HYPERTENSION IN THE TEENAGER

INTRODUCTION

The current prevalence of hypertension in children is estimated to be about 1-5%, with higher rates among minority adolescents^1-3. Primary hypertension (PH) also referred to as essential hypertension, previously considered a disease of adulthood, has now become increasingly common in the pediatric population largely due to the obesity epidemic^4,5. Obese children are three times more likely to develop hypertension than their non-obese counterparts^6,7. This review therefore focuses on obesity-related teenage hypertension. We also discuss hypertension in non-obese teenagers where significant data exist.

The relationship between obesity and hypertension has been clearly defined in multiple studies across different ethnic and gender groups^1,7-12. The etiology of obesity related hypertension has been linked to sympathetic hyperactivity, insulin resistance and vascular structure changes^13,14. Sorof et al demonstrated the presence of sympathetic nervous system hyperactivity in obese school- age children, evidenced by increased heart rate and blood pressure variability which contributed to the pathogenesis of isolated systolic hypertension in this cohort ⁷. Increased sodium content of the cerebrospinal fluid has been shown to increase sympathetic nervous system activity through activation of the renin- angiotensin- aldosterone pathway in the brain^13,14. Obese individuals have selective insulin resistance, which leads to increased sympathetic activity and alteration of vascular reactivity and resultant sodium retention as evidenced by decreased urinary sodium excretion¹⁵. The lessons learned from the study of the obese hypertensive individuals can be largely applied to the diverse population of hypertensive children.

DEFINITION AND CLASSIFICATION OF PEDIATRIC HYPERTENSION

Pediatric hypertension is usually asymptomatic and can easily be missed by healthcare professionals. The National Heart, Lung and Blood Institute (NHLBI) of the National Institute of Health (NIH) commissioned the Task Force on Blood Pressure Control in Children to develop normative standards for blood pressure. These standards were derived from the survey of more than 83,000 person-visits of infants and children. The percentile curves describe age-specific and gender-specific distributions of systolic and diastolic BP in infants and children adjusted for height ¹⁶ and have been updated periodically.

Hypertension in children and adolescents is diagnosed based on age, gender and height- specific references. Hypertension is defined as systolic and/ or diastolic BP greater than the 95^th percentile for age, gender and height on three or more separate occasions. BP greater than 90^th percentile but less than the 95^th percentile for age, sex and height defines “pre-hypertension” and represents a category of patients at high risk for developing hypertension ^2,3,17-19. It is crucial for the health care providers to be aware that the BP at the 90^th percentile for an older child often exceeds the adult threshold for pre-hypertension of 120/80mmHg. As a result, beginning at 12 years of age, the BP range that defines pre-hypertension includes any BP reading of greater than 120/80mmHg, even if it is less than the 90^th percentile ¹⁶. We now know that pre-hypertension may not be completely benign and the rate of progression to hypertension was reported to be 7% per year over a 2-year interval ¹⁸. Stage I hypertension refers to systolic and or diastolic BP greater than the 95th percentile but less than or equal to the 99th percentile plus 5 mm Hg. There is no data on the progression from stage I to stage II hypertension in children. Stage II hypertension is defined as systolic and/or diastolic BP greater than the 99^th percentile plus 5 mm Hg. This represents a more severe form of hypertension, commonly associated with target organ damage. An analysis by the National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and Adolescents revealed an increased risk for left ventricular hypertrophy (LVH) ²⁰ in participants with stage II hypertension. Surprisingly, in some studies children and adolescents with pre-hypertension have also been found to have a substantially increased left ventricular mass index with a two-fold higher prevalence of LVH than their normotensive counterparts^21-23. Classification of hypertension is summarized in Table 1.

Table 1.

Definition and classification of hypertension in children

Normotensive children	Systolic and/ or diastolic blood pressure < 90th percentile for sex, age and height
Pre-hypertension	Systolic and/or diastolic blood pressure greater than the 90th but less than the 95th percentile or blood pressure > 120/80mmHg but less than the 95th percentile.
Stage I Hypertension	Systolic and/ or diastolic blood pressure greater than the 95th but less than the 99th percentile plus 5mmHg
Stage II Hypertension	Systolic and/or diastolic blood pressure greater than the 99th percentile plus 5mmHg for sex, age and height

Adapted from Lurbe E, Alvarez J, Redon J. Diagnosis and treatment of hypertension in children. Current hypertension reports 2010;12:480-6; with permission.¹²⁰

Primary and Secondary Hypertension

Based on the etiology, hypertension can be categorized as primary or essential hypertension (PH) when there is no identifiable cause and secondary hypertension (SH) when there is an underlying cause for hypertension. PH is now the most common cause of hypertension in adolescents and young adults. It is usually characterized by stage I (mild) hypertension and associated with a positive family history of hypertension²⁴. SH should be considered in very young children, those with stage II hypertension and in children with clinical features that suggest systemic diseases associated with hypertension. SH may be due to:

• an underlying renal parenchymal disease,

• endocrine disease,

• vascular or

• neurological condition.

Key Message:

• Diagnosis of pediatric hypertension is often missed due to the absence of symptoms

• Hypertension is diagnosed based on age, gender and height-specific references

• 3 stages of hypertension are:

  • ✓pre-hypertension
  • ✓stage I hypertension
  • ✓stage II hypertension

• Based upon etiology, hypertension can be either primary (no identifiable cause) or secondary (underlying cause present)

RISK FACTORS FOR ESSENTIAL HYPERTENSION

A parental family history of hypertension is linked to a twofold-increased risk of developing essential hypertension in children and young adults^24-27. This association led to extensive research to elucidate the underlying genetic etiology of PH. Family studies have shown that 20- 40% of cases seen are genetically determined. Different monogenic causes of PH have been established including mutations in the corticosteroidogenic genes, CYP11B1, and HSD11B2 ^28-30, mutations in the epithelial sodium channel (SCNN1B, SCNN1G), in the WNK serinethreonine kinase, ^31,32 and polymorphisms in the renin-angiotensin-aldosterone system (RAAS) ^30,33,34. However, pure monogenic causes of PH are still rare.

In a 10- year longitudinal study, African American children were shown to have a significantly greater elevation in systolic BP compared with white children from childhood to adulthood even after adjusting for height, body mass index and socioeconomic status^35-38. Recently, mutations in the apolipoprotein-L1 gene in chromosome 22 were discovered and seem to explain the increased prevalence of hypertension-associated nephropathy in the African American population^39,40. These mutations are thought to have an autosomal recessive pattern of inheritance and patients who are homozygous for the mutations have a higher likelihood for developing hypertension associated nephropathy, focal segmental glomerulosclerosis and HIV associated nephropathy^40-43.

Increasing age and body mass index (BMI) have also been significantly associated with the development of hypertension ⁴⁴ with a higher prevalence in African Americans and Asians⁴⁵. There is a growing body of evidence on the inverse relationship between birth weight and hypertension in children and adolescents. A strong association has been observed among patients with a history of low birth weight and intrauterine growth retardation and a more significant relationship is seen when adjustments are made for current body weight. ^46-50.

In a recent study by Yang et al, children were found to consume between 1,300mg and 8,100mg of sodium a day (mean of 3,387mg)⁵¹. Those with the highest sodium intake were shown to be twice as likely to have elevated blood pressures compared to those with lower sodium intake. This effect was more pronounced in the overweight and obese children. Overweight or obese children in the highest quartile of sodium consumption had more than three times the risk of elevated or high blood pressure as overweight children in the lowest quartile of sodium consumption⁵¹.

Key message:

• Risk factors for developing primary hypertension:

• ○ Family history has been linked to increased risk

• ○ Racial predilection has been seen, African-American population being at higher risk

• ○ Increasing age and body mass index

• ○ Low birth weight and intra-uterine growth retardation

• ○ Increased sodium consumption

DIAGNOSIS OF HYPERTENSION

Clinical evaluation of a hypertensive teen

History

A thorough history is essential in guiding the evaluation and management of a hypertensive adolescent. Detailed information regarding the timing when elevated BP were first noted and the presence of co-morbid conditions is crucial for establishing the diagnosis. For this age group, the clinical history should include questions about the use of anabolic steroids, stimulants and caffeine containing energy drinks which can elevate the BP⁵². A history of snoring in an obese individual should prompt the evaluation for obstructive sleep apnea. History suggestive of renal disease or an endocrine tumor should be elicited.

Physical Examination

A comprehensive physical examination could suggest the underlying cause of hypertension in children and the presence of target organ damage. Attention to the body mass index is essential to identify overweight and obese patients. Table 2 summarizes the physical findings and laboratory investigations to look for common causes of secondary hypertension in the adolescent.

Table 2.

Physical findings and Diagnostic Evaluation of a Hypertensive Adolescent

Physical Examination	Etiology	Investigation
General: Overweight, obese, acanthosis nigricans	Primary hypertension/metabolic syndrome	Urinalysis, fasting blood sugar, lipid panel. ABPM to rule out white coat hypertension
Edema, pallor, palpable kidneys on abdominal exam (Polycystic kidney disease), rash, arthralgia, growth retardation	Renal parenchymal disease	Urinalysis, serum creatinine, electrolytes, protein/ creatinine, ANA, dsDNAse, complements C3/C4, renal ultrasound
Tachycardia, widened pulse pressure, enlarged thyroid, weight loss, tremor	Hyperthyroidism	Thyroid function test: Free T4 and TSH
Moon facies, acne, hirsutism, truncal obesity, striae	Cushing's syndrome, steroid therapy, Liddle syndrome	Serum electrolytes, cortisol level, serum aldosterone
Weak lower extremity pulses, BP in upper limbs more than 10mmHg greater than lower extremity BP	Coarctation of the aorta	Echocardiography
Abdominal bruit	Renal artery stenosis	Renal artery angiography, captopril scintigraphy.
Tachycardia, flushing, visual disturbances, episodic hypertension	Pheochromocytoma	24-hour urine metanephrine. I131 or I123 meta-iodo-benzyl- guanidine
Café-au lait spots, axillary or inguinal freckling	Neurofibromatosis	CT scan or MRI
Bradycardia, widen pulse pressure	CNS lesion: tumor, bleed	CT scan or MRI

Blood Pressure Measurement

To obtain an accurate resting BP, patients should be allowed to sit for at least 5 minutes with the back supported and both feet on the ground¹⁶. A study of 390 children evaluated at 580 visits by Podoll et al revealed that 74% of BP readings were predominantly higher at the vital sign station using oscillometric devices compared with reading taken by auscultation in the examination room by personnel trained according to the Fourth Task Force recommendations.^16,53 Mean differences of 13.2 ± 8.9mmHg for systolic and 9.6 ± 7.6mmHg for diastolic BP were seen. This highlights the importance of proper technique and the need to carefully re-evaluate initial elevated BP readings⁵³.

Blood pressure should be measured with an appropriate-sized cuff in an upper extremity. The preferred method of measurement is by auscultation especially since the normative BP tables for children are based on similar measurements. An appropriate-sized cuff should have an inflatable bladder width that spans at least 40% of the patient’s arm circumference measured at the midpoint between the olecranon (elbow) and the acromion (shoulder). The bladder length should cover 80 to 100% of the arm circumference¹⁶. While previous recommendations to determine cuff adequacy included cuff length, current recommendations are based on the cuff width only. Previous recommendations from The Working Group of the Task Force on high blood pressure in children and adolescents was that the width of the BP cuff should cover at least three quarters of the length of the arm measured from the acromion to the olecranon ⁵⁴. This was however found to result in an exaggeration in pediatric cuff choice. A review by Arafat et al evaluated the appropriateness of this recommendation and reported that if three quarters of the arm length is used to determine cuff size, there would be an overestimation in pediatric cuff selection ⁵⁵. An update on the Task Force recommendations in 1996 included recommendations for the cuff width of 40% of the mid upper arm circumference with no reference to cuff length or the reason for the change in recommendations ⁵⁴. The updated recommendation is thought to be due to the fact that the bladder width should be 40% to 50% of the mid upper arm circumference supported by evidence that the correct bladder width to arm circumference ratio is 0.4 ⁵⁵.

BP readings are overestimated when the cuff size is too small increasing the possibility of a wrong diagnosis of hypertension. Elevated BP readings that exceed the 90^th percentile obtained by oscillometric devices should be confirmed by auscultation.

In the outpatient setting, documented elevations in blood pressures on 3 separate occasions at least one week apart are essential to confirm the diagnosis. Alternatively, ambulatory blood pressure monitoring (ABPM) could be performed to arrive at the diagnosis of hypertension^56-58.

Ambulatory Blood Pressure Monitoring (ABPM)

ABPM forms the basis for the diagnosis when there is discordance in BP readings between daytime ambulatory BP measurements and office BP readings. It is particularly useful in patients with white coat or isolated clinic hypertension and masked hypertension. White coat hypertension is defined as office hypertension and ambulatory normotension while masked hypertension, the opposite, refers to ambulatory hypertension and office normotension.

ABPM utilizes oscillometric measures to obtain BP measurements. BP are measured every 20 to 30 minutes in the patient's home environment over a 24 hour period. Patients are advised to continue their routine activities but avoid rigorous activities during this monitoring period. A record of the actual sleep and wake times is maintained by the patients to enable evaluation of nocturnal dipping patterns and nocturnal hypertension. In our practice, we measure BP every 30 minutes during the day and every hour at night. An adequate ABPM report should have at least 40 to 50 BP readings with at least one reading every hour including at nighttime⁵⁹. BP load is the percent of BP above the 95^th percentile for age, gender and height in the 24-hour period. Based on the ABPM, hypertension is defined as elevated mean systolic BP above the 95^th blood pressure percentile and/ or an elevated BP load above 25%. Normative standards have been established and are available for ambulatory BP measurements⁶⁰.

Twenty-four hour ABPM has become commonplace in pediatric nephrology clinics for diagnosing white coat hypertension and masked hypertension and there is growing evidence supporting its use in the pediatric population. ^57,58,60-64. Nephrology groups own and perform ABPM; it is less commonly performed by the cardiologist and rarely by the endocrinologist. Recently Davis et al recommended incorporating ABPM in the primary care setting to increase diagnostic accuracy of hypertension and avoid unnecessary treatment ⁶⁵. This makes it important for primary care providers to be familiar with the role of ABPM for their patients with discordant BP readings or other diagnostic challenges.

The prevalence of white coat hypertension and masked hypertension in the general population are reported to be 1% and 10% respectively⁶⁶. Patients with white coat hypertension have a lower risk for cardiovascular mortality than those with masked or sustained hypertension, although they have a greater risk for developing sustained hypertension later^67-69. White coat hypertension in children is not associated with the development of LVH or hypertension-related kidney damage unlike PH, which has been linked to microalbuminuria ^70-72. It has however been related to a slight increase in left ventricular mass index intermediate in range between normotensive and hypertensive subjects. This finding was highlighted in a study by Lande et al where 81 patients were divided in three groups matched for age and BMI. They were studied and found to have mean left ventricular mass indices of 29.2, 32.3 and 25.1 g/m² in the normotensive, white coat hypertensive and sustained hypertensive groups respectively⁷³. White coat hypertension has been associated with increased pulse wave velocity which is a marker of increased arterial stiffness and it might signify a greater cardiovascular risk than previously thought ⁷⁴.

Masked hypertension has also been found to be associated with increased cardiovascular mortality and other target organ damage in adults⁷⁵. In a study of 592 children aged between 5 and 18 years, Lurbe et al showed that patients with masked hypertension were more likely to be obese and have a family history of hypertension and were at an increased risk of developing sustained hypertension. Masked hypertension was shown to be a precursor of sustained hypertension and LVH in young children and adolescents⁶⁶. The risk for LVH was found to be similar between participants with stage 1 hypertension and masked hypertension⁷².

ABPM has been demonstrated to be more closely associated with target organ damage and increased left ventricular mass index, leading to increased cerebrovascular events and a concomitant increase in cardiovascular mortality risk. ^73,76,77 White coat hypertension is linked to a low risk for stroke, a finding by Verdicchia et al who reported a hazard ratio for stroke of 1.15 and 2.01 in patients with white coat hypertension and sustained hypertension respectively ⁷⁸. Researchers from the Dublin outcome study proposed ambulatory arterial stiffness index as a novel marker of cardiovascular mortality. ^79-81.

Investigations in a Hypertensive Adolescent

I. Initial Investigations

Initial evaluation should include a urinalysis, serum creatinine and echocardiography to evaluate for LVH. Renal sonography need not be routinely performed in the obese adolescent with a normal physical examination and normal urinalysis results. This was confirmed in a retrospective study by Tuli et al were routine renal imaging in 50 children did not provide any additional diagnostic information to the initial evaluation ⁸². These recommendations are similar to the evaluation of an adult hypertensive patient.

II. Subsequent Investigations

This includes fasting blood sugar and lipid profile in the obese teenager to rule out co-morbid conditions.

III. Selected Tests in Unusual Cases

Further investigations should be guided by the history, risk factors and symptoms identified as outlined in Table 2.

Key Message:

• Detailed history and comprehensive physical examination is important to look for underlying cause of hypertension and other co-morbid conditions

• Blood pressure estimation by proper technique is crucial

• Elevated BP readings >90^th percentile obtained by oscillometric devices should be confirmed by auscultation

• BP readings are overestimated when the cuff size is small

• Elevated blood pressure on 3 separate occasions at least one week apart are essential to confirm the diagnosis

• Ambulatory BP monitoring may be performed to diagnose hypertension in cases of discordance between ambulatory BP and office BP readings

MANAGEMENT OF A HYPERTENSIVE TEEN

After the diagnosis of hypertension is reached, management should be tailored to the individual patient⁵². Figure 1 shows an algorithm for the management of teenage hypertension according to the severity.

Figure 1.

Management of hypertension based on severity.

Adapted from Lande et al and The Fourth Task Force for the Diagnosis, Evaluation and Treatment of High Blood Pressure in Children and Adolescents; and Lande MB, Flynn JT. Treatment of hypertension in children and adolescents. Pediatric nephrology (Berlin, Germany) 2009;24:1939-49; with permission.^16,52

I. Therapeutic Lifestyle Modification

This is the first line of management of pediatric hypertension and can be the sole modality of therapy in patients diagnosed with pre-hypertension and stage I hypertension. It focuses on dietary management, increased physical activity, stress reduction and avoidance of illicit drug and tobacco use^83-85. Dietary management should include an age appropriate, salt-restricted diet with emphasis on weight loss in the overweight or obese children. To have a better chance of success, the entire family should adopt these lifestyle modifications and a primary provider can be instrumental in this endeavor.

II. Pharmacological Therapy

The available evidence on the therapeutic management of pediatric hypertension is based on available evidence and consensus expert opinion when such evidence is lacking. The Fourth Task Force report on High Blood Pressure in Children and Adolescents include the following indications for pharmacological therapy¹⁶:

• Symptomatic hypertension

• Persistent hypertension despite lifestyle modification

• Secondary hypertension

• Presence of hypertensive target organ damage such as LVH, hypertensive retinopathy, microalbuminuria

• Presence of co-morbid conditions that increase cardiovascular risk like diabetes mellitus ¹⁶

For patients with uncomplicated PH, the target BP is less than the 95^th percentile for age, gender, and height; while it is less than the 90^th percentile for patients with co-morbid conditions like diabetes, chronic kidney disease and in those with evidence of target organ damage¹⁶.

Choice of antihypertensive medications

There are no specific recommendations on the optimal first line agent for the treatment of pediatric hypertension^52,86. The classes of antihypertensive medications that can be used in the pediatric hypertensive patient include:

• calcium channel blockers (CCB),

• angiotensin converting enzyme inhibitors (ACEI),

• angiotensin receptor blocker (ARB),

• diuretics, beta-blockers (BB),

• alpha-blockers,

• central acting agents, vasodilators,

• combined alpha and beta-adrenergic antagonists,

• renin inhibitors and

• aldosterone receptor blockers ^87,88.

Commonly used formulations from the different classes are shown in Table 3.

Table 3.

Classes of Antihypertensive Medications Available in the Market

1. Calcium Channel Blockers	Amlodipine, Felodipine, Isradipine, Nifedipine, Diltiazem and Verapamil.
2. Angiotensin Converting Enzyme Inhibitors	Enalapril, Fosinopril, Lisinopril, Quinapril, Captopril, Benzepril and Ramipril
3. Angiotensin Receptor Blocker	Valsartan Losartan Candesartan, Azilsartan, Olmesartan and Irbesartan.
4. Diuretics	Chlorothiazide, Hydrochlorothiazide, Chlorthalidone, Amiloride, 1Spirinolactone,
5. Beta Adrenergic Antagonists	Atenolol, Metoprolol, Propanolol, Labetalol, Timolol, Nadolol and Nevibolol.
6. Peripheral Alpha Antagonists	2Doxazosin, Prazosin, Terazosin, Phentolamine and Phenoxybenzamine
7. Central Acting Agents	Clonidine, Methyl dopa, Guanfacine and Guanethidine
8. Vasodilators	Hydralazine, Minoxidil and Reserpine
9. Aldosterone Antagonists	Eplerenone, 2Spirinolactone
10. Combination drugs	Amlodipine/ Benazepril, Lisinopril/ Hydrochlorothiazide, Losartan/ Hydrochlorothiazide, Bisoprolol/ Hydrochlorothiazide, Olmesartan/ Hydrochlorothiazide, Olmesartan, Olmesartan/ Hydrochlorothiazide/ Amlodipine

The general practice is to choose an agent from one of these classes and titrate the dose to achieve therapeutic effect while monitoring for side effects.^52,89. Combination therapy is recommended if BP control is not achieved with a single drug^16,90. Home BP measurements can be obtained to monitor the patient's response to therapy.

Less than a quarter of all drugs are approved by the FDA for use in children. Despite this, almost all the antihypertensive agents available in the United States have been used in pediatric patients. The Food and Drug Administration Modernization Act (FDAMA) in 1997, resulted in companies being incentivized to conduct clinical trials in pediatrics and has resulted in wider availability of pediatric approved anti-hypertensive agents and dosing recommendations⁹¹. The drugs initially approved and the current FDA approved antihypertensive agents in children are outlined in Table 4.

Table 4.

FDA Approved Antihypertensives

PRE FDAMA	POST FDAMA
1. Propanolol	1. Children above 1 month     - Enalapril
2. Propanolol LA	2. Children above the age of 1 year     - Candesartan
3. Oral Clonidine	3. Children above 6 years     - Lisinopril     - Losartan     - Valsartan     - Amlodipine
4. Transdermal Clonidine	4. Children above 12 years     - Guanfacine
5. Hydralazine
6. Minoxidil
7. Hydrochlorothiazide

Abbreviation: FDAMA, Food and Drug Administration Modernization Act

Adapted from Welch WP, Yang W, Taylor-Zapata P, Flynn JT. Antihypertensive drug use by children: are the drugs labeled and indicated? Journal of clinical hypertension (Greenwich, Conn) 2012;14:388-95; with permission.

Knowledge of the underlying etiology can provide a pathophysiologic approach to guide therapy⁸⁵. For instance patients with hypertension secondary to steroid use would benefit from diuretic therapy with hydrochlorothiazide given that the underlying mechanism for hypertension in this setting is sodium and water retention.

Treatment with an ACEI or an ARB would be the appropriate therapy for a patient with diabetes to help prevent the progression of diabetic nephropathy.

BB are beneficial in treatment of hypertension associated with hyperthyroidism. BB are indicated after effective alpha blockade in the pre-operative treatment of pheochromocytoma to control the tachycardia associated with high circulating catecholamine levels and alpha blockade. They should be administered only after adequate alpha- blockade, to prevent unopposed alpha-adrenergic activity. BB should be avoided in patients with asthma and diabetes. They are associated with weight gain and should be used with caution in the obese patient.

There is no ideal first line agent for the treatment of PH in the teenager. Among the different antihypertensive classes, ACEI, ARB, CCB, BB or diuretics are frequently used as first line agents. There is no evidence in pediatric hypertension that one agent is superior to another. An ideal first line agent should be effective, have short and long term safety, be readily available, palatable, affordable, have long acting formulations and be easy to administer⁸⁶. Pediatricians should be familiar with one or two agents from each class and their side effect profile.

It is recommended that a single agent be used at the minimum dose during initiation of pharmacological therapy. Table 5 shows the initial doses of commonly used agents. The dose can be titrated every 2 weeks to achieve control, sooner if the patient is symptomatic. A second agent should be added when the maximum dose is reached or if the patient develops side effects.

Table 5.

Doses of Common Antihypertensive Agents for Out Patient Treatment of Hypertension

CLASS	DRUG	DOSE
Angiotensin Converting Enzyme Inhibitors	Captopril	Initial: 0.3–0.5 mg/kg/dose Maximum: 6 mg/kg/day
	Enalapril	Initial: 0.08 mg/kg/day up to 5 mg/day Maximum: 0.6 mg/kg/day up to 40 mg/day
	Lisinopril	Initial: 0.07 mg/kg/day up to 5 mg/day Maximum: 0.6 mg/kg/day up to 40 mg/day
Angiotensin Receptor Blockers	Losartan	Initial: 0.7 mg/kg/day up to 50 mg/day Maximum: 1.4 mg/kg/day up to 100 mg/day
Alpha and Beta Blockers	Labetalol	Initial: 1–3 mg/kg/day Maximum: 10–12 mg/kg/day up to 1,200 mg/day
Beta Blockers	Atenolol	Initial: 0.5–1 mg/kg/day Maximum: 2 mg/kg/day up to 100 mg/day
	Metoprolol	Initial: 1–2 mg/kg/day Maximum: 6 mg/kg/day up to 200 mg/day
	Propanolol	Initial: 1–2 mg/kg/day Maximum: 4 mg/kg/day up to 640 mg/day
Calcium Channel Blockers Diuretics	Amlodipine Hydrochlorothiazide	Children 6–17 years: 2.5–5 mg once daily < 6 months old: 2- 4 mg/kg/day 6 months to 2 years: 1- 2 mg/kg/day; maximum 37.5mg 2- 12 years: 1- 2 mg/kg/day; maximum 100mg/day

*In my practice, I typically start a hypertensive teenager on amlodipine, lisinopril or hydrochlorothiazide, not in any particular order.

Adapted from The fourth report on the diagnosis, evaluation, and treatment of high blood pressure in children and adolescents. Pediatrics 2004;114:555-76; with permission.

Following documentation of elevated blood pressures on 3 consecutive occasions, at least 1 week apart, hypertensive patients should receive non-pharmacological therapy including life style modification. Pharmacological therapy should be instituted in symptomatic patients and stage 2 hypertension and, prompt referral should be made to the nephrologist.

Benefits of Anti-hypertensive therapy

There are reports to show the reversal of target organ damage following the institution of antihypertensive therapy in children ^92,93,94. Seeman et al reported a regression in LVH in a small pediatric cohort treated with ramipril monotherapy over a 6-month period⁹³.

Other forms of therapy

Bariatric surgery has a role in the treatment of hypertension in the morbidly obese adult and might become an option in the obese pediatric adolescent in the future. A recent study by Visockiene et al demonstrated an improvement in metabolic syndrome including hypertension with up to 30% reduction in weight⁹⁵.

Renal nerve denervation is a therapeutic option in adults with resistant hypertension, which refers to uncontrolled hypertension despite therapy with 3 or more antihypertensives. Studies in animals and humans have shown that the renal nerves play a role in blood pressure regulation. The efficacy of renal nerve denervation was demonstrated in the Symplicity HTN-2 trial where participants with resistant hypertension were randomized to either a treatment arm managed with renal denervation and baseline antihypertensives or the control arm managed with only baseline antihypertensives. A significant change of −32/-12mmHg in blood pressure in the treatment arm compared to a +1/0mmHg change in the control arm was observed 6 months after intervention. These blood pressure changes persisted at 2 years in a follow up study^96-98. While renal nerve denervation has not yet been performed in the pediatric population, it might have a role in the future for the treatment of resistant hypertension in the adolescent hypertensive patient.

Key Message:

• Life-style modification can be the sole modality of treatment in many adolescents with hypertension

• Indications for pharmacotherapy include:

  • ✓ symptomatic hypertension
  • ✓ secondary hypertension
  • ✓ persistent hypertension despite life-style modification
  • ✓ presence of target organ damage (LVH, retinopathy, microalbuminuria)
  • ✓ presence of co-morbid conditions

• Target BP is less than 95th percentile for uncomplicated primary hypertension; less than 90th percentile for patients with co-morbid conditions (diabetes, kidney disease, evidence of target organ damage)

• No specific recommendations regarding optimal first line agent for treatment of pediatric hypertension

• Knowledge of underlying etiology and co-morbid conditions may guide therapy

SPORTS PARTICIPATION FOR THE HYPERTENSIVE ADOLESCENT

There is no evidence to support restricting the hypertensive youth from sports participation. There are no reports of sudden cardiac death associated with sports in hypertensive athletes in the absence of underlying cardiovascular disease like hypertrophic cardiomyopathy^52,99.

The AAP recommendations for sports participation in the hypertensive individual includes unrestricted competitive sports participation for individuals with prehypertension or stage 1 hypertension without end organ damage like LVH¹⁰⁰. A regular exercise routine and dietary change should be encouraged to promote weight management and BP control as part of lifestyle modification. Individuals with stage 2 hypertension without evidence of end organ damage should be restricted from isometric exercises like weight lifting and push-ups, which can result in an acute rise in BP. This restriction should be in place until BP control is achieved with lifestyle modification and or drug therapy. With attendant cardiovascular disease, eligibility for sports participation should be based on the nature and severity of the coexistent cardiovascular disease ¹⁰⁰.

Recommendations from the American College of Sport Medicine include developing a training regimen for the hypertensive athlete, which consists of dynamic and resistance exercises¹⁰¹. Expert opinion recommendations include limiting competitive and highly static sports only in the athlete with uncontrolled stage II hypertension or in the presence of target organ damage¹⁶.

Key Message:

• Unrestricted competitive sports participation for adolescents with prehypertension, stage 1 hypertension and well-controlled stage 2 hypertension with no target organ damage

• Limit competitive and highly static sports for athletes with uncontrolled stage 2 hypertension or with target organ damage

SCREENING CHILDREN FOR HYPERTENSION

AAP recommendations

The American Academy of Pediatrics, the European Society of Hypertension and the European Society of Cardiology recommend regular blood pressure screening in children above the age of 3 years at routine health visits. Despite these recommendations, hypertension in children is still under-diagnosed by clinicians^102,103. The presence of elevated BP is more likely to be overlooked in children with normal weight and those without a family history of cardiovascular disease. Children whose blood pressures are less than 120/80mmHg; a measurement which is viewed as normal in adults but which could portend problems in children depending on age, gender, and height; were eight times more likely to have their elevated BP missed. This underscores the need for better BP monitoring in children and adolescents in an attempt to prevent the long-term complications of hypertension¹⁰⁴.

On the contrary, a recent review by Thompson et al found that there is limited direct evidence supporting hypertension screening ¹⁰⁵ for prevention of cardiovascular diseases. Further study is needed to address the gaps identified on the utility of aggressive hypertension screening in children.

Key message:

• Regular BP screening is recommended in children above 3 years of age

• Hypertension is under-diagnosed in children

• Elevated blood pressure is more likely to be missed in those with normal body weight and negative family history

COMPLICATIONS OF HYPERTENSION IN ADOLESCENTS

Although the long term complications of hypertension such as stroke, cardiac failure, myocardial infarction and kidney disease are rare in the pediatric population, hypertension in children has been shown to be predictive of hypertension in adulthood^106-111.

Childhood hypertension has been associated with risk factors of cardiovascular disease including LVH and increased arterial wall thickness^{22,72,112-119}. LVH is the most frequently reported form of end organ damage in hypertensive children and adolescents with a prevalence of 14 to 26% ¹²⁰. Hypertensive children have an increased left ventricular mass index even after adjustments for age, sex and body mass index which is associated with an increased risk of cardiovascular mortality²³. This risk is amplified by arterial stiffening, a cardinal feature in hypertensive individuals.

A correlation between hypertension and lower neurocognitive test scores was seen in the NHANES III survey¹²¹. This association was further highlighted in a study conducted by Lande et al of 32 newly diagnosed hypertensive children and adolescents aged between 10 and 18 enrolled from a hypertension clinic. These patients were found to have significantly reduced cognitive function compared with the normotensive controls matched for age, sex, weight, race, IQ and socioeconomic status¹²². This cognitive impairment might represent an early manifestation of hypertensive damage to the brain that may precede more overt complications like stroke^108,123,124. A follow-up study showed that treatment of these hypertensive children resulted in an improvement of their cognitive executive function¹²⁵. This highlights the role of early diagnosis and optimal treatment.

Renal dysfunction represents a form of hypertension related end organ damage, which manifests as a reduction in glomerular filtration rate and an elevated urine microalbumin excretion. Microalbuminuria correlates well with progression of nephropathy and is a surrogate of increased cardiovascular mortality¹²⁰. The utility of routine screening for microalbuminuria in the hypertensive child has not been proven.

Uncontrolled hypertension can cause damage to the retinal vasculature¹²⁶ and the report from the National High Blood Pressure Education Program (NHBPEP) recommends that hypertensive children undergo a retinal exam for evidence of target organ damage⁵⁴. Retinopathy is very rare in teenagers with isolated hypertension. A study of 83 hypertensive children found just mild abnormalities on retinal examination in only 3 children¹²⁷.

There is growing evidence that there is increased mortality risk with childhood obesity related to an increased incidence of hypertension, ischemic heart disease, diabetes and stroke ¹²⁸. This further highlights the importance of advocating lifestyle modification in the treatment of the overweight or obese individual to reduce the risk of premature mortality.

KEY POINTS.

• Over the last two decades, essential hypertension has become common in children and adolescents and is related to the obesity epidemic.

• Hypertension is under-recognized in children and diagnosis is based on sex-, ageand height- specific normative standards.

• Modifiable risk factors for essential hypertension in children like obesity and sodium consumption should be addressed during treatment.

• Primary care physicians may play an important role in reduction of cardiovascular mortality by early detection, appropriate management and referral when needed.

Key Message.

• Long-term cardiovascular complications may not be seen in pediatric ages

• Hypertension in childhood and adolescence predict hypertension as adults

• Childhood hypertension is associated with LVH and increased arterial wall thickness

• Lower neurocognitive scores and renal injury has been described with hypertension

SUMMARY.

With the advent of the obesity epidemic, primary hypertension has become an important cause of pediatric hypertension. In concert with obesity, diseases like diabetes mellitus, metabolic syndrome, obstructive sleep apnea, dyslipidemia, orthopedic complications and psychosocial issues have emerged as common pediatric issues. Insulin resistance, sympathetic over activity and vascular structure abnormalities explain the association between obesity and hypertension in the pediatric population. Complications of uncontrolled hypertension including left ventricular hypertrophy and renal dysfunction have become more prevalent in this population as a result. Early diagnosis and management of hypertension is important in preventing long-term complications. The value of weight loss in blood pressure control has been demonstrated in clinical studies and remains the first line of therapy in the pediatric patient who presents with hypertension. Pharmacological therapy is necessary for treatment of symptomatic hypertension and in the presence of target organ damage in order to prevent and in some cases reverse established complications.