Proarrhythmia Associated With Cisapride in Children

DISCUSSION

Prolongation of the QTc may be congenital in nature or acquired. Congenital or idiopathic prolonged QTc may be sporadic or inherited. The most common type of hereditary prolonged QT syndrome is Romano-Ward syndrome, characterized by autosomal dominant transmission, prolongation of the QTc on ECG, ventricular tachyarrhythmias, in particular torsades de pointes, syncope, and sudden death.^13,14

Acquired long QTc may be attributable to electrolyte abnormalities such as hypocalcemia, hypokalemia, hypomagnesemia, metabolic disturbances, or drug-induced. Typically these proarrhythmic medication side effects are seen with drug overdose, liver disease, or concomitant administration of a drug that interferes with hepatic cytochrome P450 3A4 enzymatic metabolism (ie, ketoconazole, macrolide antibiotics, cimetidine).^2-7 It has been previously shown that other noncardiac medications such as the nonsedating antihistamines (terfenadine, astemizole) have significant actions on the cardiac potassium channels.⁷ The molecular or ionic mechanism involved with the use of cisapride on ventricular repolarization and the action on potassium or other ion channels have recently been studied in isolated guinea pig hearts, and cisapride was shown to be a potent inhibitor of the rapid delayed rectifier potassium current (I_kr).¹⁵

Further work at the ion channel level, whole animal electrophysiology model,¹⁶ and human myocyte studies will help to elucidate the exact mechanisms of cisapride-associated proarrhythmia and repolarization delay. Although the efficacy of cisapride administration in children with GERD has been established, the safety attributable to potential malignant ventricular arrhythmias has recently been questioned. Lewin et al⁸ reported QTc prolongation as well as 2 to 1 atrioventricular conduction, and T-wave alternans, during cisapride therapy in a 2-month-old infant. Cisapride-induced arrhythmias have been reported in several other recent pediatric and adult case reports over the past several years, including some fatal events.^17-21

The results of this present study suggest that cisapride may cause prolongation of ventricular repolarization in children. Many of these patients may have been entirely asymptomatic without signs of arrhythmia or cardiotoxicity, despite the QT prolongation. There does not appear to be increased heterogeneity of repolarization (QT dispersion) or delayed depolarization (QRS prolongation) in this small sample. The proarrhythmia may be exacerbated by medications that inhibit cytochrome P450 3A4 hepatic metabolism, overdosage, or other mechanisms that may result in decreased serum clearance. Cisapride may not, therefore, be the drug of choice in treating GERD in children who have impairment of hepatic metabolism attributable to liver disease, or with concomitant administration of drugs metabolized via the cytochrome P450 3A4 enzymatic system. In addition, caution should be used in patients who have ventricular repolarization abnormalities and in patients who are maintained on class III antiarrhythmic agents and other medications that prolong the repolarization phase of the cardiac action potential. Potential risks versus benefits should be evaluated carefully, and we suggest that ECG intervals be monitored routinely in children maintained on cisapride, particularly when administered in combination with other medications that affect cytochrome P450 3A4 metabolism or ventricular repolarization. The nature of the QTc prolongation, although unknown, may be related to dosing and serum levels, and/or an idiosyncratic reaction in children who may have a partial channel defect that is unmasked by the drug.

As with other medications, there may be a lower therapeutic index in children compared with adults on cisapride, particularly regarding its apparent repolarization prolonging action. Given the results of this study, as well as previous case reports of proarrhythmia associated with QT prolongation, further clinical, animal, and molecular research is warranted on the effect of cisapride on cardiac ion channels and receptor sites.

A potential limitation of this study is the small sample size, particularly of patients on multiple medications. However, the high incidence of QT prolongation remains surprising and unexpected. Patients in the study group may not have been as healthy as normal controls and may have greater likelihood of electrolyte abnormalities and metabolic disturbances secondary to GERD. Hepatic and renal dysfunction and/or metabolic disturbances were not clinically suspected, although during the course of this study liver enzymes, electrolytes, blood urea nitrogen, and creatinine were not systematically assessed. It is also suggested that 12 lead resting ECGs be obtained before and after initiation of cisapride therapy in future larger-scale prospective studies.