Primary and secondary paediatric hypertension

Abstract

 

High blood pressure (BP) or hypertension is a well known risk factor for developing heart attack, stroke, atrial fibrillation and renal failure. Although in the past hypertension was supposed to develop at middle age, it is now widely recognized that it begins early during childhood. As such, approximately 5–10% of children and adolescents are hypertensive. Unlike that previously reported, it is now widely accepted that primary hypertension is the most diffuse form of high BP encountered even in paediatric age, while secondary hypertension accounts just for a minority of the cases. There are significant differences between that outlined by the European Society of Hypertension (ESH), the European Society of Cardiology (ESC), and the last statement by the American Academy of Pediatrics (AAP) concerning the BP cut-offs to identify young hypertensive individuals. Not only that, but the AAP have also excluded obese children in the new normative data. This is undoubtedly a matter of concern. Conversely, both the AAP and ESH/ESC agree that medical therapy should be reserved just for nonresponders to measures like weight loss/salt intake reduction/increase in aerobic exercise. Secondary hypertension often occurs in aortic coarctation or chronic renal disease patients. The former can develop hypertension despite early effective repair. This is associated with significant morbidity and is arguably the most important adverse outcome in about 30% of these subjects. Also, syndromic patients, for example those with Williams syndrome, may suffer from a generalized aortopathy, which triggers increased arterial stiffness and hypertension. This review summarizes the state-of-the-art situation regarding primary and secondary paediatric hypertension.

Introduction

High blood pressure (BP) or hypertension is a well known modifiable risk factor for developing myocardial infarction, stroke, atrial fibrillation and progressive renal impairment.^1–4 Like many other chronic diseases, hypertension starts very early in childhood and tends to persist after reaching adulthood. It is the so-called ‘tracking’ of BP, as already proved by many studies in the field.^5,6 Preventing the complications of hypertension is critically dependent on making an early diagnosis of high BP and recognizing the related initial damage. Unfortunately, there is still a significant gap between the suggestions reported in the literature and clinical practice.⁴ Another interesting point is that – unlike that thought in the past – primary hypertension is the most diffuse form of high BP in children and adolescents, while secondary hypertension is the prevalent form of hypertension during neonatal life and early childhood.⁶

This review asks the questions: what is the definition of high BP in childhood, what is the prevalence of paediatric hypertension, which predisposing factors give rise to high BP and what strategies in childhood could we employ to detect and reduce hypertension? The most frequently encountered forms of secondary hypertension, for example coarctation of the aorta (CoA), renal insufficiency and systemic aortopathies with increased arterial stiffness, are described as well.

Definition of high blood pressure in childhood

BP should be checked once a year in all children starting from the age of 3 years.⁷ Nomograms with normal BP values in childhood and adolescence have been made available in the USA as well as in the Old Continent since many years ago. The first paediatric BP normative tables – stated in the form of sex-specific centile curves showing the distributions of SBP and DBP values for an age ranging between 5 and 17 years, after corrections for the patients’ height and weight – were released in the United States in 1987,⁸ with periodical updates in 1996 and 2004.^9,10 Concerning Europe, in the recommendations released by the European Society of Hypertension (ESH) in 2009, for the first time hypertension in children was discussed.¹¹ After a 13-year gap, the American Academy of Pediatrics (AAP) released practice Guidelines for Screening and Management of High Blood Pressure in Children and Adolescents. They included 30 key action statements and 27 additional recommendations which were endorsed by the American Heart Association (AHA). In the AAP guidelines, the previous 2004 cut-offs to define normal BP and hypertension were significantly changed with the aim of simplifying diagnosis, enhancing the need for checking BP in paediatric age and aligning with the American College of Cardiology (ACC) and AHA practice guidelines released the same year.^12,13 As such, before the age of 13 years, BP is considered increased if the systolic and/or diastolic values are over the 95th centile in three separate office examinations. In addition, hypertension is subdivided into stage 1 HTN (≥ 95th centile) and stage 2 hypertension (≥ 95th centile + 12 mmHg). This is after having screened over 50 000 American children and adolescents by means of the auscultatory method and assessed approximately. 15 000 studies on paediatric BP published since the 2004 report.¹³ If there is discrepancy between systolic and diastolic values concerning categorization, BP should be classified using the higher value.¹³ In adolescents aged 13 years or more a simplified BP classification matching the ACC/AHA adult BP guidelines was chosen, so that a cut-off of 120/80 mmHg was used to detect raised BP, irrespective of sex.¹³ Furthermore, unlike the 2004 Fourth Report, the 2017 BP tables did not include overweight and/or obese subjects, but only individuals with a normal weight. BP cut-off values were recalculated after such an exclusion. The decision is based on the well established association between overweight/obesity and high BP.¹⁴ For the Authors, including overweight and obese individuals in BP nomograms would represent a bias. As a result, the related reference values are a few mmHg lower than the previous values. Simplified tables were provided to make diagnosis of HTN in the primary care setting (see Table 1).¹³ On the contrary, the 2009 ESH recommendations provided an algorithm for the diagnosis of HTN in paediatric age. High BP is diagnosed when systolic and/or diastolic values are over the 95th centile.¹¹ Furthermore, hypertension was subdivided into stage 1 (from 95th to 99th centile + 5 mmHg) and stage 2 (> 99th centile + 5 mmHg). BP values between the 90th and 95th centiles (high-normal BP) require accurate surveillance based on repeated BP measurements over a period of months. Immediate pharmacological therapy is not needed at this stage.¹¹ The European recommendations were then updated and guidelines released in 2016. The agreement was that, for individuals of both sexes aged 16 years or more, the definition of hypertension should no longer rely on centiles, but it should be graded as for adults (e.g. high-normal BP: 130--139/85--89 mmHg and hypertension: 140/90 mmHg or more). Again, hypertension was subdivided into grade 1 (95th--99th centile + 5 mmHg) and grade 2 (>99th centile + 5 mmHg; see Table 2).¹⁵ On balance, the most important differences between the American and European Guidelines are the criteria for diagnosing and classifying high BP in the young and the age at which equate adolescents with adult patients, which in turn have a strong impact on the estimation of paediatric high BP prevalence. Again, in a very recent Consensus document released by the European Society of Cardiology (ESC), it was agreed that hypertension should be defined in accordance with that suggested by the AAP up to age 16 years. For those aged 16 years or over, a cut-off of 130/85 mmHg was endorsed. The need for developing European-specific normative standards was highlighted as well.¹⁶

Table 1 - High blood pressure in children and adolescents according to the American Academy of Pediatrics 2017 guidelines¹³

Grading	Children 1–12 years (percentile)	Adolescents ≥13 years (mmHg)	Action
Normal blood pressure	<90th percentile	<120/<80	Check blood pressure during the subsequent routine examinations
Elevated blood pressure (previously termed prehypertension)	Between ≥90th percentile and <95th percentile or between 120/80 mmHg and <95th percentile (the latter is lower than in the past)	Between 120/<80 and 129/<80	First approach: lifestyle modifications; check blood pressure Second approach: if blood pressure is still elevated, seek any blood pressure difference between upper and lower limbs. If there is no difference, keep with life style modification and check blood pressure again after 6 months Third approach: if blood pressure is still high, 24-h ambulatory blood pressure monitoring is indicated. If blood pressure normalizes, check blood pressure on an annual basis
Stage 1 hypertension	≥95th percentile or <95th percentile + 12 mmHg or between 130/80 and 139/89 mmHg (cut-off values which are lower than in the past) (Previous definition: blood pressure between 95th and 99th percentile +5 mmHg)	Between 130/80 and 139/89	First approach: if the child is asymptomatic, lifestyle modifications are indicated along with a further blood pressure check after 1–2 weeks by using the auscultatory method Second approach: if blood pressure is still at grade 1, blood pressure difference between upper and lower limbs should be checked. If there is no significant difference, healthy diet and weight loss are suggested. Blood pressure should be re-checked after 3 months Third approach: if blood pressure is still at grade 1, 24-h ambulatory blood pressure monitoring is indicated. Primary or secondary hypertension should be diagnosed, and medical therapy should be started. Specialist consultation should be asked for in case of secondary hypertension. If the child is symptomatic, all that above stated should be brought forward
Stage 2 hypertension	≥95th percentile + 12 mmHg, or ≥140/90 mm Hg (cut-off values, which are lower than in the past) (previous definition: blood pressure >99th percentile +5 mmHg)		First approach: if the child is asymptomatic, blood pressure difference between upper and lower limbs should be checked and lifestyle modifications suggested as well. Blood pressure should be re-checked after 1 week and eventually the child should be referred to a cardiologist consultation within 1 week Second approach: if blood pressure is still at grade 2, a complete examination is needed, 24-h ambulatory blood pressure monitoring included. Medical therapy should be started or the child should be referred to a cardiologist consultation within 1 week. If the child is symptomatic or if blood pressure exceeds 95th percentile (or it is >180/120 mm Hg in adolescents), the patient should be addressed to the Admission and Emergency Department

Table 2 - Paediatric hypertension according to the ESH guidelines 2009 and 2016^11,15

Normal-high pressure: 90th--95th centile

Hypertension (stage 1): 95th--99th centile + 5 mmHg

Hypertension (stage 2): over 99th centile + 5 mmHg

Sixteen years and over: like in adult patients, e.g. normal-high blood pressure: 130–139/85–89 mmHg and high blood pressure: >140/90 mmHg

Due to the lack of data on cardiovascular morbidity and mortality correlated with high BP in children, the definition of hypertension in paediatric age is a statistical value based on the normal distribution of BP values in the paediatric population.¹⁷

Measuring BP in a medical setting has its own limitations, including the option of missing the ‘white-coat HTN’ (i.e. not only BP ≥95° when measured by a physician, but also <95° when checked at home with a less than 25% difference between the two measurements) as well as the ‘masked HTN’ (i.e. not only BP <95° when measured by a physician, but also ≥95° when checked at home with a more than 25% difference between the two measurements).¹⁸ White-coat hypertension is common in children with obstructive sleep apnoea syndrome, while masked hypertension can be found in renal transplant recipients.^19,20 AAP guidelines suggest using a 24-h ambulatory blood pressure monitor (ABPM) as the only reliable way to overcome these issues or when BP is borderline. Not only that, but ABPM measurement is well correlated to preclinical damage to the heart, brain, retina, kidneys and arterial blood vessels. ABPM should be performed by using a device that is validated in paediatric ages. Not only does ABPM allow hypertension to be diagnosed, but it also provides useful information to refine high BP diagnosis itself. Concerning ABPM, reference values exist only for children taller than 120 cm and of white descent. ABPM should be performed in all children aged 5 years or over whose BP is categorized as ‘elevated’ for at least 1 year or in those with ‘stage 1’ hypertension in at least three consecutive examinations.^11,21 Regular ABPM is indicated in children with chronic renal disease, secondary hypertension, type 1 and 2 diabetes, obstructive sleep apnoea syndrome, preterm birth and in those previously surgically treated for organ transplant or aortic coarctation. AAP 2017 guidelines agree with suggestions by the ACC/AHA in 2014 concerning ABPM interpretation.^13,21 ABPM is decidedly indicated in white-coat hypertension, as individuals with the latter have increased left ventricular mass compared with normotensive children and also an increased risk of progressing towards sustained high BP.²² For technical reasons, ABPM should be limited to individuals aged at least 5 years who are capable of tolerating the procedure and for whom there are reference values to interpret the related BP measurements. The list of validated ABPM devices, including those which can be used in paediatric age, can be detected at the link www.dableducational.org. Home BP measurement is not recommended to make a diagnosis of hypertension in paediatric ages for many reasons, poor correlation with BP measured in medical settings and with ABPM included.²¹

Prevalence of paediatric hypertension

The first studies about the prevalence of hypertension in the young date back to the 40s of the last century. They were carried out in the USA.²³ Currently, the prevalence of paediatric hypertension in the USA is estimated on the basis of the data collected during the National Health and Nutrition Examination Survey (NHANES), by means of a single BP measurement. According to NHANES, high BP is more common in men, in those of Hispanic and African--American descent, and during adolescence as well.¹³ However, with repeated BP checks, the prevalence of the disease tends to decrease gradually because of BP variability itself as well as an improvement in the expertise in the BP-measuring technique (the so-called regression towards the mean). This is a principle that occurs in every event in nature. In fact, when taking a couple of independent measurements from the same distribution, samples far from the mean on the first check will be closer to the mean on the second check. Regression towards the mean is the name of this mathematical inevitability. Any measurement of any variable shows such regression to the mean.²⁴ On balance, hypertension prevalence in American children and adolescents seems to be approximately 3.5%.⁷

The prevalence of paediatric hypertension in Europe shows some fluctuations, depending on the fact that the survey was conducted by means of a single or multiple BP checks.²⁵ Overall, the averaged prevalence of paediatric high BP in Europe is around 5%, with some peaks.⁷ A quite recent screening, which was carried out in Greece, found that the prevalence of high BP in that country was shocking and likely the highest reported in Europe so far, as 15.7% of the sample had stage 1 hypertension, whereas 7.3% had stage 2 hypertension. Isolated systolic hypertension was the most frequently encountered type.²⁶ However, these worrisome results were based on a single BP check and so that is a matter of concern. Again, not only was the BP assessed through a single measurement, but also BP nomograms that were not population-specific were used as reference values, thus probably leading to an overestimation of the phenomenon.²⁷ In a previous survey conducted in another Southern European country, for example Italy, with more accuracy and many measurements rather than a single one before classifying a child as hypertensive, the prevalence of hypertension was 9.4%, isolated diastolic hypertension being the most frequent subtype (4.6%).²⁵ Also, a strong link with overweight/obesity, prematurity at birth/low birthweight, familial history of hypertension and sedentary life was found.^14,28 In the UK, specific-population nomograms were released, which had been built by pooling together BP data from some nationally representative surveys, namely the Health Surveys for England 1995–8, the Scottish Health Surveys 1995 and 1998, and the National Diet & Nutrition Survey 1997. Hypertension was defined as BP over the 98th percentile, and high-normal BP as BP between the 91st and 98th percentiles. BP was measured three times by means of an oscillometric device after a 10- to 15-min rest period. The first reading was discharged and the mean between the second and third readings was used for analysis. As such, the prevalence of paediatric HTN was 8.5% for SBP and 0.5% for DBP.²⁹ Again, in a multicentre study, the prevalence of high BP in adolescents was estimated at 16.4% in central Europe (Germany, Austria, Switzerland).³⁰ The reality is that each country should develop its own nomograms to avoid any underestimation or overestimation of the disease prevalence. Clinicians from every ethnic group or country in the world, through recording BP in children and adolescents routinely, should release their own national BP reference values relating to age, sex and height, derived from their genetic, nutritional, cultural, ethnic and social backgrounds.^5,21,25

Factors giving rise to hypertension in paediatric age

Many risk factors are correlated with paediatric hypertension in various studies, with overweight/obesity being a major one. The link between obesity and increased BP is further proved by the fact that an overweight child is three times more likely to develop hypertension than a child with a normal BMI.³¹ Along with overweight/obesity, obstructive sleep apnoea, increased sodium intake, strong family history, diabetes, increased uric acid levels, ethnicity, artificial feeding, prematurity at birth/low birthweight are some of the already established risk factors for developing high BP in the young.³¹

Specifically, when examining each of the above-stated risk factors, the exact pathophysiological link between overweight/obesity and hypertension is still poorly understood and likely multifactorial. It involves inulin-resistance, sympathetic nervous system activation, rennin–angiotensin–aldosterone system activation, renal sodium retention, leptine resistance, imbalance in the vasodilation-vasoconstriction arterial mechanism or in the hypothalamus–pituitary–adrenal gland axis.³²

The pathophysiology of high BP in obstructive sleep apnoea is multifaceted and relies on a number of factors, such as an increase in sympathetic tone, peripheral vasoconstriction, night-time fluid shift, raised rennin–angiotensin–aldosterone activity and unbalanced baroreceptor reflexes.³³

The pathophysiological relationship between sodium intake and hypertension has been widely discussed. Increased salt consumption may trigger water retention, thus causing high blood flow in arterial vessels. The mechanism of pressure natriuresis has been suggested as a physiologic phenomenon wherein a BP surge in the kidney arteries causes increased salt and water excretion.³⁴

Regarding family history, normotensive offspring with hypertensive parents have higher BP values and impaired large and small arterial elasticity in comparison to normotensive offspring of normotensive parents. These differences were evident in men but not in women.³⁵ For adolescents with weight and waist circumstance within normal range, those with a positive history of hypertension in parents have a significantly two-fold increased risk for high BP compared with those without.³⁶

Concerning diabetes, the rate of hypertension in children with type 1 diabetes is reported to be between 6 and 16%.³⁷ Two major studies aimed at better refining the features of diabetes in youth have contributed to understanding the pathophysiology of the disease in this population, namely the SEARCH for Diabetes in Youth (SEARCH) and Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY). Historically, type 1 diabetes has been more frequently encountered in children and adolescents than type 2. However, things are changing, as type 2 diabetes is no longer uncommon in paediatric age, and the rise of the disease goes together with the obesity epidemic. In relation to new diagnoses of diabetes in American people aged less than 18 years, one out of three individuals is diagnosed with type 2 diabetes, and two out of three have type 1 diabetes. Both types of diabetes cause progressive renal dysfunction, microalbuminuria and in turn poor BP control.³⁸

Hyperuricemia-induced hypertension can be subdivided into two phases: a first acute step, which was driven by uric acid itself and mediated by oxidative stress, inflammation, endothelial dysfunction and renin–angiotensin–aldosterone system hyperactivity, and a second chronic step, which is characterized by arterial wall hypertrophy, renal microvascular changes and interstitial inflammation.³⁹

The rate of paediatric hypertension shows fluctuations depending on ethnicity as well. In the USA, the highest prevalence of high BP was seen in Hispanic, followed by African--American adolescents. However, obese white adolescents have the highest prevalence of sustained hypertension compared with obese African--American adolescents. Although obesity remains the strongest predictor of early hypertension, the strength of this link is particularly evident in white adolescents, whilst it is less strong in African--American adolescents.⁴⁰

Artificial feeding, which is rich in salt, may trigger an early rise in BP. Conversely, breast feeding in infancy drops SBP in later life, although this effect is modest in comparison to that suggested in small studies, as shown in a meta-analysis on 29 studies in the field.⁴¹

Individuals formerly born preterm may develop arterial -- particularly isolated systolic -- hypertension more often than their counterparts born at term. Many factors affect this tendency, such as an incomplete nephrogenesis, which implies the presence of kidneys with a reduced nephrons number and consequent decrease in haematic filtration, augmented sodium absorption and activation of the rennin–angiotensin–aldosterone system, increased arterial stiffness as a consequence of an elastin deficiency previously detected in anatomic specimens of human immature aorta, and reduced endothelial nitric oxide excretion, owing to raised hematic levels of ADMA, a strong direct inhibitor of nitric oxide, which exerts a strong vasoconstrictor action.^42,43

Controversial data are in literature concerning sex influence in developing paediatric hypertension, with some studies showing a prevalence in men, others in women and others showing no difference between sexes at all.^44–46

Strategies in childhood to detect and reduce hypertension

Hypertensive children and adolescents are often asymptomatic and the detection of high BP is a casualty in most cases. Family history, secondary hypertension exclusion, salt intake reduction with diet and increasing aerobic exercise are emphasized in both AAP and ESH Guidelines. Specifically, a combination of the DASH (Dietary Approach to Stop Hypertension) diet -- which is vegetable, fruit and skim milk rich and with scarce salt -- and anaerobic exercise (30–60 min sessions with 3–5 sessions/week) are very effective. Weight loss is encouraged as well.^13,21,47 The initial treatment should be attempted for no less than 6 months.

Both the AAP and ESH agree that medical therapy should be reserved for nonresponders to the above-stated measures only. Medical therapy is not influenced by race, ethnicity and gender.

The goal of BP control is lowering BP under the 90th percentile, as organ damage has been demonstrated even in children and adolescents with BP values between the 90th and 95th percentiles. Not only that, but with BP under the 90th percentile, a reduction in cardiac mass has been demonstrated as well.^48,49 In children with chronic kidney disease, the goal of the medical therapy is lowering BP to under the 50th percentile. Proteinuria should be taken under control as well.

Taking medicines is not without any risks, most of all because data on long-term safety and tolerability in children are lacking.⁵⁰ Antihypertensive therapy is indicated in children when high BP persists notwithstanding multiple attempts to modify lifestyle or in those suffering from symptomatic hypertension or stage 2 hypertension without modifiable risk factors (e.g. obesity) or any stage of hypertension when the latter is associated with chronic renal disease or diabetes. Medical therapy is indicated in those with left ventricular hypertrophy as well.^13,21 Unlike that outlined in the 2004 Fourth Report, in 2017, AAP guidelines echocardiography is limited to those hypertensive children requiring medical therapy. Yearly cardiac ultrasound scans are no longer required in children with diagnosed HTN.^10,13

On the basis of the trials carried out in adulthood, beta blockers as a first-line therapy in children are advised against. Long-acting calcium channel blockers, thiazide diuretics, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers should be preferred.^13,21 In the recent ESC Consensus document, angiotensin receptor blockers, dihydropyridine calcium channel blockers and diuretics were suggested as a first-line therapy.¹⁶ Combination therapy is sometimes used in clinical practice, although there are very few studies in the field. A combination of propranolol/chlorthalidone was given to approximately. 100 children with essential hypertension aged 8–18 years. A statistically significant decrease in both SBP and DBP was noted.⁵¹ Another study examining the safety and efficacy of the association of bisoprolol/hydrochlorothiazide in children versus placebo was carried out. However, there was no statistical difference in the percentage of patients achieving target BP control.⁵²

Unlike those occurring in adulthood, antihypertensive therapy indications in paediatric age are generally based on single-centre studies with a limited number of patients rather than on double-blinded trials. Many medications are provided off-label, especially in Europe. See Table 3, which summarizes the most often used antihypertensive drugs in paediatric age with a comparison to the adult dosage.^21,53,54

Table 3 - Antihypertensive drugs, which are frequently used in paediatric age with comparison to adult dose

Drug class	Drug	Daily paediatric dose	Daily adult dose
Angiotensin-converting enzyme inhibitor	Captopril	Newborns: 0.03–0.1 mg/kg Children: 1.5 mg/kg	Up to 150 mg
	Enalapril	0.08–0.58 mg/kg (up to 40 mg)	Up to 40 mg
	Ramipril	6 mg/m2	Up to 10 mg
	Fosinopril	0.1–0.6 mg/kg (up to 40 mg)	Up to 40 mg
	Lisinopril	0.07–0.6 mg/kg (up to 40 mg)	Up to 40 mg
Angiotensin receptor blocker	Losartan	0.7–1.4 mg/kg (up to 100 mg)	Up to 100 mg
	Valsartan	1.3–2.7 mg/kg (up to 160 mg)	Up to 320 mg
	Candesartan	1–6 years: 0.2–0.4 mg/kg 6–17 years: less than 50 kg: 4–16 mg 6–17 years: over 50 kg 8–32 mg	Up to 32 mg
	Olmesartan	20 to less than 35 kg: 10–20 mg equal to/over 35 kg: 20–40 mg	Up to 40 mg
Calcium channel blocker	Amlodipine	0.12–0.3 mg (up to 10 mg)	Up to 10 mg
	Nifedipine	0.5–1 mg/kg	Immediate release: up to 180 mg Extended-release: 120 mg
Diuretics	Furosemide	0.5–2 mg/kg	Up to 600 mg
	Hydrochlorothiazide	0.5–1 mg/kg	Up to 100 mg
	Spironolactone	1 mg/kg	Up to 100 mg
Beta blocker	Propranolol	1 mg/kg	Up to 320 mg
	Atenolol	1 mg/kg	Up to 200 mg
	Metoprolol	1–2 mg/kg (up to 200 mg)	Up to 200 mg
	Carvedilol	0.08–1.5 mg/kg	Up to 50 mg

Therapy should be monitored. In children requiring just lifestyle modifications, the suggested follow-up is 3–6 months long. Conversely, in those on antihypertensive treatment, a tighter follow-up is required, with examinations every 4–6 weeks with the aim of eventually increasing drugs or starting a combination therapy. Medications effectiveness can be verified by using ABPM as well.^13,21

Resistant hypertension (i.e. persistence of high BP notwithstanding already taking three medications belonging to different classes, one of them being a diuretic) therapy implies checking BP by means of an adequately sized cuff and ABPM; salt intake reduction; secondary HTN exclusion; exclusion of any substance able to lead to high BP (for instance liquorice); adding one more antihypertensive agents.^13,21

In hypertensive crisis with potentially life-threatening complications such as encephalopathy, heart failure or acute kidney injury, the goal of the therapy is a 25% reduction in the initial BP values to be reached within 8 h. In fact, a BP drop that is too fast may induce harmful organ hypoperfusion. Intravenous (i.v.) therapy is indicated with sodium nitroprusside, fenoldopam or clonidine.⁵⁵ Sublingual drops of nifedipine can be administered in place of i.v. therapy. Its action is usually quick and with negligible side effects. The suggested dose is 0.25 mg/kg to avoid hypotension.⁵⁶

Secondary hypertension

This is essentially caused by CoA or renal diseases. Sometimes, it is triggered by genetically related arteriopathies such as in Williams-Beuren Syndrome (WBS). Other less common causes of secondary hypertension are Cushing syndrome, pheochromocytoma, hyperthyroidism, hyperparathyroidism and primary aldosteronism (Conn's disease).

CoA is way more than a simple discrete narrowing of the aortic isthmus, which can be treated surgically or by means of a percutaneous intervention. It is often linked to a wider vasculopathy leading to significant prevalence of hypertension by adolescence, and subsequent risk of early morbidity and death.⁵⁷ Although early surgery may prevent or delay the occurrence of hypertension, approximately one-third of patients will develop high BP by adolescence despite early surgery.⁵⁸ One may argue that hypertension is likely to be the most important outcome variable in CoA individuals. A number of CoA patients with normal resting BP have an exaggerated BP response to exercise, which may predict the onset of hypertension at rest as well.^59,60 The origin of hypertension in this setting is still a matter of debate with a combination of autonomic nervous system (arterial baroreceptors located in the aortic arch) imbalance,^61,62 impaired vascular elasticity^63,64 and overactivity of the renin–angiotensin system^65,66 being the most likely underlying cause. HTN in CoA individuals is often under-recognized or not treated aggressively enough.⁶⁷

BP should be measured at the right arm with an appropriately sized cuff located at the level of the heart. In fact, in the setting of CoA, BP may be underestimated if checked at the left arm. If CoA is suspected, BP should be measured at both upper limbs end eventually at lower limbs as well.^13,21

Reno-vascular hypertension is one of the most common causes of secondary hypertension. The most frequently encountered causes of this kind of hypertension are:

• (1) renal artery stenosis;
• (2) fibromuscular dysplasia;
• (3) arteritides such as Takayasu's, antiphospholipid antibody or mid-aortic syndrome;
• (4) extrinsic compression of a renal artery;
• (5) renal artery dissection or infarction;
• (6) radiation fibrosis;
• (7) obstruction from aortic endovascular grafts.^68,69

All children aged less than 3 years should have their BP checked yearly if affected by urinary tract malformations or recurrent infections. In those with chronic kidney disease, regular checks by means of ABPM are indicated.^13,21 With suppressed renin activity or increased aldosterone to renin ratio (>10 ng/ml/h), or hypokalaemia, especially in children with a family history of HTN, secondary reno-vascular hypertension should be suspected.^13,21 Reno-vascular hypertension should also be suspected in case of stage 2 hypertension, significantly elevated DBP, considerable size mismatch between the two kidneys, or onset of epigastric sounds on abdominal auscultation. As such, a renal ultrasound scan with colour-Doppler is suggested in all children aged more than 8 years who are not obese. Even though renal angiography is the ‘gold standard’ to make a diagnosis of reno-vascular hypertension, also angio-CT and angio-MRI are good diagnostic tools. Unlike the previous Guidelines on high BP in children, the 2017 Recommendations do not suggest renal scintigraphy (with or without captopril) or routine microalbuminuria and uric acid checks.^13,21 AAP Guidelines highlight the need for a strict BP and proteinuria control in all children with high BP of reno-vascular origin, as proteinuria is a risk factor for developing end-stage renal disease, which in turn worsens high BP in a vicious cycle.^13,21

WBS is quite a rare disease whose prevalence is 1/7500.⁶⁵ It is caused by a microdeletion of 26–28 genes, including elastin and NCF1 genes, in the chromosome region 7q11.23.^70,71 The main phenotype features are elfin facies (100%), short stature, developmental delay (75%), cardiovascular (80%) and genitourinary defects and infantile hypercalcaemia (15–45%).^70,72 CHD is quite common in WBS, with supravalvular aortic stenosis, pulmonary artery branches stenosis, supravalvar pulmonary stenosis, stenosis of the thoracic or abdominal aortic portion, renal or intracranial arteries and/or vessels at other sites.^70,72 WBS patients are at a high risk of systemic hypertension. Loss of function in the elastin gene is linked with increased intima-media thickness with thick irregular elastic fibres, collagen spiralling pattern and hypertrophied smooth muscle cells.⁷¹ These arterial abnormalities lead to focal stenosis, generalized vascular narrowing and hypertension.⁷² Vascular stiffness usually increases as time goes by⁷³ and it is also altered in WBS patients with normal BP values.⁷⁴ High BP arises in around 50% of WBS patients, at any age. Although in many individuals it remains unexplained, it is frequently related to renal artery stenosis (50%) and/or aortic coarctation and/or sympathetic hyperactivity.^70,71

Conclusion

The most diffuse form of high BP in the young is primary hypertension. Like many other chronic diseases, we should be screening for hypertension earlier to prevent the burden of hypertension in adulthood.^5,75 All children over the age of 3 should have their BP checked regularly. New normative standards have been suggested. Adolescents are equated to adult patients starting from the age of 13 years in the American guidelines and from 16 years in the European documents. Adopting uniform definitions of high BP in teenagers and adults is with the aim of facilitating transition from paediatric facilities to adult healthcare. Uniformity in defining BP cut-offs is still lacking, with discrepancy between AAP and European guidelines. In the former, excluding obese individuals from the hypertension classification is somewhat high-handed as well. Despite the endorsement of ABPM, there are no reference values in children as well as no studies on lifestyle modification to prevent hypertension onset and drug therapy at this age.⁷⁶ The most diffuse forms of secondary paediatric hypertension are those caused by aortic coarctation and renal diseases. There is no doubt that early hypertension prevention represents one of the most exciting challenges to in turn prevent the onset of cardiovascular diseases later on.⁷⁷

Acknowledgements

Conflicts of interest

There are no conflicts of interest.