Avram Benatar

The effect of cisapride on the corrected QT interval and QT dispersion in premature infants.

Background Cisapride is used frequently in premature neonates as a gastrointestinal prokinetic drug. Concerns exist, however, about its safety because of its effect on the QT interval. Premature infants could be at higher risk for side effects because of their immaturity. This prospective study investigated the pharmacokinetics of cisapride and its effects on corrected QT interval (QTc) and QT dispersion in premature infants. Methods Electrocardiogram examination was performed just before and after 72 hours of treatment with cisapride (0.2 mg/kg per dose, four times daily) in 10 premature infants. Trough and anticipated peak plasma level of cisapride and norcisapride were quantified after 72 hours of treatment. Results were compared with a cohort of 41 term infants aged 0 to 3 months receiving cisapride treatment. Results The QTc interval increased significantly from 423 ms to 461 ms after 72 hours of treatment (P = 0.0007). No effect was seen on QT dispersion (44.3 ms vs. 45.9 ms). The change in QTc interval was inversely related to postnatal age (R2 = 0.52;P = 0.02), whereas there was no correlation with gestational age or plasma levels of cisapride or norcisapride. Trough and anticipated peak plasma levels of cisapride and norcisapride were significantly higher in the premature infants compared with the term infants aged 0 to 3 months (P < 0.001). Conclusions Premature infants less than 1 month of age could be at higher risk for cardiac side effects of cisapride when used in the same dosage as in older infants. The daily dose should be reduced (0.1 mg/kg per dose, maximum four times daily), and the QTc interval should be monitored closely. The benefits and safety of cisapride in premature infants less than 1 month of age should be reconsidered.

Epidemiology and Outcome of Tachyarrhythmias in Tertiary Pediatric Cardiac Centers

Introduction: Little is known about the real importance of pediatric arrhythmias. Methods: We analyzed the epidemiology, presentation and outcome of all clinically relevant tachyarrhythmias followed up in our pediatric institutions from 1995 to 2006. Results: A total of 250 cases were identified. The mean age ± SD at diagnosis was 4.7 ± 5.3 years, 45 cases were neonatal (18%). Supraventricular arrhythmias were noted in 210 children (84%), ventricular arrhythmias in 40 (16%). The most frequent symptoms were palpitations (n = 71) and syncope (n = 48) in older children, as well as monitoring of diseases (n = 62) and heart failure (n = 49) in younger patients. Recurrence was noted under or after therapy in 75 cases, mostly in cases diagnosed beyond infancy. At long-term follow-up, 169 patients have no recurrence without treatment (of whom 34 had required catheter ablation), 71 are under therapy and 10 died. Conclusion: Supraventricular arrhythmias in younger children are often an incidental diagnosis, respond to antiarrhythmic therapy and have a high incidence of resolution. In older children with supraventricular arrhythmias and in those with ventricular arrhythmias, delayed diagnosis or misdiagnosis is not rare, the arrhythmias are unlikely to resolve spontaneously and long-term antiarrhythmic treatment or catheter ablation is necessary.

Cisapride Plasma Levels and Corrected Qt Interval in Infants Undergoing Routine Polysomnography

Background Reported QTc prolongation associated with cardiac arrhythmia in a small number of children undergoing cisapride therapy and lack of pharmacokinetic correlation provided the impetus for this prospective study. The authors evaluated the relation between cisapride plasma concentrations, the electrocardiographic QT interval, and cardiac rhythm in infants undergoing routine 8-hour polysomnography. Methods A total of 211 infants were enrolled: 84 (17 born prematurely) undergoing cisapride therapy for at least 4 days for suspected gastroesophageal reflux and 127 controls (10 born prematurely), aged between 1 week and 13.5 months. Infants underwent continuous bipolar limb lead I recording during routine 8-hour polysomnography. QT intervals and heart rate were measured at hourly intervals. The morning after polysomnography, 12-lead electrocardiography was performed (1 hour after cisapride administration). Cisapride plasma concentrations were determined immediately before and 1 to 2 hours after administration. Serum electrolyte concentrations were measured. Results The administered cisapride dose ranged from 0.35 to 1.55 (mean, 0.81, median 0.79) mg · kg −1 · d −1 . Cisapride plasma concentrations were significantly higher in infants younger than 3 months of age. Cisapride-treated infants younger than 3 months of age had longer QTc intervals compared with age-matched controls. Heart rate was similar for cisapride-treated and control infants. No arrhythmia or atrioventricular conduction abnormalities were observed. Conclusions At comparable doses of cisapride and comparable plasma concentrations, the QTc was significantly higher in infants younger than 3 months of age. This confirms age-dependent cisapride pharmacokinetics in the first 10 to 12 weeks strongly correlated with changes in body weight and may also suggest an altered ability of infants younger than 3 months of age to metabolize cisapride. The clinical significance and risk of the increased QTc interval is unclear. Cisapride should be judiciously prescribed in infants younger than the age of 3 months and electrocardiography should be performed before and during therapy.

Cisapride and Proarrhythmia in Childhood

Statements appearing here are those of the writers and do not represent the official position of the American Academy of Pediatrics, Inc. or its Committees. Comments on any topic, including the contents of Pediatrics, are invited from all members of the profession: those accepted for publication will not be subject to major editorial revision but generally must be no more than 400 words in length. The editors reserve the right to publish replies and may solicit responses from authors and others.

The T wave as a marker of dispersion of ventricular repolarization in premature infants before and while on treatment with the I Kr channel blocker cisapride

AIMS Measurement of electrocardiographic intervals to assess dispersion in ventricular repolarization may be helpful in the assessment of the risk of ventricular arrhythmia. We measured QTc, QT dispersion, and T wave intervals in premature infants before and while on treatment with the I(Kr) blocker cisapride as markers for dispersion in ventricular repolarization. METHODS AND RESULTS We enrolled 15 non-ventilated premature infants with a mean gestational age of 30.5 weeks, ranging from 26.5 to 33.5 weeks, and mean postnatal age of 24 days, with a range from 5 to 51 days. A digital 12 lead electrocardiogram was recorded prior to and 3 days after administering cisapride at a dose of 0.8 mg/kg/day. Serum electrolytes were simultaneously measured. Electrocardiographic measurements before and after included: QT, QTc Bazett, QT dispersion, R-R, T wave interval peak to end, T wave interval peak to end/onset Q to T wave peak, T wave axis, T wave maximum voltage and QRS-T angle. A paired t test and analysis of variance was used to compare the variables before and during treatment. The QTc, T wave interval peak to end and the ratio T wave interval peak to end/onset Q to T peak increased significantly following treatment with cisapride. Results expressed as before and during treatment were for QTc: 429 (65) ms versus 454 (29) ms p < 0.02; for T wave interval peak to end: 65 (11) ms versus 103 (24) p <0.01, for the ratio T wave interval peak to end/onset Q to T peak: 0.32 (0.06) versus 0.55 (0.16) p < 0.001. Treatment with the I(Kr) blocker did not significantly alter the QT dispersion, T wave voltage, angle or QRS-T angle. CONCLUSION The interval from the peak to the end of the T wave and the ratio of this value to the onset Q to T peak interval, represents regional dispersion of repolarization across the ventricular wall. This is a potentially useful clinical index in the assessment of arrhythmic risk in premature infants being treated by blockade of the I(Kr) channels.

7219 Cisapride plasma levels and effects on qtc interval and heart rate infants.

Aims : This prospective study was conducted to evaluate the effects of cisapride, in relation to plasma levels, on QTc duration and heart rate in infants. Methods : 41 infants, age 3 51 weeks, since more than 3 days on cisapride, were included and had a continuous ECG recording (bipolar limb lead) during the night, reviewed digitised on screen. Heart rate, QT and QTc duration (Bazett formula) were measured in 3 consecutive beats at hourly intervals for 8 hours and compared to classic ECG. Plasma cisapride and norcisapride levels (peak and basal levels), calcium, magnesium, potassium and albumin levels were determined. Cisapride rate and dose was registered. Concomitant administered medication was also listed. Results : Cisapride was given between 2 and 8 times daily, resulting in a dose of 0.41 to 1.55 (mean 0.82) mg/kg/day. Mean QTc duration during the night was 416.33 (range 362 489), and mean QTc on day-ECG was 436.33 (range 391 500). QTC was >450 in 3 infants on the night ECG, and in 10 on the day-ECG, including all 3 with a night-time QTc duration >450. Albumin, calcium, potassium and magnesium levels were in all infants within normal ranges. Cisapride and norcisapride plasma stable (cisa: 42.6 + 36.6; median 33.6, range 0.0 156.0 ng/ml; norcisa 11.3 + 7.8, median 10.2, range 1.7 31.4 ng/ml) and peak levels (cisa 57.0 + 35.8, median 48.3, range 5.3 171.0 ng/ml; norcisa 13.7 + 8., median 11.6, range 2.5 32.5 ng/ml) have been qualified, and seem not directly related to gestational age, the daily cisapride dose, frequency of administration, concomitant medication, or QTc duration (Bazett Formula) or heart rate. A detailed statistical analysis is in progress. Discussion and conclusion : QTc duration depends on the method applied, and normal ranges are not available. A duration of 500 was reached in one infant on day-ECG (487 on night ECG), with a dose of 0.92 mg/kg/day, administered in 5 doses a day, without any concomitant medication, and with a QTc duration on day-ECG of