{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,5,8]],"date-time":"2025-05-08T13:14:08Z","timestamp":1746710048234,"version":"3.40.5"},"reference-count":29,"publisher":"American Academy of Pediatrics (AAP)","issue":"4","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2001,4,1]]},"abstract":"<jats:sec><jats:title>Objective.<\/jats:title><jats:p>Gastrointestinal prokinetic agents, such as cisapride, are commonly used in pediatric practice to improve gastric emptying, to decrease emesis, to improve lower esophageal sphincter tone, and to improve irritability and feeding aversion associated with gastroesophageal reflux (GER). Although cisapride seems to be effective in infants from 2 months to 14 years old, data for younger and preterm infants are not available. Whether reflux is a significant cause of reflex apnea or feeding intolerance in the preterm infant is controversial. The objective of this 1-year prospective study, started 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 made empirically. The clinical bias was that persistent apnea, not responding to caffeine, was caused by GER. We reasoned that a systematic approach to the diagnosis and treatment of reflux would improve the care of preterm infants and reduce the risk of toxicity, especially if an increased dose of cisapride showed no improvement in reflux or apnea.<\/jats:p><\/jats:sec><jats:sec><jats:title>Study Design.<\/jats:title><jats:p>Twenty-four preterm infants (24\u201336 weeks' gestational age) had clinical apnea\/pH studies when they were referred by the attending neonatologist for suspected GER. These infants were born at 28.8 \u00b1 3.1 weeks with birth weight of 1169 \u00b1 387 g (range: 631-2263 g). Each infant was studied before and 8 days after starting cisapride treatment. Cisapride dose was 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 using EsopHogram software. A single sensor pH catheter was inserted to \u223c2 cm above the esophageal gastric junction. GER was defined as a drop in esophageal pH below 4.0 for a least 5 seconds, or pathologic GER was defined as a reflux index (RI) &amp;gt;2 standard deviation (SD) from the mean based on published norms for term infants. The following parameters were calculated from the pH recording: number of reflux events per 24 hours, duration of the longest episode, number of episodes &amp;gt;5 minutes per 24 hours, and RI, ie, percentage of time with pH &amp;lt;4.0. Each study had a combined time-lapse video recording and multichannel digital recording. Recorded parameters were: continuous pulse oximetry, electrocardiogram, respiratory effort (piezo sensor), and airflow (temperature sensor at nostrils and mouth). The recording was scored for central apneas of 10 to 14 seconds and \u226515 seconds (prolonged) and \u226510 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 follow-up electrocardiograms were performed because of concern about prolonged QTc and cardiac arrhythmias. The infants were 35.6 \u00b1 4.5 weeks postconceptional age when first studied. Twelve infants (mean birth weight: 1821 \u00b1 749 g; gestational age: 32 \u00b1 2 weeks; postconceptional age: 35.6 \u00b1 2.6 weeks) were identified retrospectively as controls because their baseline GER parameters were within the normal range using Vandenplas' criteria.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results.<\/jats:title><jats:p>Overall, cisapride treatment significantly improved the RI from 16.6 \u00b1 15.2 to 9.1 \u00b1 8.4 SD. The number of reflux episodes \u22655 minutes was reduced from 7.1 \u00b1 5.8 to 4.3 \u00b1 4.4 SD. No significant 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 0.25 mg\/kg\/dose every 6 hours. Although 0.09 mg\/kg\/day is the minimum effective dose, 67% of our infants did respond to this low dose. Cisapride was discontinued in 3 infants because of prolonged QTc \u22650.450 seconds (0.473 in 1 and 0.470 in 2). More data about the effect of cisapride 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 for central and obstructive apnea were similar before and after cisapride, mixed apnea was less during treatment. There was a significant decrease (0.32 \u00b1 0.40 to 0.12 \u00b1 0.17\/hour) in RAAP when the one infant who had increased reflux on increased dose of cisapride was excluded as an outlier. The statistical difference, before and after cisapride, for the group is significant with the outlier omitted. The clinical significance is unclear because \u223c50% of the infants had minimal changes in their apnea indexes. Furthermore, \u223c40% of infants did not have RAAP. Although there was a significant reduction in reflux after cisapride treatment in the symptomatic 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 &amp;lt;2 SD of Vandenplas' normative values (&amp;lt;3.2%).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion.<\/jats:title><jats:p>A low dose of cisapride was effective in decreasing, but not normalizing, the RI in the majority of the preterm infants. Our data extend the findings of Vanderplas and colleagues who found that cisapride decreases prolonged episodes of reflux in term infants (2\u20134 months old). Although mixed apnea was significantly decreased and there was decreased RAAP after cisapride treatment, there are insufficient data in this study to claim that the treatment of reflux will significantly decrease apnea severity or improve the management of preterm infants with persistent apnea. Cisapride has been 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 should be performed to establish safety and efficacy for the management of reflux, feeding intolerance, and apnea in the preterm infant.<\/jats:p><\/jats:sec>","DOI":"10.1542\/peds.107.4.e58","type":"journal-article","created":{"date-parts":[[2004,8,13]],"date-time":"2004-08-13T23:55:51Z","timestamp":1092441351000},"page":"e58-e58","source":"Crossref","is-referenced-by-count":15,"title":["Cisapride Decreases Gastroesophageal Reflux in Preterm Infants"],"prefix":"10.1542","volume":"107","author":[{"given":"Ronald L.","family":"Ariagno","sequence":"first","affiliation":[{"name":"From the Department of Pediatrics, Stanford University, Palo Alto, California;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Myrna A.","family":"Kikkert","sequence":"additional","affiliation":[{"name":"From the Department of Pediatrics, Stanford University, Palo Alto, California;"},{"name":"Leiden University, School of Medicine, Leiden, The Netherlands; and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Majid","family":"Mirmiran","sequence":"additional","affiliation":[{"name":"From the Department of Pediatrics, Stanford University, Palo Alto, California;"},{"name":"Netherlands Institute for Brain Research, Amsterdam, The Netherlands."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carol","family":"Conrad","sequence":"additional","affiliation":[{"name":"From the Department of Pediatrics, Stanford University, Palo Alto, California;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roger B.","family":"Baldwin","sequence":"additional","affiliation":[{"name":"From the Department of Pediatrics, Stanford University, Palo Alto, California;"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"417","published-online":{"date-parts":[[2001,4,1]]},"reference":[{"key":"2021121003434921600_B1","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1097\/00005176-199810000-00009","article-title":"Gastroesophageal reflux in preterm infants: norms for extended distal esophageal pH monitoring.","volume":"27","author":"Ng","year":"1998","journal-title":"J Pediatr Gastroenterol Nutr"},{"key":"2021121003434921600_B2","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1111\/j.1651-2227.1995.tb13623.x","article-title":"Developmental maturation of gastro-oesophageal reflux in preterm infants.","volume":"84","author":"Jeffery","year":"1995","journal-title":"Acta Paediatr"},{"key":"2021121003434921600_B3","doi-asserted-by":"crossref","first-page":"894","DOI":"10.1016\/S0022-3476(82)80507-6","article-title":"Movement and gastroesophageal reflux in awake term infants with \u201cnear miss\u201d SIDS, unrelated to apnea.","volume":"100","author":"Ariagno","year":"1982","journal-title":"J Pediatr"},{"key":"2021121003434921600_B4","doi-asserted-by":"crossref","first-page":"680","DOI":"10.1007\/BF01959521","article-title":"Gastroesophageal reflux and apneic pauses during sleep in infancy: no direct relation.","volume":"149","author":"Paton","year":"1990","journal-title":"Eur J Pediatr"},{"key":"2021121003434921600_B5","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1159\/000243184","article-title":"Sleep apneas and acid esophageal reflux in control infants and in infants with an apparent life-threatening event.","volume":"57","author":"Kahn","year":"1990","journal-title":"Biol Neonate"},{"key":"2021121003434921600_B6","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1007\/s004310050564","article-title":"The relation between gastro-oesophageal reflux, sleeping-position and sudden infant death and its impact on positional therapy.","volume":"156","author":"Vandenplas","year":"1997","journal-title":"Eur J Pediatr"},{"key":"2021121003434921600_B7","doi-asserted-by":"crossref","first-page":"120S","DOI":"10.1016\/S0002-9343(97)00336-7","article-title":"Reflux associated apnea in infants: evidence for a laryngeal chemoreflex.","volume":"103","author":"Thach","year":"1997","journal-title":"Am J Med"},{"key":"2021121003434921600_B8"},{"key":"2021121003434921600_B9","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1097\/00005176-198703000-00010","article-title":"Continuous 24-hour esophageal pH monitoring in 285 asymptomatic infants 0\u201315 months old.","volume":"6","author":"Vandenplas","year":"1987","journal-title":"J Pediatr Gastroenterol Nutr"},{"key":"2021121003434921600_B10","doi-asserted-by":"crossref","first-page":"116","DOI":"10.2165\/00003495-199447010-00008","article-title":"Cisapride: an updated review of its pharmacology and therapeutic efficacy as a prokinetic agent in gastrointestinal motility disorders.","volume":"47","author":"Wiseman","year":"1994","journal-title":"Drugs"},{"key":"2021121003434921600_B11","first-page":"423","article-title":"Cisapride for gastroesophageal reflux disease: a placebo-controlled, double-blind study.","volume":"90","author":"Richter","year":"1995","journal-title":"Am J Gastroenterol"},{"key":"2021121003434921600_B12","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1046\/j.1365-2036.1999.00525.x","article-title":"Cisapride 20 mg b.d. for preventing symptoms of GERD induced by a provocative meal. 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