Arterial hypertension in children: clinical guidelines

List of Abbreviations

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Terms and Definitions

Arterial hypertension in children and adolescents is defined as a condition in which the average SBP and/or DBP level, calculated based on three separate measurements, is ≥ the 95th percentile value of the population BP distribution curve for the corresponding age, sex, and height, while in adolescents older than 16 years, BP is ≥ 140/90 mm Hg [1, 2].

Arterial hypertension in adults is defined as a syndrome of elevated office blood pressure (BP) in hypertensive disease and symptomatic hypertension above threshold values determined as a result of epidemiological and randomized controlled trials that have demonstrated an association with increased cardiovascular risk and the expediency and benefit of treatment aimed at reducing BP below these BP levels [3, 4].

White-coat arterial hypertension – elevated BP during single BP measurements at physician visits, but normal BP values during home measurements and according to 24-hour ambulatory blood pressure monitoring (ABPM) results [1-3].

Secondary or symptomatic hypertension – elevated BP caused by known underlying causes, namely the presence of pathological processes in various organs and systems [2, 3].

High normal BP – SBP and/or DBP whose level is ≥ the 90th and < the 95th percentile of the population BP distribution curve for the corresponding age, sex, and height, or ≥ 120/80 mm Hg (even if this value is < the 90th percentile), but < the 95th percentile. For adolescents older than 16 years, BP values in the range of 130-139/85-90 mm Hg may be used [2, 3].

Hypertensive disease (essential hypertension) – a chronically progressive disease whose main manifestation is the arterial hypertension syndrome not associated with pathological processes in which BP elevation is caused by known factors (symptomatic arterial hypertension). This term was proposed by G.F. Lang in 1948 and corresponds to the term "essential hypertension" used in other countries [3].

Evidence-based medicine – the proper, sequential, and conscious use of current best evidence (results of clinical trials) in combination with individual clinical experience and taking into account patient values and preferences in the process of making decisions about the health and treatment of the patient [5].

Isolated systolic hypertension – elevation of SBP ≥ 140 mm Hg with DBP < 90 mm Hg [3].

Normal BP – SBP and DBP whose level is ≥ the 10th and < the 90th percentile of the population BP distribution curve for the corresponding age, sex, and height [1, 2].

Masked arterial hypertension – normal BP values during single/office measurements, but elevated mean SBP and DBP values according to 24-hour ABPM data [2, 3].

Primary or essential hypertension – an independent disease in which the main clinical symptom is elevated SBP and/or DBP with undetermined causes.

Pulse pressure – the difference between SBP and DBP.

Working group for the development/updating of clinical guidelines – a team of specialists working together and in coordination to develop/update clinical guidelines and bearing joint responsibility for the results of this work.

Resistant hypertension – diagnosed in cases where the prescription of three antihypertensive drugs (including a diuretic) in optimal or maximum tolerated doses fails to achieve target BP in adherent patients. Furthermore, the lack of BP control is confirmed by out-of-office BP measurement (ABPM or home BP monitoring), and secondary causes of hypertension are excluded [3, 4].

Syndrome – a stable set of multiple symptoms with a unified pathogenesis.

Level of certainty of evidence – the degree of confidence that the obtained effect from a medical intervention is true [6].

Level of recommendation consensus (grade of recommendation) – the degree of confidence in the reliability of the intervention's effect and that following the recommendations will bring more benefit than harm in a specific situation [6].

Chronic kidney disease – a supra-nosological concept uniting all patients with signs of renal damage and/or decreased function assessed by the glomerular filtration rate, persisting for 3 months or more [2-4].

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Arterial hypertension in children and adolescents is defined as a condition in which the average SBP and/or DBP level, calculated based on three separate measurements, is ≥ the 95th percentile value of the population BP distribution curve for the corresponding age, sex, and height, while in adolescents older than 16 years, BP is ≥ 140/90 mm Hg. Arterial hypertension can be primary (essential) or secondary (symptomatic) [1, 2, 7, 8].

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

The causes of hypertension in children depend on the age of disease onset. Symptomatic hypertension predominates in early childhood and preschool children, whereas essential hypertension is more common in school-age children, particularly those older than 13 years [1, 2, 7-9]. The most frequent known causes of hypertension in order of their relative frequency across various age periods are presented in Table 1.

When hypertension is detected, a differential diagnostic workup is mandatory to determine the cause of hypertension. The most frequent causes of secondary (symptomatic) hypertension are congenital and acquired renal diseases, renal vascular pathology, adrenal cortex and medulla disorders, aortic coarctation, and systemic vasculitides (polyarteritis nodosa, Takayasu arteritis) [1, 2, 7-9].

Heredity is believed to play a certain role in the development of hypertension in childhood. The importance of heredity in the pathogenesis of arterial hypertension is indicated by the following facts:

• high correlation of BP in monozygotic twins compared to dizygotic twins; these data established that differences in human systemic BP levels are determined by genetic factors by 30-60%.

• higher BP values in children with a family history of hypertension compared to children whose parents are healthy.

According to family studies, genetic factors determine 15-40% of office systolic BP and 15-30% of diastolic BP [9]. Genetic factors make an even greater contribution to ABPM parameters, particularly nighttime BP, determining 69% of systolic BP and 51% of diastolic BP [10]. No gene or genes responsible for the onset of hypertension have yet been discovered. It is believed that BP level is inherited polygenically.

It has been established that the polymorphism of the angiotensin-converting enzyme (ACE) gene determines the activity of this enzyme. DD carrier status of the ACE gene polymorphism is regarded as an independent risk factor for the development of essential hypertension and is associated with increased ACE activity, which stimulates the adrenal medulla and cortex, causing an increase in vascular smooth muscle tone and total peripheral vascular resistance, as well as an elevation in very-low-density lipoprotein cholesterol, reflecting the pleiotropic effect of this gene. The expression of the angiotensinogen T174M gene determines angiotensinogen activity. Carrier status for the mutant allele of the T174M angiotensinogen gene is associated with increased ACE activity. The VNTR polymorphism of the endothelial nitric oxide synthase (eNOS) gene determines the vasogenic effect of NO. Carrier status for the 4a mutant allele of the eNOS gene determines a predisposition to vasoconstrictor reactions and the development of essential hypertension [3, 9].

Rare monogenic hereditary syndromes characterized by severe resistant hypertension exist [2, 4, 7]. Monogenic forms of hypertension include:

• Syndrome of apparent mineralocorticoid excess.

• Familial hyperaldosteronism type 1 (glucocorticoid-remediable aldosteronism).

• Pseudohypoaldosteronism type 2 (Gordon syndrome).

• Pseudoaldosteronism (Liddle syndrome).

• Arterial hypertension with brachydactyly syndrome.

Medication-induced hypertension occurs as a side effect of certain medications (amphetamines, pressor agents, steroids and nonsteroidal anti-inflammatory drugs, tricyclic antidepressants, oral contraceptives, calcineurin inhibitors), drugs of abuse, and other stimulants, including herbal products (dietary supplements) [2,7,8].

Table 1. Most common causes of arterial hypertension in various age periods

1.3 Epidemiology of the Disease or Condition

Cardiovascular diseases occupy a leading position in the structure of non-communicable pathology in adults and are the main cause of early disability and premature death in most economically developed countries [3,4]. According to recent epidemiological studies, there is a significant increase in both high-normal BP and hypertension among children and adolescents. This applies most to adolescents, with hypertension detected in 4% to 22% of those examined, depending on the age of the subjects and the chosen criteria [1,2,7-9].

The sharp increase in the prevalence of hypertension worldwide is driven by the growing number of overweight and obese children and adolescents. Body mass index has been established to be the most important factor determining blood pressure levels in children and adolescents [7,8,11]. Thus, while the prevalence of hypertension is 1.4% among children with normal weight, according to various sources, it rises to 7.1-27% in overweight children, and to 25-47% in obese children [12-14]. The risk of hypertension is 4 times higher with a BMI greater than the 99th percentile and 2 times higher with a BMI between the 95th and 99th percentiles, while the presence of obesity in childhood significantly increases the likelihood of developing hypertension and metabolic disorders in adulthood [15-17]. The prevalence of hypertension is higher in children with other chronic diseases and special conditions, such as chronic kidney disease, sleep-disordered breathing, and prematurity [18-22]. In addition, significant risk factors for the development of essential hypertension in children include hereditary predisposition, excess dietary salt, low physical activity, and a number of others [7,9,11,23].

1.4 Features of Coding the Disease or Condition

I10 – Essential (primary) hypertension

I11 – Hypertensive heart disease

I12 – Hypertensive renal disease

I13 – Hypertensive heart and renal disease

I15 – Secondary hypertension

P29.2 – Neonatal hypertension

1.5 Classification of the disease or condition

Blood pressure levels are categorized as normal, high-normal, and arterial hypertension.

Normal BP – average SBP and DBP levels across three visits that are less than the 90th percentile for age, sex, and height, or less than 120/80 mm Hg for children under 16 years and less than 130/85 mm Hg for adolescents older than 16 years.

High-normal (synonym: elevated) BP – average SBP and/or DBP levels across three visits equal to or exceeding the 90th percentile, but less than the 95th percentile for age, sex, and height. Experts from the American Academy of Pediatrics suggest considering blood pressure values equal to or exceeding 120/80 mm Hg as elevated (even if this value is less than the 90th percentile), but less than the 95th percentile [1,2,7,8].

In adolescents older than 16 years, uniform criteria can be used to diagnose high-normal BP: ≥ 130-139/85-89 mm Hg [7].

Arterial hypertension – average SBP and/or DBP levels across three visits equal to or exceeding the 95th percentile for age, sex, and height in children aged 1 to 16 years. In adolescents older than 16 years, uniform criteria can be used to diagnose hypertension: ≥ 140/90 mm Hg (Table 2) [7]. The use of a uniform criterion is proposed to establish better continuity in the diagnosis of hypertension in children and adults. The uniform criteria for grading hypertension in adolescents older than 16 years correspond to the uniform criteria used for grading hypertension in adults. Using uniform criteria is more convenient for clinical practice as it reduces the time spent working with percentile tables.

Arterial hypertension is subdivided into 2 grades. The BP level for grade 1 hypertension ranges from the 95th to the 99th percentile + 5 mm Hg for children under 16 years and 140-159/90-99 mm Hg for adolescents ≥ 16 years. The BP level for grade 2 hypertension is greater than the 99th percentile + 5 mm Hg for children under 16 years and ≥ 160/100 mm Hg for adolescents ≥ 16 years.

Isolated systolic hypertension (ISH) is also distinguished when only systolic blood pressure is elevated [2-4].

Criteria for arterial hypertension in neonates and infants (0-1 year). To determine BP in neonates, it is recommended to use data [24] that include values for the 50th, 95th, and 99th percentiles according to gestational age for infants from 26 to 44 weeks of postmenstrual age (see Appendix A3, Tables 1 and 2). Neonates with BP values at the 99th percentile require a more thorough diagnostic workup and sometimes pharmacological therapy. For patients with borderline BP values, clinical monitoring may be sufficient.

Table 2. Classification of arterial hypertension in children and adolescents

1.6 Clinical presentation of the disease or condition

Primary arterial hypertension is most commonly detected in children older than 6 years against the background of a positive family history of hypertension in 1st- and 2nd-degree relatives, frequently associated with overweight or obesity. The magnitude of BP elevation is typically lower compared to secondary hypertension, and the hypertension is more often systolic in nature. A definitive diagnosis can be made only after excluding secondary causes of hypertension. In most cases, primary hypertension is asymptomatic. Symptoms (headache, dizziness, palpitations, emotional lability, etc.) are nonspecific and usually caused by autonomic dysfunction [9].

Renal and renovascular hypertension. This ranks first among symptomatic forms of hypertension. The main causes of renal hypertension include acquired diseases (glomerulonephritis, pyelonephritis, hemolytic-uremic syndrome, renal trauma), renal amyloidosis, renal tumors, and hereditary renal pathology (autosomal dominant polycystic kidney disease, Alport syndrome, renal hypoplasia). Causes of renovascular hypertension include fibromuscular dysplasia of the renal artery, renal artery aneurysm, renal artery hypoplasia, arteriovenous fistula, panarteritis, extrinsic compression of the renal artery (due to a tumor process), thrombosis or embolism, and renal artery and/or vein stenosis. Clinical markers of renovascular hypertension include: severe grade 2 hypertension, more often diastolic in nature; a systolic bruit may be auscultated over the projection of the renal arteries (in the abdominal region); asymmetric BP in the limbs; and potential widespread vasospasm and neuroretinopathy [7-9].

Congenital renal artery stenosis is the most frequent cause of renovascular hypertension in children. It is characterized by a high, persistent elevation of BP, predominantly diastolic in character, which is refractory to antihypertensive therapy. A systolic bruit is frequently heard in the umbilical region as well as the epigastric region corresponding to the origin of the renal artery from the abdominal aorta. Target-organ damage develops early: left ventricular hypertrophy, marked funduscopic changes [7-9].

Fibromuscular dysplasia of the renal arteries is more common in females. The stenosis is most frequently localized in the middle segment of the renal artery, although distal stenosis is also possible. The artery has a "string-of-beads" appearance, and the collateral network is not prominent [7-9].

Nonspecific aortoarteritis («pulseless disease» or Takayasu disease) is a relatively rare pathology in children. The clinical manifestations of the disease are characterized by marked polymorphism. The initial stage of the disease is dominated by general inflammatory symptoms manifested by fever, myalgia, arthralgia, and erythema nodosum. These changes correspond to the initial stage of vascular inflammation. Subsequent clinical manifestations are associated with the development of arterial stenosis, followed by ischemia of the corresponding organ. Asymmetry or absence of pulse and blood pressure in the radial arteries is characteristic, and a systolic murmur is detected over the affected arteries. Aortic valve involvement (regurgitation) and mitral valve involvement (regurgitation), development of myocarditis, possible pulmonary hypertension, and symptoms of heart failure are frequently detected. Hypertension is malignant in nature and is associated with stenotic and thrombotic occlusion of the renal arteries, aortic regurgitation with damage to the baroreceptors of the carotid and aortic sinuses, reduced aortic elasticity, and stenosis of the carotid arteries, leading to cerebral ischemia and irritation of the chemoreceptors and vasomotor centers of the medulla oblongata [7,9].

Polyarteritis nodosa. The disease is characterized by malignant hypertension, specific skin changes combined with abdominal and coronary pain, polyneuritis, hyperthermia, and pronounced inflammatory blood changes. The underlying mechanism is vasculitis of small and medium-sized arteries, leading to renal artery involvement [7-9].

Coarctation of the aorta occurs in 8% of patients with congenital heart defects and is the most common cause of hypertension in young children. The clinical presentation depends on the location and degree of aortic narrowing and the development of collaterals. The main symptom is the absence or weakening of the pulse in the lower extremities, while the pulse in the upper extremities is enhanced. Blood pressure in the arms is equal to or significantly higher than blood pressure in the legs. In severe cases, blood pressure in the legs is lower by 20–30 mm Hg or more compared to blood pressure in the arms. Headaches frequently occur. A rough systolic murmur is auscultated over the cardiac region and above the clavicles, radiating to the back. A pink skin color of the face and chest is combined with pale, cold skin on the lower extremities. Pulsation in the jugular fossa and the carotid artery region is often present. An extensive network of collaterals forms on the skin of the chest. The main treatment method is surgical. It should be emphasized that even after successful surgical resection of aortic coarctation, a high risk of developing hypertension persists, ranging from 17 to 77% [25,26].

Endocrine forms of hypertension. According to epidemiological data, secondary forms of hypertension due to endocrine causes are a relatively rare condition (0.05%–6%) in the structure of hypertension [27,28]. Features of endocrine forms of hypertension include a paroxysmal course of hypertension, resistance or insufficient efficacy of standard antihypertensive therapy, and onset of the disease before 6 years of age.

Adrenal diseases accompanied by hypertension:

1. Primary Hyperaldosteronism

2. Cushing's syndrome

3. Tumors with hyperproduction of corticosteroids

4. Congenital disorders of corticosteroid biosynthesis

5. Diseases of the adrenal medulla – pheochromocytoma

Primary aldosteronism – Conn syndrome. The main manifestation of the disease is associated with the hyperproduction of aldosterone by the zona glomerulosa of the adrenal cortex. The leading symptoms are a combination of hypertension and hypokalemia. Hypertension can be either labile or stable; the malignant form is rare. Symptoms of hypokalemia are characterized by muscle weakness, transientpareses, cramps, and tetany. Excessive aldosterone secretion leads to impaired electrolyte transport in the kidneys with the development of hypokalemic tubulopathy. Polyuria, nocturia, and hyposthenuria are observed [7,8].

Pheochromocytoma is a benign tumor of the adrenal medulla consisting of chromaffin cells that produce large amounts of catecholamines. The incidence of pheochromocytoma ranges from 0.2% to 2% among all cases of hypertension. In 90% of cases, pheochromocytoma is localized in the adrenal medulla. In 10%, extra-adrenal localization of pheochromocytoma is noted—paraganglioma in the sympathetic paraganglia along the thoracic and abdominal aorta, in the renal hilum, and in the urinary bladder.

According to its clinical course, pheochromocytoma is divided into three forms:

1. Asymptomatic latent, with very rare increases in blood pressure.

2. With a paroxysmal course against the background of normal blood pressure in the intercritical period.

3. With mild hypertensive crises against the background of persistently elevated blood pressure.

During crises, blood pressure rises instantly within a few seconds, fluctuating from 180 to 220 mm Hg, maximally up to 250–300 mm Hg for systolic blood pressure and up to 110–130 mm Hg for diastolic blood pressure. Outside of a crisis, blood pressure may be within normal limits, less frequently moderately elevated. Triggering factors for catecholamine release are physical and emotional overexertion, trauma, and surgery. Patients experience a sense of fear, are pale, and develop a sharp pulsating headache accompanied by dizziness, palpitations, sweating, hand tremor, nausea, vomiting, and abdominal pain. ECG records repolarization abnormalities and cardiac arrhythmias. Stroke and myocardial infarction may develop [7,8].

Cushing syndrome. Moon face, plethora, fat pad, hirsutism, central obesity, skin atrophy, purple striae, bruising, and carbohydrate metabolism disorders are characteristic [7,8].

Hypertension associated with thyroid disease. Hyperthyroidism is accompanied by symptoms of thyrotoxicosis: weight loss with maintained appetite, tachycardia, arrhythmia, and anxiety. Hypothyroidism is characterized by increased sweating, fatigue, drowsiness, pallor, memory impairment, and a tendency toward constipation [7,8].

Hypertension associated with obstructive sleep apnea syndrome. It is more common in adolescents with obesity. Characteristic features include snoring, morning headaches, daytime sleepiness, memory and attention impairment, and poor nocturnal sleep [21].

Monogenic forms of hypertension are extremely rare and are characterized by pronounced resistant hypertension refractory to standard antihypertensive therapy [7-9]:

• Syndrome of apparent mineralocorticoid excess is an inherited autosomal recessive disorder caused by a mutation in the HSD11B2 (16q22) gene encoding 11β-hydroxysteroid dehydrogenase type 2. Clinical manifestations, such as growth retardation, polyuria, and polydipsia, appear at an early age.

• Familial hyperaldosteronism type 1 (glucocorticoid-remediable aldosteronism). Inheritance is autosomal dominant, occurring due to mutations in the CYP11B1 or CYP11B2 genes located on the long arm of chromosome 8 (8q24). It is characterized by increased aldosterone synthesis. Clinical manifestations include growth retardation, polyuria, and polydipsia. Normalization of aldosterone levels occurs with glucocorticoid administration.

• Familial hyperaldosteronism type 2. An inherited autosomal dominant disorder caused by excessive autonomous aldosterone synthesis associated with a mutation in the CLCN2 gene encoding chloride channel type 2, located on the long arm of chromosome 3 (3q27). It is characterized by a lack of response to glucocorticoids.

• Familial hyperaldosteronism type 3. An inherited autosomal dominant disorder caused by a mutation in the KCNJ5 (11q23) gene encoding a G-protein-coupled potassium channel. Clinical manifestations include early development of severe arterial hypertension, growth retardation, and polyuria.

• Familial hyperaldosteronism type 4. An inherited autosomal dominant disorder caused by a mutation in the CACNA1H (16p13) gene encoding calcium channels. Clinical manifestations include arterial hypertension in the first decade of life, variable malformations, intellectual disability, growth retardation, and polyuria.

• Familial hyperaldosteronism type 5. An inherited autosomal dominant disorder caused by a mutation in the CACNA1D (3p14.3) gene encoding calcium channels. Clinical manifestations include arterial hypertension in the first decade of life, seizures, neurological disorders, growth retardation, and polyuria.

• Gordon syndrome (pseudohypoaldosteronism type 2). Inheritance is autosomal dominant, occurring due to mutations in the WNK4 (17q21.2), WNK1 (12p13.3), KLHL3 (5q31), and CUL3 (20q36.2) genes, which leads to impaired function of the epithelial thiazide-sensitive sodium-chloride cotransporter, increased sodium reabsorption, and the formation of volume-dependent hypertension. Main clinical manifestations include growth retardation, dyshidrosis, muscle weakness, and nausea.

• Liddle syndrome (pseudohypoaldosteronism). Inheritance is autosomal dominant, caused by mutations in genes located on the short arm of chromosome 16: SCNN1A (12p13.31), SCNN1B (16p12.2-p12.1), and SCNN1G (16p12.2), which encode the synthesis of the α, β, and γ subunits of the amiloride-sensitive epithelial sodium channel in the distal renal tubules. Clinical manifestations: growth retardation, polyuria, early onset.

• Hypertension with brachydactyly syndrome is an inherited autosomal dominant disorder associated with a mutation in the PDE3A gene (12p12), which encodes phosphodiesterase 3A. The disease is characterized by accelerated proliferation of vascular smooth muscle cells leading to peripheral vasoconstriction, and dysregulation of parathyroid hormone resulting in pseudohypoparathyroidism. Characteristic features include short stature, brachydactyly, and cerebral and spinal vascular anomalies.

2. Diagnostics, medical indications and contraindications for diagnostic methods

Methods for measuring blood pressure in peripheral arteries

Auscultatory method for measuring blood pressure in peripheral arteries

• Measurement of peripheral blood pressure using the auscultatory Korotkoff method is recommended as the most accurate method for detecting arterial hypertension in children [2,7,8].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

Comments. Blood pressure in children's peripheral arteries is measured using a mechanical sphygmomanometer (blood pressure monitor) with an aneroid gauge and a phonendoscope (stethoscope) [1,2,7,8].

Comments. The arm circumference is measured using a tape measure with an accuracy of 0.5 cm at the midpoint between the olecranon and the acromion of the scapula. The recommended cuff width is presented in Appendix A3 (Table 3). The width of the inner (rubber) bladder of the cuff should be 40% of the arm circumference, and the length of the rubber bladder should cover 80% to 100% of the arm circumference. The cuff is applied so that the center of the rubber bladder is positioned over the brachial artery on the inner surface of the arm, with the lower edge of the cuff 2–2.5 cm above the antecubital fossa. The snugness of the cuff is determined by the ability to pass one finger between the cuff and the patient's arm surface [1,2,7,8].

Comments. * Unless the child has aortic arch anomalies, such as a right aortic arch or a left aortic arch with an aberrant right subclavian artery; ** during the initial assessment, blood pressure is measured on both the right and left arms, and subsequently on the arm with the higher readings.

Comments. The cuff is applied to the patient's thigh so that the center of the rubber bladder is positioned over the femoral artery on the inner surface of the thigh, with the lower edge of the cuff 2–2.5 cm above the popliteal crease; an index finger should easily pass between the cuff and the patient's thigh. The stethoscope bell should be placed over the femoral artery projection in the popliteal fossa. Using a disproportionately large cuff yields falsely low blood pressure readings, while a small cuff overestimates the measurements [1,2,7,8].

Oscillometric method for measuring blood pressure

Comments. When measuring peripheral blood pressure with an automated electronic oscillometric blood pressure monitor, repeated measurements are necessary, as the initial reading is typically higher [2,8].

Blood pressure measurement in peripheral arteries in newborns and infants

Comments. * The automated electronic oscillometric upper-arm blood pressure monitor must be certified for use in newborns and programmed with an initial inflation pressure appropriate for infants (typically ≤120 mmHg);

Rules for blood pressure measurement in newborns:

- 1.5 hours after feeding or a medical intervention;

- the newborn is lying in the prone or supine position;

- a cuff corresponding to the arm circumference is used**;

- measurement is performed on the right upper extremity;

- after cuff placement, the infant is left undisturbed for 15 minutes (sleeping or quietly awake);

- three consecutive blood pressure readings are taken at 2-minute intervals; if an automated device is used, the first result is generally discarded.

**The cuff length should be 80% to 100% of the arm circumference; it is suggested to use cuffs with a width-to-arm-circumference ratio of 45% to 55% [24].

Comments. Data on normal blood pressure values in children aged 1 to 12 months are limited, and reference values for determining the 95th percentile of blood pressure are lacking. Current data indicate that blood pressure remains relatively stable in children between the neonatal period and one year of age, making it acceptable to use normative data for one-year-old children to diagnose hypertension in infants aged 1 to 12 months (see Appendix A3, Table 2).

24-hour ambulatory blood pressure monitoring

Indications for 24-hour ambulatory blood pressure monitoring (ABPM) in children and adolescents

- to confirm hypertension (and determine its phenotype) in children and adolescents with persistently high blood pressure for at least 1 year;

- when office blood pressure values correspond to stage 1 hypertension (across three visits) to rule out "white-coat hypertension" and avoid prescribing unjustified antihypertensive therapy;

- to confirm hypertension in the presence of significant blood pressure variability during one or more doctor visits;

- in cases of hypertension resistant to ongoing pharmacotherapy;

- to assess blood pressure control in children with target organ damage;

- to rule out "masked hypertension" in the presence of target organ damage (left ventricular hypertrophy, microalbuminuria) and normal office/clinical blood pressure levels;

- in patients at high risk for hypertension, including those with type 1 and type 2 diabetes mellitus, chronic kidney disease, severe obesity with sleep-disordered breathing, post-operative coarctation of the aorta, and renal, liver, or heart transplants (Table 3);

- in patients with normal office/clinical blood pressure levels but a hypertensive response to exercise;

- before starting antihypertensive pharmacotherapy and during treatment to assess its effectiveness;

- in scientific research.

GPP CLoE 5Level of recommendation evidence C (level of data reliability – 5)

Table 3. High-risk conditions indicating the need for ABPM

Interpretation of ABPM results

ABPM results should be interpreted by a competent specialist; only ABPM recordings of adequate quality should be interpreted: 40–50 measurements per 24 hours, 65%–75% of all possible recordings [1, 28].

Mean BP values (systolic, diastolic) are evaluated taking into account sex, age, or height using special percentile tables developed on the basis of a representative sample of healthy children aged 5 to 16 years [30] (see Appendix A3, tables 7–10).

In addition to mean systolic and diastolic BP values, the following are evaluated [1, 28]:

• maximum and minimum BP values during various periods of the day;

• "blood pressure load" indices (hypertension time index, hypertension area index) for 24 hours, daytime, and nighttime;

• BP variability;

• circadian index (degree of nocturnal BP reduction);

• morning BP surge (magnitude and rate of the morning BP surge);

• duration of hypotensive episodes (hypotension time index and hypotension area index).

Time index (TI) of hypertension, or the "proportion of elevated blood pressure," makes it possible to assess the duration of elevated BP during the day. This parameter is calculated as the percentage of measurements exceeding normal BP values over 24 hours or separately for each time period.

The criterion for hypertension in children and adolescents during the daytime is the 95th percentile value for the corresponding sex, age, and height, and during the nighttime, a BP value 10% lower than during the daytime.

The hypertension time index in healthy children and adolescents should not exceed 10%.

"White-coat" hypertension is diagnosed when the hypertension time index ranges from 10% to 25%. Labile hypertension is diagnosed when the hypertension time index is from 25% to 50%. Stable hypertension is diagnosed when the hypertension time index is greater than 50% during the daytime and/or nighttime.

"White-coat" hypertension – a condition in which office BP measured during doctor visits is above the 95th percentile, but BP values are normal during home measurements and according to ABPM results. Diagnostic criteria for white-coat hypertension are mean SBP and DBP values according to ABPM below the 95th percentile for the corresponding height, age, and sex, while the number of recorded BP elevations above the 95th percentile is less than 25%.

Masked hypertension – normal BP values during single/office measurements, but elevated values according to ABPM.

Area index is calculated as the area of the figure bounded by the elevated BP curve and the normal blood pressure level.

BP variability is calculated using the standard deviation of the mean BP value. Standards for BP variability have not been established for children and adolescents. For adolescents aged 16 years and older, currently existing variability standards for older age groups can be used: for daytime and nighttime SBP, 15 mmHg; for daytime DBP, 14 mmHg; and for nighttime DBP, 12 mmHg.

Circadian index (CI – the degree of nocturnal BP reduction) shows the difference between mean daytime and nighttime BP values as a percentage of the daytime mean value. The optimal degree of nocturnal BP reduction is from 10% to 20% compared to daytime parameters. Based on the CI value, four groups of patients are distinguished:

1) normal (optimal) degree of nocturnal BP reduction ("dippers") - CI 10–20%;

2) insufficient degree of nocturnal BP reduction ("non-dippers") - 0 < CI < 10%;

3) increased degree of nocturnal BP reduction ("over-dippers") - CI > 20%;

4) sustained elevation of nocturnal BP ("night-peakers") - CI < 0.

Contraindications to ABPM and potential complications

Comments. Potential complications during ABPM: forearm and hand edema; petechial hemorrhages; contact dermatitis [1, 2].

Comments. Additionally, there are currently no reference data for children with a height <120 cm, which complicates the interpretation of ABPM parameters [1, 2].

Ambulatory blood pressure monitoring (ABPM) is a method for assessing the 24-hour BP rhythm in children and adolescents in natural conditions using portable BP monitors. The results of blood pressure level assessment obtained during 24-hour ambulatory monitoring are of greater importance for diagnosis and management choices in patients with elevated BP than office BP values [28–30].

Mean BP values (systolic, diastolic) provide an idea of the patient's BP level, most accurately reflect the true level of hypertension, and allow for the diagnosis of white-coat hypertension and masked hypertension [28–30]. There is a close correlation between ambulatory and office BP values in normotensive patients. At the same time, in individuals with hypertension, SBP values according to ABPM are higher compared to office measurements. This pattern is characteristic of both children and adults.

"White-coat" hypertension syndrome is detected in half of children with high-normal BP and hypertension measured during doctor visits [31]. In a number of studies, white-coat hypertension is not associated with target organ damage [30], however, there is evidence that left ventricular hypertrophy was detected in adolescents with white-coat hypertension and a hypertensive response to physical exertion [32]. The possibility of the transformation of white-coat hypertension in children into stable hypertension in adulthood requires further study. BP control in such children and adolescents should be performed using ABPM once a year.

Masked hypertension occurs in 5.8% of children and adolescents who underwent ABPM and is most commonly diagnosed in children with obesity and secondary hypertension (against the background of chronic kidney disease [CKD] and corrected aortic coarctation), and is associated with the risk of target organ damage [35]. The probability of developing sustained hypertension in patients with masked hypertension is much higher (7/100 patients per year) compared to normotensive patients (0.6/100 patients per year) according to 3-year follow-up data [34].

ABPM results are more informative for predicting target organ damage and show greater reproducibility compared to single office BP measurements [28].

Monitor programming (measurement schedule)

The measurement schedule defines daytime (06:00–24:00) and nighttime (00:00–06:00) periods. Measurement frequency is set to once every 15 minutes during the day and once every 30 minutes at night. Sleep and wake periods are logged by the patient pressing the «event» button on the monitor. The start of the nighttime period (for calculations) is set approximately 1 hour after, and the daytime period 1 hour before pressing the «event» button. During data statistical processing, shifting the daytime period by ± 1 hour does not affect the mean values. Editing the duration of daytime and nighttime intervals is also possible after transferring data from the monitor to a computer.

Monitor installation technique

The monitor is placed in a pouch and secured to the patient's body. The cuff is selected according to the child's arm circumference (see Appendix A3, Table 3). To prevent discomfort associated with prolonged measurements (local sweating, mechanical skin irritation, etc.), the cuff can be applied over a thin undershirt or short-sleeved t-shirt. The cuff is secured so that the tubing connector or the «arteria» marker is positioned approximately over the brachial artery. The outlet tube should point upward so the patient can put on other clothing over the cuff if necessary. After installing the monitor, explain the rules of conduct to the child during measurements and demonstrate a single measurement.

During ABPM, the child's daily routine should remain normal; however, during intense physical, emotional, or mental exertion, the child or their parents must make a corresponding note in the diary. The child will know a measurement is starting when the arm is squeezed as pressure builds up in the cuff. At this moment, if the patient was walking or running, they must stop, lower the arm with the cuff alongside the body, relax the arm muscles as much as possible, and keep their fingers still. If the patient was sitting or lying down, the arm should be left in the position it was in when the device triggered. Scheduled measurements involve smooth inflation of air into the cuff and stepwise pressure reduction. In the event of a failed measurement, the monitor reinflates the cuff after pressure reduction. Monitors are equipped with an «extra measurement» button that the patient can press if they experience a headache, chest pain, dizziness, etc. At that moment, an unscheduled BP and heart rate measurement will take place. When programming the monitors, it is advisable to disable the warning beep and display so that scheduled measurement results are not shown, which helps reduce children's excessive fixation on the device and prevents anxiety caused by high BP readings.

Home blood pressure measurement in peripheral arteries

Comments. Home blood pressure monitoring (or self-monitoring of BP) should not be used to diagnose hypertension, white-coat hypertension, or masked hypertension, but it can be a useful adjunct to office BP measurements and ABPM data after a hypertension diagnosis has been established.

Numerous studies have shown that parents can perform repeat BP measurements on children at home. Home BP measurement (or self-monitoring) offers convenience and the opportunity to obtain repeated measurements over a long period. Furthermore, automated electronic oscillometric blood pressure monitors are easy to use and help avoid potential errors such as inaccurate reporting and digit preference when recording BP [7,8].

Comments. BP measurement is performed in a quiet room, with the patient sitting, back and arm supported, after a 5-minute rest. Two measurements are taken 1–2 minutes apart, and the mean BP value is calculated. «Home» blood pressure is the average of these readings. BP values from the first day of measurement are excluded from the analysis.

There are several practical challenges with home BP measurement. There is no consensus regarding how many home measurements over what period are required to assess BP in children. Normative data for evaluating BP in children are lacking (except for a single relatively small study) [7]. In addition, it must be taken into account that only a few automated devices have been validated for use in the pediatric population, and available cuff sizes for them are limited [7,8].

Diagnostic criteria, principles of diagnosis formulation

Screening schedules and indications for blood pressure measurement in children

Comments. The necessity and timing of BP screening in the pediatric population have been widely debated for several years. The guidelines of the European Society of Hypertension [7] and the American Academy of Pediatrics concluded that BP screening should be performed in all children and adolescents starting from 3 years of age [8], allowing for early diagnosis of asymptomatic forms of hypertension in childhood.

Comments. Risk groups include children and adolescents with overweight and/or obesity (BMI ≥95th percentile), chronic kidney disease, type 1 and type 2 diabetes mellitus, coarctation of the aorta (including in operated children), patients taking medications that raise BP, and children with symptoms potentially related to hypertension (headaches, epistaxis) [2,7,8].

Comments. Indications for classifying a child as being at risk for developing hypertension include [2,7,8]:

• premature birth at a gestational age of less than 32 weeks, low birth weight;

• presence of neonatal pathology requiring resuscitation;

• presence of congenital heart defects, including operated ones;

• history of recurrent urinary tract infections, persistent hematuria and/or proteinuria;

• presence of chronic kidney disease (chronic renal failure) or urological anomalies;

• family history of congenital kidney disease;

• organ or bone marrow transplantation performed;

• presence of a malignant disease;

• use of medications that increase BP;

• presence of systemic diseases in the child that may manifest as hypertension (neurofibromatosis, tuberous sclerosis, sickle cell anemia, etc.);

• documented cases of intracranial hypertension.

Blood pressure level assessment algorithm

Comments.  Diagnostic criteria for hypertension in children are based on the concept of increasing BP levels with age and the dependence of BP on body surface area. Therefore, the diagnostic methodology used in individuals over 18 years of age, based on fixed criteria, is not applicable to children. It can only be used in adolescents older than 16 years, in whom the dependence of BP on weight and height parameters is less pronounced [1,2,7-9].

Criteria for assessing BP levels and the classification of arterial hypertension in children and adolescents are presented above in Section 1.5.

Stages of BP assessment in children (Appendix B, flowchart 1):

1) Calculation of mean SBP and DBP values based on three BP measurements performed at 2-3 minute intervals.

2) Comparison of the patient's mean SBP and DBP values obtained from three-fold BP measurement at a single visit with the 90th and 95th BP percentiles corresponding to the patient's sex, age, and height percentile (see Appendix A3, Tables 4–6).

3) Comparison of mean SBP and DBP values recorded in a patient at three visits with an interval between visits ranging from 2 weeks to 6 months with the 90th and 95th BP percentiles presented in the Russian Guidelines 2009 [1], corresponding to the patient's sex, age, and height percentile (see Appendices G4–G6) to determine the criteria for normal BP, high-normal BP, or arterial hypertension. The values of the 90th and 95th BP percentiles in newborns and infants of the first year of life are presented in Appendix A3, Tables 1–2.

• In adolescents older than 16 years, it is recommended to use unified diagnostic criteria: normal BP – less than 130/85 mm Hg, high-normal BP ≥ 130/85 mm Hg and < 140/90 mm Hg, and arterial hypertension ≥ 140/90 mm Hg [1,2,7–9].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

Comments. Arterial hypertension is subdivided into two stages. The BP level for stage 1 AH ranges from the 95th to 99th percentile + 5 mm Hg for children under 16 years of age and 140–159/90–99 mm Hg for adolescents older than 16 years. The BP level for stage 2 AH is greater than the 99th percentile + 5 mm Hg for children under 16 years of age and ≥ 160/100 mm Hg for adolescents older than 16 years.

2.1 Complaints and Anamnesis

Comments. The presence of arterial hypertension, diabetes mellitus, and other cardiovascular diseases, hereditary kidney diseases (polycystic kidney disease, Alport syndrome, etc.) in the family (parents, grandparents, siblings) is ascertained [1,2,7–9].

Comments. Pregnancy and childbirth pathology, features of the early age course (premature birth, intrauterine growth restriction, bronchopulmonary dysplasia, intrauterine hypoxia, hypoxia in the first months of life, umbilical artery catheterization, renal artery/vein thrombosis, etc.), and the nature of feeding are specified) [1,2,7–9].

Comments. These include chronic kidney disease, including hereditary and acquired diseases, endocrine pathology, and neurological pathology. Data on heart diseases and systemic connective tissue diseases are collected [1,2,7–9].

Comments. Medications that can increase blood pressure include: central sympathomimetics (N06BA), systemic corticosteroids (H02A), nonsteroidal anti-inflammatory and antirheumatic drugs (M01A), nonselective monoamine reuptake inhibitors (N06AA), systemic hormonal contraceptives (G03A), calcineurin inhibitors (L04AD), and other stimulants, including herbal ones (dietary supplements) (see Appendix A3, Table 11).

- clinical symptoms – complaints (headache, vomiting, hypertensive crises, vertigo, visual disturbances, epistaxis, facial paralysis, convulsions, syncope, chest pain, tachycardia);

- presence of hypertensive crises;

- age of AH onset and duration of AH; BP level (usual, maximum, variability);

- current and prior antihypertensive therapy and its effectiveness.

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

- diabetes mellitus;

- dyslipidemia;

- weight gain and obesity;

- sleep disorders (snoring, apnea);

- dietary habits (excessive salt intake, tendency to add salt to food);

- low physical activity level;

- traumatic brain injury;

- abdominal trauma;

- precocious puberty (appearance of secondary sexual characteristics in girls under 8 years of age, in boys under 10 years of age);

- alcohol consumption, smoking;

- adverse psychological and environmental factors (nature of study and work, family atmosphere, educational and emotional status of parents or guardians, family socio-economic indicators, housing conditions, nature of parents' work, level of mutual understanding).

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

Comments. Anamnestic data are of critical importance for establishing the etiology of AH, identifying triggering factors, and determining the clinical features of the disease [1,2,7–9].

2.2 Physical Examination

Comments. Clinical examination is performed to diagnose primary or secondary AH and determine the stage of the disease, detect target organ damage, and identify concomitant CVD risk factors [1,7,8].

Table 4 summarizes the clinical symptoms that help determine the cause of secondary AH.

Table 4. Signs indicative of a possible secondary nature of AH

Comments. To identify autonomic nervous system disorders, patients are evaluated for baseline autonomic tone using the clinical scale by A.M. Wayne et al., modified for children by N.A. Belokon et al. (see Appendix A3, Table 14), which records clinical, electrophysiological, and laboratory parameters. Normally, the number of vagotonic symptoms does not exceed 8, and the number of sympathicotonic symptoms is no more than 4.

Evaluation of baseline autonomic tone is particularly relevant in patients with "white-coat" hypertension and labile arterial hypertension to incorporate differentiated correction of autonomic disorders into the treatment plan.

2.3 Laboratory Diagnostics

General (clinical) urinalysis (microscopic examination of urine sediment to detect erythrocytes, leukocytes, epithelial cells, casts, crystalline, and amorphous salts) [1,2,7-9];

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

General general-clinical blood biochemistry (determination of blood sodium level, blood potassium level, blood urea level, blood uric acid level, blood glucose level, blood creatinine level with estimated glomerular filtration rate calculation) [1,2,7-9].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

Comments. Estimation of the glomerular filtration rate in children is performed using the modified 2009 "bedside" Schwartz formula (eGFR = 41.3 × (height, cm / Cr)), the Schwartz–Lyon equation (2012), or the height-dependent Pottel formula (2012), provided that the laboratory method for creatinine determination is standardized by mass spectrometry. In children aged 1 month to 2 years, the exponential Pottel formula (2012) or FlandersMetadata (2014) should be used [35]. In children over 16 years of age, GFR should be calculated using the 2009 CKD-EPI formula (based on serum creatinine) or the 2012 CKD-EPI formula (based on serum creatinine and cystatin C), which is used in clinical practice for patients over 18 years of age [7].

Elevated serum uric acid levels are most commonly associated with overweight.

Comments. High activity of the renin-aldosterone system is characteristic of renovascular hypertension (predominantly due to elevated renin) and primary hyperaldosteronism (elevated aldosterone). Very low activity of the renin-aldosterone system is characteristic of mineralocorticoid-dependent diseases and certain monogenic forms of arterial hypertension.

Comments. Blood adrenocorticotropic hormone (ACTH) testing and the 1 mg #dexamethasone** suppression test are more commonly used in the adult population, as data in children indicate lower sensitivity and specificity [37].

#Off-label drug use in children: prescribed outside of age-related indications by decision of the medical commission, after obtaining informed consent from parents and children over 15 years of age.

Comments. These conditions are suspected in cases of malignant refractory hypertension combined with low renin levels and a family history of early-onset hypertension/death from cerebrovascular disease. Identification of the mutant gene makes it possible to verify the cause of arterial hypertension and, in some cases, administer pathogenetic therapy. Molecular genetic testing is also indicated for syndromic forms of arterial hypertension: congenital adrenal hyperplasia (11β-hydroxylase deficiency, 17α-hydroxylase deficiency), neurofibromatosis, von Hippel-Lindau disease, and multiple endocrine neoplasia syndromes.

Routine laboratory tests help detect pathological changes in target organs and identify certain risk factors. The optimal scope of investigations is determined by the medical history, clinical examination findings, and the presence of previously identified comorbidities [1,2,7-9].

When examining a patient with arterial hypertension (AH), one should proceed from simple diagnostic methods to more complex ones. The first stage involves routine tests that are mandatory for every patient with diagnosed AH. If at this stage the physician has no grounds to suspect a secondary nature of AH and the obtained data are sufficient to clearly determine the patient's risk group and, accordingly, the treatment strategy, the examination may be concluded here. The second stage involves additional tests to determine the specific form of secondary AH and to assess risk factors [1,2,7-9].

2.4 Instrumental Diagnostics

Comments. Indications and evaluation criteria for ABPM are outlined above in the section "24-Hour Ambulatory Blood Pressure Monitoring". ABPM makes it possible to verify initial deviations in 24-hour blood pressure values, perform differential diagnosis of AH by identifying labile and stable AH, diagnose masked hypertension [2,33,34], and evaluate treatment efficacy [31]. ABPM data in children help avoid overdiagnosis of AH by detecting an excessive anxiety reaction manifested as a blood pressure elevation associated with a medical examination—the "white-coat hypertension" phenomenon—and preventing the prescription of unjustified antihypertensive therapy [2,30,32].

Comments. Echocardiography (EchoCG) is a mandatory diagnostic method in AH; it allows for the exclusion of organic heart disease (congenital and acquired heart defects, cardiomyopathy) and the detection of signs of left ventricular hypertrophy. Echocardiographic criteria for hypertrophy are described in the section on target organ damage. EchoCG criteria for myocardial remodeling are outlined in the section "Diagnosis of Target Organ Damage".

• Electrocardiography (ECG) recording is recommended for all patients with AH [2,7-9].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

Comments. ECG makes it possible to evaluate signs of myocardial hypertrophy, atrial overload, and the state of the terminal part of the ventricular complex. Electrocardiographic criteria for left ventricular myocardial hypertrophy are the Sokolov-Lyon index (SVl + RV5-6 > 35 mm) and the Cornell product (R_AVL + SV₃) mm × QRS ms > 2440 mm × ms). At the same time, ECG criteria for myocardial hypertrophy in children have high specificity but low sensitivity [7].

Comments. Ophthalmoscopy is a mandatory diagnostic method in AH; it allows for the detection of changes associated with elevated blood pressure: narrowing and tortuosity of small arteries, and possible dilation of retinal veins.

Comments. Renal artery stenosis is suspected in grade 2 AH, predominantly of a diastolic or systolic-diastolic character, in children without excess body weight, frequently presenting with hypokalemia.

Comments. Renal/renovascular origin of AH is suspected in grade 2 AH, elevated diastolic blood pressure, increased kidney size on ultrasound; hypokalemia and auscultatory detection of an epigastric bruit are possible [2,7,8].

Comments. Renal vessel angiography is the gold standard for verifying renal artery pathology.

Comments. This is a preferred diagnostic method. Long-term studies have shown that blood pressure levels during physical exertion are a reliable predictor of resting blood pressure levels later in life [3,4]. A hypertensive blood pressure response to exertion is frequently detected in patients with white-coat hypertension [34,44]. A hypertensive exercise blood pressure response is also associated with the development of left ventricular hypertrophy and vascular wall remodeling [42]. According to guidelines for the management of adult patients with AH, normotensive patients with a hypertensive response to exercise should undergo ABPM to rule out masked hypertension [38].

Comments. In adult patients with AH, this allows for the detection of signs of remodeling (hypertrophy) of brachiocephalic arteries through an increase in the intima-media thickness (IMT) to more than 0.9 mm. An intima-media thickness greater than 1.3 mm, or a focal thickening of 0.5 mm or 50% relative to adjacent areas in the region of the carotid bifurcation or internal carotid artery, is regarded as a sign of atherosclerotic involvement [3,4,38]. However, reference values for this parameter are still lacking in children; therefore, routine vascular studies aimed at identifying early signs of atherosclerosis—such as measuring pulse wave velocity or the carotid intima-media complex—are not advisable in children [2,7,8].

2.5 Other Procedures

Differential diagnosis of primary and secondary arterial hypertension

Primary arterial hypertension is diagnosed in the majority of cases in children older than 6 years, against the background of a positive family history of AH in first- and second-degree relatives, frequently associated with overweight or obesity. The magnitude of blood pressure elevation is generally higher in secondary AH compared to primary AH. In primary AH, a systolic pattern of hypertension is more commonly detected, whereas secondary AH typically presents with a systolic-diastolic pattern. A definitive diagnosis can be made only after secondary causes of AH have been ruled out.

Renal and renovascular hypertension. Renal and renovascular hypertension, associated with congenital or acquired pathology of the kidneys and renal vessels, ranks first in prevalence among secondary forms of arterial hypertension. The main causes of renal hypertension include acquired diseases (glomerulonephritis, pyelonephritis, renal neoplasms) and hereditary kidney pathologies (hereditary polycystic kidney disease, Alport syndrome). The pathogenesis of symptomatic hypertension in renal disease is driven by: increased activity of the renin-angiotensin-aldosterone system, impaired water-salt metabolism with suppression of the kidney's depressor function, and disturbed production of kinins and prostaglandins. The main causes of renovascular hypertension include: congenital malformations of the renal vessels, fibromuscular dysplasia of the renal vessels, aortoarteritis, and periarteritis nodosa. Clinical markers of renovascular hypertension include: pronounced grade 2 hypertension, predominantly diastolic in character; in most cases, patients have normal body weight; a systolic murmur may be auscultated over the projection of the renal arteries (in the abdominal region); blood pressure asymmetry in the extremities; widespread arteriospasm and neuroretinopathy are possible. An elevated renin level against the background of decreased renal blood flow is characteristic. Instrumental examination for diagnosis verification should include: duplex scanning of the renal arteries, scintigraphy of the kidneys and urinary system, renal angiography or magnetic resonance imaging, and contrast urography.

Congenital renal artery stenosis is the most frequent cause of renovascular hypertension in children. It is characterized by a high, persistent elevation of blood pressure, predominantly diastolic in nature, refractory to antihypertensive therapy. Physical examination frequently reveals a systolic murmur in the umbilical region, as well as in the epigastric region corresponding to the origin of the renal artery from the abdominal aorta. Changes in target organs develop early: left ventricular hypertrophy, pronounced fundus changes.

Fibromuscular dysplasia of the renal arteries is more common in females. According to angiograms, stenosis is most frequently localized in the middle third of the renal artery. The artery has a "string of beads" appearance, and the collateral network is not prominent. The main treatment modalities are transluminal balloon angioplasty of the renal artery and renal artery stenting.

Nonspecific aortoarteritis—"pulseless disease" or Takayasu's disease—is a relatively rare pathology in children. Clinical manifestations of the disease are characterized by marked polymorphism. In the initial stage of the disease, general inflammatory symptoms predominate, manifested by fever, myalgia, arthralgia, and erythema nodosum. These changes correspond to the initial stage of vascular inflammation. Subsequent clinical manifestations are associated with the development of arterial stenosis, leading to ischemia of the corresponding organ. Clinical symptoms of Takayasu's disease are characterized by asymmetry or absence of pulse and blood pressure in the radial arteries, and a systolic murmur is detected over the affected arteries. Involvement of the aortic valve (insufficiency) and mitral valve (insufficiency), development of myocarditis, possible pulmonary hypertension, and symptoms of heart failure are characteristic. Hypertension is malignant in nature and is associated with stenotic and thrombotic occlusion of the renal arteries, aortic regurgitation with damage to the baroreceptors of the carotid and aortic sinuses, decreased aortic elasticity, and stenosis of the carotid arteries leading to cerebral ischemia and irritation of chemoreceptors and vasomotor centers of the medulla oblongata.

Periarteritis nodosa. The disease is characterized by malignant hypertension, specific skin changes combined with abdominal and coronary pain, polyneuritis, hyperthermia, and pronounced inflammatory blood changes. The underlying mechanism is vasculitis of small and medium-sized arteries, leading to renal artery involvement. The diagnosis is verified using skin biopsy.

Coarctation of the aorta occurs in 8% of patients with congenital heart defects and is the most common cause of hypertension in infants and young children. The clinical picture depends on the location and degree of aortic narrowing and the development of collaterals. The main symptom is the absence or weakening of the pulse in the lower extremities, while the pulse in the upper extremities is amplified. Blood pressure in the arms is equal to or significantly higher than in the legs. In severe cases, blood pressure in the legs is lower by 20 mmHg or more compared to the arms. A harsh systolic murmur is auscultated over the cardiac region and above the clavicles, radiating to the back. Radiography reveals cardiomegaly in children during the first year of life. In older children with late diagnosis and developed collaterals, rib notching is detected at the sites of intercostal artery localization. A pink coloration of the skin of the face and chest is combined with pale, cold skin on the lower extremities. Pulsation is frequently present in the jugular fossa and carotid artery regions. An extensive network of collaterals forms on the skin of the chest. The primary treatment method is surgical. It should be emphasized that even after successful surgical resection of aortic coarctation with anastomosis placement, there remains a high risk of developing hypertension, ranging from 17 to 77% [47,48]. At the same time, office blood pressure readings are usually normal, while hypertension is more frequently detected through home measurements or ambulatory blood pressure monitoring (ABPM). To diagnose hypertension following surgical treatment of aortic coarctation, ABPM must be performed to detect masked hypertension [49].

Arterial hypertension of endocrine origin. According to epidemiological data, secondary forms of hypertension due to endocrine causes are relatively rare (0.05% - 6%) [36]. Features of endocrine forms of hypertension include a crisis-like course of hypertension, resistance or insufficient efficacy of standard antihypertensive therapy (blood pressure target values are not achieved despite dose titration of medications and their combinations), and disease onset prior to 6 years of age. The list of diagnostic procedures in patients with suspected secondary hypertension of endocrine origin is presented in Table 5.

Table 5. List of diagnostic procedures in patients with suspected secondary hypertension of endocrine origin

# Off-label drug use in children: prescribed outside of age indications by decision of the medical commission, after obtaining informed consent from parents and children over 15 years of age.

Monogenic forms of arterial hypertension include:

• Apparent mineralocorticoid excess syndrome;

• Glucocorticoid-remediable aldosteronism (pseudohyperaldosteronism type 1);

• Pseudohypoaldosteronism type 2 (Gordon syndrome);

• Pseudoaldosteronism (Liddle syndrome);

The diseases are characterized by severe hypertension and refractoriness to standard antihypertensive therapy.

Apparent mineralocorticoid excess syndrome – an autosomal recessive disorder caused by mutations in the HSD11B2 gene located on the long arm of chromosome 16 (16q22), leading to impaired cortisol metabolism. Clinical manifestations include growth retardation and polyuria. Main laboratory criteria: hypokalemia, metabolic alkalosis, low plasma renin and aldosterone, normal mineralocorticoids, decreased ACTH.

Glucocorticoid-remediable aldosteronism (pseudohyperaldosteronism, type 1). Autosomal dominant inheritance, caused by mutations in CYP11B1 or CYP11B2 genes located on the long arm of chromosome 8. Clinical manifestations include growth retardation and polyuria. Characterized by impaired cortisol metabolism. Main laboratory criteria: hypokalemia, metabolic alkalosis, low renin, high aldosterone, normalization of aldosterone levels during glucocorticoid therapy.

Pseudohypoaldosteronism type 2, Gordon syndrome. Autosomal dominant inheritance, caused by mutations in WNK4 (17q21.2), WNK1 (12p13.3), KLHL3 (5q31), CUL3 (20q36.2) genes, leading to impaired function of the epithelial thiazide-sensitive sodium-chloride cotransporter, increased sodium reabsorption, and the development of volume-dependent hypertension. Main clinical manifestations: growth retardation, dyshidrosis, muscle weakness, nausea; laboratory criteria: hyperkalemia with normal glomerular filtration rate, hyperchloremic metabolic acidosis, low plasma renin and aldosterone.

Pseudohypoaldosteronism (Liddle syndrome). Inheritance is autosomal dominant, caused by mutations in genes located on the short arm of chromosome 16 SCNN1A (12p13.31), SCNN1B, and SCNN1G (16p12.2). Clinical manifestations include growth retardation and polyuria. It is characterized by impaired activity of the renal amiloride-sensitive epithelial sodium channel, which leads to increased sodium reabsorption and suppression of aldosterone secretion. The disease debuts very early. Main laboratory criteria: hypokalemia, metabolic alkalosis, low blood renin and aldosterone.

Diagnosis of target organ damage

Left ventricular hypertrophy

Comments. To determine the LVMI, the myocardial mass value should be divided by the height raised to the power of 2.7. Echocardiographic criteria for LV hypertrophy corresponding to an LVMI value (in g/m^2.7) ≥ 95th percentile according to age and sex are given in Appendix A3, Table 15.

Left ventricular myocardial hypertrophy (LVH) is the most significant and overt target organ damage in children and adolescents. LVH is defined if the left ventricular mass or relative wall thickness is ≥ 95th percentile according to age and sex [1,7,8,39,41,42].

30–40% of children with primary hypertension have a left ventricular mass index (LVMI) greater than the 95th percentile [7,8,42]. The echocardiographic criterion for LVH corresponding to the 99th percentile of the population distribution curve in patients older than 8 years is considered to be: in boys, LVMI ≥ 47.58 g/m^2.7; in girls, LVMI ≥ 44.38 g/m^2.7 [39]. A strict criterion for pronounced myocardial hypertrophy is an LV mass index in children older than 8 years, regardless of sex, ≥ 51 g/m^2.7 or in adolescents with normal body weight ≥ 116 g/m² of body surface area for boys and 95 g/m² for girls [2,7,8]. 10–15% of children and adolescents with hypertension have pronounced hypertrophy greater than 51 g/m^2.7 [7,8].

The relative wall thickness of the left ventricle is calculated using the formula: RLVWT = 2PWT / LVIDd, where PWT is the left ventricular posterior wall thickness in mm, and LVIDd is the left ventricular internal diameter at end-diastole in mm.

The type of left ventricular remodeling is currently considered an important criterion not only for the severity of the disease, but also for the prognosis of hypertension. Based on the ratio of the left ventricular posterior wall thickness (PWT) to its radius, as well as taking into account the LVMI value, the type of left ventricular remodeling can be determined. Concentric LV hypertrophy, eccentric LV hypertrophy, and concentric LV myocardial remodeling are distinguished (Table 6). Concentric LV hypertrophy is more common in severe hypertension. Concentric LV myocardial remodeling is associated with the development of diastolic dysfunction and increased peripheral vascular resistance [7,8].

Table 6. Left ventricular myocardial remodeling patterns

Renal involvement

Comments. Elevated BP can cause renal damage manifesting as albuminuria or proteinuria. Hematuria and proteinuria indicate glomerular injury [2,7,8,27,37].

Ocular damage

Comments. Data on the prognostic significance of retinal angiopathy for the course of hypertension in children are scarce. Retinal angiopathy occurs in half of children with hypertension [2,35].

Brain damage

Comments. Persistent severe hypertension can cause brain damage with the development of various symptoms: stroke, visual disturbances, cerebral crises. Brain damage may be promoted by acute hypertensive crises (severe headache, dizziness, visual disturbances, seizures, altered consciousness, facial nerve palsy). In these cases, brain MRI may reveal small silent brain infarcts, microhemorrhages, or posterior reversible encephalopathy syndrome [2,46].

Vascular changes

Risk factors for cardiovascular diseases

In adults, cardiovascular risk factors, in addition to hypertension, include smoking, a family history of early cardiovascular disease, metabolic risk factors: overweight and obesity, dyslipidemia and carbohydrate metabolism disorders, hyperuricemia, high resting heart rate, etc. [3,4,23].

Comments. Given the lack of long-term follow-up data for adolescents with hypertension and cardiovascular risk factors, it is not feasible to use the risk stratification criteria for cardiovascular complications developed for adults [3,4] in children. One should be limited to identifying these risk factors in order to develop a management program for their elimination to reduce the future risk of cardiovascular disease [2,7-9]. At the same time, the impact of excess weight on BP levels has been proven, and overweight and obesity in childhood are considered risk factors for hypertension in children and in adult life [7,8].

Metabolic syndrome

Metabolic syndrome in adults and children represents a combination of the most dangerous cardiovascular risk factors: abdominal obesity, elevated blood pressure / hypertension, elevated triglyceride levels, reduced HDL cholesterol levels, and varying degrees of carbohydrate metabolism disorders (ranging from impaired glucose tolerance to type 2 diabetes mellitus) [3,23,51].

Comments. Abdominal obesity is assessed by waist circumference (WC) (see Appendix A3, Table 17) and is a necessary (mandatory) component of metabolic syndrome.

Comments. Currently, for the diagnosis of metabolic syndrome (MS) in children and adolescents, it is proposed to use the adult criteria for metabolic syndrome developed by the International Diabetes Federation (2005) for adults and adapted for children and adolescents in 2007 (see Appendix A3, Table 18) [7,51]. A diagnosis of MS can be established from 10 years of age if a child or adolescent presents with abdominal obesity + any 2 other above-mentioned components of MS [51].

Metabolic syndrome is not diagnosed before the age of 10 years. However, if in addition to abdominal obesity a child has hypertension or a positive family history of metabolic syndrome or type 2 diabetes mellitus, such children should be classified into the risk group and evaluated for carbohydrate and lipid metabolism parameters, along with implementing preventive measures [23,51].

Other diagnostic examinations

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

3.1 General principles of management of patients with arterial hypertension

The goal of hypertension treatment is to achieve sustained normalization of blood pressure levels in order to reduce the risk of early cardiovascular disease development.

Objectives of hypertension treatment:

• achieving the target blood pressure level, which should be below the 95th percentile, and if well tolerated, down to the 90th percentile for a given age, sex, and height in children under 16 years of age, and less than 130/85 mm Hg in adolescents aged 16 years and older;

• improving the patient's quality of life;

• preventing target organ damage or reversing existing changes in them;

• preventing hypertensive crises.

3.2 Non-drug treatment

Comments. Non-pharmacological treatment includes the following components: reducing excess body weight, optimizing physical activity, smoking cessation, abstaining from alcohol and energy drinks, diet optimization, and reducing psycho-emotional stress [30,38].

Reduction of excess body weight

Comments. Reducing excess body weight lowers blood pressure and contributes to the normalization of comorbid risk factors, such as lipid profile disorders and left ventricular hypertrophy. Body mass index and the magnitude of age-related weight gain correlate with the risk of developing hypertension. In addition, BMI reduction is associated with an enhancement of the pharmacological effect [56].

Optimization of physical activity

• To maintain good health, children (over 5 years of age) are recommended to engage in 30–60 minutes of moderate (predominantly aerobic) exercise daily and 30 minutes 3–4 times a week in vigorous dynamic physical activity [1,2,23].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

Comments. The characteristics of sports disciplines depending on the intensity of the dynamic component are presented in Table 7. Moderate physical activity helps increase calorie expenditure (Table 8).

Table 7. Characteristics of sports disciplines depending on the intensity of the dynamic component

Table 8. Physical activity and calorie expenditure

Comments. It is advisable to measure BP in peripheral arteries every two months to assess the effect of physical exercise on BP levels [2,54-57]. Regular physical exercise helps control body weight, reduce BP, and eliminates risk factors for cardiovascular diseases and lipid metabolism disorders; it increases high-density lipoprotein cholesterol levels, prevents vascular dysfunction, and reduces intima-media thickness, the earliest marker of subclinical atherosclerosis [54-57].

A meta-analysis of 12 randomized controlled trials found that aerobic exercise reduces both systolic and diastolic blood pressure levels. It has been shown that a decrease in BP due to normalized physical activity is associated with the regression of left ventricular hypertrophy [56]. Regular physical exercise is recognized as an important factor in eliminating insulin resistance [57].

Examples of moderate physical activity:

• Brisk walking (3 km in 30 minutes).

  • Cycling (8 km in 30 minutes).

  • Fast-paced dancing (duration 30 minutes).

  • Playing basketball (for 15-20 minutes).

  • Playing volleyball (for 45 minutes).

Comments. In grade 2 hypertension, participation of children and adolescents in sports competitions is restricted. Physical activities with a prominent static component (weightlifting, windsurfing, bodybuilding) and a high dynamic component are discouraged (Table 8). Preference should be given to sports with a low dynamic component [1,2,56].

If hypertension is combined with other cardiovascular diseases, the possibility of participating in competitions is determined by their diagnosis and the severity of the condition [2].

Smoking cessation

• Complete smoking cessation, including passive smoking, is recommended for all patients with hypertension [1,7,8,52,58].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

Comment. At each patient visit, the physician should ask whether the patient smokes. If "no", support this choice; if "yes", insist on cessation. The physician should inform the child about the negative consequences of smoking at their age, emphasize the benefits of quitting (improved hypertension prognosis, reduced frequency of colds, enhanced athletic performance, the ability to spend money on more interesting things, improved appearance—an important aspect for girls). Smoking parents should be aware that the likelihood of their children starting to smoke is very high [1,2].

The physician should advise an adolescent who has decided to quit smoking to:

- Avoid situations that trigger smoking.

- Visit the physician initially every two weeks, and then as needed to maintain a "non-smoking status".

- Increase physical activity and limit the intake of high-calorie foods to avoid weight gain.

- Get support from parents and peers in the intention to quit smoking [1,2].

Alcohol abstinence

Dietary rationalization

• Dietary therapy is recommended for all patients with arterial hypertension as a necessary component of combination treatment [1,2,8,23,59-63].

GCR BLEL 2Grade of Recommendations B (Level of Evidence – 2)

Comments. Main approaches to designing a dietary menu in patients with arterial hypertension:

- ensuring the physiological needs of children for energy and essential nutrients: proteins, fats, and carbohydrates in accordance with age;

- inclusion of the required amount of all essential food elements (essential amino acids, polyunsaturated fatty acids, dietary fibers, vitamins, minerals) in the diet;

- optimal fat composition of the diet, with a restriction of saturated fats, containing vegetable fats of at least 30% of the total fat content in the diet, and an optimal ratio of omega-3 and omega-6 unsaturated fatty acids [1,4].

- modification of dietary carbohydrate composition, taking into account the glycemic index of foods and their dietary fiber content;

- restriction of sodium intake, optimization of its ratio with potassium, in accordance with age-related physiological requirements;

- formation of a rational dietary regimen in patients with arterial hypertension [1,2,23,53,60].

- dietary therapy in arterial hypertension aims to normalize blood pressure by reducing the excitability of the central nervous system, improving the functional state of the kidneys and adrenal cortex, and thereby normalizing water-electrolyte balance and vascular tone (Table 9) [1,2].

Several studies have demonstrated that reducing the consumption of sugar and easily digestible carbohydrates, increasing the consumption of vegetables and fruits (at least 400 g in the daily diet) and dietary fiber helps lower blood pressure [2,7,23,53,60]. These recommendations are of particular importance for patients with diabetes mellitus and metabolic syndrome [60]. A clear correlation has been found between salt intake and blood pressure levels. Limiting salt to 2 g per day is associated with a decrease in blood pressure, especially in individuals with overweight [61].

It is very important to build sustainable motivation for adherence to a rational diet, especially in overweight patients, as it has been established that weight reduction significantly lowers blood pressure and enhances the pharmacological effect in individuals with arterial hypertension [62,63].

Table 9. Dietary recommendations for children and adolescents with arterial hypertension

3.3 Treatment of autonomic disorders

• To correct autonomic disorders in children with arterial hypertension and high-normal blood pressure, it is recommended to use non-pharmacological interventions [1,2]:

- General medical massage

- Acupuncture point stimulation using other physical factors

- Gas baths (oxygen, carbon dioxide, nitrogen)

- Air-bubble baths (pearl baths)

- Medicinal mineral baths

- Iodine-bromine bath

- Therapeutic shower

- Clinical psychological training

FoR CLoE 5Level of Recommendation C (Level of Evidence – 5)

Randomized clinical trials on the use of medications to correct autonomic disorders in the treatment of hypertension in children have not been conducted.

3.4 Antihypertensive pharmacotherapy

Comments. Achieving the target BP level prevents target organ damage and reduces the risk of potential cardiovascular diseases later in life.

Table 10. Target blood pressure levels during ongoing antihypertensive therapy in children with arterial hypertension

Comments. Doses of the main antihypertensive medicinal products used in the treatment of children and adolescents with hypertension and recommended based on the results of controlled randomized controlled trials (RCTs), case series (CS), and expert opinion (EO) are presented in Appendix A3, Table 19.

Comments. The drug groups listed above may be used in the treatment of certain secondary forms of hypertension in children.

Comments. To date, a number of randomized placebo-controlled clinical trials have been conducted showing that major classes of antihypertensive agents are effective in lowering BP and exhibit minimal adverse effects [52,64-66]. There are isolated studies comparing the efficacy of drugs from different classes, which revealed no significant differences between the use of ACE inhibitors and angiotensin II receptor blockers [66]. Long-term studies on the safety of antihypertensive agents in children and their impact on the development of cardiovascular complications are lacking [2,7,8,52].

ACE inhibitors (C09A)

• ACE inhibitors (C09A) are recommended as first-choice drugs in the treatment of hypertension in children [1,7,8,52,67,68,69].

GCR ALOE 2Grade of Recommendation A (Level of Evidence – 2)

Comments. ACE inhibitors (ACEIs) are highly effective, safe drugs with cardioprotective effects and a positive impact on renal function. One of the first RCTs investigating the use of ACEIs for the treatment of hypertension in children was a study involving #enalapril** (C09AA02). Dosages ranged from 2.5 to 20 mg for children weighing less than 50 kg and from 5 to 40 mg for adolescents weighing more than 50 kg. A statistically significant reduction in both systolic and diastolic BP was demonstrated. The results of the study made it possible to prescribe the drug in children starting from the first months of life. As a rule, ACE inhibitors are used in children ≥ 6 years of age and with a glomerular filtration rate ≥ 30 mL/min/1.73 m². At the same time, it should be kept in mind that in some cases ACEIs cannot completely suppress the excessive activity of the RAAS, since 70% of angiotensin is synthesized via alternative enzymes (chymase, cathepsin). This explains the phenomenon of the escape of the antihypertensive effect of ACEIs, especially against the background of a high-salt diet.

Main side effects: first-dose hypotension, hyperkalemia, dry cough, azotemia, angioedema. Side effects are relatively rare, similar to those in adult patients, and include hypotension and dizziness (in 1.7% of cases), headache (in 3%), hyperkalemia, elevated blood creatinine levels, and very rarely, acute kidney injury and angioedema, which are mediated by increased bradykinin levels [69]. However, cough is much less common in children than in adult patients [70].

Contraindications: hyperkalemia, bilateral renal artery stenosis; the potential teratogenic effect of these drugs should be kept in mind, and their use in sexually active adolescent girls is permissible only with safe and reliable contraception.

Special indications: diabetes mellitus, metabolic syndrome, LVH, chronic kidney disease, proteinuria.

Special precautions: blood potassium level test, blood creatinine level test, differential white blood cell count (complete blood count with differential) every 8 weeks of treatment; in adolescent female patients, urine test for human chorionic gonadotropin every 8 weeks of treatment.

Drugs used (see Appendix A3, Table 19):

#Captopril** (C09AA01) – oral tablets are prescribed to children at a starting dose of 0.3–0.5 mg/kg per dose 3 times daily; the maximum dose is 6 mg/kg daily (up to 100–150 mg daily) in 3 divided doses [68].

#Enalapril** (C09AA02) – oral tablets are prescribed to children at a starting dose of 0.08 mg/kg daily (up to 5 mg daily) in 1–2 doses; the maximum dose is 0.6 mg/kg daily (up to 40 mg daily) in 1–2 doses [68].

#Fosinopril (C09AA09) – oral tablets are prescribed to children at a starting dose of 0.1 mg/kg daily (up to 5 mg daily) in 1 dose; the maximum dose is 0.6 mg/kg daily (up to 40 mg daily) in 1 dose [68].

#Lisinopril** (C09AA03) – oral tablets are prescribed to children at a starting dose of 0.07 mg/kg daily (up to 5 mg daily) in 1 dose; the maximum dose is 0.6 mg/kg daily (up to 40 mg daily) in 1 dose [68,71].

#Ramipril (C09AA05) – oral tablets are prescribed to children at a starting dose of 1.5 mg/m² (2.5 mg daily) in 1 dose; the maximum dose is 6 mg/m² daily (up to 10 mg daily) in 1 dose [72].

# The drug is approved in the Russian Federation for the treatment of arterial hypertension in individuals over 18 years of age. Off-label use in children: prescribed outside of age indications by decision of a medical commission, after obtaining informed consent from parents and children over 15 years of age.

Angiotensin II receptor blockers (C09C)

• Angiotensin II receptor blockers (ARBs) (C09C) are recommended as first-line drugs in the treatment of arterial hypertension in children. Indications are similar to those for ACE inhibitors [2,7,8,66-68,73-77].

GCR ALOE 2Grade of Recommendation A (Level of Evidence – 2)

Comments. The greatest number of randomized clinical trials on the treatment of arterial hypertension in children has focused on the efficacy and safety of ARBs. Drugs of this class inhibit vasoconstriction, reduce left ventricular hypertrophy, decrease proteinuria, and are well tolerated by patients. The efficacy of #Losartan** (C09CA01), #Valsartan (C09CA03), #Candesartan (C09CA06), #Olmesartan medoxomil (C09CA08), and #Irbesartan (C09CA04) has been demonstrated for blood pressure reduction (by 6-13 mm Hg) in children with arterial hypertension. Data have been obtained on the potential use of #Valsartan in children from 6 months of age, with no differences observed between low and high doses. Side effects of ARBs were reported relatively rarely: hypotension and dizziness (in 1.3% of patients), headache (in 1.7%), and hyperkalemia (in less than 1%). A comparative study of #Enalapril** and #Losartan**, and #Enalapril** and #Valsartan for the treatment of arterial hypertension showed an equivalent degree of blood pressure reduction.

Main side effects, contraindications, special indications, and special notes are the same as those for ACE inhibitors. Unlike ACE inhibitors, angiotensin II receptor blockers do not cause cough. Due to their teratogenic effect, the use of ARBs in sexually active adolescent girls is likewise permissible only with safe and reliable contraception.

Drugs used (see Appendix A3, Table 19):

#Losartan** (C09CA01) – oral tablets are prescribed to children at a starting dose of 0.7 mg/kg daily (up to 50 mg daily) in 1 dose; the maximum dose is 1.4 mg/kg daily (up to 100 mg daily) in 1 dose [67,68].

#Irbesartan (C09CA04) – oral tablets are prescribed to children at a starting dose of 2 mg/kg (75–150 mg) daily in 1 dose; the maximum dose is 4 mg/kg (300 mg) daily in 1 dose [73].

#Candesartan cilexetil (C09CA06) – oral tablets are prescribed at a starting daily dose for children aged 1–6 years: 0.2 mg/kg; aged 6–17 years (<50 kg): 4 mg; aged 6–17 years (>50 kg): 8 mg in 1–2 divided doses; the maximum daily dose is for children aged 1–6 years: 0.4 mg/kg; aged 6–17 years (<50 kg): 16 mg; aged 6–17 years (>50 kg): 32 mg in 1–2 divided doses [68,77].

#Valsartan (C09CA03) – oral tablets are prescribed to children at a starting dose of 1.3 mg/kg daily (up to 40 mg daily) in 1 dose; the maximum dose is 2.7 mg/kg (up to 160 mg daily) in 1 dose [66,68].

#Olmesartan medoxomil (C09CA08) – oral tablets are prescribed at a starting dose of 10 mg daily for children over 6 years of age weighing less than 35 kg, with a maximum dose of 20 mg daily; for children weighing more than 35 kg, the starting dose is 20 mg daily in 1 dose, and the maximum dose is 20 mg daily for children weighing up to 35 kg, and 40 mg daily in 1 dose for children weighing more than 35 kg [68].

# The drug is approved in the Russian Federation for the treatment of arterial hypertension in individuals over 18 years of age. Off-label use in children: prescribed outside of age indications by decision of a medical commission, after obtaining informed consent from parents and children over 15 years of age.

Dihydropyridine derivatives (C08CA)

• Currently, in the treatment of arterial hypertension in children when ACE inhibitors and angiotensin II receptor blockers are ineffective or not tolerated, long-acting dihydropyridine derivatives (C08CA) (#Amlodipine**, #Felodipine, #Nifedipine**) are recommended. Dihydropyridine derivatives are metabolically neutral and have no adverse effect on carbohydrate, lipid, or purine metabolism [7,8,52,78,79].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

Comments. Clinical studies have provided data on the efficacy of dihydropyridine derivatives primarily in children over 6 years of age. Specifically, the efficacy and safety of #Amlodipine** have been demonstrated, with a pronounced dose-dependent reduction in systolic and diastolic blood pressure established. The effect was independent of sex, race, or pubertal stage, and the drug was well tolerated. A study investigating the effects of #Felodipine showed a lesser degree of blood pressure reduction, but the drug was also well tolerated.

Main side effects: dizziness, facial flushing, peripheral edema, gastrointestinal disturbances, palpitations, muscle weakness, mood lability.

Contraindications: pregnancy, marked aortic stenosis.

Special indications: systolic hypertension, metabolic syndrome, left ventricular hypertrophy.

Special notes regular assessment of the patient's emotional state and muscle tone is required.

Drugs used (see Appendix A3, Table 19):

#Amlodipine** (C08CA01) – oral tablets are prescribed to children at a starting dose of 0.06–0.3 mg/kg daily in 1–2 doses; the maximum dose is 0.6 mg/kg/day (up to 10 mg daily) in 1–2 doses [7,8].

#Felodipine (C08CA02) – oral tablets are prescribed to children at a starting dose of 2.5 mg daily in 1 dose; the maximum dose is up to 10 mg daily in 1 dose [7,8,79].

#Nifedipine** (C08CA05) – extended-release oral tablets are prescribed to children at a starting dose of 0.25–0.5 mg/kg daily in 1–2 doses; the maximum dose is 3 mg/kg daily (up to 120 mg daily) in 1–2 doses [7,8].

# The drug is approved in the Russian Federation for the treatment of arterial hypertension in individuals over 18 years of age. Off-label use in children: prescribed outside of age indications by decision of a medical commission, after obtaining informed consent from parents and children over 15 years of age.

Thiazide diuretics (C03A), thiazide-like diuretics (C03B)

• Thiazide diuretics as antihypertensive agents are recommended for use in children with arterial hypertension at low doses; high doses are not used due to the potential for complications and adverse metabolic effects [7,8,80-84].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

Comments. No randomized clinical trials have been conducted on the use of thiazide diuretics for the treatment of arterial hypertension in children.

Main side effects: hypokalemia, hyperuricemia, hyperlipidemia, hyperglycemia, erectile dysfunction in adolescent males, orthostatic hypotension. Due to the potential for side effects, monthly ECG monitoring and blood potassium, glucose, and lipid levels are required.

Special indications: obesity, systolic hypertension.

Special notes: use with caution due to the potential for side effects; monitoring of blood potassium, glucose, and lipid levels, as well as ECG monitoring every 4 weeks of treatment, is required.

Drugs used (see Appendix A3, Table 19):

#Hydrochlorothiazide** (C03AA03) – administered orally to children at a starting dose of 0.5–1 mg/kg per day in 1–2 doses, maximum dose is 3 mg/kg per day (up to 50 mg per day) [7].

#Chlortalidone (C03BA04) – administered orally to children at a starting dose of 0.3 mg/kg per day in 1 dose; maximum dose is 2 mg/kg per day (up to 50 mg per day) in 1 dose [7, 8].

#Indapamide** (C03BA11) – administered orally as prolonged-release tablets to adolescents at a dose of 1.5 mg per day in 1 dose [84].

# The drug is approved in the Russian Federation for the treatment of arterial hypertension in individuals over 18 years of age. Off-label use in children: prescribed outside of age indications by decision of a medical commission, after obtaining informed consent from parents and children over 15 years of age.

Beta-blockers (C07A)

Beta-blockers (BBs) block β1- and β2-adrenergic receptors and reduce adrenergic influences on the heart (decreasing heart rate and myocardial contractility), as well as decrease renin secretion (via blockade of β1-receptors in the juxtaglomerular apparatus).

Comments. BBs may be prescribed as an antihypertensive agent in children with prominent tachycardia and hypersympathicotonia [2, 7, 8, 85–87].

• If it is necessary to use drugs of this group in patients with hypertension, it is recommended to use long-acting BBs with minimal adverse metabolic effects (#metoprolol** (C07AB02) [85], #bisoprolol** (C07AB07) [88]).

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

Comments. It was previously believed that beta-blockers, along with thiazide diuretics, were the primary drugs for treating hypertension in children [83]. RCTs have demonstrated the efficacy and safety of #metoprolol** (succinate) for treating hypertension in children [85], as well as #bisoprolol** [88]. There is no experience with other beta-blockers. Beta-blockers may be prescribed according to indications in the treatment of secondary hypertension, typically in combination with drugs from other groups.

• If it is necessary to use drugs of this group in young children with hypertension, it is recommended to use the short-acting BB #propranolol** (C07AA05) [7].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

Main side effects: bradycardia, atrioventricular block, depression, emotional lability, insomnia, memory impairment, fatigue, bronchospastic reactions, hyperglycemia, hyperlipidemia, muscle weakness, erectile dysfunction in adolescent males.

Contraindications: obstructive pulmonary diseases, conduction disorders, depression, hyperlipidemia, diabetes mellitus, hypertension in athletes and physically active patients.

Special indications: hyperkinetic circulatory type, tachyarrhythmias, hypersympathicotonia.

Special notes: monitoring of blood glucose and lipid levels, ECG monitoring every 4 weeks from the start of treatment, regular assessment of the patient's emotional state and muscle tone.

Drugs used (see Appendix A3, Table 19):

#Metoprolol** (C07AB02) – administered orally to children at a starting dose of 0.5–1 mg/kg per day in 2 doses, maximum dose is 2 mg/kg per day in 2 doses [85].

#Bisoprolol** (C07AB07) – administered orally to children at a starting dose of 0.02–0.19 mg/kg per day (average 0.06 mg/kg per day) in 1 dose, maximum dose is 0.02–0.4 mg/kg per day (average 0.14 mg/kg per day) in 1 dose [88].

#Propranolol** (C07AA05) – administered orally to children at a starting dose of 1 mg/kg per day in 2–3 doses, maximum dose is 4 mg/kg per day (up to 640 mg) in 2–3 doses [7].

# The drug is approved in the Russian Federation for the treatment of hypertension in individuals over 18 years of age. Off-label use of the drug in children: prescribing outside of age indications is carried out by decision of the medical commission, after obtaining informed consent from parents and children over 15 years of age.

Combination therapy

In the treatment of hypertension in adult patients, combination therapy is conventionally used (preferably as a fixed-dose combination) [3, 4]. Monotherapy is prescribed only in patients with hypertension and low cardiovascular risk. Combination therapy has a number of advantages: potentiation of the antihypertensive effect; compensation for counter-regulatory mechanisms triggered at the initial stage of treatment; reduction of side effects and improved treatment tolerability; more effective prevention of target-organ damage and reduction of cardiovascular risk; enhancement of organ-protective properties (renal blood flow, glomerular filtration rate, urinary sodium excretion, reduction of microalbuminuria). Combination therapy allows for lower drug doses, is more cost-effective, and significantly improves adherence to treatment.

Fixed-dose combinations of dihydropyridine derivatives with an angiotensin II receptor blocker are most commonly used in adult hypertensive patients. Examples of such fixed-dose combinations include: amlodipine + valsartan; amlodipine + lisinopril; amlodipine + telmisartan. These combinations are metabolically neutral, can be used in high- and low-renin forms of arterial hypertension, promote vasodilation, and possess natriuretic effects [3, 4, 38].

• Currently, it is not recommended to use fixed-dose combinations of antihypertensive agents in children and adolescents with hypertension; clinical trial data on the use of the aforementioned fixed-dose combinations in pediatric practice are, unfortunately, contradictory and limited [7, 8].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

Comments. Fixed-dose combinations of antihypertensive agents are approved for the treatment of hypertension in individuals over 18 years of age. For antihypertensive treatment in children and adolescents with essential hypertension, monotherapy is preferred [7, 8]. If necessary, in case of ineffectiveness of standard monotherapy, preference is given to the combined use of antihypertensive agents, specifically a combination of ACE inhibitors, angiotensin II receptor blockers, or dihydropyridine calcium channel blockers with diuretics [7, 8].

3.4.1 Treatment of resistant arterial hypertension

According to current concepts, hypertension is classified as resistant if blood pressure levels remain above target values despite taking 3 or more antihypertensive drugs (at optimal doses), one of which is a diuretic. In pediatric practice, resistant hypertension most frequently occurs against the background of secondary (symptomatic) forms and develops in association with the following conditions: obstructive sleep apnea, primary aldosteronism, chronic kidney disease, renovascular hypertension due to renal artery stenosis, pheochromocytoma, Cushing's syndrome, coarctation of the aorta. In addition, monogenic forms of arterial hypertension exist. It is extremely important to diagnose the direct cause of hypertension in a timely manner. The treatment tactics for resistant hypertension in children are similar to those in adults.

Comments. Targeted randomized clinical trials evaluating the efficacy of triple-combination antihypertensive therapy for the treatment of resistant hypertension in children and adolescents have not been conducted. The efficacy of a similar evaluation and management strategy has been proven in adults with resistant hypertension [3, 4, 8, 91–94].

Eplerenone exhibits high selectivity for human mineralocorticoid receptors and prevents the binding of mineralocorticoid receptors to aldosterone, a key hormone of the renin-angiotensin-aldosterone system involved in blood pressure regulation. In a study on the use of #eplerenone (C03DA04) as monotherapy for hypertension in children and adolescents, a significant reduction in blood pressure was observed only with oral administration of high doses of the drug – greater than 50 mg [82].

Drugs used (see Appendix A3, Table 19):

#Spironolactone** (C03DA01) – oral tablets are prescribed to children at a starting dose of 1 mg/kg/day in 1 dose, with a maximum dose of 3 mg/kg/day (up to 100 mg/day) in 1 dose [7].

#Eplerenone (C03DA04) – oral tablets are prescribed at a starting dose of 25 mg/day in 2 divided doses, with a maximum dose of up to 100 mg/day in 2 divided doses [7].

The management strategy for patients with refractory hypertension and frequent hypertensive crises may also include the administration of alpha- and beta-blockers acting on alpha- and beta-adrenoreceptors: #carvedilol** (C07AG02) oral tablets are prescribed to children at a starting dose of 0.05–0.2 mg/kg/day in 2 divided doses; the dose can be titrated at intervals of 1–2 weeks to a target maintenance dose of 0.2–1 mg/kg/day with a recommended maximum dose of 2 mg/kg/day [95]. Additionally, selective alpha-blockers can be used in children as part of treatment regimens for specific causes of secondary hypertension, such as pheochromocytoma and paraganglioma: #prazosin** (C02CA01) oral tablets at a starting dose of 0.05–0.1 mg/kg/day in 2–3 divided doses, with a gradual dose increase every 3 days up to a maximum dose of 0.5 mg/kg/day, and #doxazosin** (C02CA04) oral tablets at a starting dose of 1 mg/day in 1 dose, with dose titration at intervals of 1–2 weeks by 1–2 mg up to a maximum dose of 4 mg/day [89].

# The drug is approved for the treatment of hypertension in individuals over 18 years of age. Off-label use in children: prescribing outside of age indications is carried out by decision of the medical commission, after obtaining informed consent from the parents and children over 15 years of age.

3.5 Treatment of arterial hypertension in special patient groups

Features of treatment for nephrogenic arterial hypertension

• For children with nephrogenic hypertension (excluding patients with salt-losing forms of kidney disease), especially in the presence of hypervolemia, it is recommended to follow a low-salt diet: avoid adding salt during cooking and at the table, and use products with a salt content <0.5 g/100 g of product (indicated on the product label) [7, 8, 52, 61].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

• For patients with chronic kidney disease (CKD), the target blood pressure is recommended to be < 90th percentile by sex, age, and height for children under 16 years of age and less than 130/80 mmHg for patients aged 16 years and older. If antihypertensive therapy is well tolerated in patients under 16 years of age, the blood pressure level may be lowered to <75th percentile for non-proteinuric variants of nephropathies and <50th percentile for proteinuric variants [7, 8, 52, 66, 96].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

• For patients ≥ 16 years of age with proteinuric variants of kidney disease, it is recommended to lower the 24-hour mean blood pressure (according to ABPM) to 125/75 mmHg. It should be kept in mind that patients must not experience episodes of hypotension detected either by office measurements or by ABPM [7, 8, 68, 81, 96].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

Comments. The choice of a drug from the ACE inhibitor/angiotensin II receptor blocker group is determined by renal and hepatic function. Doses of drugs must be adjusted according to the eGFR. Treatment is carried out under the control of blood creatinine and potassium levels every 5–10 days from the moment of initiation and dose escalation. If blood creatinine increases by ≤ 25% from baseline during therapy, routine monitoring of blood creatinine and potassium is performed in 4–6 days; with a further progressive increase in blood creatinine, the dose must be reduced or the drug discontinued. An increase in blood creatinine > 25% from baseline and blood potassium > 5.5 mmol/L requires a dose reduction or discontinuation of the drug, with a follow-up check of blood creatinine and potassium in 4–6 days.

Comments. Hypovolemia is characteristic of children with nephrotic syndrome exacerbation, polyuria (tubulopathies, polycystic kidney disease, tubulointerstitial nephritis). It manifests as tachycardia, prolonged capillary refill time in the pressure test, acrocyanosis, peripheral hypothermia, elevated hematocrit and blood urea. Capillary refill time is determined by applying pressure to the skin over the central sternum for 5 seconds, followed by assessing the time it takes for the pale spot to regain its normal color. Normally, capillary refill time is 2–3 seconds. Delayed skin color recovery after pressure indicates impaired tissue perfusion. In the case of nephrogenic hypertension accompanied by hypervolemia (renal acute renal failure and acute kidney injury, the acute phase of glomerulonephritis, concomitant heart failure), the drugs of choice are diuretics. Hypervolemia is characterized by tachycardia, increased amplitude of jugular venous pulsation, respiratory disorders, and warm extremities.

Treatment of nephrogenic hypertension in children is carried out according to generally accepted principles: from monotherapy to combination treatment, and from low therapeutic doses to moderate-high doses. Recommended drug combinations: ACE inhibitors/angiotensin II receptor blockers + dihydropyridine derivatives, ACE inhibitors/angiotensin II receptor blockers + thiazide diuretics (especially in adolescents and patients with a tendency to hyperkalemia); the combination of ACE inhibitors/angiotensin II receptor blockers + beta-blockers is less effective; the use of the combination of ACE inhibitors + angiotensin II receptor blockers is not indicated [89, 90].

Therapy at effective doses should be continued in patients under blood pressure monitoring throughout the entire period that risk factors promoting hypertension persist, but for at least 3 months. Adjustment of antihypertensive drug doses is carried out taking into account blood pressure levels from office measurements/ABPM, eGFR, and blood potassium.

The scope of antihypertensive therapy is reviewed when the child's physical development parameters (body weight, height) change, when triggering factors are eliminated or arise (immunosuppressive therapy), when disease activity changes, or upon correction of comorbid conditions, but at least once every 3 months.

Treatment of monogenic forms of arterial hypertension

Table 11 presents drugs for the treatment of monogenic forms.

Table 11. Treatment of monogenic forms of arterial hypertension

Drugs used (see Appendix A3, Table 19):

#Spironolactone** (C03DA01) – oral tablets are prescribed to children at a starting dose of 1 mg/kg/day in 1 dose, with a maximum dose of 3 mg/kg/day (up to 100 mg/day) in 1 dose [7].

#Eplerenone (C03DA04) – oral tablets are prescribed at a starting dose of 25 mg/day in 2–3 divided doses, with a maximum dose of up to 100 mg/day in 2–3 divided doses [7].

#Hydrochlorothiazide** (C03AA03) – oral tablets are prescribed to children at a starting dose of 0.5–1 mg/kg/day in 1 dose, with a maximum dose of 3 mg/kg/day (up to 50 mg/day) in 1–2 divided doses [7].

# The drug is approved for the treatment of hypertension in individuals over 18 years of age. Off-label use in pediatric practice: prescribing outside of age indications is performed by decision of the medical commission, after obtaining informed consent from parents and children over 15 years of age.

3.6 Treatment of emergency conditions (hypertensive crises)

A hypertensive crisis is a sudden, severe condition caused by a sharp increase in blood pressure. Hypertensive crises most commonly occur in symptomatic hypertension (acute glomerulonephritis, systemic connective tissue diseases, renovascular pathology, pheochromocytoma, traumatic brain injury, etc.).

Hypertensive crises are divided into two types:

- the first type – complicated hypertensive crisis, characterized by a sudden, sharp rise in blood pressure with the emergence of target-organ symptoms (central nervous system, heart, kidneys);

- the second type – uncomplicated hypertensive crisis, presenting as a sympathoadrenal paroxysm with prominent autonomic symptoms.

The clinical presentation of a hypertensive crisis is characterized by a sudden deterioration in general condition; an increase in systolic blood pressure (usually above 150 mmHg) and/or diastolic blood pressure (above 95 mmHg), and a severe headache. The patient may experience dizziness, visual disturbances (veil before the eyes, flashing spots), nausea, vomiting, chills, facial pallor or flushing, and a sense of fear. In cases of a complicated hypertensive crisis, hypertensive encephalopathy may develop, manifesting as headache, altered mental status, seizures, or visual disturbances. Reversible abnormalities on brain MRI are possible.

The main goal of managing a hypertensive crisis is the controlled reduction of blood pressure to a safe level to prevent complications.

Comments. During the first 6–12 hours, the mean arterial pressure should be reduced by 25% from baseline, during the first 24 hours – by another 30%, and subsequently over 48–72 hours, it is advisable to lower blood pressure to the 95th percentile (if hypertension is not accompanied by target-organ damage) or to the 90th percentile (if hypertension is accompanied by internal-organ damage or hypertensive encephalopathy).

Blood pressure should be lowered very slowly in hypertensive encephalopathy (due to the risk of ischemic stroke) and, conversely, quite rapidly in aortic pathology (dissecting aneurysm, coarctation).

• To manage a hypertensive crisis, it is recommended to establish the calmest possible environment and administer antihypertensive drugs [7,8,52,68,81,101,102].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

vasodilators used in cardiac diseases (C01D);

alpha-adrenoceptor antagonists (C02CA);

beta-adrenoceptor blocking agents (C07A);

dihydropyridine derivatives (C08);

diuretics (C03);

centrally acting adrenergic agents (C02A).

GPP CLoE 5Level of recommendation evidence C (level of data reliability – 5)

• In a complicated hypertensive crisis and/or poor tolerance of oral medications in children requiring emergency medical care, it is recommended to use intravenous drug administration and continuous intravenous drug infusions [7,8,100,102,103].         

LoR CLoE 5 Level of Recommendation C (Level of Evidence – 5)

• For uncomplicated hypertensive crises without target-organ damage in children, it is recommended to use oral agents for emergency care [7,8,100,102].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

Drugs used for the treatment of hypertensive crises in children are presented in Appendix A3, Table 20).

Vasodilators used in cardiac diseases (C04D)

Comments. Sodium nitroprusside dihydrate (C02DD01) is an arteriolar and venous vasodilator that increases renal, mesenteric, and coronary blood flow with minimal impact on cardiac output, controlling blood pressure upon intravenous administration. It is prescribed to children as an intravenous infusion at an initial dose of 0.3–3 mcg/kg/min with a gradual increase up to 8–10 mcg/kg/min in children presenting with a hypertensive crisis with life-threatening manifestations. It must be administered exclusively via IV infusion using an infusion pump, preferably volumetric (the use of standard IV sets is excluded due to insufficient dosing accuracy). Prolonged use (>72 hours) or renal impairment may lead to metabolic acidosis. Blood cyanide levels should be monitored [8,104].

#Nitroglycerin** (C01DA02) is prescribed as an intravenous infusion at a dose of 0.1–2 mcg/kg/min for children with a hypertensive crisis with life-threatening manifestations. Onset of action is within 1–2 minutes of administration; it may cause methemoglobinemia and predominantly venous vasodilation – it is effective in heart failure, though data on its efficacy in children are insufficient [7].

#Off-label drug use in pediatric practice: prescribing outside of age indications is performed by decision of the medical commission, after obtaining informed consent from parents and children over 15 years of age.

Beta-adrenoceptor blocking agents (C07A)

Comments. #Esmolol** (C07AB09) is an ultra-short-acting selective b₁-blocker without intrinsic sympathomimetic or membrane-stabilizing activity. The hypotensive effect of the drug is due to negative chronotropic and inotropic effects, reduced cardiac output, and decreased systemic vascular resistance. When administered intravenously, the effect appears within 5 minutes. Due to the risk of adverse effects, intravenous infusion of the drug at a rate of 100–500 mcg/kg/min is preferred. The elimination half-life is 9 minutes. Adverse effects: hypotension, marked bradycardia, decreased myocardial contractility, pulmonary edema [7,8,100,102,105].

#Off-label drug use in pediatric practice: prescribing outside of age indications is performed by decision of the medical commission, after obtaining informed consent from parents and children over 15 years of age.

Alpha-adrenoceptor antagonists (C02CA)

Comments. #Urapidil** (C02CA06) for managing a hypertensive crisis in children is administered intravenously via continuous IV infusion at a starting dose of 0.5–4 mg/kg per hour, followed by a maintenance dose of 0.2–2 mg/kg per hour; the drug is administered in the supine position with continuous blood pressure monitoring in peripheral arteries [7].

#Off-label drug use in pediatric practice: prescribing outside of age indications is performed by decision of the medical commission, after obtaining informed consent from parents and children over 15 years of age.

Calcium channel blockers (C08)

Comments. #Nifedipine** (C08CA05) is an effective drug for managing hypertensive crises. It inhibits calcium ion influx into vascular smooth muscle cells, reducing their contractility. This results in the dilation of peripheral arteries and arterioles. The drug is administered sublingually or orally at a dose of 0.25 mg/kg. The effect develops within 6 minutes, reaching a maximum at 60–90 minutes. Adverse effects include tachycardia, angina pectoris, facial flushing, and ankle edema [7,8,100,102,106].

#Off-label drug use in pediatric practice: prescribing outside of age indications is performed by decision of the medical commission, after obtaining informed consent from parents and children over 15 years of age.

Diuretics (C03)

Comments. Furosemide** (C03CA01) is administered as an intravenous bolus at a dose of 0.5–5 mg/kg depending on the clinical situation. It is an effective blood pressure-lowering agent in patients with heart failure and pulmonary edema [7,102].

Centrally acting adrenergic agents (C02A)

Alpha-adrenergic agonists

Comments. #Clonidine** (C02AC01) decreases the excitability of the vasomotor center, causes peripheral vasodilation, and slightly reduces cardiac output. It also has a sedative effect. Adverse effects include dry mouth, weakness, and drowsiness. Prolonged continuous use leads to tolerance. For hypertensive crisis management, it may be prescribed to children in oral tablets at a dose of 2–10 mcg/kg per dose every 6–8 hours, or as an intravenous bolus at a dose of 2–6 mcg/kg per administration [7,100].

#Off-label drug use in pediatric practice: prescribing outside of age indications is performed by decision of the medical commission, after obtaining informed consent from parents and children over 15 years of age.

Comments. The mechanism of action of methyldopa** (C02AB02) is similar to that of #clonidine**(C02AC01) and is mediated by a decrease in the excitability of the vasomotor center; however, unlike #clonidine**, it does not produce such pronounced sedative and hypnotic effects. Its use does not impair renal perfusion, despite the reduction in systemic BP. It can be used in most complicated hypertensive crises and serves as an alternative to traditional antihypertensive agents for treating patients with renal impairment. Methyldopa** is prescribed in children over 3 years of age for the management of crises without life-threatening manifestations in oral tablets at a starting dose of 5 mg/kg per day in 2–4 divided doses; the maximum dose for children is 40 mg/kg per day (up to 3 g/day) [7,8,100].

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Comments. In children and adolescents with primary hypertension grades 1 and 2, the development of an individualized psychological rehabilitation program is advisable; goals and objectives of rehabilitation measures are formulated based on the rehabilitation diagnosis and rehabilitation potential; the motor regimen is determined; rehabilitation methods are defined (medications, electrosleep, pulsed current electrophoresis, individualized clinical and psychological counseling); forms of medical rehabilitation at various stages of its application and during different periods of the disease course are selected (individual or group sessions); and counseling is provided to the legal representatives of children in need of medical rehabilitation.

Sanatorium-and-spa treatment

The main objective of the sanatorium-and-spa stage of treatment for children with hypertension is measures aimed at achieving the target BP level, preventing hypertensive crises and target organ damage, improving autonomic regulation of cardiac activity, increasing body resistance, and sanitizing foci of chronic infection [112,113].

Indications for referring children with arterial hypertension (AH) to sanatorium-and-spa treatment are formulated in Order of the Russian Ministry of Health No. 1029n dated September 28, 2020, "On Approval of the Lists of Medical Indications and Contraindications for Sanatorium-and-Spa Treatment."

Indications for sanatorium-and-spa treatment: high-normal BP, labile hypertension, primary hypertension grades 1 and 2, stage I hypertension.

Contraindications for referring children and adolescents with hypertension to sanatorium-and-spa organizations: circulatory failure of any stage, daily sympathoadrenal crises, paroxysmal tachycardia with frequent attacks, atrial fibrillation, complete atrioventricular block, complex cardiac arrhythmias, as well as general contraindications for sanatorium-and-spa treatment.

Methods of rehabilitation for children with hypertension in sanatorium-and-spa organizations include [112,113]:

1. Climatic regimen appropriate to the season of the year and the patient's clinical and functional status.

2. Medical nutrition.

3. Adequate physical load taking into account exercise tolerance in the form of a course of small-group or individual sessions.

4. Medical therapeutic massage of the collar zone and medical massage of the scalp.

5. Physical methods of treatment for children and adolescents with hypertension: sedative, hypotensive, vasodilating, cardiotonic, and autonomic-correcting methods (prescribed according to standard methodologies).

6. Clinical and psychological counseling; individual or group psychotherapy according to indications.

Motor regimen

- morning hygienic gymnastics with self-monitoring of heart rate, therapeutic gymnastics;

- fresh air walks along the seaside and in park areas;

- structured therapeutic walking prescribed adequately to the patient's condition at a pace of 70–80 steps per minute according to regimen I and 80–90 steps per minute according to regimen II, with short rests (3–5 min) on a bench; pulse is measured before and after therapeutic walking to monitor exercise tolerance;

- terrain cure (terrenkur) – alternating walking on flat terrain with ascents from 3° to 15°. Walking pace – slow (60–80 steps per minute).

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

Comments. Patients with grade 2 hypertension are recommended to follow physical activity prescribed under regimen I. If an increase in BP, a hypertensive crisis, worsening tolerance to physical and emotional loads, or deterioration of myocardial functional capabilities is recorded during the sanatorium-and-spa stage of treatment, it is recommended to transfer the child to regimen I (sparing) until the end of the sanatorium stay.

5. Prevention and Dispensary Observation

5.1 Principles of clinical follow-up (dispensary observation)

Dispanserization (active health monitoring) is a method of active dynamic observation of the health status of the population, including children and adolescents. Dispensary observation is subject to all children and adolescents with a family history of hypertension, high-normal BP, and hypertension.

Dispanserization includes the following activities:

1) registering all children and adolescents with a family history of hypertension, high-normal BP, and hypertension;

2) periodic medical examinations of these individuals to prevent the progression of hypertension;

3) implementation of a set of health-improving and therapeutic measures aimed at normalizing BP;

4) conducting medical-vocational counseling and vocational guidance for children and adolescents with hypertension, taking into account their gender and age.

Children and adolescents with a family history of hypertension and high-normal BP should be examined by a pediatrician once every 6 months (the examination is limited to anthropometric measurements and triple BP measurement on peripheral arteries). This cohort should be assigned to health group II, or health group III if autonomic dysfunction is present (in the absence of funduscopic or ECG changes).

Upon confirmation of the diagnosis of hypertension (essential or symptomatic), the child or adolescent is monitored by a pediatrician once every 3–4 months.

To determine the scope of diagnostic procedures, develop a non-pharmacological and pharmacological treatment strategy, and address cardiovascular disease risk factors, the child must be consulted by a pediatric cardiologist.

According to indications, the child or adolescent may be consulted by a nephrologist, ophthalmologist, and neurologist. Mandatory examinations (see the section "Diagnosis and Differential Diagnosis of Arterial Hypertension") are performed at least once a year, and additional ones according to indications (Tables 4 and 5).

Children and adolescents with grade 1 hypertension without other risk factors or target organ damage are included in health group III. Children and adolescents with grade 1 hypertension who have other risk factors and/or target organ damage, as well as those with grade 2 hypertension, are included in health group IV. Upon the development of heart failure, children and adolescents with hypertension are classified into health group V.

All data are entered into the child's medical history and medical record.

5.2 Primary prevention of arterial hypertension

Primary prevention begins with the identification of risk factors for hypertension and cardiovascular diseases during routine preventive medical check-ups of children and adolescents, such as a family history (presence of hypertension, early cardiovascular diseases, and diabetes mellitus in parents), overweight or obesity, and low physical activity (physical activity limited to physical education classes within the school curriculum). BP measurement on peripheral arteries must be performed at every visit at least once a year for all children starting from 3 years of age, and at every visit for patients in risk groups (see the section "Diagnosis and Differential Diagnosis of Arterial Hypertension").

Primary prevention of hypertension is carried out:

a) at the population level (targeting the entire population);

b) in risk groups (children with a family history, high-normal BP, overweight or obesity, and low physical activity).

Preventive interventions should aim at:

a) maintaining a normal body weight or reducing excess body weight (see recommendations for non-pharmacological treatment);

b) optimization of physical activity (see recommendations for non-pharmacological treatment);

c) rationalization of diet (see recommendations for non-pharmacological treatment).

6. Organization of Medical Care

6.1 Indications for hospitalization and discharge of patients with arterial hypertension

Indications for elective hospitalization:

• diagnostic uncertainty and the need for special investigative methods (diagnostic procedures that cannot or should not be performed in an outpatient setting) to clarify the cause of elevated BP (exclusion of secondary hypertension);

• persistent BP elevation, difficulties in selecting pharmacotherapy in an outpatient setting (comorbidity, frequent hypertensive crises);

• malignant refractory hypertension;

• when a teenager transitions from pediatric care to the adult healthcare network, the transfer epicrisis must reflect information regarding the etiology, clinical manifestations, and complications of hypertension, as well as the administered therapy with an efficacy analysis, which will ensure continuity in patient monitoring.

Indications for emergency hospitalization:

• hypertensive crisis refractory to pre-hospital management;

• hypertensive crisis in pheochromocytoma;

• hypertensive crisis with complications requiring intensive care.

Indications for discharging the patient from the hospital:

• established clinical diagnosis of hypertension using special investigative methods to clarify the cause of elevated BP;

• selected pharmacotherapy achieving the target BP level or a 25–30% reduction in BP from baseline values at discharge from the hospital;

• stabilization of laboratory parameters of comorbid conditions affecting the severity and course of the underlying disease;

• resolved hypertensive crisis, absence of complications requiring intensive care, stabilization of BP levels.

Other organizational technologies

When analyzing the performance of a medical organization regarding patients with hypertension, it is advisable to assess the following indicators:

• percentage of patients who reached the target BP level, which should be below the 90th percentile for the given age, sex, and height; for adolescents older than 16 years – below 130/85 mmHg at 3, 6, and 12 months of follow-up;

• percentage of patients receiving combination antihypertensive therapy to assess the risk of adverse drug reactions and polypharmacy, as well as to identify resistant hypertension;

• adolescents with elevated BP or hypertension (regardless of whether they are receiving antihypertensive therapy) should generally be transferred to the adult network to an appropriate specialist. Information regarding the etiology of hypertension and the patient's past manifestations and complications of hypertension must be handed over.

6.2. Regulatory and legal documents governing the provision of medical care to children with arterial hypertension

1. Order of the Ministry of Health of the Russian Federation No. 700n dated October 7, 2015 (as amended on December 9, 2019) "On the Nomenclature of Specialties of Specialists with Higher Medical and Pharmaceutical Education" (Registered with the Ministry of Justice of the Russian Federation on November 12, 2015, registration No. 39696).

2. Order of the Ministry of Health of the Russian Federation No. 206n dated May 2, 2023 "On Approval of Qualification Requirements for Medical and Pharmaceutical Workers with Higher Education" (Registered with the Ministry of Justice of the Russian Federation on June 1, 2023, registration No. 73677).

3. Order of the Ministry of Health of the Russian Federation No. 274n dated April 21, 2022 “On Approval of the Procedure for Providing Medical Care to Patients with Congenital and (or) Hereditary Diseases” (Registered with the Ministry of Justice of the Russian Federation on July 13, 2022, registration No. 69251).

4. Order of the Ministry of Health of the Russian Federation No. 878n dated October 23, 2019 "On Approval of the Procedure for Organizing Medical Rehabilitation for Children" (Registered with the Ministry of Justice of the Russian Federation on December 23, 2019, registration No. 56954).

5. Order of the Ministry of Health of the Russian Federation No. 231n dated March 19, 2021 (as amended on February 21, 2022) "On Approval of the Procedure for Monitoring the Volume, Timing, Quality, and Conditions of Provision of Medical Care under Compulsory Medical Insurance to Insured Persons, as well as its Financial Provision" (Registered with the Ministry of Justice of the Russian Federation on May 13, 2021, No. 63410).

6. Order of the Russian Ministry of Health No. 108n dated February 28, 2019 (as amended on December 13, 2022) "On Approval of the Rules of Compulsory Medical Insurance" (Registered with the Ministry of Justice of the Russian Federation on May 17, 2019, No. 54643).

7. Order of the Ministry of Health of the Russian Federation No. 789n dated December 13, 2022 "On Amendments to the Rules of Compulsory Medical Insurance Approved by Order of the Ministry of Health of the Russian Federation No. 108n Dated February 28, 2019" (Registered with the Ministry of Justice of the Russian Federation on December 30, 2022, No. 71905).

8. Amendment 14.1 to Article 37. Organization of Medical Care of Federal Law No. 323-FZ dated November 21, 2011 (as amended on June 11, 2022, with amendments dated July 13, 2022) "On the Fundamentals of Protecting Public Health in the Russian Federation" (with amendments and additions, entered into force on June 29, 2022) "Standards of medical care for children and clinical guidelines may include a medicinal product registered in the territory of the Russian Federation and used in accordance with indications (characteristics) of the medicinal product not specified in its instructions for use, provided that such medicinal product complies with the requirements established by the Government of the Russian Federation. The list of diseases or conditions (groups of diseases or conditions) in which the use of a medicinal product in accordance with indications (characteristics) of the medicinal product not specified in its instructions for use is permitted, is established by the Government of the Russian Federation.

9. Decree of the Government of the Russian Federation No. 1180-r dated May 16, 2022 "List of Diseases or Conditions (Groups of Diseases or Conditions) in Which the Use of a Medicinal Product in Accordance with Indications (Characteristics) of the Medicinal Product Not Specified in Its Instructions for Use Is Permitted".

10. Resolution of the Government of the Russian Federation No. 1799 dated October 27, 2023 "On Approval of Requirements for a Medicinal Product Registered in the Territory of the Russian Federation Used in Accordance with Indications (Characteristics) of the Medicinal Product Not Specified in Its Instructions for Use, the Inclusion of Which Is Permitted in Standards of Medical Care for Children and Clinical Guidelines".

11. Order of the Ministry of Health of the Russian Federation No. 1008n dated September 23, 2020 "On Approval of the Procedure for Providing Patients with Medical Nutrition" (Registered with the Ministry of Justice of the Russian Federation on September 30, 2020, registration No. 60137).

12. Order of the Ministry of Health and Social Development of the Russian Federation No. 366n dated April 16, 2012 "On Approval of the Procedure for Providing Pediatric Care" (with amendments and additions).

13. Order of the Ministry of Health of the Russian Federation No. 440n dated October 25, 2012 "On Approval of the Procedure for Providing Medical Care in the Profile 'Pediatric Cardiology'".

14. Order of the Ministry of Health of the Russian Federation No. 203n dated May 10, 2017 "On Approval of Criteria for Assessing the Quality of Medical Care".

15. Order of the Ministry of Health of the Russian Federation No. 514n dated August 10, 2017 "On the Procedure for Conducting Preventive Medical Examinations of Minors".

16. Order of the Ministry of Health of the Russian Federation No. 92n dated March 7, 2018 "On Approval of the Regulation on the Organization of Primary Health Care for Children".

17. Order of the Ministry of Health of the Russian Federation No. 302n dated May 16, 2019 "On Approval of the Procedure for Minors Undergoing Clinical Follow-up (Dispensary Observation), Including During the Period of Education and Upbringing in Educational Organizations".

18. Order of the Ministry of Health of the Russian Federation No. 103n dated February 28, 2019 "On Approval of the Procedure and Deadlines for the Development of Clinical Guidelines, Their Revision, the Standard Form of Clinical Guidelines, and Requirements for Their Structure, Composition, and Scientific Validity of Information Included in Clinical Guidelines" (Registered on May 8, 2019, No. 54588).

19. Letter of the Ministry of Health and Social Development of the Russian Federation No. 14-5/10/2-4265 dated May 29, 2009 "On Referring Children for Sanatorium-Resort Treatment to Sanatorium-Resort Organizations Under the Jurisdiction of the Ministry of Health and Social Development of Russia".

20. Order of the Russian Ministry of Health No. 1029n dated September 28, 2020 "On Approval of Lists of Medical Indications and Contraindications for Sanatorium-Resort Treatment" (Registered with the Ministry of Justice of Russia on October 27, 2020, No. 60589).

7. Additional Information

Lowering blood pressure and maintaining it at the target level improves the prognosis of children and adolescents with hypertension, prevents the persistence of arterial hypertension in later life, which significantly reduces the risk of cardiovascular complications in adulthood.

Other important areas in the treatment of arterial hypertension are:

Maximum reduction of the risk of cardiovascular complications, reduction of mortality;

Correction of all modifiable cardiovascular risk factors (smoking, dyslipidemia, obesity, hyperglycemia);

Prevention, slowing down the progression rate, and/or reduction of target organ damage;

Treatment of comorbid conditions (renal pathology, timely correction of congenital heart defects).

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

Leontieva I.V. – MD, Professor (Moscow) – Co-chair of the Working Group, member of the ADKR

Kislyak O.A. – MD, Professor (Moscow) – Co-chair of the Working Group, member of the RMOAG

Aleksandrov A.A. – MD, Professor (Moscow) – Co-chair of the Working Group, member of the RMOAG

Ushakova S.A. – MD (Tyumen) – Secretary of the Working Group, member of the ADKR

Aksenova M.E. – PhD (Moscow)

Balykova L.A. – MD, Professor, Corresponding Member of the RAS (Saransk), member of the ADKR

Kozlova L.V. – MD, Professor (Smolensk), member of the ADKR

Kovalev I.A. – MD, Professor (Moscow), member of the ADKR

Kurganova A.V. – PhD (Yevpatoria)

Nikitina I.L. – MD, Professor (Saint Petersburg), member of the ADKR

Plotnikova I.V. – MD (Tomsk), member of the ADKR

Rozanov V.B. – MD (Moscow), member of the RMOAG

Sadykova D.I. – MD, Professor (Kazan), member of the ADKR

The members of the Working Group confirmed that they have no financial support or conflicts of interest. If a conflict of interest was reported, the member(s) of the Working Group were excluded from the discussion of sections related to the area of conflict of interest.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

1. Pediatricians

2. Pediatric cardiologists of pediatric cardiology departments

3. Pediatric cardiologists of cardiology offices in children's polyclinics

Description of methods used to assess the quality and strength of evidence: the evidence base for the recommendations includes publications from the Cochrane Library, EMBASE, MEDLINE, and PubMed databases. The search depth was 5 years.

Methods used to assess the quality and strength of evidence:

• expert consensus;

• assessment of significance in accordance with the rating scheme.

Methods used for analyzing evidence:

• reviews of published meta-analyses;

• systematic reviews with evidence tables.

Methods used for formulating recommendations: expert consensus.

Economic analysis

Cost analysis was not performed, and pharmacoeconomic publications were not analyzed.

Recommendation validation method

• External expert review.

• Internal expert review.

Description of the recommendation validation method

The draft version of these recommendations was peer-reviewed by independent experts, who were primarily asked to comment on whether the interpretation of the evidence underlying the recommendations is easy to understand. Comments were received from primary care pediatric cardiologists regarding the clarity of presenting the importance of the proposed recommendations as a tool for daily practice. All comments received from experts were carefully systematized and discussed by the authors of the recommendations.

Consultation and peer review

The draft recommendations were reviewed by independent experts who evaluated the clarity and accuracy of the interpretation of the evidence base underlying the recommendations.

Authors

For the final edition and quality control, the recommendations were re-analyzed by the working group members, who concluded that all remarks and comments from the experts had been taken into account, and the risk of systematic bias in the development of the recommendations was minimized.

Table 1. Scale for assessing levels of evidence (LE) for diagnostic methods (diagnostic interventions)

Table 2. Rating scale for levels of evidence (LE) for preventive, therapeutic, and rehabilitation methods (interventions)

Table 3. Rating scale for grades of recommendation (GR) for preventive, diagnostic, therapeutic, and rehabilitation methods (interventions)

Procedure for updating clinical guidelines

The mechanism for updating clinical guidelines provides for their systematic revision at least once every three years, as well as upon the emergence of new evidence-based medicine data on the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

Table 1. Blood pressure values in newborns according to gestational age*

SBP – systolic blood pressure, DBP – diastolic blood pressure, MBP – mean blood pressure.

*Dionne J. et al. Pediatric NephrologyHypertension in infancy: diagnosis, management and outcome //January 2012, Volume 27, Issue 1, pp 17–32.

Table 2. Blood pressure (BP) percentiles in boys and girls at 1 year of age*

*Mattoo K. Evaluation and diagnosis of hypertension in infants between one month and one year of age // UpToDate This topic last updated: Jun 11, 2020. 

Table 3. Recommended cuff sizes according to arm circumference*

* Lurbe E., Agabiti-Roseic E., Cruickshankd J.K, Dominiczake A., Erdinef S., Hirthg A., et.al. 2016 European Society of Hypertension guidelines for the management of high blood pressure in children and adolescents. J Hypertens. 2016 Oct;  34(10):1887-920. doi: 10.1097/HJ.0000000000001039

Table 4. Height percentile values (cm) in boys and girls aged 1 to 17 years *

*Diagnosis, treatment, and prevention of arterial hypertension in children and adolescents. Russian Guidelines (2nd revision). 2009; 8(4): 1-32.

Table 5. BP values corresponding to the 90th, 95th, and 99th percentiles according to age and height percentile for boys*

*Diagnosis, treatment, and prevention of arterial hypertension in children and adolescents. Russian Guidelines (2nd revision) 2009; 8(4): 1-32.

Table 6. BP values corresponding to the 90th, 95th, and 99th percentiles by age and height percentile for girls*