7th Brazilian Guideline of Arterial Hypertension: Chapter 10 - Hypertension in Children and Adolescents

Arterial hypertension was identified as the major source of combined mortality and morbidity, representing 7% of global disability-adjusted life years. 1 The adoption of the BP definitions and normalization of the "National High Blood Pressure Education Program" (NHBPEP) 2004 2 has standardized the BP classification in the pediatric population. The percentage of children and adolescents diagnosed with AH is estimated to have doubled in the past two decades. The current prevalence of AH in the pediatric population is around 3% to 5%, 3-5 while that of PH reaches 10% to 15%, 3,4,6,7 and such values are mainly attributed to the large increase in childhood obesity.8The etiology of pediatric AH can be either secondary, most often associated with nephropathies, or primary, attributed to genetic causes with environmental influence, predominating in adolescents.
Pediatric AH is usually asymptomatic, but as many as 40% of hypertensive children have LVH at the initial diagnosis of AH. Although oligosymptomatic in childhood, LVH is a precursor of arrhythmias and HF in adults.In addition, pediatric AH is associated with the development of other changes in target organs, such as increased carotid IMT, arterial compliance reduction, and retinal arteriolar narrowing. Early diagnosis and treatment of childhood AH are associated with a lower risk for AH and for increased carotid atheromatosis in adult life. [bib_ref] Ideal cardiovascular health in childhood and cardiometabolic outcomes in adulthood: the Cardiovascular..., Laitinen [/bib_ref] Therefore, periodical BP measurements in children and adolescents are recommended, even contradicting the U.S. Preventive Services Task Force's suggestion, which considers the evidence of benefits of primary AH screening in asymptomatic children and adolescents insufficient to prevent CVD in childhood or adulthood.

## Definitions and diagnosis

## Definition and etiology
Children and adolescents are considered hypertensive when SBP and/or DBP are greater than or equal to the 95 th percentile for age, sex and height percentile, on at least three different occasions.Prehypertension in children is defined as SBP/DBP  the 90 th percentile < the 95 th percentile, and in adolescents as BP levels  120/80 mm Hg and < the 95 th percentile. Stage 1 AH is considered for readings between the 95 th percentile and the 99 th percentile plus 5 mm Hg, while stage 2 AH, for readings > stage 1. The height percentiles can be obtained by using Centers for Disease Control and Prevention's (CDC) growth charts. In addition, normal and high BP levels for children and adolescents are available in mobile apps, such as PA Kids and Ped(z).
In the pediatric population, WCH and MH can be diagnosed based on established normality criteria for ABPM.After a detailed clinical history and physical examination, children and adolescents considered hypertensive should undergo investigation. The younger the child, the greater the chance of secondary AH. Parenchymal, renovascular and obstructive nephropathies account for approximately 60-90% of the cases, and can affect all age groups (infants, children and adolescents), being more prevalent in younger children with higher BP elevations. Endocrine disorders, such as excessive mineralocorticoid, corticoid or catecholamine secretion, thyroid diseases and hypercalcemia associated with hyperparathyroidism, account for approximately 5% of secondary AH cases. Coarctation of the aorta is diagnosed in 2% of the cases, and 5% of secondary AH cases are attributed to other etiologies, such as adverse effects of vasoactive and immunosuppressive drugs, steroid abuse, central nervous system changes, and increased intracranial pressure.
Primary AH is more prevalent in overweight or obese children and adolescents with family history of AH. Currently, primary AH seems to be the most common form of AH in adolescence, being, however, a diagnosis of exclusion, and, in that population, secondary causes should be investigated whenever possible.

## Diagnosis

## Method for bp measurement
Measuring BP in children is recommended at every clinical assessment after the age of 3 years, abiding by the standards for BP measurement.Children under the age of 3 years should have their BP assessed on specific situations.For BP measurement, children should be calm and sitting for at least 5 minutes, with back supported and feet on the floor, having refrained from consuming stimulant foods and beverages. The BP should be taken at heart level on the right arm, because of the possibility of coarctation of the aorta. [fig_ref] Table 1 -: Specific recommendations for BP measurement in children and adolescents Auscultatory method [/fig_ref] shows the specific recommendations for auscultatory BP measurement in children and adolescents. Whenever BP is high on the upper limbs, SBP should be assessed on the lower limbs. Such assessment can be performed with the patient lying down, with the cuff placed on the calf, covering at least two-thirds of the knee-ankle distance. The SBP reading on the leg can be higher than that on the arm because of the distal pulse amplification phenomenon. A lower SBP reading on the leg as compared to that on the arm suggests coarctation of the aorta. [fig_ref] Table 2 -: Blood pressure levels for boys by age and height percentile2 [/fig_ref] show the BP percentiles by sex, age and height percentile. [fig_ref] Figure 2 -: Blood pressure levels for girls, from birth to the age of 1... [/fig_ref] show BP values for boys and girls, respectively, from birth to the age of 1 year based on data from the Report of the Second Task Force on Blood Pressure Control in Note: Adolescents with BP  120/80 mm Hg should be considered prehypertensive, even if the 90 th percentile value is greater than that. This can occur for SBP in patients older than 12 years, and for DBP in patients older than 16 years.
For children/adolescents, ABPM is indicated to investigate WCH and MH, and to follow prehypertensive or hypertensive patients up.The prevalence of WCH has been reported as between 22% and 32%. The use of ABPM should be restricted to patients with borderline or mild AH, because patients with high office BP readings are more likely to be hypertensive. [bib_ref] Evaluation of white coat hypertension in children: Importance of the definitions of..., Sorof [/bib_ref] 

## Anamnesis
A careful recollection of data on birth, growth and development, personal antecedents, and renal, urological, endocrine, cardiac and neurological diseases should be performed. The following patterns should be characterized: physical activity; dietary intake; smoking habit and alcohol consumption; use of steroids, amphetamines, sympathomimetic drugs, tricyclic antidepressants, contraceptives and illicit substances; and sleep history, because sleep disorders are associated with AH, overweight and obesity. In addition, family antecedents for AH, kidney diseases and other CVRF should be carefully assessed.

## Physical examination
On physical examination, BMI should be calculated. [bib_ref] Blood pressure: effect of body mass index and of waist circumference on..., Guimaraes [/bib_ref] Growth delay might suggest chronic disease, and persistent tachycardia might suggest hyperthyroidism or pheochromocytoma. Pulse decrease on the lower limbs leads to the suspicion of coarctation of the aorta. Adenoid hypertrophy is associated with sleep disorders. Acantosis nigricans suggests insulin resistance and DM. Abdominal fremitus and murmurs can indicate renovascular disease. 18

## Complementary tests
Laboratory and imaging tests are aimed at defining the etiology of AH (primary or secondary) and detecting TOD and CVRF associated with AH [fig_ref] Table 4 -: Initial investigation of children and adolescents with AHComplete blood countRenal function and... [/fig_ref].Target-organ assessment should be performed in all children and adolescents with stage 1 and 2 AH. Sleep study by use of polysomnography or home respiratory polygraphy is indicated for children and adolescents with sleep disorders detected on anamnesis.To investigate secondary AH, see Chapter 12. [fig_ref] Table 5 -: Complementary tests to confirm the etiology of secondary AH in children and... [/fig_ref] shows some tests for children and adolescents suspected of having secondary AH.

## Therapeutic aspects
In children and adolescents with confirmed AH, therapeutic management is guided by the AH etiology definition, CV risk assessment, and TOD characterization.

## Nonpharmacological management
Nonpharmacological management should be introduced to all pediatric patients with BP levels above the 90 th percentile. 2 (GR: IIa; LE: C). It includes body weight loss, a physical exercise program, and dietary intervention.Body weight reduction yields good results in the treatment of obese hypertensive children, [bib_ref] Blood pressure and physical fitness in a population of children-the Odense Schoolchild..., Hansen [/bib_ref] similarly to physical exercise, which has better effect on SBP levels. [bib_ref] Blood pressure and physical fitness in a population of children-the Odense Schoolchild..., Hansen [/bib_ref] Regular aerobic activity is recommended as follows: moderate-intensity physical exercise, 30-60 minutes/day, if possible, every day. Children with AH can practice resistance or localized training, except for weight lifting. Competitive sports are not recommended for patients with uncontrolled stage 2 AH.Dietary intervention can comprise sodium restriction, [bib_ref] Changing sodium intake in children: the Minneapolis Children's Blood Pressure Study, Gillum [/bib_ref] and potassium and calcium supplementation; the efficacy in that population, however, is yet to be proven. [bib_ref] Blood pressure response to potassium supplement in normotensive adults and children, Miller [/bib_ref] 

## Pharmacological management
Pharmacological therapy should be initiated for children with symptomatic AH, secondary AH, presence of TOD, types 1 and 2 DM, CKD and persistent AH nonresponsive to nonpharmacological therapy. 2 (GR: IIa; LE: B). The treatment is aimed at BP reduction below the 95 th percentile in non-complicated AH, and BP reduction below the 90 th percentile in both complicated AH, characterized by TOD and comorbidities (DM, CKD), and secondary AH. 2 (GR: IIa; LE: C). The treatment should begin with a first-line antihypertensive agent, whose dose should be optimized, and, if target BP level is not attained, other pharmacological groups should be added in sequence. A recent systematic reviewhas identified neither a randomized study assessing the efficacy of antihypertensive drugs on TOD, nor any consistent dose-response relationship with any drug class assessed.
The adverse events associated with the use of antihypertensive agents for children and adolescents have been usually of mild intensity, such as headache, dizziness, and upper respiratory tract infections. All classes of antihypertensive drugs seem safe, at least in the short run.The only randomized, double-blind, controlled study, by Schaefer et al., comparing the efficacy and safety of drugs of parallel groups and assessing hypertensive children on enalapril or valsartan, has shown comparable results regarding the efficacy and safety of both drugs. [bib_ref] Efficacy and safety of valsartan compared to enalapril in hypertensive children: a..., Schaefer [/bib_ref] In secondary AH, the antihypertensive drug choice should be in consonance with the pathophysiological - When using the oscillometric device, it requires validation. - Detection of AH by use of the oscillometric device requires confirmation with auscultation. - Use appropriate cuff size; air bag width: 40% of arm circumference in the middle point between the acromion and olecranon, and air bag length: 80-100% of arm circumference.
- Conditions under which children < 3 years old should have BP measured: neonatal intensive care; congenital heart diseases, kidney diseases, treatment with drugs known to raise BP, and evidence of increased intracranial pressure. [fig_ref] Table 1 -: Specific recommendations for BP measurement in children and adolescents Auscultatory method [/fig_ref] principle involved, considering the comorbidities present. For example, non-cardioselective BBs should be avoided in individuals with upper airway reactivity, because of the risk for bronchospasm. [bib_ref] Beta-adrenergic blocking drugs in the treatment of hypertension, Prichard [/bib_ref] In pregnancy, ACEIs and ARBs are contraindicated, because of their potential for fetal malformation. [bib_ref] Pregnancy outcome following exposure to angiotensin converting enzyme inhibitors or angiotensin receptor..., Bullo [/bib_ref] The use of those drugs for childbearingage girls should be always accompanied by contraceptive guidance. [bib_ref] Pregnancy outcome following exposure to angiotensin converting enzyme inhibitors or angiotensin receptor..., Bullo [/bib_ref] [bib_ref] Rational use of antihypertensive medications in children, Ferguson [/bib_ref] For renovascular AH, of ACEIs or ARBs are indicated in association with vasodilators and DIUs. In cases of coarctation of the aorta, in the preoperative period, the initial drug is usually a BB. If the AH persists postoperatively, the BB can be maintained, replaced or associated with an ACEI or ARB. For AH associated with DM and CKD, an ACEI or ARB is initially used. The use of ACEI and ARB relaxes the efferent arteriole, reducing the glomerular capillary hydrostatic pressure, and posing a risk for AKI in situations of hypovolemia. Similarly, those drugs are contraindicated for patients with bilateral renal artery stenosis. [bib_ref] Pregnancy outcome following exposure to angiotensin converting enzyme inhibitors or angiotensin receptor..., Bullo [/bib_ref] [bib_ref] Rational use of antihypertensive medications in children, Ferguson [/bib_ref] [bib_ref] Effect of antihypertensive drugs on blood pressure and proteinuria in childhood, Simonetti [/bib_ref] For obese adults, ACEIs, ARBs, CCBs, BBs and DIUs are effective in reducing BP. [bib_ref] Best strategies for hypertension management in type 2 diabetes and obesity, Allcock [/bib_ref] In adults, ACEIs and ARBs seem to reduce the risk of developing DM and to increase insulin sensitivity. [bib_ref] Does it matter how blood pressure is lowered in patients with metabolic..., Sharma [/bib_ref] [bib_ref] The effects of telmisartan treatment on the abdominal fat depot in patients..., Murakami [/bib_ref] [fig_ref] Table 6 -: Most frequently used oral drugs for management of pediatric chronic arterial hypertension2 [/fig_ref] shows the updated pediatric doses of the most frequently prescribed hypotensive agents to treat CAH. [bib_ref] Rational use of antihypertensive medications in children, Ferguson [/bib_ref] Hypertensive crisis Hypertensive emergency is characterized by acute BP elevation associated with TOD, which can comprise neurological, renal, ocular and hepatic impairment or myocardial failure, and manifests as encephalopathy, [fig_ref] Table 1 -: Specific recommendations for BP measurement in children and adolescents Auscultatory method [/fig_ref] convulsions, visual changes, abnormal electrocardiographic or echocardiographic findings, and renal or hepatic failure. [bib_ref] First-attack pediatric hypertensive crisis presenting to the pediatric emergency department, Yang [/bib_ref] Hypertensive urgency is described as BP elevation above the 99 th percentile plus 5 mm Hg (stage 2), associated with less severe symptoms, in a patient at risk for progressive TOD, with no evidence of recent impairment. Oral drugs are suggested, under monitoring, with BP reduction in 24-48 hours.In HE, the BP reduction should occur slowly and progressively: 30% reduction in the programed amount in 6-12 hours, 30% in 24 hours, and final adjustment in 2-4 days. [bib_ref] The emergency management of severe hypertension, Adelman [/bib_ref] Very rapid BP reduction is contraindicated, because it leads to hypotension, failure of self-regulating mechanisms, and likelihood of cerebral and visceral ischemia. [bib_ref] Management of hypertensive emergencies, Deal [/bib_ref] The HE should be treated exclusively with parenteral drugs. In Brazil, the most frequently used drug for that purpose is SNP, which is metabolized into cyanide, which can cause metabolic acidosis, mental confusion, and clinical deterioration. Thus, SNP administration for more than 24 hours requires monitoring of serum cyanide levels, especially in patients with renal failure. [bib_ref] The emergency management of severe hypertension, Adelman [/bib_ref] [bib_ref] Management of hypertensive emergencies, Deal [/bib_ref] After patient's stabilization with SNP, an oral antihypertensive agent should be initiated, so that the SNP dose can be reduced. The use of SNP should be avoided in pregnant adolescents and patients with central nervous system hypoperfusion.
Special clinical conditions can be managed with more specific hypotensive agents for the underlying disease. Patients with catecholamine-producing tumors can be initially alpha-blocked with phenoxybenzamine, or prazosin if the former is not available, followed by the careful addition of a BB. After BP control and in the absence of kidney or heart dysfunction, a sodium-rich diet [fig_ref] Table 7 -: Major pediatric drugs and doses used to control hypertensive emergency 2,95,96 IV [/fig_ref] shows the most frequently used drugs in pediatric HE. [bib_ref] Pediatric hypertensive emergencies, Baracco [/bib_ref] 
[fig] Figure 2 -: Blood pressure levels for girls, from birth to the age of 1 year 97 [/fig]
[table] Table 1 -: Specific recommendations for BP measurement in children and adolescents Auscultatory method.  Use 1 st Korotkoff sound for SBP, and 5 th Korotkoff sound for DBP. [/table]
[table] Table 2 -: Blood pressure levels for boys by age and height percentile2 [/table]
[table] Table 3 -: Blood pressure levels for girls by age and height percentile2 [/table]
[table] Table 4 -: Initial investigation of children and adolescents with AHComplete blood countRenal function and electrolytes (including calcium, phosphorus and magnesium)Renal US with Doppler of renal arteries [/table]
[table] Table 5 -: Complementary tests to confirm the etiology of secondary AH in children and adolescentsMeasurement of urine electrolytes, proteinuria and urine creatinine Plasma levels of renin (or plasma renin activity) and aldosterone, salivary cortisol test, PTH, TSH, free T4 and T3Hemoglobin electrophoresisSpecific auto-antibodies: FAN, anti DNA, ANCA p, ANCA c Urine catecholamines and metanephrines (or plasma metanephrine) and MIBG scintigraphy [/table]
[table] Table 6 -: Most frequently used oral drugs for management of pediatric chronic arterial hypertension2 [/table]
[table] Table 7 -: Major pediatric drugs and doses used to control hypertensive emergency 2,95,96 IV: intravenous; IM: intramuscular; min: minute; h: hour. [/table]