PEDIATRIC HYPERTENSION

PEDIATRIC HYPERTENSION Robert C. Holleman, Jr., MD Associate Professor of Clinical Pediatrics Pediatric Nephrology and Hypertension USC School of Medicine 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? 1

Pediatric Hypertension " Can A we primary still blame care the problem? kidney? Blood Pressure Measurement Patient Issues #! 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 Blood Pressure Measurement Technical Issues #! Calibration and upkeep #! Auscultatory - Gold standard - K1 = SBP, K5 = DBP - Mercury vs Aneroid #! Oscillometric - Dinamap #! Observer bias 2

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 3

Definition of Hypertension Based on avg SBP and/or DBP on 3 occasions #! Normal BP: < 90 th %tile for age, sex, ht. #! Pre-HTN: > 90 th %tile, < 95 th %tile #! Stage 1 HTN: 95 th %tile 99 th %tile + 5 #! Stage 2 HTN: > 99 th %tile + 5 #! Malignant HTN: signs or symptoms of target organ damage/disease What is Pre-Hypertension? #! Replaces borderline or high normal BP #! BP > 90 th %tile but < 95 th %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: 95 th %tile #! Average BP: 135/83 Reference Values 90 th %tile: 136/84 95 th %tile: 140/89 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 4

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 90 th %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 U.S. Preventive Services Task Force (USPSTF) 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 #! 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 5

BP Screening: current practice Hypertension Screening During Ambulatory Pediatric Visits in the United States, 2000-2009 - Shapiro DJ et al, Pediatrics, 2012 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% 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 6

Epidemiology #! Estimated pediatric prevalence 5% #! Higher in minority populations #! > #! BP # BMI #! Essential HTN is the most prevalent form Epidemiology: Risk Factors Low birth weight Family History Obesity Race Diet Na intake Stress Pathophysiology Hormonal regulation Genetics Environment #! BP = CO x PVR #! CO influenced by "! SV! contractility! HR! preload #! PVR influenced by "! elasticity! afterload! vasoconstriction #! BP follows a circadian rhythm 7

Pathophysiology From: Ingelfinger; Pediatr Clin N Am, 53(2006) We have a big problem 8

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 ESSENTIAL 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 SECONDARY HTN #! Renal causes most common #! DDx varies with age #! Malignant HTN more common #! Signs/symptoms more likely 9

Renal Causes of Secondary HTN #! Parenchymal Disease (70-80%) & Reflux nephropathy/scarring & Obstructive uropathy & Inherited disease (PKD, TS) & Chronic glomerular disease #! Renovascular Disease (5-10%) & Dysplasia/hypoplasia & 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 #! Drugs & Central (" ICP, seizures, spinal cord lesions) & Peripheral (Guillain-Barre, dysautonomia) & Caffeine & Nicotine & Steroids & Decongestants & Cocaine & Methamphetamine & $-agonists & ADHD meds & OCPs 10

Most Common Causes By Age NEONATE #! RA thrombosis #! RV thrombosis #! Congenital uropathy #! Coarctation #! RA stenosis #! BPD FIRST 6 YEARS #! Renal parenchymal dz #! RA stenosis #! Coarctation #! Endocrine causes #! Essential HTN Decreasing frequency Most Common Causes By Age 6-10 YEARS ADOLESCENCE #! Renal parenchymal dz #! Essential HTN #! RA stenosis #! Endocrine causes #! Essential HTN #! Renal parenchymal dz #! Substance abuse #! Endocrine causes Decreasing frequency 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 11

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 Consider the following questions: #! Is the HTN real and sustained? #! Is there a definable cause? #! Is there target organ disease? #! Are there other cardiovascular risk factors? Step 1 ' History #! Perinatal complications including prematurity #! UTIs or voiding dysfunction #! Growth and development #! Medications/Drugs #! Full ROS #! Complete family history 12

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 PHASE 2 if indicated #! VCUG, Renal scan +/- captopril #! Urine Pro:Cr #! 24hr urine for protein, catecholamines #! Thyroid function tests #! Renin*, aldosterone* #! Plasma and urine steroids * Consider in phase 1 if high suspicion of 2º HTN, impressive family history, infant/ toddler, or if abnormal electrolytes 13

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 Diet Wt Loss Exercise * Blood Pressure Lifestyle modification Stress management 14

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 Lowers blood pressure #! % sympathetic tone and SVR #! Contributes to weight loss #! Lowers insulin levels #! For most kids with HTN it s ok to play Treatment Algorithm Risk Assessment Co-Morbid Risk Factors Target Organ Dz (TOD) Chronic Disease #! Family History: HTN, CVD, CVA #! Obesity #! Dyslipidemia #! Hyperinsulinemia #! LVH #! Retinopathy #! Proteinuria or microalbuminuria #! Chronic disease: - DM, CKD 15

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 16

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 17

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 18

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 2 nd 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 2 nd 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 $-Blockers #! % 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 #-Blockers #! May cause dizziness, HA, fatigue, palpitations, first dose effect #! Seldom used in kids; used in pheo and? utility in dysmetabolic synd #! Prazosin, Doxazosin, Phenoxybenzamine 19

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. 20

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 > 95 th %tile or the blood pressure load 21

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 22

Pediatric Nephrology Program University of S.C. School of Medicine 23