Nonemergent treatment of hypertension in children and adolescents

INTRODUCTION — It has become clear that hypertension (HTN) begins in childhood and adolescence and that it contributes to the early development of cardiovascular disease (CVD). In hypertensive adults, multiple randomized trials have shown that reduction of blood pressure (BP) by antihypertensive therapy reduces cardiovascular morbidity and mortality. Based upon these observations, identifying children with HTN and successfully treating their HTN should have an important impact on long-term outcomes of CVD. (See "Goal blood pressure in adults with hypertension".)

Issues related to the ambulatory (outpatient) treatment of persistent HTN in children and adolescents will be reviewed here. The epidemiology, etiology, diagnosis, and evaluation of HTN are discussed separately. (See "Epidemiology, risk factors, and etiology of hypertension in children and adolescents" and "Definition and diagnosis of hypertension in children and adolescents" and "Evaluation of hypertension in children and adolescents".)

The treatment of hypertensive emergencies and urgencies in children is also presented elsewhere. (See "Initial management of hypertensive emergencies and urgencies in children".)

DEFINITIONS — In children, definitions based upon the 2017 American Academy of Pediatrics (AAP) guidelines for screening and managing high blood pressure for children and adolescents for high blood pressure (BP) in children and adolescents are used to classify BP measurements for two different age groups in the United States (table 1) [1]. BP percentiles are based upon sex, age, and height (table 2 and table 3). (See "Definition and diagnosis of hypertension in children and adolescents", section on 'Definitions'.)

Childhood HTN is also divided into two categories depending upon whether or not an underlying cause can be identified (table 4):

●Primary HTN – No identifiable cause is found.

●Secondary HTN – An underlying cause is identified.

RATIONALE FOR INTERVENTION — Pediatric hypertension is associated with an increased long-term risk for CVD and progression of chronic kidney disease (CKD) and end-stage kidney disease (ESKD) in adults.

Cardiovascular disease — Although there is no direct evidence that initiating therapy to lower blood pressure (BP) in children and adolescents with persistent HTN lowers the risk of subsequent CVD, there is strong indirect evidence that HTN in childhood and adolescence contributes to premature atherosclerosis and increases the risk of CVD [1-3]. These data suggest that lowering the BP in hypertensive children would reduce the risk of accelerated atherosclerosis and, subsequently, premature CVD in adults.

●HTN is a well-established risk factor for CVD in adults, which appears to be true for persistent childhood HTN. Children and adolescents who are hypertensive or have prehypertension are more likely to be hypertensive as adults. An Israeli study of 16 to 19 year old adolescents with persistent HTN reported an increased risk of cardiovascular death in midlife after adjusting for confounding factors [4]. (See "Definition and diagnosis of hypertension in children and adolescents", section on 'Tracking'.)

●HTN is a risk factor for accelerated atherosclerosis in children and young adults. (See "Overview of risk factors for development of atherosclerosis and early cardiovascular disease in childhood", section on 'Hypertension' and "Overview of risk factors for development of atherosclerosis and early cardiovascular disease in childhood", section on 'Atherosclerotic changes in childhood'.)

●In children and adolescents, noninvasive methods of assessment of vascular changes related to atherosclerosis demonstrate an association of higher BP with predictors of CVD including arterial stiffness measured by pulse wave velocity [5,6], arterial calcification [7,8], and carotid intima media thickness (CIMT) evaluated by computed tomography (CT) or carotid ultrasound [8-11].

●Among children and adolescents with borderline or established primary HTN, left ventricular hypertrophy (LVH) has been reported in up to 40 to 45 percent of cases [12,13]. LVH increases with greater body mass index (BMI). Longitudinal data from the Bogalusa Heart study have shown that elevated childhood BP and BMI were associated with an increased risk of LVH in adulthood [14-16]. In adults, LVH is a known risk factor for CVD.

Limited pediatric data also show that antihypertensive therapy is associated with LVH regression [17-21]. In one study in children with primary and secondary HTN, the prevalence of LVH decreased from 42 percent to 11 percent after six months of treatment with ramipril, an angiotensin-converting enzyme (ACE) antihypertensive agent [18].

Chronic kidney disease and end-stage kidney disease — Untreated HTN is associated with progressive CKD. In children with chronic kidney disease (CKD), strict blood pressure control has been shown to slow the progression of kidney disease (see "Chronic kidney disease in children: Complications", section on 'Hypertension').

In addition, it appears that essential HTN during late adolescence increases the risk of ESKD in adulthood. This was illustrated in a large retrospective study of almost 2.7 million healthy adolescents recruited to the Israeli army (age 16 to 19 years of age) that reported 2189 individuals (0.1 percent) developed ESKD (defined as requiring hemodialysis, peritoneal dialysis, or undergoing renal transplantation) at a median follow-up of 19.6 years (range 10.4 to 31.2) [22]. Individuals progressing to ESKD included 42 of the 7997 individuals (0.5 percent) diagnosed with HTN (defined as BP >140/90) at the time of conscription. In a multivariable regression analysis, HTN at the time of conscription doubled the risk of ESKD (hazard ratio 1.98, 95% CI 1.42-2.77). Although the incidence of ESKD was low in this cohort, these results highlight the long-term potentially avoidable adverse effects of pediatric HTN on the development of ESKD.

MANAGEMENT APPROACH — Treatment for chronic HTN includes both nonpharmacologic and pharmacologic interventions. Management decisions are dependent upon the severity of HTN, the underlying cause, and the presence of other cardiovascular disease (CVD) risk factors. Our management approach, which is consistent with the 2017 American Academy of Pediatrics (AAP) guidelines, is based upon defined target blood pressure (BP) thresholds and goals.

Target blood pressure goals — In children and adolescents with high BP, the desired goal is to lower BP to an optimal level that reduces the risk of premature cardiovascular disease (CVD). However, no data are available to define these pediatric goals because long-term epidemiologic data linking cardiovascular events to childhood BP values are lacking. As a result, target BP goals have been determined by expert opinion. In the 2017 AAP guidelines, the target BP goal for children diagnosed with hypertension treated with nonpharmacologic and/or pharmacologic therapy is a reduction of systolic and diastolic BP below the 90^th percentile or <130/80 in adolescents (13 years or older) [1].

Chronic kidney disease — For children with chronic kidney disease (CKD), both the European Society of Hypertension (ESH) and AAP have more rigorous target goals because aggressive BP control has been shown to slow the progression of CKD. (See "Chronic kidney disease in children: Complications", section on 'Hypertension'.)

●The ESH guidelines suggest:

•For children with nonproteinuric CKD, 24-hour BP targeted goal is <75^th percentile

•For children with proteinuric CKD, 24-hour BP targeted goal is <50^th percentile

●The 2017 AAP guideline suggests a BP targeted goal of mean arterial BP <50^th percentile based on 24-hour ambulatory blood pressure monitoring (ABPM) [1].

Who should be treated — The initiation and aggressiveness of the therapy are generally based upon the severity of HTN, and the presence of end-organ damage, symptoms, or other CVD risk factors. Therapy includes nonpharmacologic and pharmacologic interventions and is focused upon achieving the previously discussed BP target goals. (See 'Nonpharmacologic therapy' below and 'Choice of drug' below.)

Our management approach is consistent with the 2017 AAP guidelines based on defined BP categories and the presence of other conditions associated with cardiovascular disease (table 1) [1]:

●In children with elevated BP, nonpharmacologic therapy (eg, diet and exercise) is initiated to reduce their BP to below the 90^th percentile or <120/80 mmHg in adolescents who are 13 years or older. Although the 2017 AAP guidelines suggest a target goal <130/80 mmHg, we prefer the lower goal of <120/80 mmHg that is consistent with an upper limit of a normal BP for children and adolescents. (See 'Nonpharmacologic therapy' below and "Evaluation of hypertension in children and adolescents", section on 'Laboratory evaluation'.)

●In children with stage 1 primary hypertension (HTN) without evidence of end-organ damage or CVD risk factors, nonpharmacologic therapy is the initial intervention. If BP target goals are not met within four to six months after initial therapy (ie, BP below the 90^th percentile), pharmacologic therapy is initiated.

●In children with stage 1 HTN who are symptomatic or have evidence of end-organ damage (eg, left ventricular hypertrophy, retinal changes) or CVD risk factors, both nonpharmacologic and pharmacologic therapy are started. (See "Ocular effects of hypertension" and "Evaluation of hypertension in children and adolescents", section on 'Detection of end-organ damage'.)

●In children with stage 2 HTN, treatment with both nonpharmacologic and pharmacologic therapy is initiated. Patients with stage 2 HTN and neurologic symptoms including headache, mental status changes, and neurologic findings should be emergently evaluated and treated. (See "Initial management of hypertensive emergencies and urgencies in children".)

●In children with secondary HTN, therapy should be directed to correcting the underlying cause, if possible. If the underlying cause cannot be corrected so that HTN is abolished, pharmacologic and nonpharmacologic therapy are initiated dependent on the elevation of BP. (See "Epidemiology, risk factors, and etiology of hypertension in children and adolescents", section on 'Secondary hypertension'.)

●For patients with chronic kidney disease (CKD), both nonpharmacologic and pharmacologic therapy is provided for any child with elevated BP or HTN. (See "Chronic kidney disease in children: Complications", section on 'Hypertension'.)

●For patients with diabetes mellitus (DM), both nonpharmacologic and pharmacologic therapy is provided for any child with any stage of HTN. (See "Chronic complications and screening in children and adolescents with type 2 diabetes mellitus", section on 'Hypertension' and "Complications and screening in children and adolescents with type 1 diabetes mellitus", section on 'Hypertension'.)

General principles when starting pharmacologic therapy — Based on strong indirect evidence of the association between pediatric hypertension and cardiovascular disease (CVD), antihypertensive drug therapy is used for children with persistently high BP, especially those with evidence of end-organ damage or other CVD risk factors and those with symptomatic hypertension. (See 'Rationale for intervention' above and 'Who should be treated' above.)

The principles of antihypertensive drug therapy are based upon the following step-wise approach [1]:

●First-line drug therapy should combine efficacy with minimum side effects. Starting doses should be the lower end of the known effective dose (table 5).

●If the target BP is still not achieved, a second drug from a different class is added when the initial drug dose reaches the highest recommended level or if the patient begins to experience side effects from the initial drug. We typically use thiazide diuretic as the second agent.

●To improve compliance, long-acting agents should be used whenever possible. For once-daily medications, we let the patient decide on morning versus evening intake as long as it is taken consistently around the same time.

●Nonpharmacologic therapy is continued even if pharmacologic therapy is initiated.

●ABPM is useful to assess response to therapy especially when clinic or home BP monitoring is insufficient to determine treatment effectiveness.

Choice of drug — Data comparing antihypertensive drugs in children are lacking and hence it is not possible to make an evidence-based choice [23]. Therefore, the recommendations on the choice of agent for initial therapy are based upon the underlying cause of HTN, concurrent disorders, and the preference and experience of the responsible clinician [24,25]. Data from adult trials and limited pediatric information have provided information regarding the choice of antihypertensive drugs for children with a specific underlying medical condition, such as primary HTN, CKD, and diabetes mellitus (DM). (See "Choice of drug therapy in primary (essential) hypertension".)

Primary hypertension — In children, there has not been a consensus on the best initial pharmacologic agent to treat primary HTN. The 2017 AAP guidelines suggest that pharmacologic therapy be initiated with one of the following classes: thiazide diuretics, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or calcium channel blockers (CCBs) (table 5) [1]. In our practice, we typically start with an agent that blocks the renin/angiotensin system (ie, ACE inhibitor or ARB) or a CCB for adolescent females who are sexually active and are unlikely to follow appropriate counseling on contraception. Patients on ACE/ARB need ongoing monitoring for changes in serum creatinine and potassium, particularly after medication initiation or significant dose increases. (See 'Antihypertensive drugs' below.)

Clinical short-term trials have shown that ACE inhibitors and CCBs are effective, safe, and well tolerated in children, but these two classes of drugs are more expensive than thiazide diuretics. However, diuretic therapy is associated with metabolic complications (eg, hypokalemia, glucose intolerance, weight gain, adverse lipid effects) and the need for periodic blood chemistry monitoring [26]. In addition, thiazide diuretics may alter glucose metabolism, which may be an important concern for children who are overweight or obese who are at risk for developing type 2 DM [27]. (See 'Thiazide diuretics' below.)

As a result, the use of ACE inhibitors, ARBs, or CCBs has been advocated as the initial therapy for primary HTN, particularly in children who are overweight or obese. However, thiazide diuretics are a reasonable alternative for patients who are compliant with medication and dietary sodium restriction, and have no evidence of hyperglycemia, hyperlipidemia, or hyperuricemia.

If the target BP goal is not met with the maximum allowable dose of the initial medication (ACE inhibitor, ARB, or CCB), we add a thiazide diuretic as a second agent, since salt and water retention commonly occur with antihypertensive therapy [1]. Other alternative approaches include switching agents between drug classes or the use of a beta blocker.

Data on the initial use of combination therapy of thiazide diuretics and other classes of antihypertensive medications (beta blockers, ACE inhibitors, and CCBs) are limited in children with primary HTN, and it is not recommended. (See "Choice of drug therapy in primary (essential) hypertension".)

Secondary hypertension

Renovascular disease — In children with renovascular disease, we use CCBs rather than an ACE inhibitor or ARB because of the concern that ACE inhibitors and ARBs reduce glomerular filtration rate (GFR) and may cause renal function impairment and hyperkalemia. However, the use of ACE/ARB is not contraindicated in unilateral RAS as long as there is appropriate monitoring of renal function and serum potassium and follow-up for adjustment of medication if there is evidence of renal impairment or an increase in potassium level.

In some cases, endovascular or surgical intervention is warranted, especially for those patients who fail to respond to antihypertensive medications [28].

Chronic kidney disease — Studies on the use of ACE inhibitors in children are limited, but are consistent with the adult data demonstrating their benefit in delaying progression of renal insufficiency. ACE inhibitor or ARB therapy appears most beneficial in patients with renal disease associated with proteinuria and should be used as the initial therapy in these patients [1,29,30]. (See "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults".)

However, ACE inhibitors or ARBs reduce GFR, so close monitoring for possible increases in creatinine and potassium is needed. A more complete discussion on treatment of HTN in children with CKD is discussed separately. (See 'ACE inhibitors' below and 'ARBs' below and "Chronic kidney disease in children: Complications", section on 'Hypertension'.)

Diabetes mellitus — Limited studies in children with type 1 diabetic nephropathy are consistent with data from randomized controlled trials in adults that demonstrate ACE inhibitors and ARBs delay the progression of diabetic nephropathy and decrease albuminuria in both type 1 and type 2 diabetes [29]. Thus, ACE inhibitors, or, if not tolerated, ARBs, are the preferred drugs in children with diabetes because of their potential renoprotective properties. (See "Treatment of diabetic kidney disease" and "Complications and screening in children and adolescents with type 1 diabetes mellitus", section on 'Hypertension' and "Chronic complications and screening in children and adolescents with type 2 diabetes mellitus", section on 'Hypertension'.)

HTN in type 2 diabetes is often related to obesity; thus, weight reduction is an important component of HTN therapy in these patients.

Sexually active females — ACE inhibitors and ARBs are contraindicated in pregnancy because of known adverse effects on the fetus. As a result, in sexually active female patients, we will initiate treatment with a CCB. However, if a sexually active female patient is treated with either an ACE inhibitor or ARB, she should be counseled on its effect on the fetus and the need for immediate reporting of suspected pregnancy. (See "Adverse effects of angiotensin converting enzyme inhibitors and receptor blockers in pregnancy" and "Treatment of hypertension in pregnant and postpartum patients", section on 'Overview of antihypertensive drugs used in pregnancy'.)

Follow-up care — Continued follow-up is required to monitor the response to pharmacotherapy and to detect any drug-related adverse effect. After initiation of pharmacologic therapy, we generally reassess the BP every 4 to 6 weeks for dose adjustments and the need for a second or third agent [1]. If there is a good response and the target BP is met and no additional changes are needed, the time interval for follow-up is gradually increased to three to six months.

Children and adolescents who are treated with only nonpharmacologic interventions are monitored at longer intervals every three to six months [1]. These visits assess the success of nonpharmacologic measures and the need to initiate pharmacologic therapy and reinforcing adherence.

Home monitoring of BP eliminates the "white-coat effect," and is a useful adjunct to office visits [1]. During home monitoring, parents/caregivers are asked to send a log of the readings in a couple of weeks after medication initiation or adjustments. ABPM is used to assess response to therapy when clinic or home monitoring is insufficient to determine treatment effectiveness.

Discontinuation of therapy — Gradual discontinuation of therapy is most likely to be effective in children with mild initial HTN who are well controlled on a single drug and who can be maintained on nonpharmacologic therapy, such as weight loss and sodium restriction. This "step-down" approach can be tried in those selected patients who fulfill these criteria. These patients will require ongoing nonpharmacologic therapy and BP monitoring after drug therapy is discontinued.

Patients with secondary HTN in whom a cause has been identified and corrected may also be able to discontinue medication. However, patients with prolonged secondary HTN as may be the case for those with coarctation of the aorta or renal artery stenosis, may still have elevated BP or develop HTN even after successful repair and require pharmacologic therapy. So clinicians need to be aware of the risk of persistent HTN based on the underlying etiology. (See "Management of coarctation of the aorta", section on 'Systemic hypertension'.)

Sports participation — Recommendation on the level of sports participation is typically made based on the degree of BP elevation, as recommended by the 2017 AAP guidelines on pediatric HTN [1]:

●Children with stage 2 HTN should be restricted from high-static sports (figure 1) even if there is no evidence of end-organ injury. These would include sports classified as IIIA to IIIC in the linked graphic, which categorizes sports based on their cardiovascular (CV) demands. Children with stage 2 HTN, once treated and documented to be normotensive, may be allowed to participate in these sports with ongoing monitoring.

●Children and adolescents with HTN may participate in competitive sports once evaluation has been completed for hypertensive target organ effects and risks.

NONPHARMACOLOGIC THERAPY

Overview — Nonpharmacologic therapy is provided for all children with high blood pressure (BP). In our practice, the following nonpharmacologic measures are used to treat hypertensive children and those with high BP [1,25]:

●Weight reduction for children who are overweight with elevated BP or HTN.

●Regular exercise and restriction of sedentary activity.

●Dietary modification, including salt restriction.

●Nonpharmacologic measures to reduce other cardiovascular disease (CVD) risk factors, such as preventing or treating dyslipidemia and avoiding smoking, alcohol, caffeine, and energy drinks. (See "Pediatric prevention of adult cardiovascular disease: Promoting a healthy lifestyle and identifying at-risk children" and "Dyslipidemia in children and adolescents: Management".)

The long-term beneficial effects of these measures were shown in a prospective study of 798 participants that measured BP in children at 9, 12, or 15 years and at follow-up 20 years later [31]. Resolution of elevated BP as adults was observed in approximately 44 percent of participants with elevated childhood BP measurements. Factors associated with resolution of pediatric elevated BP included significant decrease in body mass index (BMI), decrease in alcohol consumption, increase in vegetable consumption, and improved socioeconomic status.

Weight reduction — Dietary counseling with a nutritionist can provide customized recommendations to decrease daily caloric intake. Dietary modification should be coupled with a decrease in time spent on sedentary activities and initiation of a regular exercise regimen. In some cases, referral to pediatric obesity centers for appropriate dietary, pharmacologic, and/or surgical therapy may be warranted. (See "Clinical evaluation of the child or adolescent with obesity".)

Although data in children are not as robust as in adults, several studies and a systemic review of the literature have reported weight reduction was associated with lower BP values in hypertensive children [32-37]. A 2014 systematic review showed obesity intervention regimens modestly reduced BP with a mean decrease of 1.64 mmHg (95% CI -2.56 to -0.71) in systolic BP (SBP) and 1.44 mmHg (95% CI -2.28 to -0.60) in diastolic BP (DBP), which is similar to results seen in adults [37]. In this review, interventions that combined diet and physical activity were more effective in lowering BP than diet or physical activity alone. (See "Overweight, obesity, and weight reduction in hypertension".)

Exercise — Exercise lowers BP, decreases the risk of atherosclerosis and CVD, and prevents and treats metabolic syndrome [33,38-43]. Children should be instructed to participate in moderate to vigorous aerobic activity in 30- to 60-minute sessions for at least three to five days per week. An expert panel sponsored by the United States National Heart, Lung, and Blood Institute (NHLBI) has developed age-based recommendations for daily physical activity for children (table 6).

Data has shown short-term physical activity leads to a small but not significant reduction of BP [42]. However, it appears that sustained regular physical activity is effective in lowering BP, and the more vigorous the activity the greater the impact on reducing BP [38,44].

As cited above, the antihypertensive effect of physical activity combined with weight loss is greater than that with weight loss or exercise alone. However, the combination of weight loss and physical training may not improve the adverse effects of obesity on left ventricular function or size in adolescents [45].

Diet — There are limited data on the effect of dietary changes upon BP in children. However, it is generally accepted based upon adult trials that a reduction in salt intake and an increased intake of fresh fruits, vegetables, and low-fat dairy products (eg, the Dietary Approaches to Stop Hypertension [DASH] diet [46]) are beneficial in children and adolescents with HTN [1].

Salt restriction — The benefit of salt restriction for children with HTN is based on indirect data from well-controlled trials in adults and observational pediatric data [34,47-49]. In particular, there appears to be a greater benefit in salt restriction for Black individuals and patients with established HTN or renal insufficiency. Based on the available evidence, the 2017 AAP guidelines recommend that dietary sodium be restricted to <2300 mg/day. In younger children, the normal requirement of sodium is between 2 to 3 mEq/kg per day. (See "Salt intake and hypertension".)

In our practice, we begin dietary salt modification with a no-added-salt diet. This also includes a reduction in or elimination of foods containing large amounts of salt (eg, potato chips, pretzels, processed foods). Parents and caregivers are encouraged to read food package labels to determine the sodium content of prepared foods and avoid those with high salt content. In addition, lunches provided by school programs need to be evaluated to ensure avoiding foods with high salt content. (See "Patient education: Low-sodium diet (Beyond the Basics)".)

Energy drinks — Energy drinks may contain a high amount of sugar, caffeine, and other stimulants. They can cause excessive weight gain and increase in blood pressure or worsening of blood pressure in those with elevated BP or hypertension [50,51]. As a result, they should be avoided in children with elevated BP.

Potassium intake and the DASH diet — Pediatric data from observational studies and clinical trials in adolescents have shown that diets rich in fresh vegetables and fruits, reduced fat (whole grains, low-fat milk products, fish and poultry), and reduced sodium (eg, the Dietary Approaches to Stop Hypertension [DASH] diet) are associated with reducing elevated BP [52-56]. As a result, a diet such as the DASH diet with a high intake of potassium and low intake of fat and sodium is recommended for children with high BP (table 7) [1]. (See "Diet in the treatment and prevention of hypertension", section on 'Our approach: Comprehensive dietary modification'.)

Avoidance of excess alcohol — Multiple studies in adults have shown a clear association between excess alcohol intake and the development of HTN. The applicability of these findings to children has not been well studied. Nevertheless, excess alcohol intake should be avoided to improve weight loss, BP control, and other health concerns. (See "Cardiovascular benefits and risks of moderate alcohol consumption".)

Smoking — In hypertensive children and adolescents, smoking and exposure to tobacco smoke should be avoided because it increases the risk of CVD, as well as lung cancer. (See "Smoking and hypertension" and "Secondhand smoke exposure: Effects in children", section on 'Cardiovascular disease'.)

Dyslipidemia — Dietary measures should be initiated in children with dyslipidemia, another CVD risk factor, which is discussed separately. (See "Dyslipidemia in children and adolescents: Management", section on 'Dietary modification'.)

ANTIHYPERTENSIVE DRUGS

Overview — The following sections describes the antihypertensive drugs used in the treatment of pediatric HTN. The initial choice of antihypertensive agent is discussed in the section on management approach. (See 'Choice of drug' above.)

The number of antihypertensive drugs in children that have been systematically studied has increased due to the 1997 US Food and Drug Administration Modernization Act (FDAMA) and the 2002 Best Pharmaceuticals for Children Act (BPCA). As a result, efficacy and safety evaluation are available for antihypertensive medications that have been introduced subsequently. However, the legislation did not affect older commonly used drugs whose patent protection had expired. As a result, data are sparse on the effects of different older classes of antihypertensive medications in children [57]. In addition, most trials are of variable quality, funded by pharmaceutical companies, of short duration, and typically have outcome measures that are limited to lowering BP and not end-organ damage.

The 2017 AAP high BP guidelines includes dosing recommendations for antihypertensive drugs (table 5) [1]. These recommendations were based upon data from industry-sponsored clinical trials and single-center observational studies. When data were not available, recommendations were based on collective clinical experience and consensus opinions from experts in the field.

The following sections describes the antihypertensive drugs used in the treatment of pediatric HTN. The initial choice of antihypertensive agent is discussed in the section on management approach. (See 'Choice of drug' above.)

ACE inhibitors — Angiotensin-converting enzyme (ACE) inhibitors (eg, captopril, enalapril, lisinopril, and fosinopril) are well tolerated and widely used in hypertensive children. They inhibit the production of angiotensin II by blocking the ACE. In children, efficacy and dosing data are available for enalapril, lisinopril, benazepril, and fosinopril.

●Captopril was the first available ACE inhibitor used in pediatrics, but it has been supplanted by longer acting ACE inhibitors.

●Enalapril has received US Food and Drug Administration (FDA) approval as an antihypertensive drug for children following completion of both a pharmacokinetic and a dose-dependent trial. The former demonstrated similar pharmacokinetics in infants and children when compared with adults [58], while the latter demonstrated a dose-dependent response with a low incidence of side effects [59].

●Lisinopril is effective and safe [60]. Based upon a dose that ranged between 0.1 and 0.2 mg/kg, pharmacokinetics of lisinopril in children were similar to those reported in adults with a peak serum concentration between five and six hours after administration [61].

●Fosinopril has been shown to reduce BP in children [62], although dosing recommendations are limited to children greater than 50 kg. There appear to be differences in dose response based upon ethnicity. Black children appear to require a higher dose per body weight to achieve similar BP reduction compared with other children (ie, White, Asian, and Hispanic children) [63].

Studies in adults suggest that the antihypertensive effect of ACE inhibitors is increased by concurrent salt restriction [64]. Salt restriction increases renin release, making the BP more angiotensin II-dependent and therefore more responsive to therapy with an ACE inhibitors. (See "Renin-angiotensin system inhibition in the treatment of hypertension".)

ARBs — Angiotensin-receptor blockers (ARBs) block the binding of angiotensin II to the AT1 receptor. ARBs used in children include candesartan, irbesartan, losartan, olmesartan, and valsartan, which have been FDA approved [57,65-70]. However, in a larger efficacy study, irbesartan failed to show a beneficial effect in hypertensive children between 6 and 16 years of age. As a result, irbesartan is not recommended as a pediatric antihypertensive agent [71]. A review of the literature reported that ARBs were effective and safe in lowering BP and proteinuria in children [72].

ARBs are a good alternative if there are significant side effects (eg, cough) associated with the use of an ACE inhibitor. However, the use of both is not recommended based on multiple studies in adult patients that demonstrated an increased risk of adverse effects (eg, hypotension, syncope, worsening of renal function, and hyperkalemia). (See "Major side effects of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers", section on 'Combination of ACE inhibitors and ARBs'.)

Thiazide diuretics — There is an extensive clinical experience but limited published efficacy data regarding the use of thiazide diuretics in children [73]. Thiazide diuretics may be used as an initial agent or as a second agent, when needed, as it enhances the effect of many other antihypertensive drugs (eg, ACE inhibitors, ARBs, and beta blockers) when given as combination therapy [74,75]. Optimal efficacy of thiazides, given alone or in combination with other drugs, requires concurrent salt restriction [76,77]. However, thiazide diuretics are associated with several adverse effects including hypokalemia, hyponatremia, hyperuricemia, hyperglycemia, hyperlipidemia, hypomagnesemia, and an increased incidence of type 2 diabetes mellitus, so ongoing monitoring of laboratory tests is needed. (See "Salt intake and hypertension" and "Use of thiazide diuretics in patients with primary (essential) hypertension", section on 'Side effects'.)

Calcium channel blockers — Increasing experience with long-acting CCBs (such as extended-release nifedipine and amlodipine) demonstrates their efficacy and safety in children with HTN, particularly primary HTN [78-82]. However, a randomized, placebo-controlled three-week trial of extended release felodipine failed to show a fall in systolic BP (SBP) greater than placebo at any dose in 133 children with primary HTN [83].

A limitation of long-acting CCBs is the minimum dose formulation that is currently available, resulting in a range of mean daily dose from 0.06 to 0.23 mg/kg per day [78,80]. Thus, smaller children who received a larger dose of medication per body weight may be more likely to experience dose-related adverse effects. (See "Major side effects and safety of calcium channel blockers".)

CCBs are contraindicated in patients with sinus node dysfunction (see "Sinus node dysfunction: Treatment"), but is the preferred class of antihypertensive agents in patients with HTN and diminished renal function or hyperkalemia or sexually active females who are unlikely to follow appropriate counseling on contraception.

The use of short-acting nifedipine is not recommended in hypertensive children given concerns about its safety and the inability to accurately administer small doses [84].

Beta blockers — Beta blockers were among the first and most widely used antihypertensive drugs in children. However, beta blockers are not recommended as initial therapy in children because of the expanded adverse outcomes associated with beta blockers (eg, impaired glucose tolerance and interference in lipid metabolism) and is less effective than other antihypertensive agents in preventing stroke in adults with primary hypertension. In addition, beta blockers can cause increased bronchial obstruction and airway reactivity in children with asthma. Beta blockers may be used as second or third agents for patients who fail to respond to initial monotherapy. (See "Major side effects of beta blockers" and "Treatment of hypertension in asthma and COPD", section on 'Beta blockers' and "Choice of drug therapy in primary (essential) hypertension".)

Most of the original studies in children were performed with propranolol, which has been largely replaced by better tolerated, longer-acting, and more selective drugs such as atenolol, metoprolol, and bisoprolol. Both bisoprolol and metoprolol have been shown to be effective in reducing BP in children [57]. These agents are available in combination with hydrochlorothiazide. Labetalol is another beta blocker agent, which also has alpha blocking activity [74,85,86]. Esmolol is an intravenous beta blocker agent, primarily used to treat postoperative or intraoperative tachycardia and HTN [87].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hypertension in children".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: High blood pressure in children (The Basics)")

●Beyond the Basics topics (see "Patient education: High blood pressure in children (Beyond the Basics)" and "Patient education: High blood pressure treatment in children (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Management – Treatment for chronic hypertension (HTN) includes both nonpharmacologic and pharmacologic interventions. Management decisions are dependent upon the severity of HTN (table 1), the underlying cause, the presence of other cardiovascular disease (CVD) risk factors, and defining target blood pressure (BP) goals, which are consistent with the American Academy of Pediatrics (AAP) guidelines. (See 'Management approach' above.)

•Target BP goal – In our practice, for children diagnosed with HTN and treated with nonpharmacologic and/or pharmacologic therapy, the target BP goal is a reduction of systolic and diastolic BP below the 90^th percentile or <130/80 in adolescents (13 years or older). A lower goal is used for children who have CKD. (See 'Target blood pressure goals' above.)

•Nonpharmacologic therapy – Nonpharmacologic therapy is provided for all children with elevated BP and any stage of HTN. This consists of weight reduction for children who are overweight, regular exercise (table 6), restriction of sedentary activity, dietary salt restriction, and prevention of other CVD risk factors (eg, dyslipidemia and smoking). (See 'Nonpharmacologic therapy' above and 'Who should be treated' above.)

•Pharmacologic therapy

-For children with elevated BP, we suggest not to initially administer pharmacologic therapy and only continue nonpharmacologic therapy (Grade 2C).

-For asymptomatic children with stage 1 HTN, we suggest not to initially administer pharmacologic therapy and continue only to provide nonpharmacologic therapy to lower BP to target goals (Grade 2C). Pharmacologic therapy is considered if BP target goals are not met after six months of nonpharmacologic therapy.

-For children with stage 1 HTN who are symptomatic or have evidence of end-organ target damage (eg, left ventricular hypertrophy), we suggest administering pharmacologic therapy in addition to nonpharmacologic therapy versus only nonpharmacologic therapy to reach target BP goals (Grade 2C).

-For children with stage 2 HTN, management includes both pharmacologic and nonpharmacologic therapy. Children with neurologic symptoms should be evaluated and treated emergently. (See "Epidemiology, risk factors, and etiology of hypertension in children and adolescents", section on 'Secondary hypertension'.)

-For children with CKD, both nonpharmacologic and pharmacologic therapy is provided for any child with elevated BP or HTN. (See "Chronic kidney disease in children: Complications", section on 'Hypertension'.)

-For children with diabetes mellitus (DM), both nonpharmacologic and pharmacologic therapy is provided for any child with any stage of HTN. (See "Chronic complications and screening in children and adolescents with type 2 diabetes mellitus", section on 'Hypertension' and "Complications and screening in children and adolescents with type 1 diabetes mellitus", section on 'Hypertension'.)

•Choice of antihypertensive agent – Data comparing antihypertensive drugs in children are lacking and hence it is not possible to make an evidence-based choice. Recommendations on the choice of agent for initial therapy are based upon the underlying cause of HTN, concurrent disorders, and the preference and experience of the responsible clinician. (See 'Antihypertensive drugs' above.)

In general, a single agent is first administered and a second agent from a different class is only added when initial drug dose reaches the highest recommended level or if the patient begins to experience side effects from the initial drug. Thiazide diuretic is the most commonly used second antihypertensive agent. (See 'General principles when starting pharmacologic therapy' above.)

In our practice, the following classes of antihypertensive agents are used initially based on the clinical context.

-Primary hypertension – Angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or calcium channel blockers (CCBs). (See 'Primary hypertension' above.)

-Renal vascular disease – CCB rather than ACE inhibitor or ARB because of concerns of a reduction in glomerular filtration rate with ACE inhibitors and ARBs. (See 'Renovascular disease' above.)

-Chronic kidney disease – ACE inhibitor or ARB as data suggest that these agents slow the progression of CKD but close monitoring of kidney function is required. (See "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults" and 'ACE inhibitors' above and 'ARBs' above and "Chronic kidney disease in children: Complications", section on 'Hypertension'.)

-Diabetes mellitus – ACE inhibitor or ARB as data suggest that these agents slow the progression of diabetic nephropathy. (See "Treatment of diabetic kidney disease" and "Complications and screening in children and adolescents with type 1 diabetes mellitus", section on 'Hypertension' and "Chronic complications and screening in children and adolescents with type 2 diabetes mellitus", section on 'Hypertension'.)

-Sexually active females – CCB as ACE inhibitors and ARBs are contraindicated in pregnancy because of known teratogenic adverse effects. (See "Adverse effects of angiotensin converting enzyme inhibitors and receptor blockers in pregnancy" and "Treatment of hypertension in pregnant and postpartum patients", section on 'Overview of antihypertensive drugs used in pregnancy'.)

●Follow-up – Continued follow-up is required to monitor the response to pharmacotherapy, detect any drug-related adverse effect and make dosing changes or introduce additional agents to achieve target BP goal. (See 'Follow-up care' above.)

●Sports participation – The level of sports participation is based on the degree of BP elevation and evidence of end-organ damage. (See 'Sports participation' above.)