Murmurs Cardiac Monitoring for ADHD Medications Kerry L. Rosen, MD, FACC, FAAP Director, Outpatient Cardiology Services Associate Professor of Clinical Pediatrics The Ohio State University

Here is the problem …

Is it innocent ? …

Murmurs Murmurs Murmurs Innocent Murmurs Newborn Murmurs Innocent Murmurs of Childhood

Murmur: Some Definitions Classic 1983 college radio album from R.E.M.

Murmur: Some Definitions 1. a half suppressed or muttered complaint 2. a low indistinct but often continuous sound 3. a soft or gentle utterance 4. an atypical sound of the heart typically indicating a functional or structural abnormality Therefore, a murmur is just a sound or a noise… nothing is necessarily opening, closing, blocking or leaking … but, it may be …

Murmur: Some Definitions Systolic Ejection Murmur “crescendo – decrescendo” type of murmur “diamond” shaped murmur typically related to outflow tract issue: LVOT turbulence or flow aortic or pulmonary valve stenosis

Murmur: Some Definitions Systolic Regurgitant Murmur “pan-systolic” type of murmur “flat” shaped murmur typically related to: Tricuspid or Mitral valve regurgitation VSD shunt * perimembranous type VSD ** small muscular VSDs often “short” systolic murmur

Murmur: Some Definitions Continuous Murmur “machinery” type of murmur definition: “continues beyond the 2nd heart sound” (+/- be heard “continuously” throughout the cardiac cycle) typically related to: Patent Ductus Arteriosus Aorto – pulmonary collateral Surgical shunt (aorta- pulmonary artery) Arteriovenous malformation (head/liver) Venous Hum (innocent murmur)

Murmur: Some Definitions Diastolic Murmur Usually “decresendo” Usually pathologic, if present Timing with pulse, s1 and s2 typically related to: Aortic Valve regurgitation Pulmonary valve regurgitation

Common Newborn Murmurs “Transitional Murmurs” Pulmonary Artery Branch Flow Murmur Flow Murmurs

Newborn: Transitional Murmurs Fetal to newborn transition Tricuspid regurgitation *** low/medium pitched systolic regurgitant murmur at the left sternal border – transient Ductus arteriosus closing continuous … or … systolic regurgitant … or … short systolic murmur – variable/ transient

Newborn: “PPS” or Branch Pulmonary Artery Flow Murmur “PPS” – Peripheral Pulmonary “Stenosis” Birth to 2 weeks, especially premature babies Characteristic “I-III/VI short mid-systolic murmur at the high left/right sternal border, radiating well to the axilla and back” Turbulence  Murmur – due to relative acute angle of the pulmonary artery bifurcation Murmur typically resolves by 6 months of life DDx: pulmonary valve stenosis, VSD, true branch PS - Valve PS: more “harsh”, click present - True Branch PS: persists beyond 6 months (*time to refer) - True Branch PS: (William’s, Allagille’s, Rubella) - VSD - more harsh, longer systolic sound, louder anteriorly

Newborn: “Flow Murmurs” Can have typical “Still’s murmur” Pulmonary flow murmur/ Left ventricular outflow murmur Characteristic “low/ medium pitched short crescendo - decrescendo systolic murmur… localized to the left sternal border”

Newborn Murmurs: Infant with “CHF” - tachypnea, retractions - poor feeding, failure to thrive - cardiomegaly on chest radiograph Don’t forget to listen to the head, listen to the liver  Can diagnose: arteriovenous malformations (AVMs) - large physiologic “left to right shunt” - increased pulmonary blood flow - cardiomegaly and “heart failure”

So Far…Common Newborn Murmurs “Transitional Murmurs” Pulmonary Artery Branch Flow Murmur Flow Murmurs

Next… Common Innocent Murmurs of Childhood Still’s Murmur Pulmonary Outflow Murmur Venous Hum

Still’s Murmur 1. Can occur at any age, but most common in late preschool to early school age 2. Low-pitched, I-III/VI: “musical, twanging- string, vibratory or groaning quality” 3. Left sternal border and apex… 4. Systolic ejection murmur/ “crescendo-decrescendo” shape 5. Usually no radiation; occasionally radiates to the upper sternal border or carotids 6. NO suprasternal notch thrill (seen in aortic stenosis) 7. Variable intensity: may or may not be heard… or louder with exercise, fever, anemia or any increased cardiac output state 8. *** Decreased intensity with standing or Valsalva maneuver PE Key: Listen with patient SUPINE and STANDING – this changes physiology - venous return to the heart

Innocent Pulmonary Flow Murmur 1. Second most common innocent murmur of childhood Left upper sternal border, may radiate faintly to axilla Characteristic: I-III/VI “blowing, non-musical, low-medium pitched, mid systolic crescendo - decrescendo murmur” 4. Increased intensity with exercise, fever, anemia 5. *** Decreased intensity with standing and inspiration *** Caused by turbulence/ “vibration” in the pulmonary artery No click (as seen in pulmonary valve stenosis) Not “as harsh” as seen in pulmonary valve stenosis PE Key: TOUCH the patient: suprasternal notch thrill Precordial thrill: grade IV murmur

Still’s vs. Pulmonary Flow Murmur

Innocent Murmur – Venous Hum 1. Very common between ages 2 and 5 years 2. Soft, blowing, low/medium pitched, I-III/VI continuous murmur 3. Heard best at the right upper sternal border/ right infraclavicular area…occasionally heard in the left infraclavicular area 4. Murmur disappears with supine position, positional changes of the head … compressing the jugular vein ! 5. Caused by turbulent flow in the jugular vein/ SVC PE Key: Turn the head- “look at dad” “look at the door” “look at the picture on the wall”

Innocent Murmur? Am I missing … ? ASD: fixed split S2, higher pitched murmur, radiates to lungs – axilla and back AS/PS: higher pitched, more “harsh,” typically has systolic “click” VSD: long systolic murmur, “flat” in contour or “regurgitant”, higher pitched/ “harsh” MR: long, flat, regurgitant murmur, mostly apex HCM: SEM - typically does not decrease with standing, murmur can actually increase PDA: continuous murmur…does not change with head positional changes Typically – no change with standing/positional changes

Innocent Murmurs – What You Can Do History: prematurity intermittent nature normal growth and development negative family history Physical Exam: characteristic qualities of innocent murmur - practice second heart sound: - inspiration- splits – “physiologic splitting” - expiration- single – “physiologic splitting” - no increased intensity, pounding or loud - no click, no thrill (grade IV/VI murmur) no suprasternal notch thrill - positional changes - supine and standing

ALL are OK reasons to refer a murmur Murmurs – When to Refer ? If you are not sure If you are worried something is pathologic If you are not worried, but want reassurance ALL are OK reasons to refer a murmur Really Sick Baby: blue, shock, respiratory distress  Transfer or NICU care with cardiology available Loud murmur, but baby is stable… Get data to be reassured: - RA/ leg BP, pulse Ox, CXR, ECG - can “DC” baby and have seen in a few days Murmur – not so bad/loud/ stable (+/- extra data)  “Routine” cardiology evaluation- 1-3 weeks

Cardiovascular Monitoring/ ADHD Medications Feb 2005: Health Canada/ Adderall XR U.S Post marketing reports sudden death (SD) in pediatric patients  Health Canada (FDA equivalent) suspends sales of Adderall XR  US FDA “Public Heath Advisory for Adderall and Adderal XR” - FDA was aware of SD reports - Factors potentially associated with SD include: structural abnormalities- coronary artery, HCM, BAV & cardiac hypertrophy; increased or toxic levels, family hx (FH) of ventricular arrhythmias & extreme exercise/ dehydration Aug 2005: FDA adds warning to Adderall labeling: “Sudden Death and Preexisting Structural Cardiac Abnormalities” - “SD has been reported… misuse may cause SD…” - “Adderall XR generally should not be used in children or adults with structural cardiac abnormalities” Aug 2005: Health Canada reinstates Adderall XR with above warning

Cardiovascular Monitoring/ ADHD Medications June 2005: FDA Pediatric Advisory Committee Review post marketing reports for methylphenidate/ amphetamines Could not determine whether adverse CV events were “causally associated with the treatment” Feb 2006: FDA Drug Safety & Risk Management Advisory Committee 1999-2003 - 25 people (19 children) taking ADHD meds died suddenly - 43 people (26 children) CV events- stroke, arrest, palpitations - BLACK BOX WARNING (8 to 7 vote) - “stimulant medications” - REC- clinicians continue to follow AAP guidelines re: assess/mgt of ADHD March 2006: FDA Pediatric Advisory Committee 1992-2005 - 11 SD methylphenidates, 13 SD amphetamines - 3 sudden deaths associated with atomoxetine (2003-2005) “Highlight section/ new labeling format”: “children with structural heart defects, cardiomyopathy, or heart-rhythm disturbances may be at risk for adverse cardiac events, including sudden death”  develop booklet re: risk/benefit/adverse events

Cardiovascular Monitoring/ ADHD Medications Feb 2007: FDA Press Release: “FDA Directs ADHD Drug Manufacturers To Notify Patients About CV Adverse Events & Psychiatric Adverse Events” Develop Patient Medication Guides Patients being considered for Rx with ADHD medications… develop treatment plan that includes a careful health history and evaluation of current status, particularly cardiovascular and psychiatric problems (including assessment for a family history of such problems) All mention risk of sudden death in patients who have heart problems/defects or family history of heart problems April 2008: AHA Scientific Statement: Cardiovascular Monitoring of Children and Adolescents with Heart Disease Receiving Medications for ADHD in the AHA journal, Circulation ”The use of selective ECG screening in this population is thought to be medically indicated and of reasonable cost”

Cardiovascular Monitoring/ ADHD Medications April 2008: AHA Scientific Statement: Cardiovascular Monitoring of Children and Adolescents with Heart Disease Receiving Medications for ADHD in the AHA journal, Circulation ”the consensus of the committee is that is reasonable and useful to obtain ECGs as part to the evaluation of children being considered for stimulant drug therapy” (class I: evidence and/or agreement that given procedure/treatment is beneficial, useful, effective and should be performed. Benefit >>> Risk, AHA, ACC) The above should NOT have been stated as a class I recommendation, The recommendation should be/ is a class II recommendation

American Heart Association/ American College of Cardiology Classification of Recommendation and Level of Evidence

Cardiovascular Monitoring/ ADHD Medications Class II Recommendation: Condition for which there is conflicting evidence and/or a divergence of opinion about the usefulness/ efficacy of a procedure or treatment June-Aug 2008: AAP Statement: AAP does NOT recommend routine use of ECGs before initiating stimulant therapy for ADHD American Academy of Pediatrics American Academy of Child and Adolescent Psychiatry The Society for Developmental and Behavioral Pediatrics The National Initiative for Children’s Healthcare Quality The National Association of Nurse Practitioners Children and Adults with Attention Deficit/ Hyperactivity Disorder June-Aug 2008: AHA Scientific Statement is revised (level II rec for ECG) - “it is reasonable to consider adding an ECG, which is of reasonable cost, to the history and physical examination in the CV evaluation of children who need to received treatment with drugs for ADHD”

Cardiovascular Monitoring/ ADHD Medications AHA Scientific Statement: Cardiovascular Monitoring of Children and Adolescents with Heart Disease Receiving Medications for ADHD ”The use of selective ECG screening in this population is thought to be medically indicated and of reasonable cost” (initial recommendation) VERSUS “it is reasonable to consider adding an ECG, which is of reasonable cost, to the history and physical examination in the CV evaluation of children who need to receive treatment with drugs for ADHD” (final/ revised recommendation)

Risk of Sudden Cardiac Death in Children Hypertrophy cardiomyopathy Long QT syndrome/ Brugada Syndrome Other cardiomyopathies- arrhythmogenic right ventricular dysplasia Coronary artery anomolies Primary ventricular fibrillation/ tachycardia Wolfe-Parkinson-White syndrome Prevention of Sudden Cardiac Death Secondary Prevention- Defibrillation/ Automated External Defibrillators (AED) Primary Prevention (mass ECG screening) - very controversial - Europe, Italy, Japan vs. US recommendations - cost-effectiveness, feasibility issues, medical-legal implications - US AHA Athletic Screening Statement, 2007- include personal and family medical history and physical examination (no ECG)

CV side effects of ADHD medications Tachycardia- increase in HR ~ 1-2 bpm BP- increase in systolic and diastolic BP ~ 3-4 mmHg No study has demonstrated a significant change in QT or QTc intervals (exception: imipramine, TCAs- rarely used in ADHD) Because the risk of sudden death in the population of patients pharmacologically treated for ADHD is no higher than that in the general population, performance of screening tests would not seem to be any more indicated than in the general population, and the AHA, along with the AAP, does not recommend routine screening for children and adolescents because of problems with the sensitivity and specificity of the ECG as a general screening test (AAP, Pediatrics statement) There does not seem to be compelling findings of a medication- specific risk necessitating changes in our stimulant treatment of children and adolescents with ADHD (AAP, Pediatrics statement)

???? So… What IS recommended ???? After ADHD diagnosis is made, but before ADHD medication is initiated: Patient History- symptoms Review of all medications Complete Family History Thorough Physical Examination It is reasonable to consider adding an ECG, which is of reasonable cost, to the history and physical examination in the CV evaluation of children who need to receive treatment with drugs for ADHD If possible, ECGs should be read by a pediatric cardiologist or a cardiologist or physician with expertise in reading pediatric ECGs Pediatric Cardiology Consultation should be obtained before starting ADHD medication if there are significant findings on history, FH, PE or ECG If ECG obtained before age 12 years, a repeat ECG may be useful after child is > 12 years; also, repeat ECG may be useful with change in patient symptoms or change in family history

Practice Tool: Patient History & Family History

Practice Tool: Physical Examination

Practice Tool: ECG Findings

Practice Tool: ECG Findings

Practice Tool: ECG Findings

Ongoing assessment- patients being treated Review of symptoms and family history BP & pulse- 1-3 months, then every 6-12 months Any cardiac symptoms- referral and evaluation ECG- reasonable to consider Patients with Structural Heart Disease NO clinical studies or data indicating that children with most types of CHD are at significant risk while on these medications Reasonable to use medications with caution Careful monitoring should be performed after initiation of medication If arrhythmias are treated and controlled, on approval of a pediatric cardiologist, patient can be restarted on medication

AAP summary/ recommendations

AHA Scientific Statement