence of secondary hypertension. Consequently, a judicious workup should be performed, as outlined in the section entitled ‘Screening of secondary forms of hypertension’.
Treatment of associated risk factors
The new guidelines of the American Academy of Pediatrics (AAP) recommend measuring lipoproteins starting at age 2 in overweight or hypertensive or diabetic children or in those with a family history of dyslipidemia or early coronary artery disease . If lipid values are within age-specific and gender-specific normal ranges, children should be retested in 3–5 years. For those out of normal ranges, initial treatment should be focused on recommending a diet low in cholesterol (<200 mg/day) and saturated fat (<7% of calories) supplemented with plant sterols and dietary fibers (child's age + 5 g/day up to 20 g at 15 years of age) . Increased physical activity may be useful for modifying HDL-C and triglycerides. According to the AAP, statins should be considered for children 8 years and older if any of the following conditions exists: LDL-C remains 190 mg/dl (4.94 mmol/l) or more; LDL-C remains 160 mg/dl (4.16 mmol/l) or more and there is a family history of early coronary artery disease or the presence of other risk factors as obesity, hypertension and smoking; LDL-C remains 130 mg/dl (3.38 mmol/l) or more in children with diabetes mellitus. The Food and Drug Administration (FDA) and European Medicines Agency (EMEA) have approved the use of pravastatin for children with familial hypercholesterolemia who are 8 years and older. It should be noted, however, that AAP recommendations are controversial: they are not evidence based and the long-term effects of statins on children are unknown. The use of ezetimibe is approved in the United States (but not in Europe) only for those rare children with familial homozygous hypercholesterolemia or with sitosterolemia. Bile-acid sequestrants are difficult to tolerate over the long term. Fibrates may be used in adolescents with triglycerides 500 mg/dl or more who are at increased risk of pancreatitis [159,160].
Increasing prevalence of pediatric type 2 diabetes coincides with increasing obesity in children. Most obese children have insulin resistance (60%), 5% have impaired glucose tolerance (IGT), 1% impaired fasting glucose and 0.2% type 2 diabetes . Reducing overweight and IGT may help prevent or delay the development of type 2 diabetes in high-risk youths. Behavioral modification (dietary changes and ≥60 min daily of physical activity), using techniques to motivate children and families , is effective at reducing insulin levels and reverting IGT to normal. Metformin is the only oral medication that has been adequately studied in children and approved by the FDA and some European agencies for use in children over 10 years of age with type 2 diabetes. In morbidly obese insulin-resistant children, metformin has been shown to have favorable effects on body composition, fasting insulin and fasting glucose . A clinical trial to investigate whether aggressive pharmacological reduction in insulin resistance early in the course of type 2 diabetes is superior to lifestyle modification in adolescents is in progress .
Screening of secondary forms of hypertension
Usually, sustained hypertension in children and adolescents is classified as secondary when a specific cause can be found, which can often be corrected with specific intervention. The most common causes of hypertension can change during childhood. Essential hypertension is rarely seen in infants and young children, but its prevalence increases significantly in adolescence . A good general rule to follow is that the likelihood of identifying a secondary cause of hypertension is inversely related to the age of the child and directly related to the degree of BP elevation . Consequently, the evaluation of children with hypertension, especially young children and those with severe hypertension, should be comprehensive and aimed at identifying known causes of the disease.
The distribution of causes clearly varies with age. Renal parenchymal disorders  with renovascular disease and coarctation of the aorta account for 70%  to 90%  of all cases. These figures vary depending not only on age, but also on referral center and referral bias. In a number of cases, hypertension is related to the prescription of drugs with hypertensive potential. Other causes of sustained hypertension, tumors and central nervous and endocrine disorders, though infrequent, must be considered once the more common causes have been excluded. An emerging cause of secondary hypertension is a single gene mutation that produces large changes in BP .
Hypertension may be seen in up to 2% of all term or preterm infants in neonatal intensive care units. Although the definition of hypertension in this age group has not been completely standardized, useful data have been published  and may be used to facilitate diagnosis in these infants. As in older children, the causes of hypertension in neonates are numerous, with the two largest categories being renal (vascular and parenchymal) diseases. More specifically, umbilical artery catheter-associated thromboembolism affecting either the aorta and/or the renal arteries probably accounts for the majority of cases of hypertension seen in a typical neonatal intensive care unit . A careful history and physical examination will usually identify the cause in most cases, without the need for extensive laboratory or radiological testing.
In very young children (<6 years), hypertension is most often the result of renal parenchymal diseases such as glomerulonephritis, renal scarring, polycystic kidney, renal artery stenosis and renal dysplasia. Cardiovascular disorders like coarctation of the aorta are less frequent causes of hypertension in this age group. Late in the first decade and throughout the second, essential hypertension is the most common cause of sustained hypertension, particularly in those children with mild asymptomatic disease .
Faced with a child with chronic hypertension of unknown cause, a diagnostic evaluation should take into account level of BP, age, sex, clinical findings and family history. A careful selection of the necessary test often shortens the diagnostic process (Box 9), but a detailed description of the selection process is beyond the scope of this guide [173,174].
Depending on the underlying cause of hypertension, investigative procedures such as monitoring plasma electrolytes and creatinine, GFR measurements at intervals, renal and renovascular imaging by ultrasound and isotopic studies, possibly repeat angiography [digital subtraction angiography (DSA), CO2 angiography (CO2), MR angiography (MRA) or CT angiography (CTA)] will need to be undertaken. For pheochromocytoma or paraganglioma, repeat catecholamine measurements or I123 MIGB scanning may be indicated. Cautious reduction of therapy after long-term BP control achieved may be indicated, even discontinuing therapy in some patients. Life-long follow-up, however, is indicated in the majority of children. Home monitoring of BP can greatly facilitate this management. In children with renal hypertension, regular ABPM measurements at 6–12-month intervals are indispensible to rule out selective nocturnal hypertension.
In several places, these guidelines have acknowledged, and lamented, the lack of solid, trial-based evidence for recommendations on diagnosis and management of pediatric hypertension. Areas requiring urgent gain of knowledge are listed in Box 10. A commitment to find answers to the outlined issues should guide concerted actions over the next several years in Europe.
Implementation of guidelines
In order to limit, and even reduce, the burden of hypertension in children and adolescents, and its complications, the present guidelines should be successfully implemented. This requires synergistic actions at various levels: learned societies and international expert committees, general practitioners, pediatricians, nurses and other healthcare providers, schools, parents and policy makers. A converging action is the only means to close the gap between experts' recommendations and undiagnosed hypertension in children and adolescents, undetected target organ damage and poor BP control. The role of learned societies, particularly the ESH, is crucial not only for spreading the guidelines all over European countries, but also for obtaining their acceptance by national hypertension societies and leagues.
In parallel, a concerted public action is needed both to improve identification and treatment of high BP among children and adolescents and to encourage lifestyle factors, namely healthy nutrition, low salt intake, nonsmoking, alcohol avoidance, and exercise activity, as preventive and curative measures. Only an aggressive public policy initiative will lead healthcare providers, insurers and other payers to increase the reimbursement of costs associated with the investigation and long-term treatment of high BP in children and adolescents. Indeed, a comprehensive preventive program in each European country involving all the above actors, as well as families and school teachers, is a prerequisite to promote management implementation in practice and improve childhood and adolescent health.
The writing committee is well aware of the fact that issuing these guidelines does not imply implementation. However, these guidelines represent a consensus among all specialists involved in the detection and control of high BP in children and adolescents. Although for several aspects scientific evidence derived from trials is not available in children, and these guidelines are likely to be modified in forthcoming years depending on new evidence if the studies here recommended will be promptly initiated, the recommendations of the present document synthesize a considerable amount of scientific data and clinical experience, and represent best clinical wisdom upon which physicians, nurses and families should base their decisions. In addition, because they call attention to the burden of hypertension in children and adolescents, and its contribution to the current epidemic of cardiovascular disease, these guidelines should encourage public policy makers, to develop a global effort to improve identification and treatment of high BP among children and adolescents.
1 Guidelines Committee. 2003 European Society of Hypertension
: European Society of Cardiology guidelines for the management of arterial hypertension. J Hypertens
2 Mancia G, De Backer G, Dominiczak A, Cifkova R, Fagard R, Germano G, et al
. 2007 Guidelines for the management of arterial hypertension: The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension
(ESH) and of the European Society of Cardiology (ESC). J Hypertens 2007; 25:1105–1187.
3 Zanchetti A, Grassi G, Mancia G. When should antihypertensive drug treatment be initiated and to what levels should systolic blood pressure be lowered? A critical reappraisal. J Hypertens 2009; 27:923–934.
4 Lewington S, Clarke R, Qizilbash N, Peto R, Collins R, Prospective studies Collaboration. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet 2002; 360:1903–1913.
5 National Center of Health Statistics. National Health and Nutrition Examination Survey: blood pressure levels of persons 6–74 years, US, 1971–74. Vital Health Stat
11. 1977; 203
6 National Heart, Lung, and Blood Institute. Report of the Task Force on Blood Pressure Control in Children. Pediatrics
7 National Heart, Lung, and Blood Institute. Report of the Second Task Force on Blood Pressure Control in Children 1987. Pediatrics
8 Bao W, Threefoot SA, Srinivasan SR, Berenson GS. Essential hypertension predicted by tracking of elevated blood pressure from childhood to adulthood: the Bogalusa Heart Study. Am J Hypertens 1995; 8:657–665.
9 Lauer RM, Mahoney LT, Clarke WR. Tracking of blood pressure during childhood: the Muscatine Study. Clin Exp Hypertens A 1986; 8:515–537.
10 Vos LE, Oren A, Bots ML, Gorissen WH, Grobbee DE, Uiterwaal CS. Does a routinely measured blood pressure in young adolescence accurately predict hypertension and total cardiovascular risk in young adulthood? J Hypertens 2003; 21:2027–2034.
11 Sun SS, Grave GD, Siervogel RM, Pickoff AA, Arslanian SS, Daniels SR. Systolic blood pressure in childhood predicts hypertension and metabolic syndrome later in life. Pediatrics 2007; 119:237–246.
12 Nelson MJ, Ragland DR, Syme SL. Longitudinal prediction of adult blood pressure from juvenile blood pressure levels. Am J Epidemiol 1992; 136:633–645.
13 Mahoney LT, Clarke WR, Burns TL, Lauer RM. Childhood predictors of high blood pressure. Am J Hypertens 1991; 4:608S–610S.
14 Lurbe E. Hypertension and target organ damage in children and adolescents. J Hypertens 2007; 25:1998–2000.
15 Sinha MD, Reid CJ. Evaluation of blood pressure in children. Curr Opin Nephrol Hypertens 2007; 16:577–584.
16 Daniels SR, Loggie JM, Khoury P, Kimball TR. Left ventricular geometry and severe left ventricular hypertrophy in children and adolescents with essential hypertension. Circulation 1998; 97:1907–1911.
17 Brady TM, Fivush B, Flynn JT, Parekh R. Ability of blood pressure to predict left ventricular hypertrophy in children with primary hypertension. J Pediatr 2008; 152:73e1–78e1.
18 Lande MB, Carson NL, Roy J, Meagher CC. Effects of childhood primary hypertension on carotid intima media thickness. A matched controlled study. Hypertension 2006; 48:40–44.
19 Davis PH, Dawson JD, Riley WA, Lauer RM. Carotid intimal-medial thickness is related to cardiovascular risk factors measured from childhood through middle age: the Muscatine Study. Circulation 2001; 104:2815–2819.
20 Juonala M, Jarvisalo MJ, Maki-Torkko N, Kahonen M, Viikari JS, Raitakari OT. Risk factors identified in childhood and decreased carotid artery elasticity in adulthood: the Cardiovascular Risk in Young Finns Study. Circulation 2005; 112:1486–1493.
21 Ferreira I, Twisk JW, van Mechelen W, Kemper HC, Seidell JC, Stehouwer CD. Current and adolescent body fatness and fat distribution: relationships with carotid intima-media thickness and large artery stiffness at the age of 36 years. J Hypertens 2004; 22:145–155.
22 Stabouli S, Kotsis V, Zakopoulos N. Ambulatory blood pressure monitoring and target organ damage in pediatrics. J Hypertens 2007; 25:1979–1986.
23 Grunfeld B, Perelstein E, Simsolo R, Gimenez M, Romero JC. Renal functional reserve and microalbuminuria in offspring of hypertensive parents. Hypertension 1990; 15:257–261.
24 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. National Heart, Lung, and Blood Institute, Bethesda, Maryland. Pediatrics
25 de Man SA, André JL, Bachmann HJ, Grobbee DE, Ibsen KK, Laaser U, et al
. Blood pressure in childhood: pooled findings of six European studies. J Hypertens 1991; 9:109–114.
26 Menghetti E, Virdis R, Strambi M, Patriarca V, Riccioni MA, Fossali E, et al
. Blood pressure in childhood and adolescence: the Italian normal standards. Study Group on Hypertension of the Italian Society of Pediatrics. J Hypertens 1999; 17:1363–1372.
27 Park MK, Menard SM, Schoolfield J. Oscillometric blood pressure standards for children. Pediatr Cardiol 2005; 26:601–607.
28 Jackson LV, Thalange NK, Cole TJ. Blood pressure centiles for Great Britain. Arch Dis Child 2007; 92:298–303.
29 Munkhaugen J, Lydersen S, Wideroe TE, Hallan S. Blood pressure reference values in adolescents: methodological aspects and suggestions for Northern Europe tables based on the North Trondelag Health Study II. J Hypertens 2008; 26:1912–1918.
30 Sung RY, Choi KC, So HK, Nelson EA, Li AM, Kwok CW, et al
. Oscillometrically measured blood pressure in Hong Kong Chinese children and associations with anthropometric parameters. J Hypertens 2008; 26:678–684.
31 MacMahon S, Peto R, Cutler J, Collins R, Sorlie P, Neaton J, et al
. Blood pressure, stroke and coronary heart disease. Part 1: Prolonged differences in blood pressure – prospective observational studies corrected for the regression dilution bias. Lancet 1990; 335:765–774.
32 Lurbe E, Cremades B, Rodríguez C, Torró I, Alvarez V, Redón J. Factors related to quality of ambulatory blood pressure monitoring in a pediatric population. Am J Hypertens 1999; 12:929–933.
33 O'Brien E, O'Malley K. Evaluation of blood pressure measuring devices with special reference to ambulatory systems. J Hypertens Suppl 1990; 8:S133–S139.
34 Association for the Advancement of Medical Instrumentation. American National Standard. Electronic or automated sphygmomanometers ANSI/AAMI SP10-1992
. Arlington, VA, USA: AAMI; 1993.
35 O'Brien E, Pickering T, Asmar R, Myers M, Parati G, Staessen J, et al
, on behalf of the Working Group on Blood Pressure Monitoring of the European Society of Hypertension
. International protocol for validation of blood pressure measuring devices in adults. Blood Press Monit 2002; 7:3–17.
36 Park MK, Menard SW, Yuan C. Comparison of auscultatory and oscillometric blood pressure. Arch Pediatr Adolesc Med 2001; 155:50–53.
37 Podoll A, Grenier M, Croix B, Feig DI. Inaccuracy in pediatric outpatient blood pressure measurement. Pediatrics 2007; 119:e538–e543.
38 Gillman MW, Cook NR. Blood pressure measurement in childhood. Epidemiological studies. Circulation 1995; 92:1049–1057.
39 Beevers G, Lip GY, O'Brien E. ABC of hypertension. Blood pressure measurement. Part I: Sphymgomanometry – factors common to all techniques. BMJ 2001; 322:981–985.
40 O'Brien E. Ambulatory blood pressure measurement is indispensable to good clinical practice. J Hypertens Suppl 2003; 21:S11–S18.
41 Urbina E, Alpert B, Flynn J, Hayman L, Harshfield GA, Jacobson M, et al
, American Heart Association Atherosclerosis, Hypertension, and Obesity in Youth Committee. Ambulatory blood pressure monitoring in children and adolescents: recommendations for standard assessment: a scientific statement from the American Heart Association Atherosclerosis, Hypertension, and Obesity in Youth Committee of the council on cardiovascular disease in the young and the council for high blood pressure research. Hypertension 2008; 52:433–451.
42 O'Brien E, Sheridan J, O'Malley K. Dippers and nondippers. Lancet 1988; 2:397.
43 Pickering TG, James GD, Boddie C, Harshfield GA, Blank S, Laragh JH. How common is white-coat hypertension? JAMA 1988; 259:225–228.
44 Pickering TG, Davidson K, Gerin W, Schwartz JE. Masked hypertension. Hypertension 2002; 40:795–796.
45 Lurbe E, Redon J, Liao Y, Tacons J, Cooper RS, Alvarez V. Ambulatory blood pressure monitoring in normotensive children. J Hypertens 1994; 12:1417–1423.
46 Wühl E, Witte K, Soergel M, Mehls O, Schaefer F, German Working Group on Pediatric Hypertension. Distribution of 24-h ambulatory blood pressure in children: normalized reference values and role of body dimensions. J Hypertens 2002; 20:1995–2007.
47 Zanchetti A, Mancia G, Black HR, Oparil S, Waeber B, Schmieder RE, et al
. Facts and fallacies of blood pressure control in recent trials: implications in the management of patients with hypertension. J Hypertens 2009; 27:673–679.
48 Stergiou G, Alamara C, Salgami E, Vaindirlis I, Dacou-Voutetakis C, Mountokalakis T. Reproducibility of home and ambulatory blood pressure in children and adolescents. Blood Press Monit 2005; 10:143–147.
49 Stergiou GS, Christodoulakis G, Giovas P, Lourida P, Alamara C, Roussias LG. Home blood pressure monitoring in children: how many measurements are needed? Am J Hypertens 2008; 21:633–638.
50 Parati G, Stergiou GS, Asmar R, Bilo G, de Leeuw P, Imai Y, et al
, on behalf of the ESH Working Group on Blood Pressure Monitoring. European Society of Hypertension
guidelines for blood pressure monitoring at home: a summary report of the Second International Consensus Conference on Home Blood Pressure Monitoring. J Hypertens 2008; 26:1505–1526.
51 Stergiou GS, Yiannes NG, Rarra VC, Panagiotakos DB. Home blood pressure normalcy in children and adolescents: the Arsakeion School study. J Hypertens 2007; 25:1375–1379.
52 Stergiou G, Nasothimiou E, Giovas P, Kapoyiannis A, Vazeou A. Diagnosis of hypertension in children and adolescents based on home versus ambulatory blood pressure monitoring. J Hypertens 2008; 26:1556–1562.
53 Wühl E, Hadtstein C, Mehls O, Schaefer F, Escape Trial Group. Home, clinic, and ambulatory blood pressure monitoring in children with chronic renal failure. Pediatr Res 2004; 55:492–497.
54 Lurbe E, Parati G. Out-of-office blood pressure measurement in children and adolescents. J Hypertens 2008; 26:1536–1539.
55 Sorof JM, Poffenbarger T, Franco K, Portman R. Evaluation of white-coat hypertension in children: importance of the definitions of normal ambulatory blood pressure and the severity of casual hypertension. Am J Hypertens 2001; 14:855–860.
56 Stabouli S, Kotsis V, Toumanidis S, Papamichael C, Constantopoulos A, Zakopoulos N. White-coat and masked hypertension in children: association with target-organ damage. Pediatr Nephrol 2005; 20:1151–1155.
57 Lurbe E, Torro I, Alvarez V, Nawrot T, Paya R, Redon J, Staessen JA. Prevalence, persistence, and clinical significance of masked hypertension in youth. Hypertension 2005; 45:493–498.
58 Dillon MJ. Investigation and management of hypertension in children. A personal perspective. Pediatr Nephrol 1987; 1:59–68.
59 Swinford RD, Portman RJ. Diagnostic evaluation of pediatric hypertension. In: Portman RJ, Sorof JM, Ingelfinger JR, editors. Pediatric hypertension. Totowa: Humana Press; 2004. pp. 405–420.
60 Brewer ED. Evaluation of hypertension in childhood diseases. In: Avner ED, Harmon WE, Niaudet P, editors. Pediatric nephrology. Philadelphia: Lippincott Williams and Wilkins; 2004. pp. 1179–1197.
61 Dillon MJ. The diagnosis of renovascular disease. Pediatr Nephrol 1997; 11:366–372.
62 Rees L, Webb NJA, Brogan PA, editors. Paediatric nephrology
. Oxford: Oxford University Press; 2007.
63 Devereux RB, Alonso DR, Lutas EM, Gottlieb GJ, Campo E, Sachs I, Reichek N. Echocardiographic assessment of left ventricular hypertrophy: comparison to necropsy findings. Am J Cardiol 1986; 57:450–458.
64 de Simone G, Devereux RB, Daniels SR, Koren M, Meyer RA, Laragh JH. Effect of growth on variability of left ventricular mass: assessment of allometric signals in adults and children and their capacity to predict cardiovascular risk. J Am Coll Cardiol 1995; 25:1056–1062.
65 Daniels SR, Kimball TR, Morrison JA, Khoury P, Meyer RA. Indexing left ventricular mass to account for differences in body size in children and adolescents without cardiovascular disease. Am J Cardiol 1995; 76:699–701.
66 Litwin M, Niemirska A, Sladowska J, Antoniewicz J, Daszkowska J, Wierzbicka A, et al
. Left ventricular hypertrophy and arterial wall thickening in children with essential hypertension. Pediatr Nephrol 2006; 21:811–819.
67 Hanevold C, Waller J, Daniels S, Portman R, Sorof J, International Pediatric Hypertension Association. 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.
68 McNiece KL, Gurpa-Malhotra M, Samuels J, Bell C, Garcia K, Poffenbarger T, et al
, National High Blood Pressure Education Program Working Group. 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.
69 Virkola K, Pesonen E, Akerblom HK, Siimes MA. Cholesterol and carotid artery wall in children and adolescents with familial hypercholesterolemia: a controlled study by ultrasound. Acta Paediatr 1997; 86:1203–1207.
70 Zhu W, Huang X, He J, Li M, Neubauer H. Arterial intima-media thickening and endothelial dysfunction in obese Chinese children. Eur J Pediatr 2005; 164:337–344.
71 Sorof JM, Alexandrov AV, Garami Z, Turner JL, Grafe RE, Lai D, Portman RJ. Carotid ultrasonography for detection of vascular abnormalities in hypertensive children. Pediatr Nephrol 2003; 18:1020–1024.
72 Jourdan C, Wühl E, Litwin M, Fahr K, Trelewicz J, Jobs K, et al
. Normative values for intima-media thickness and distensibility of large arteries in healthy adolescents. J Hypertens 2005; 23:1707–1715.
73 Assadi F. Relation of left ventricular hypertrophy to microalbuminuria and C-reactive protein in children and adolescents with essential hypertension. Pediatr Cardiol 2008; 29:580–584.
74 Daniels SR, Lipman MJ, Burke MJ, Loggie JM. The prevalence of retinal vascular abnormalities in children and adolescents with essential hypertension. Am J Ophthalmol 1991; 111:205–208.
75 Mitchell P, Cheung N, de Haseth K, Taylor B, Rochtchina E, Wang JJ, et al
. Blood pressure and retinal arteriolar narrowing in children. Hypertension 2007; 49:1156–1162.
76 Williams SS. Advances in genetic hypertension. Curr Opin Pediatr 2007; 19:192–198.
77 Lifton RP. Molecular genetics of human blood pressure variation. Science 1996; 272:676–680.
78 Baker EH, Dong YB, Sagnella GA, Rothwell M, Onipinla AK, Markandu ND, et al
. Association of hypertension with T594M mutation in beta subunit of epithelial sodium channels in black people resident in London. Lancet 1998; 351:1388–1392.
79 Dluhy RG, Lifton RP. Glucocorticoid-remediable aldosteronism. J Clin Endocrinol Metab 1999; 84:4341–4344.
80 Wilson FH, Disse-Nicodeme S, Choate KA, Ishikawa K, Nelson-Williams C, Desitter I, et al
. Human hypertension caused by mutations in WNK kinases. Science 2001; 293:1107–1112.
81 Geller DS, Farhi A, Pinkerton N, Fradley M, Morits M, Spitzer A, et al
. Activating mineralocorticoid receptor mutation in hypertension exacerbated by pregnancy. Science 2000; 289:119–123.
82 Zhao LQ, Han S, Tian HM. Progress in molecular-genetic studies on congenital adrenal hyperplasia due to 11β-hydroxylase deficiency. World J Pediatr 2008; 4:85–90.
83 Torrance B, McGuire KA, Lewanczuk R, McGavock J. Overweight, physical activity and high blood pressure in children: a review of the literature. Vasc Health Risk Manag 2007; 3:139–149.
84 Garrison RJ, Kannel WB, Stokes J 3rd, Castelli WP. Incidence and precursors of hypertension in young adults: the Framingham offspring study. Prev Med 1987; 16:235–251.
85 Berenson GS. Obesity: a critical issue in preventive cardiology – the Bogalusa Heart Study. Prev Cardiol 2005; 8:234–241.
86 Graf C, Rost SV, Koch B, Heinen S, Falkowski G, Dordel S, et al
. Data from the StEP TWO programme showing the effect on blood pressure and different parameters for obesity in overweight and obese primary school children. Cardiol Young 2005; 15:291–298.
87 Lurbe E. Childhood blood pressure: a window to adult hypertension. J Hypertens 2003; 21:2001–2003.
88 Ogden CL, Troiano RP, Briefel RR, Kuczmarski RJ, Flegal KM, Johnson CL. Prevalence of overweight among preschool children in the United States, 1971 through 1994. Pediatrics 1997; 99:E1.
89 Hughes JM, Li L, Chinn S, Rona RJ. Trends in growth in England and Scotland, 1972 to 1994. Arch Dis Child 1997; 76:182–189.
90 Genovesi S, Giussani M, Pieruzzi F, Vigorita F, Arcovio C, Cavuto S, et al
. Results of blood pressure screening in a population of school-aged children in the province of Milan: role of overweight. J Hypertens 2005; 23:493–497.
91 Genovesi S, Antolini L, Giussani M, Pieruzzi F, Galbiati S, Valsecchi MG, et al
. Usefulness of waist circumference for the identification of childhood hypertension. J Hypertens 2008; 26:1563–1570.
92 Barker DJ, Osmond C, Golding J, Kuh D, Wadsworth ME. Growth in utero, blood pressure in childhood and adult life, and mortality from cardiovascular disease. BMJ 1989; 298:564–567.
93 Law CM, de Swiet M, Osmonde C, Fayers PM, Barker DJ, Cruddas AM, Fall CH. Initiation of hypertension in utero and its amplification throughout life. BMJ 1993; 306:24–27.
94 Whincup PH, Bredow M, Payne F, Sadler S, Golding J. Size at birth and blood pressure at 3 years of age. The Avon Longitudinal Study of Pregnancy and Childhood (ALSPAC). Am J Epidemiol 1999; 149:730–739.
95 Eriksson JG, Forsén T, Tuomilehto J, Winter PD, Osmond C, Barker DJ. Catch-up growth in childhood and death from coronary heart disease: longitudinal study. BMJ 1999; 318:427–431.
96 Bansal N, Ayoola OO, Gemmell I, Vyas A, Koudsi A, Oldroyd J, et al
. Effects of early growth on blood pressure of British European and South Asian origin infants at one year of age: The Manchester Children's Growth and Vascular Health Study. J Hypertens 2008; 26:412–418.
97 Van Houtten VA, Steegers EA, Witteman JC, Moll HA, Hofman A, Jaddoe VW. Fetal and postnatal growth and blood pressure at the age of 2 years. The Generation Study. J Hypertens 2009; 27:1152–1157.
98 Geleijnse JM, Grobbee DE. High salt intake early in life: does it increase the risk of hypertension? J Hypertens 2002; 20:2121–2124.
99 Owen CG, Martin RM, Whincup PH, Smith GD, Cook DG. Effect of infant feeding on the risk of obesity across the life course: a quantitative review of published evidence. Pediatrics 2005; 115:1367–1377.
100 Salminen M, Vahlberg T, Kivela SL. Effects of family-oriented risk-based prevention on serum cholesterol and blood pressure values of children and adolescents. Scand J Prim Health Care 2005; 23:34–41.
101 Addison CC, Jenkins BW, White MS, Young L. Implementation of a cardiovascular disease prevention program among school-aged children: a pilot study. Int J Environ Res Public Health 2006; 3:274–277.
102 Hayman LL, Meininger JC, Daniels SR, McCrindle BW, Helden L, Ross J, et al
, American Heart Association Committee on Atherosclerosis, Hypertension, and Obesity in Youth, on Cardiovascular Nursing, on Epidemiology and Prevention and on Nutrition, Physical Activity, and Metabolism. Primary prevention of cardiovascular disease in nursing practice: focus on children and youth – a scientific statement from the American Heart Association Committee. Circulation 2007; 116:344–357.
103 Cutler JA, Roccella EJ. Salt reduction for preventing hypertension and cardiovascular disease: a population approach should include children. Hypertension 2006; 48:818–819.
104 Mu JJ, Liu ZQ, Liu WM, Liang YM, Yang DY, Zhu DJ, Wang ZX. Reduction of blood pressure with calcium and potassium supplementation in children with salt sensitivity: a 2-year double-blinded placebo-controlled trial. J Hum Hypertens 2005; 19:479–483.
105 UK Scientific Advisory Committee on Nutrition (SACN). Report on ‘Salt and Health’. London: Her Majesty's Stationery Office; 2003. http://www.sacn.gov.uk/pdfs/sacn_salt_final.pdf
106 Ong KK, Preece MA, Emmett PM, Ahmed ML, Dunger DB, ALSPAC Study Team. Size at birth and early childhood growth in relation to maternal smoking, parity and infant breast feeding: longitudinal birth cohort study and analysis. Pediatr Res 2002; 52:863–867.
107 Ramaswamy P, Lytrivi ID, Paul C, Golden M, Kupferman JC. Regression of left ventricular hypertrophy in children with antihypertensive therapy. Pediatr Nephrol 2007; 22:141–143.
108 Seeman T, Gilik J, Vondrák K, Simkova E, Flögelová H, Hladiková M, Janda J. Regression of left-ventricular hypertrophy in children and adolescents with hypertension during ramipril monotherapy. Am J Hypertens 2007; 20:990–996.
109 Matteucci MC, Picca S, Chinali M, Mastrostefano A, De Simone G, Mehls O, et al
, and the ESCAPE Study Group. Regression of left ventricular hypertrophy and normalization of myocardial contractility by ACE inhibition in children with CKD. Pediatr Nephrol 2007; 22:1459 [abstract].
110 Wühl E, Mehls O, Schaefer F, ESCAPE Trial Group. Antihypertensive and antiproteinuric efficacy of ramipril in children with chronic renal failure. Kidney Int 2004; 66:768–776.
111 Wühl E, Mehls O, Schaefer F, ESCAPE trial group. Long-term dissociation of antiproteinuric and antihypertensive efficacy of ACE inhibition in children with chronic renal failure. COD.OC 16. Pediatr Nephrol 2006; 21:1505 [abstract].
112 Wühl E, Mehls O, Schaefer F, ESCAPE Trial Group. Nephroprotection by intensified blood pressure control: final results of the ESCAPE trial. J Hypertens 2008; 26(Suppl 1):S37 [abstract].
113 Chinali M, de Simone G, Matteucci MC, Picca S, Mastrotefano A, Anarat A, et al
, ESCAPE Trial Group. Reduced systolic myocardial function in children with chronic renal insufficiency. J Am Soc Nephrol 2007; 18:593–598.
114 Raile K, Galler A, Hofer S, Herbst A, Dunstheimer D, Busch P, Holl RW. Diabetic nephropathy in 27,805 children, adolescents and adults with type 1 diabetes. Effect of diabetes duration, A1C, hypertension, dyslipidemia, diabetes onset, and sex. Diabetes Care 2007; 30:2523–2528.
115 Lurbe E, Redon J, Kesani A, Pascual JM, Tacons J, Alvarez V, Batlle D. Increase in nocturnal blood pressure and progression to microalbuminuria in type 1 diabetes. N Engl J Med 2002; 347:797–805.
116 Ettinger LM, Freeman K, DiMartino-Nardi JR, Flynn JT. Microalbuminuria and abnormal ambulatory blood pressure in adolescents with type 2 diabetes mellitus. J Pediatr 2005; 147:67–73.
117 Gimpel CH, Wühl E, Arbeiter K, Drozdz D, Trivelli A, Charbit M, et al
. Superior consistency of ambulatory blood pressure monitoring in children: Implications for clinical trials. J Hypertens 2009; 27:1568–1574.
118 Regulation (EC) No. 1901/2006 of the European Parliament and of the Council of 12 December 2006 on medicinal products for paediatric use and amending Regulation (EEC) No. 1768/92, Directive 2001/20/EC, Directive 2001/83/EC and Regulation (EC) No 726/2004. Official Journal of the European Union 27/12/2006.
119 Food and Drug Administration Modernization Act, 1997. Best Pharmaceuticals for Children Act; 2002.
120 Simonetti G, Rizzi M, Donadini R, Bianchetti MG. Effects of antihypertensive drugs on blood pressure and proteinuria in childhood. J Hypertens 2007; 25:2370–2376.
121 Griswold WR, McNeal R, Mendoza SA, Sellers BB, Higgins S. Propranolol as an antihypertensive agent in children. Arch Dis Child 1978; 53:594–596.
122 Bachmann H. Propranolol versus chlorthalidone: a prospective therapeutic trial in children with chronic hypertension. Helv Paediatr Acta 1984; 39:55–61.
123 Silverstein DM, Champoux E, Aviles DH, Vehaskari VM. Treatment of primary and secondary hypertension in children. Pediatr Nephrol 2006; 21:820–827.
124 Falkner B, Lowenthal DT, Affrime MB. The pharmacodynamic effectiveness of metoprolol in adolescent hypertension. Pediatr Pharmacol (New York) 1982; 2:49–55.
125 Batisky DL, Sorof JM, Sugg J, Llewellyn M, Klibaner M, Hainer JW, et al
, Toprol-XL Pediatric Hypertension Investigators. 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.
126 Flynn JT, Warnik SJ. Isradipine treatment of hypertension in children: a single-center experience. Pediatr Nephrol 2002; 17:748–753.
127 Flynn JT, Pasko DA. Calcium channel blockers: pharmacology and place in therapy of pediatric hypertension. Pediatr Nephrol 2000; 15:302–316.
128 Flynn JT, Newburger JW, Daniels SR, Sanders SP, Portman RJ, Hogg RJ. A randomized, placebo-controlled trial of amlodipine in children with hypertension. J Pediatr 2004; 145:353–359.
129 Flynn JT, Nahata MC, Mahan JD Jr, Portman RJ, PATH-2 Investigators. Population pharmacokinetics of amlodipine in hypertensive children and adolescents. J Clin Pharmacol 2006; 46:905–916.
130 Flynn JT. Pediatric use of antihypertensive medications: much more to learn. Curr Ther Res 2001; 62:314–328.
131 Wells T, Frame V, Soffer B, Shaw W, Zhang Z, Herrera P, et al
, Enalapril Pediatric Hypertension Study Group. A double-blind, placebo-controlled, dose–response study of the effectiveness and safety of enalapril for children with hypertension. J Clin Pharmacol 2002; 42:870–880.
132 Li JS, Berezny K, Kilaru R, Hazan L, Portman R, Hogg R, et al
. Is the extrapolated adult dose of fosinopril safe and effective in treating hypertensive children? Hypertension 2004; 44:289–293.
133 Soffer B, Zhang Z, Miller K, Vogt BA, Shahinfar S. A double-blind, placebo-controlled, dose–response study of the effectiveness and safety of lisinopril for children with hypertension. Am J Hypertens 2003; 16:795–800.
134 Wells T, Rippley R, Hogg R, Sakarcan A, Blowey D, Walson P, et al
. The pharmacokinetics of enalapril in children and infants with hypertension. J Clin Pharmacol 2001; 41:1064–1074.
135 Hogg RJ, Delucchi A, Sakihara G, Wells TG, Tenney F, Batisky DL, et al
. A multicenter study of the pharmacokinetics of lisinopril in pediatric patients with hypertension. Pediatr Nephrol 2007; 22:695–701.
136 Blumer JL, Daniels SR, Dreyer WJ, Batisky D, Walson PD, Roman D, Ouellet D. Pharmacokinetics of quinapril in children: assessment during substitution for chronic angiotensin-converting enzyme inhibitor treatment. J Clin Pharmacol 2003; 43:128–132.
137 Seeman T, Dusek J, Vondrak K, Flogelova, Geier P, Janda J. Ramipril in the treatment of hypertension and proteinuria in children with chronic kidney diseases. Am J Hypertens
138 Shahinfar S, Cano F, Soffer BA, Ahmed T, Santoro EP, Zhang Z, et al
. A double-blind, dose–response study of losartan in hypertensive children. Am J Hypertens 2005; 18:183–190.
139 Sakarcan A, Tenney F, Wilson JT, Stewart JJ, Adcock KG, Wells TG, et al
. The pharmacokinetics of irbesartan in hypertensive children and adolescents. J Clin Pharmacol 2001; 41:742–749.
140 Gartenmann AC, Fossali E, von Vigier RO, Simonetti GD, Schmidtko J, Edefonti A, Bianchetti MG. Better renoprotective effect of angiotensin II antagonist compared to dihydropyridine calcium channel blocker in childhood. Kidney Int 2003; 64:1450–1454.
141 Simonetti GD, von Vigier RO, Konrad M, Rizzi M, Fossali E, Bianchetti MG. Candesartan cilexetil in children with hypertension or proteinuria: preliminary data. Pediatr Nephrol 2006; 21:1480–1482.
142 Flynn JT, Meyers KE, Neto JP, de Paula Meneses R, Zurowska A, Bagga A, et al
, Pediatric Valsartan Study Group. Efficacy and safety of the angiotensin receptor blocker valsartan in children with hypertension aged 1 to 5 years. Hypertension 2008; 52:222–228.
143 Sinaiko AR. Treatment of hypertension in children. Pediatr Nephrol 1994; 8:603–609.
144 Sorof JM, Cargo P, Graepel J, Humphrey D, King E, Rolf C, Cunningham RJ. ß-Blocker/thiazide combination for treatment of hypertensive children: a randomized double-blind, placebo-controlled trial. Pediatr Nephrol 2002; 17:345–350.
145 Von Vigier RO, Franscini LM, Bianda ND, Pfister R, Casaulta-Aebischer C, Bianchetti MG. Antihypertensive efficacy of amlodipine in children with chronic kidney diseases. J Hum Hypertens 2001; 15:387–391.
146 Ellis D, Vats A, Moritz ML, Reitz S, Grosso MJ, Janosky JE. Long-term antiproteinuric and renoprotective efficacy and safety of losartan in children with proteinuria. J Pediatr 2003; 143:89–97.
147 MacKinnon M, Shurraw S, Akbari A, Knoll GA, Jaffey J, Clark HD. Combination therapy with an angiotensin receptor blocker and an ACE inhibitor in proteinuric renal disease: a systematic review of the efficacy and safety data. Am J Kidney Dis 2006; 48:8–20.
148 Lubrano R, Soscia F, Elli M, Ventriglia F, Raggi C, Travasso E, et al
. Renal and cardiovascular effects of angiotensin-converting enzyme inhibitor plus angiotensin II receptor antagonist therapy in children with proteinuria. Pediatrics 2006; 118:e833–e838.
149 The ONTARGET Investigators. Telmisartan, ramipril or both in patients at high risk for vascular events. N Engl J Med
150 Zimmet P, Alberti G, Kaufman F, Tajima N, Silink M, Arslanian S, et al
. International Diabetes Federation Task Force on Epidemiology and Prevention of Diabetes. The metabolic syndrome in children and adolescents. Lancet 2007; 369:2059–2061.
151 Redon J, Cifkova R, Laurent S, Nilsson P, Narkiewicz K, Erdine S, Mancia G, Scientific Council of the European Society of Hypertension
. The metabolic syndrome in hypertension: European Society of Hypertension
Position Statement. J Hypertens 2008; 26:1891–1900.
152 Momma K. ACE inhibitors in pediatric patients with heart failure. Paediatr Drugs 2006; 8:55–69.
153 Moffett BS, Chang AC. Future pharmacologic agents for treatment of heart failure in children. Pediatr Cardiol 2006; 27:533–551.
154 Ng DK, Chan C, Chow AS, Chow P, Kwok K. Childhood sleep-disordered breathing and its implications for cardiac and vascular diseases. J Paediatr Child Health 2005; 41:640–646.
155 Zintzaras E, Kaditis AG. Sleep-disordered breathing and blood pressure in children: a meta-analysis. Arch Pediatr Adolesc Med 2007; 161:172–178.
156 Capdevila OS, Kheirandish-Gozal L, Dayyat E, Gozal D. Pediatric obstructive sleep apnea: complications, management, and long-term outcomes. Proc Am Thorac Soc 2008; 5:274–282.
157 Adelman RD, Coppo R, Dillon MJ. The emergency management of severe hypertension. Pediatr Nephrol 2000; 14:422–427.
158 Patel HP, Mitsnefes M. Advances in the pathogenesis and management of hypertensive crisis. Curr Opin Pediatr 2005; 17:210–214.
159 Daniels SR, Greer FR, Committee on Nutrition. Lipid screening and cardiovascular health in childhood. Pediatrics 2008; 122:198–208.
160 Lichtenstein AH, Appel IJ, Brands M, Carnethon M, Daniels S, Franch HA, Franklin B, et al
. Diet and lifestyle recommendations revision 2006: a scientific statement from the American heart association nutrition committee. Circulation 2006; 114:82–96.
161 Invitti C, Gilardini L, Pontiggia B, Morabito F, Mazzilli G, Viberti G. Period prevalence of abnormal glucose tolerance and cardiovascular risk factors among obese children attending an obesity centre in Italy. Nutr Metab Cardiovasc Dis 2006; 16:256–262.
162 Spear BA, Barlow SE, Ervin C, Ludwig DS, Saelens BE, Schettina KE, Taveras EM. Recommendations for treatment of child and adolescent overweight and obesity. Pediatrics 2007; 120:S254–S288.
163 Srinivasan S, Ambler GR, Baur LA, Garnett SP, Tepsa M, Yap F, et al
. Randomized, controlled trial of metformin for obesity and insulin resistance in children and adolescents: improvement in body composition and fasting insulin. J Clin Endocrinol Metab 2006; 91:2074–2080.
164 The TODAY Study Group, Zeitler P, Epstein L, Grey M, Hirst K, Kaufman F, Tamborlane W, Wilfley D. Treatment options for type 2 diabetes in adolescents and youth: a study of the comparative efficacy of metformin alone or in combination with rosiglitazone or lifestyle intervention in adolescents with type 2 diabetes. Pediatr Diabetes
165 Vogt BA. Hypertension in children and adolescents: definition, pathophysiology, risk factors and long-term sequelae. Curr Ther Res 2001; 62:283–297.
166 Goonasekera CD, Dillon MJ. Measurement and interpretation of blood pressure. Arch Dis Child 2000; 82:261–265.
167 Arar MY, Hogg RJ, Arant BS, Seikaly MG. Etiology of sustained hypertension in children in the Southwestern United States. Pediatr Nephrol 1994; 8:186–189.
168 Lieberman E. Hypertension in childhood and adolescence. In: Kaplan N, editor. Clinical hypertension. 5th ed. Baltimore: Williams and Wilkins; 1990. pp. 407–433.
169 Yiu VW, Dluhy RP, Lifton RP, Guay-Woodford LM. Low-peripheral plasma renin activity as a critical marker in pediatric hypertension. Pediatr Nephrol 1997; 11:343–346.
170 Zubrow AB, Hulman S, Kushner H, Falkner B. Determinants of blood pressure in infants admitted to neonatal intensive care units: a prospective multicenter study. J Perinatol 1995; 15:470–479.
171 Flynn J. Neonatal hypertension: diagnosis and management. Pediatr Nephrol 2000; 14:332–341.
172 Kay JD, Sinaiko AR, Daniels SR. Pediatric hypertension. Am Heart J 2001; 142:422–432.
173 Dillon MJ. Secondary forms of hypertension in children. In: Portman RJ, Sorof JM, Ingelfinger JR, editors. Pediatric hypertension. Totowa: Humana Press; 2004. pp. 159–179.
174 Lurbe E, Redon J. Secondary hypertension in children and adolescents. In: Mansoor GA, editor. Secondary hypertension. Totowa: Humana Press; 2004. pp. 279–306.