24-Hour Electrocardiogram before and during Cisapride Treatment in Neonates and Infants

Abstract

We studied prospectively the effects of cisapride on heart rate and rhythm using standard ECG and 24-hour ECG recordings in term and preterm neonates and infants. We studied subjects with gastroesophageal reflux disease (apparent life-threatening events, apneas, bradycardias) before and 3 days after starting cisapride (0.8 mg/kg/day in 4 doses). We performed standard ECGs for determination of corrected Q-T interval (QTc) and Q-T dispersion (QTd) and 24-hour ECG recordings for analysis of heart rate, heart rate variability, and heart rhythm. Fourteen term and 17 preterm subjects (gestational age range 28–36 weeks) were studied at a median chronological age of 29 (range 3–132) days. Cisapride significantly increased the QTc in preterm infants (before vs. after: 408 ± 7 vs. 433 ± 7 ms, p = 0.001). Two preterm and 1 term infant had a QTc >450 ms before cisapride. Four preterm (4/15 = 27%) and 2 term (2/13 = 15%) subjects had a QTc >450 ms on cisapride. After cisapride the QTd remained normal, and no relevant arrhythmias were documented on Holter recordings. Cisapride significantly decreased peak and mean heart rates of all study subjects without affecting the heart rate variability, while it increased the minimal heart rate of preterm infants only (before vs. after: 66 ± 5 vs. 78 ± 5 bpm, p = 0.02). The maximally measured R-R intervals (pauses) decreased after cisapride in preterm infants (before vs. after: 1.33 ± 0.2 s vs. 1.05 ± 0.2 s, p = 0.04). Although cisapride did cause a significant prolongation of the ventricular action potential duration in preterm infants, the QTd remained unaffected, and no clinically relevant arrhythmias were documented in this small sample. On the other hand, cisapride had a direct lowering effect on the maximal and mean heart rates of both term and preterm infants, while the drug increased the minimal heart rate and reduced the severity of bradycardia episodes in preterm infants.

QTc Interval Reference Values and Their (Non)-Maturational Factors in Neonates and Infants: A Systematic Review

“…Semama et al [ 46 ] (only term infants) and Zamora et al [ 47 ] (preterm and term infants) both published a study in 2001 with similar findings of longer QTc intervals after starting cisapride (dose ≤ 1 mg/kg/day). Zamora et al [ 48 ] subsequently published another study, to confirm a significant longer QTc interval in preterm infants whereas no significant differences were observed for term infants. Chhina et al [ 49 ] also detected a longer QTc interval after cisapride administration.…”

Qtc Interval Reference Values and Their (Non)-Maturational Factors in Neonates and Infants: A Systematic Review

“…Of the three articles analysed in this systematic review, only Djeddi et al showed significant longer QTc in infants >32 weeks GA [59]. Next to cisapride [42][43][44][45][46][47][48][49][50][51][52][53][54][55][56][57][58]74,75] and domperidone [59][60][61]73,75], doxapram has also been studied because of its presumably presence of adverse cardiac effects such as second-degree AV-block and longer QTc intervals. Doxapram hydrochloride is a powerful respiratory stimulant used for idiopathic apnea of prematurity unresponsive to methylxanthines.…”

“…Khogphatthanayothin (dose ≤1 mg/kg/day) [46,47]. Zamora et al subsequently published another study, to confirm a significant longer QTc interval in preterm infants whereas no significant differences were observed for term infants [48]. Chhina et al also detected a longer QTc interval after cisapride administration.…”

QTc Intervals Are Prolonged in Late Preterm and Term Neonates during Therapeutic Hypothermia but Normalize Afterwards

“…There are reports on QTc interval prolongation assessment for medications known to affect the QTc interval in adults during exposure in neonates. Cisapride prolonged the QTc interval in preterm and term neonates by +20 ms [ 30 , 31 ], while—in contrast to adults—domperidone showed no effect on the mean QTc interval [ 32 ]. It remains difficult to put this into perspective, especially for pharmacovigilance in the first week of life, because of maturational and non-maturational factors ( Table 1 ) [ 13 , 14 , 15 , 16 , 17 , 18 , 24 ].…”