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Proarrhythmia associated with cisapride in children
S L Hill1, J K Evangelista, A M Pizzi
1Division of Pediatric Cardiology, Floating Hospital for Children, New England Medical Center, Tufts University School of Medicine, Boston, Massachusetts, USA.
Insights
Cisapride can prolong ventricular repolarization in children with GERD, increasing arrhythmia risk. Monitor ECG intervals, especially when combined with CYP3A4 inhibitors.
Area of Science:
- Pediatric Cardiology
- Clinical Pharmacology
- Gastroenterology
Background:
- Cisapride is a prokinetic agent used for gastroesophageal reflux disease (GERD).
- Concerns exist regarding cisapride-induced ventricular proarrhythmia, particularly with CYP3A4 inhibitors.
- This study investigates cisapride's impact on ventricular repolarization in pediatric GERD patients.
Purpose of the Study:
- To evaluate the effect of cisapride on ventricular repolarization in children diagnosed with GERD.
- To assess specific electrocardiogram (ECG) parameters related to ventricular repolarization.
Main Methods:
- Prospective, blinded study design.
- Analysis of ECGs from 35 children with GERD treated with cisapride.
- Comparison with ECGs from 1000 healthy children.
- Measurement of QT interval (QTc), JT interval (JTc), and interlead dispersion.
Main Results:
- Prolonged QTc (≥450 ms) observed in 31% of cisapride-treated children.
- Prolonged JTc (≥360 ms) observed in 46% of patients.
- Two cases of torsades de pointes ventricular tachycardia occurred in patients also taking macrolide antibiotics.
- No significant increase in QT or JT dispersion was noted.
Conclusions:
- Cisapride may prolong ventricular repolarization in pediatric patients.
- Increased proarrhythmia risk is associated with CYP3A4 inhibition, overdosage, or decreased clearance.
- ECG monitoring is recommended for children on cisapride, especially with concomitant QT-prolonging medications.
Background:
Cisapride is a prokinetic agent that facilitates gastrointestinal motility and is widely used for the treatment of gastroesophageal reflux disease (GERD) in adults and children. However, reports of ventricular proarrhythmia have been noted in patients taking cisapride, particularly in conjunction with other drugs that may inhibit hepatic metabolism of cisapride via the cytochrome P450 3A4 system.
Objective:
We designed a prospective, blinded study to evaluate the effect of cisapride on ventricular repolarization in children with GERD.
Methods:
We analyzed the electrocardiograms (ECGs) from 35 children (age 0.4 to 18 years, mean 5.2 years) including measurement of the resting QT interval (QTc), JT interval (JTc), as well as QT and JT interlead dispersion markers. Data from these patients were compared with ECGs from a control group of 1000 normal children.
Results:
Eleven (31%) of 35 patients receiving cisapride had a prolonged QTc (> or = 450 ms). The JTc was prolonged > or = 360 ms in 16 of 35 patients (46%). The mean QTc in the cisapride group was 428 +/- 35 ms and mean JTc was 336 +/- 35 ms. An increased QT or JT dispersion (> 70 ms) was seen in only 3 of 35 children. Of the 11 children with QTc prolongation, 2 had documented torsades de pointes ventricular tachycardia. Both patients were taking cisapride concomitantly with a macrolide antibiotic. All other patients were treated with either cisapride alone or in conjunction with other GERD agents, such as ranitidine or omeprazole.
Conclusions:
Cisapride may cause prolongation of ventricular repolarization in children. There does not appear to be increased heterogeneity of repolarization or delayed depolarization in this small sample. The proarrhythmia may be exacerbated by medications that inhibit cytochrome P450 3A4 hepatic metabolism, overdosage, or mechanisms that result in decreased serum clearance. ECG intervals should be monitored in children maintained on cisapride, particularly when used in combination with other known QT-prolonging medications.