Cisapride decreases gastroesophageal reflux in preterm infants

Objective. Gastrointestinal prokinetic agents, such as cisapride, are commo nly used in pediatric practice to improve gastric emptying, to decrease eme sis, to improve lower esophageal sphincter tone, and to improve irritabilit y and feeding aversion associated with gastroesophageal reflux (GER). Altho ugh cisapride seems to be effective in infants from 2 months to 14 years ol d, data for younger and preterm infants are not available. Whether reflux i s a significant cause of reflex apnea or feeding intolerance in the preterm infant is controversial. The objective of this 1-year prospective study, s tarted in 1998, was to determine the efficacy of cisapride for treatment of reflux and reflux-associated apnea (RAAP) in preterm infants. Before this study, the diagnosis of reflux was often made clinically and the effect of therapy on reflux or the decision to increase the dose of cisapride was mad e empirically. The clinical bias was that persistent apnea, not responding to caffeine, was caused by GER. We reasoned that a systematic approach to t he diagnosis and treatment of reflux would improve the care of preterm infa nts and reduce the risk of toxicity, especially if an increased dose of cis apride showed no improvement in reflux or apnea. Study Design. Twenty-four preterm infants (24-36 weeks' gestational age) ha d clinical apnea/pH studies when they were referred by the attending neonat ologist for suspected GER. These infants were born at 28.8 +/- 3.1 weeks wi th birth weight of 1169 +/- 387 g (range: 631-2263 g). Each infant was stud ied before and 8 days after starting cisapride treatment. Cisapride dose wa s 0.09 to 0.25 mg/kg every 6 hours enterally. Treatment decisions regarding dose of cisapride were the responsibility of the attending neonatologist. The pH was recorded continuously for 24 hours at 0.25 Hz and was analyzed u sing EsopHogram software. A single sensor pH catheter was inserted to;2 cm above the esophageal gastric junction. GER was defined as a drop in esophag eal pH below 4.0 for a least 5 seconds, or pathologic GER was defined as a reflux index (RI) >2 standard deviation (SD) from the mean based on publish ed norms for term infants. The following parameters were calculated from th e pH recording: number of reflux events per 24 hours, duration of the longe st episode, number of episodes >5 minutes per 24 hours, and RI, ie, percent age of time with pH <4.0. Each study had a combined time-lapse video record ing and multichannel digital recording. Recorded parameters were: continuou s pulse oximetry, electrocardiogram, respiratory effort (piezo sensor), and airflow (temperature sensor at nostrils and mouth). The recording was scor ed for central apneas of 10 to 14 seconds and <greater than or equal to>15 seconds (prolonged) and greater than or equal to 10 seconds for obstructive and mixed apneas. RAAP was scored when an apnea (irrespective of the type) occurred within 1 minute of a GER event. Baseline, after cisapride, and fo llow-up electrocardiograms were performed because of concern about prolonge d QTc and cardiac arrhythmias. The infants were 35.6 +/- 4.5 weeks postconc eptional age when first studied. Twelve infants (mean birth weight: 1821 +/ - 749 g; gestational age: 32 +/- 2 weeks; postconceptional age: 35.6 +/- 2. 6 weeks) were identified retrospectively as controls because their baseline GER parameters were within the normal range using Vandenplas' criteria. Results. Overall, cisapride treatment significantly improved the RI from 16 .6 +/- 15.2 to 9.1 +/- 8.4 SD. The number of reflux episodes greater than o r equal to5 minutes was reduced from 7.1 +/- 5.8 to 4.3 +/- 4.4 SD. No sign ificant effect was seen on the total number of refluxes (/24 hours). Eight infants (33%) had no decrease in the RI after a week of treatment. Three of these infants improved after cisapride dose was increased from 0.09 to 0.2 5 mg/kg/dose every 6 hours. Although 0.09 mg/kg/day is the minimum effectiv e dose, 67% of our infants did respond to this low dose. Cisapride was disc ontinued in 3 infants because of prolonged QTc greater than or equal to0.45 0 seconds (0.473 in 1 and 0.470 in 2). More data about the effect of cisapr ide on QTc interval are reported in Pediatrics in a separate article. Only 1 infant showed no improvement with increased dose. Caffeine treatment had no effect on the baseline or follow-up GER values. Although apnea indexes f or central and obstructive apnea were similar before and after cisapride, m ixed apnea was less during treatment. There was a significant decrease (0.3 2 +/- 0.40 to 0.12 +/- 0.17/hour) in RAAP when the one infant who had incre ased reflux on increased dose of cisapride was excluded as an outlier. The statistical difference, before and after cisapride, for the group is signif icant with the outlier omitted. The clinical significance is unclear becaus e similar to 50% of the infants had minimal changes in their apnea indexes. Furthermore, similar to 40% of infants did not have RAAP. Although there w as a significant reduction in reflux after cisapride treatment in the sympt omatic infant group, reflux parameters did not normalize compared with the values of the control infants or the published norms for term infants. Five infants had RIs <2 SD of Vandenplas' normative values (<3.2%). Conclusion. A low dose of cisapride was effective in decreasing, but not no rmalizing, the RI in the majority of the preterm infants. Our data extend t he findings of Vanderplas and colleagues who found that cisapride decreases prolonged episodes of reflux in term infants (2-4 months old). Although mi xed apnea was significantly decreased and there was decreased RAAP after ci sapride treatment, there are insufficient data in this study to claim that the treatment of reflux will significantly decrease apnea severity or impro ve the management of preterm infants with persistent apnea. Cisapride has b een withdrawn because of concern about the risk of cardiac toxicity. If an isoform of cisapride becomes available, which theoretically has no adverse effects on cardiac conduction, randomized, controlled clinical studies shou ld be performed to establish safety and efficacy for the management of refl ux, feeding intolerance, and apnea in the preterm infant.