1. 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

2. Here is the problem …

3. Is it innocent ? …

4. Murmurs Murmurs Murmurs Innocent Murmurs
Newborn Murmurs
Innocent Murmurs of Childhood

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

6. 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 …

7. 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

8. 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

9. 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)

10. 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

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

12. 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

13. 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

14. 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”

15. 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”

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

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

18. 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

19. 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

20. Still’s vs. Pulmonary Flow Murmur

21. 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”

22. 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

23. 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

24. 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

25. 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

26. 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
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
SD methylphenidates, 13 SD amphetamines
- 3 sudden deaths associated with atomoxetine ( )
“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

27. 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”

28. 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

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

30. 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”

31. 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)

32. 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, include personal
and family medical history and physical examination (no ECG)

33. 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)

34. ???? 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

35. Practice Tool: Patient History & Family History

36. Practice Tool: Physical Examination

37. Practice Tool: ECG Findings

38. Practice Tool: ECG Findings

39. Practice Tool: ECG Findings

40. 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

41. AAP summary/ recommendations

42. AHA Scientific Statement