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 .
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.
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 .
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.
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’.
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 .
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.
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.
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.
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