Summary

Attention deficit hyperactivity disorder (ADHD) is the most common neurobehavioral disorder of childhood with a prevalence rate of 4%–12% in community samples of US school children.[1-4] Over 2.5 million children take medications for ADHD yearly. Treatment for ADHD centers primarily on stimulants, including methylphenidates and amphetamines, but atomoxetine, guanfacine, clonidine, and antidepressants are also used. Stimulant drugs have been shown to increase or decrease heart rate and systolic blood pressure to a clinically insignificant degree. However, in some case reports, use of these medications has been associated with sudden cardiac death in pediatric ADHD patients. This raised the US Federal Drug Administration’s (FDA) concern about the use of ADHD medications in this population. This article will summarize helpful points for general pediatricians who are currently evaluating patients with ADHD needing medication, since conditions that are associated with sudden cardiac arrest/death in children are often subtle and may be missed when an ADHD drug is being considered.

Educational objectives

At the conclusion of this activity, participants will be able to:

• Identify elements of the patient history and family history that should be addressed during pretreatment cardiac evaluation in children with ADHD
• Recognize physical examination findings that require pediatric cardiology consultation prior to medication treatment for ADHD

CME credit

This is an article from The Child's Doctor, Fall 2008 issue. You must read all seven articles and complete each related quiz before receiving 2 Category 1 credits for the Fall 2008 issue.

Author disclosures

Dr. Webb owns Johnson & Johnson stock options. Dr. Webb does not refer to products that are still investigational or not labeled for the use in discussion.

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Sudden cardiac death in children and adolescents taking stimulant medications has been reported to the FDA, although no studies have proven a causal association. In 2005, the Canadian regulatory agency, Health Canada, suspended the sale of the amphetamine, Adderall XR, based on case reports of pediatric sudden deaths. Six months later, the US FDA required a warning on the Adderall label which states, "Sudden death has been reported in association with amphetamine treatment at usual doses in children with structural cardiac anomalies. Adderall XR generally should not be used in children or adults with structural cardiac abnormalities."[5] A "black box warning" about cardiovascular risks of ADHD medications followed 6 months later. On February 21, 2007, the FDA issued a press release recommending that patients with ADHD who are considering treatment "work with their physician . . . to develop a treatment plan that includes a careful health history and evaluation of current status, particularly for cardiovascular and psychiatric problems (including assessment for a family history of such problems)."[6] Similar guidelines have subsequently been developed for all stimulant medications used for ADHD.

Sudden cardiac death accounts for approximately 5%–10% of all childhood deaths each year, with an incidence of 0.8–6.2 per 100,000.[7] The most common causes of sudden cardiac death in the US are hypertrophic and other cardiomyopathies, long QT syndrome, coronary artery abnormalities, primary ventricular tachycardia or fibrillation, and Wolff-Parkinson-White syndrome.[8] Children who have undergone surgical correction of congenital heart disease are at higher risk for sudden cardiac death primarily due to cardiac arrhythmias.[9]

Children with known heart disease have most likely been more significantly affected by the recent FDA warning compared to children without known heart disease because they are inherently at higher risk for sudden cardiac death. ADHD is more prevalent in children with cardiac disease compared to the general pediatric population without heart disease. Mahle et al. reported abnormal attention scores in 45% of children with heart disease, abnormal hyperactivity scores in 39% of these children, and also estimated that two-third of children with hypoplastic left heart would have abnormal attention and hyperactivity scores.[10] Another study reported that 50% of children with total anomalous pulmonary venous return displayed hyperactivity or attention deficit.[11] Finally, ADHD has been reported to affect 35%–55% of children with 22q11 microdeletion.[12]

A recent scientific statement published by the American Heart Association (AHA) addressed the issues raised by the recent FDA actions.[4] The black box warning may have resulted in fewer patients who need treatment receiving it, whether or not they have known heart disease. This is problematic, since the untreated patient with ADHD will endure many personal difficulties and will likely use significant societal resources. The AHA statement was intended to help the clinician evaluate a child or adolescent so that as many patients as possible may take ADHD medications safely.

The AHA statement recommends, in accordance with the FDA guidelines, that the cardiac evaluation include a patient history, a family history, and a patient physical examination.[4] Table 1 summarizes specific questions to ask in the patient and family history and important findings to look for in the physical examination. If there are significant findings in any of these areas, consultation with a pediatric cardiologist is suggested.

Additionally, if the patient has known heart disease, the patient's cardiologist should be involved in the medication treatment plan. If a patient has been taking a medication for ADHD without difficulty prior to the publication of the AHA statement, there is no need to stop the medication. Updated documentation of a patient and family history and patient physical exam is reasonable.

A more controversial addition to pretreatment testing for ADHD patients is an electrocardiogram (ECG). The AHA scientific statement indicates that an ECG may add sensitivity to the pre-medication evaluation. For children on ADHD medication prior to the AHA statement, an ECG may be ordered at the discretion of the treating physician while the child remains on the medication.

The suggestion made in the AHA statement was based on evidence that the ECG increased the sensitivity for detection of heart disease in asymptomatic children, adolescents or athletes in a number of national and international studies. These studies included ECG screening of school children in Japan, athletes and newborns in Italy, athletes in Europe, and high school students in Nevada.[4] Since 2004 the International Olympic Committee has recommended pre-participation ECG screening of all Olympic athletes.[13] ECG screening in US professional basketball players is now mandated by the National Basketball Association.

There is significant controversy over the usefulness of an ECG in patients with ADHD. Other organizations, including the American Academy of Pediatrics (AAP), feel that the evidence cited does not warrant an ECG. [14] It should be noted that the AHA is not recommending a mandatory ECG, but that the test is suggested based on the reading and interpretation of the literature by the authors who prepared the scientific statement. Clearly, experts disagree on this point.[14]

To date, the US has not implemented a universal ECG screening program in all schoolchildren or all athletes because of manpower, financial and logistical reasons. The evidence from the studies noted above led the AHA writing group to suggest adding an ECG as a fourth element to the pre-treatment evaluation of a selected group of ADHD patients who need medication in order to improve sensitivity in detecting heart disease. However, as noted above, since there is ongoing disagreement regarding this suggestion, an ECG may be ordered at the discretion of the treating physician. Treatment of a patient with ADHD should not be withheld because an ECG is not done.

While side effects of ADHD medications are not usually considered dangerous, children with heart conditions should be assessed regularly, as the physician feels necessary. It is reasonable to use ADHD medications with caution in patients with known congenital heart disease and/or arrhythmias, if these patients are stable and under the care of a pediatric cardiologist.

Future studies are needed to assess the true risk of sudden cardiac death in association with ADHD medications in children and adolescents with and without heart disease. These include studies on the efficacy of ECG screening in children, as well as implementation of a sudden cardiac death/arrest registry in children.

In summary, this article provides a method for evaluation of children and adolescents with ADHD who require medication. In patients with or without heart disease, after a targeted patient and family history has been elicited, a physical examination should be conducted focused on the points in Table 1.

Sensitivity for detection of patients at risk for sudden cardiac death may be improved by adding an ECG to the pre-treatment evaluation. If an ECG is obtained, it ideally should be read by a pediatric cardiologist. If a child has known heart disease, consultation with the patient's pediatric cardiologist should occur before starting medications.

REFERENCES

[1.] Pennington BF, Ozonoff S. Executive functions and developmental psychopathology. J Child Psychol Psychiatry 1996;37:51-87.

[2.] Abikoff H, Gallagher R., Ma J. Measuring and treating organizational, time management and planning deficits in children with ADHD. J Child Adolesc Psychopharmacol 2003;13:422-423.

[3.] Castellanos FX, Tannock R. Neuroscience of attention - deficit/hyperactivity disorder: The search for endophenotypes. Nat Rev Neurosci 2002;3:617-628.

[4.] Vetter V, Elia J, Erickson C, Berger S, Blum N, Uzark K, Webb C. Cardiovascular monitoring of children and adolescents with heart disease receiving medications for attention deficit/hyperactivity disorder: A scientific statement from the American Heart Association Council on Cardiovascular Disease in the Young Congenital Cardiac Defects Committee and the Council on Cardiovascular Nursing. Circulation 2008;117:2407-2423.

[5.] US Food and Drug Administration. Detailed view: Safety labeling changes approved by FDA Center for Drug Evaluation and Research (CDER) 2005.

[6.] US Food and Drug Administration. FDA directs ADHD drug manufacturers to notify patients about cardiovascular adverse events and psychiatric adverse events. 2007.

[7.] Berger S, Kugler JD, Thomas JA, Friedberg DZ. Sudden cardiac death in infants, children, and adolescents. Pediatr Clin North Am 1999;46:221-234.

[8.] Berger S, Kugler JD, Thomas JA, Friedberg DZ. Sudden cardiac death in children and adolescents: Introduction and overview. Pediatr Clin North Am 2004;51:1201-1209.

[9.] Vetter VL. Postoperative arrhythmias after surgery for congenital heart defects. In: Zipes DP, ed. Cardiology in Review. Baltimore, Md: Williams & Wilkins; 1994.

[10.] Mahle WT, Clancy RR, Moss EM, et al. Neurodevelopmental outcome and lifestyle assessment in school-aged and adolescent children with hypolastic left heart syndrome. Pediatrics 2000;105:1082-1089.

[11.] Kirshbom PM, Flynn TB, Clancy RR, et al. Late neurodevelopmental outcome after repair of total anomalous pulmonary venous connection. J Thorac Cardiovasc Surg 2005;129:1091-1097.

[12.] Gothelf D, Gruber R., Presburger G, et al. Methylphenidate treatment for attention-deficit/hyperactivity disorder in children and adolescents with velocardiofacial syndrome: An open-label study. J Clin Psychiatry 2003;64:1163-1169.

[13.] International Olympic Committee Medical Commission, I.O.C., Lausanne recommendation. Sudden Cardiovascular Death in Sport, 2004.

[14.] Perrin JM, Friedman R, Knilans TK, the Black Box Working Group and the Section on Cardiology and Cardiac Surgery. Cardiovascular monitoring and stimulant drugs for attention-deficit/hyperactivity disorder. Pediatrics 2008 Aug; 122:451-453.