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Robert C. Holleman, Jr., MD Associate Professor of Clinical Pediatrics Pediatric Nephrology and Hypertension

USC School of Medicine

PEDIATRIC HYPERTENSION

Disclosures

!! I have no financial or industry relationships to disclose

!! I will not be discussing any off lable medications

Objectives/Questions !! How do we measure and define HTN in children? !! Who should be screened? !! What are the most common causes of pediatric

HTN? !! What is the appropriate diagnostic plan? !! When do we treat with medication? !! What drug(s) do we choose? !! What is the utility of 24hr ambulatory BP

monitoring?

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Pediatric Hypertension

Can we still blame the kidney?

"

A primary care problem?

Blood Pressure Measurement #! Arm/cuff size

- Bladder width > 40% mid arm circumference

- Bladder length 80-100% mid arm circumference

#! Comfort/Cooperation #! At rest for 3-5 minutes #! Clothing out of the way #! Right arm, heart level #! At least 2 readings

Patient Issues

Blood Pressure Measurement

#! Calibration and upkeep #! Auscultatory

- “Gold standard” - K1 = SBP, K5 = DBP - Mercury vs Aneroid

#! Oscillometric - Dinamap

#! Observer bias

Technical Issues

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How do we define Hypertension?

#! BP level associated with increased morbidity and mortality

#! Method of measurement - Casual (office) BP - 24hr ambulatory BP (BP load)

#! Large pediatric variation by age, size and sex

#! Task Force data

Blood Pressure Charts 1996 2004

Diagnosis: Fourth Taskforce

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Definition of Hypertension

#! Normal BP: < 90th %tile for age, sex, ht. #! Pre-HTN: > 90th %tile, < 95th %tile #! Stage 1 HTN: 95th %tile – 99th %tile + 5 #! Stage 2 HTN: > 99th %tile + 5 #! Malignant HTN: signs or symptoms of

target organ damage/disease

Based on avg SBP and/or DBP on 3 occasions

What is “Pre-Hypertension?”

#! Replaces “borderline” or “high normal” BP #! BP > 90th %tile but < 95th %tile #! Adolescents with BP > 120/80 #! Implement healthy lifestyle changes and

identify other cardiovascular disease risk factors

#! At risk for future HTN so follow up is key

Adolescent Example #! 17 year old male #! Height: 95th %tile #! Average BP: 135/83

90th %tile: 136/84 95th %tile: 140/89

Reference Values

Normal BP by standard definition but BP > 120/80

Recommendation of the Fourth Report is to classify this patient as pre-hypertension

Difficulty in reconciling outcome based adult data with normative based pediatric data

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BP Screening: Argument For #! HTN is the most common primary diagnosis in

the U.S. with healthcare costs in the billions #! High BP in adults is an independent risk factor

for the development of cardiovascular disease, stroke, and chronic kidney disease

#! More than 7 million premature deaths worldwide annually in adults attributable to HTN

#! HTN accounts for 40% of cardiovascular mortality, more than any other risk factor including smoking

BP Screening: Argument For #! BP tracking: childhood BP predicts adult BP

$$ Childhood HTN is the strongest predictor of adult HTN $$ BP at the 90th %tile in childhood increases risk of adult HTN x 2.4

#! Childhood HTN is associated with increased carotid intima-media thickness, endothelial dysfunction and increased vascular stiffness " markers for adult atherosclerosis

#! The rationale for childhood BP screening as an important strategy for increasing health and decreasing cardiovascular mortality in adults has been endorsed by:

$$ American Academy of Pediatrics $$ European Society of Hypertension $$ American Heart Association $$ National Heart Lung and Blood Institute

BP Screening: Argument Against

#! Lack of prospective, longitudinal clinical studies #! Potential harm of screening: stress, anxiety, labeling #! Potential harm of unnecessary testing and treatment #! Prevalence inadequate to justify widespread screening

“current evidence is insufficient to assess the balance of benefits and harms of screening for primary hypertension in asymptomatic

children and adolescents to prevent subsequent cardiovascular disease in childhood or adulthood.”

- Moyer V, Pediatrics, 132(5), 2013

U.S. Preventive Services Task Force (USPSTF)

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BP Screening: current practice

Type of Visit 2000-2009 2000-2001 2008-2009

All Visits 35% 26% 41%

Preventive Care Visits 67% 51% 71%

Preventive Care Visits + Overweight/Obese 84% 71% 81%

Hypertension Screening During Ambulatory Pediatric Visits in the United States, 2000-2009

- Shapiro DJ et al, Pediatrics, 2012

Data from the National Ambulatory Medical Care Survey and the National Hospital Ambulatory Medical Care Survey

#! 93,534 ambulatory visits for children age 3 to 18 sampled #! BP screening more likely in older kids and kids who were overweight/obese #! Non factors in screening frequency included: race, gender, region, practice

setting and use of an EMR

Who should be screened and how? #! All children > 3 years of age at least annually #! Preferred method is auscultation with an

age/size appropriate cuff #! Abnormal BP obtained by oscillometric device

should be repeated by auscultation #! Elevated BP must be confirmed on repeat

visits before diagnosing HTN

The Fourth Report on the Diagnosis, Evaluation, and Treatment

of High Blood Pressure in Children and Adolescents

Conditions requiring BP screening prior to age 3 years #! History of prematurity, very low birth weight,

or complicated NICU stay #! Congenital heart, renal, or urologic disease #! Recurrent UTIs, hematuria, proteinuria #! Solid organ or bone marrow transplant #! Treatment with drugs known to cause " BP #! Systemic disease associated with HTN #! Evidence of increased intracranial pressure

The Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in Children and Adolescents

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Epidemiology #! Estimated pediatric prevalence 5% #! Higher in minority populations #! > #! BP # BMI #! Essential HTN is the most prevalent

form

Epidemiology: Risk Factors

Family History

Low birth weight

Obesity Race

Diet – Na intake

Stress

Pathophysiology

#! BP = CO x PVR #! CO influenced by "

! SV ! contractility ! HR ! preload

#! PVR influenced by " ! elasticity ! afterload ! vasoconstriction

#! BP follows a circadian rhythm

Hormonal regulation

Genetics Environment

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Pathophysiology

From: Ingelfinger; Pediatr Clin N Am, 53(2006)

We have a “big” problem…

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Obesity related HTN #! 35-50% of hypertensive

adolescents are obese #! The relationship between BP and

weight begins as early as age 5yrs #! HTN is three times more common

in obese children #! Obesity is an independent risk

factor for other cardiovascular morbidity " ! insulin resistance/type II DM ! dyslipidemia ! LVH

Obesity related HTN

The Perils of Insulin

" SNS Altered vascular

reactivity

Na retention " RAS

HYPERTENSION

%

Etiology of Pediatric HTN

#! No identifiable cause #! Incidence "’s with age #! Positive family history #! HTN usually less severe #! Closely related to BMI #! Stress sensitive #! Strongly predictive of

adult HTN

#! Renal causes most common

#! DDx varies with age #! Malignant HTN more

common #! Signs/symptoms more

likely

ESSENTIAL HTN SECONDARY HTN

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Renal Causes of Secondary HTN

#! Parenchymal Disease (70-80%) & Reflux nephropathy/scarring & Obstructive uropathy & Inherited disease (PKD, TS) & Dysplasia/hypoplasia & Chronic glomerular disease

#! Renovascular Disease (5-10%) & RA stenosis (FMD, NF, Williams) & RA/RV thrombosis & Vascular malformation (AVM) & External compression

#! Chronic or End Stage Kidney Disease

Other Causes of Secondary HTN

#! Cardiovascular & Coarctation & Vasculitis

#! Endocrine & Catecholamine excess (the omas ) & Corticosteroid excess (CAH, Cushings, AME) & Hypercalcemia (Hyperparathyroidism, Williams) & Hyper and hypothyroidism

Other Causes of Secondary HTN #! Neurologic

& Central (" ICP, seizures, spinal cord lesions) & Peripheral (Guillain-Barre, dysautonomia)

#! Drugs & Caffeine & Nicotine & Steroids & Decongestants & Cocaine & Methamphetamine & $-agonists & ADHD meds & OCPs

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Most Common Causes By Age

#! RA thrombosis #! RV thrombosis #! Congenital uropathy #! Coarctation #! RA stenosis #! BPD

#! Renal parenchymal dz #! RA stenosis #! Coarctation #! Endocrine causes #! Essential HTN

Decreasing frequency

NEONATE FIRST 6 YEARS

Most Common Causes By Age

#! Renal parenchymal dz #! Essential HTN #! RA stenosis #! Endocrine causes

#! Essential HTN #! Renal parenchymal dz #! Substance abuse #! Endocrine causes

Decreasing frequency

6-10 YEARS ADOLESCENCE

Genetic HTN can be more than just “essential” disease

#! Advances in positional cloning have led to the identification of specific monogenic forms of HTN

#! Suspect in kids with

difficult to control HTN and a strong family history of early onset severe HTN

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Monogenic Forms of HTN #! Glucocorticoid-remediable aldosteronism

AD; chromosome 8; % K+; % renin; " aldo #! Apparent mineralocorticoid excess

AR; chromosome 16; % K+; % renin; % aldo #! Liddle syndrome

AD; chromosome 16; % K+; % renin; % aldo #! Gordon syndrome (pseudohypoaldo type II)

AD; chromosomes 1, 17, and 12; " K+; % renin

Evaluating the Hypertensive Child

#! Is the HTN real and sustained? #! Is there a definable cause? #! Is there target organ disease? #! Are there other cardiovascular

risk factors?

Consider the following questions:

Step 1 '' History #! Perinatal complications

including prematurity #! UTIs or voiding

dysfunction #! Growth and development #! Medications/Drugs #! Full ROS #! Complete family history

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Step 2 '' Physical Exam #! Growth curve, BMI #! Other vital signs #! Dysmorphic features #! Fundoscopic changes #! Skin findings – striae,

neurocutaneous or vasculitic lesions, acanthosis

#! Genitalia – ambiguous, virilized #! Peripheral pulses, LE BPs,

bruits

Step 3 '' Staged Work UP

#! Blood work: CBC, Lytes, Ca, BUN, Cr, and fasting lipid profile

Depending on BMI consider insulin/HgbA1c

#! Complete urinalysis, urine microalbumin:Cr #! ECHO* #! RUS*

PHASE 1

* Recommended by the Task Force but physician discretion seems reasonable

Staged Work Up

#! VCUG, Renal scan +/- captopril #! Urine Pro:Cr #! 24hr urine for protein, catecholamines #! Thyroid function tests #! Renin*, aldosterone* #! Plasma and urine steroids

PHASE 2 – if indicated

* Consider in phase 1 if high suspicion of 2º HTN, impressive family history, infant/

toddler, or if abnormal electrolytes

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Staged Work Up

#! Arteriography, renal vein renin sampling #! MIBG scan #! CT scan #! MRA #! Renal biopsy

PHASE 3 – if indicated

The Therapeutic Plan

(( Non-pharmacologic tx & Good for everyone & Multifaceted

)) Antihypertensives & Who gets them? & Which ones?

Non-pharmacologic therapy “TLC”

Wt Loss

Lifestyle modification

Stress management

Exercise

Diet

** Blood Pressure

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Dietary Interventions #! Na+ restriction (< 3 gm/day)

& greater “salt sensitivity” in African Americans and obese pts

#! “DASH” diet & more fruits, veggies, and low fat dairy & theoretical benefit from K+, Ca++, and Mg++

#! Avoid caffeine/energy drinks #! Address dietary cholesterol and fat as well

as foods with high glycemic load when appropriate

The Benefits of Exercise

#! % sympathetic tone and SVR #! Contributes to weight loss #! Lowers insulin levels #! For most kids with

HTN…”it’s ok to play”

Lowers blood pressure

Treatment Algorithm Risk Assessment

#! Family History: HTN, CVD, CVA

#! Obesity #! Dyslipidemia #! Hyperinsulinemia

#! LVH #! Retinopathy #! Proteinuria or

microalbuminuria #! Chronic disease:

- DM, CKD

Co-Morbid Risk Factors

Target Organ Dz (TOD) Chronic Disease

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Target Organ Disease (TOD)

Treatment Algorithm

No Risk Factors No TOD/chronic dz

Pre-HTN Stage 1 HTN Stage 2 HTN

TLC TLC TLC + Drug Tx

Treatment Algorithm

(+) Risk Factors No TOD/chronic dz

Pre-HTN Stage 1 HTN Stage 2 HTN

TLC TLC Drug tx if no improvement

in 6-12 months

TLC + Drug Tx

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Treatment Algorithm

(+) TOD/Chronic Dz

Pre-HTN Stage 1 HTN Stage 2 HTN

TLC + Drug Tx

TLC + Drug Tx

TLC + Drug Tx

Drug Therapy - Obstacles

#! Lack of pediatric trials and dosage guidelines

#! Lack of age appropriate formulations

#! Lack of safety information

Important Legislation #! Food and Drug Administration Modernization

Act (FDAMA) in 1997 FDA will identify drugs that may benefit children and request

drug companies to conduct pediatric trials

#! Best Pharmaceuticals for Children Act (BPCA) in 2002 Established Office of Pediatric Therapeutics at FDA Provides a process for off-patent drug development

#! Pediatric Research Equity Act (PREA) in 2003 All new drug applications must contain a pediatric assessment

unless the manufacturer obtains a waiver

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Drug Therapy - Choices #! ACE inhibitors #! Ca channel blockers #! Diuretics #! Angiotensin receptor

blockers (ARBs) #! Sympathetic

antagonists - # and/or $ #! Other

Angiotensin Converting Enzyme Inhibitors (ACEI)

#! Mechanism: Ang I Ang II #! Adverse effects: cough, hypotension, %GFR,

angioedema, " K+, marrow suppression #! Contraindications: pregnancy, AKI, bilateral

renal artery stenosis, volume depletion #! The “prils”: enalapril, lisinopril, captopril #! Benefits: very effective, well tolerated,

reno-protective, % proteinuria #! Other: some resistance in African Americans

Ca Channel Blockers #! Mechanism: block influx of Ca++ into

vascular smooth muscle cells ' decrease vascular resistance

#! Adverse effects: HA, flushing, hypotension, edema, gingival hypertrophy

#! Short acting: safe when used with caution, isradipine vs. nifedipine

#! Long acting: amlodipine, nifedipine XL #! Benefits: good peds experience, well

tolerated, convenient dosing forms available

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Diuretics #! Mechanism: block renal solute reabsorption

' decreased IV volume #! Adverse effects: % K, % Na, alkalosis,

enuresis, hyperlipidemia, hypercalciuria, hyperglycemia

#! Diverse group of drugs: & THIAZIDES + #1 for chronic HTN; useful as 2nd agent or

occasionally as monotherapy; Chlorothiazide, HCTZ & LOOP agents + acute HTN in certain settings, refractory volume overload; Furosemide, Bumetanide & K+ SPARING + weak diuretics; use for mineralocorticoid excess or as 2nd diuretic if hypoK; Spironolactone, Amiloride

Angiotensin Receptor Blockers #! Mechanism: Prevents binding of ang II to

the type I receptor (vascular smooth muscle and adrenal gland) '

% vasoconstriction % aldosterone #! Adverse effects: same as ACEI except

cough #! Contraindications: same as ACEI #! The “tans”: Losartan, Irbesartan, Valsartan #! General: less pediatric experience;

adjunctive antiproteinuric effect with ACEI

Sympathetic Antagonists

#! % CO, PVR, and renin #! Avoid in pts with RAD,

IDDM, heart block #! May cause fatigue,

dizziness, orthostasis, sexual dysfunction, dyslipidemia

#! Propranolol, Atenolol, Metoprolol, Labetalol

#! % PVR #! May cause dizziness, HA,

fatigue, palpitations, “first dose effect”

#! Seldom used in kids; used in pheo and ? utility in dysmetabolic synd

#! Prazosin, Doxazosin, Phenoxybenzamine

$$-Blockers ##-Blockers

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Other Agents Used in Kids #! Clonidine:

& CNS # receptor agonist " inhibits sympathetic output

& Sedation, dry mouth, constipation, rebound HTN

& Dermal delivery option #! Hydralazine: & Direct vasodilator of arterioles

& Flushing, HA, palpitations, drug induced SLE #! Minoxidil:

& Used in refractory HTN & Same as hydralazine; increased hair growth

Drug Therapy Strategies #! If therapy needed in young child prior to

completion of work-up " Ca channel blocker

#! For patients with proteinuria, renal dz or diabetes, or evidence of renovascular hypertension " ACE Inhibitor

#! Partially controlled BP on good dose Ca channel blocker or ACEI " HCTZ

Therapy Take Home Points #! Ca channel blockers are generally the safest

choice when dosed appropriately. #! ACEIs are not to be feared and have

additional benefits. #! Diuretics are making a comeback in

pediatrics particularly in salt sensitive essential disease.

#! $-blockers have more side effects and should be reserved for difficult to control HTN.

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Remember these drugs… #! Enalapril (Vasotec)

0.1mg/kg/dose daily to bid 1mg/ml suspension, 2.5mg, 5mg, 10mg, 20mg

#! Amlodipine (Norvasc) 0.1mg/kg/dose daily to bid 1mg/ml suspension, 2.5mg, 5mg, 10mg, 20mg

#! Isradipine (Dynacirc) 0.05-0.1mg/kg/dose q 6hrs prn 1mg/ml suspension

Remember these drugs…

Amlodipine Enalapril Starting dose 0.1mg/kg (max 5mg) 0.1mg/kg (max 5mg) Interval Daily - BID Daily -BID Suspension 1mg/ml 1mg/ml Tablet strengths 2.5, 5, 10 2.5, 5, 10, 20

24hr Ambulatory BP Monitoring #! More accurate assessment

of blood pressure #! Rules out “white coat

HTN” saving $$ in work-up #! BP readings q 20-30 min #! Assess nocturnal dipping #! HTN determined by % of

readings > 95th %tile or the “blood pressure load”

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Ambulatory BP Monitoring #! Results track better than casual readings '

better predictor of adult HTN #! Results better predict the presence of TOD #! Loss or blunting of nocturnal dipping

correlates with microalbuminuria in kids with normal daytime casual BP

#! BP load < 25% considered normal; load > 40% indicates HTN

Final Thoughts #! Primary or essential HTN is the most prevalent

form in school age children #! Routine screening of annual BP is recommended

from age 3 years #! Renal parenchymal disease is the most common

cause of secondary HTN #! Cardiovascular disease risk begins in childhood

and attention to lifestyle, weight and BP will likely affect morbidity and mortality

#! For most cases, ACEIs and Ca channel blockers are the best first line drugs

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Pediatric Nephrology Program University of S.C. School of Medicine