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PEDIATRICS Vol. 107 No. 4 April 2001, p. e58
Received Jun 6, 2000; accepted Nov 22, 2000.
,
From the * Department of Pediatrics, Stanford University, Palo
Alto, California; Leiden University, School of Medicine, Leiden, The
Netherlands; and § Netherlands Institute for Brain Research, Amsterdam,
The Netherlands.
Objective. 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.
Study Design. Twenty-four preterm infants (24-36 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 ± 3.1 weeks with birth weight of 1169 ± 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 ~2 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) >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 >5 minutes per 24 hours, and RI, ie, percentage of time
with pH <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 
15 seconds
(prolonged) and 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 follow-up
electrocardiograms were performed because of concern about prolonged
QTc and cardiac arrhythmias. The infants were 35.6 ± 4.5 weeks
postconceptional 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 5 minutes was reduced from 7.1 ± 5.8 to 4.3 ± 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 0.450 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 ± 0.40 to 0.12 ± 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 ~50%
of the infants had minimal changes in their apnea indexes. Furthermore,
~40% 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 <2 SD of Vandenplas' normative values (<3.2%).
Conclusion. 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 (2-4 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. Key words: cisapride, preterm infant, reflux, apnea.
This article has been cited by other articles:
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  D. E Elder, L. Russell, D. Sheppard, G. L Purdie, and A. J Campbell Car seat test for preterm infants: comparison with polysomnography Arch. Dis. Child. Fetal Neonatal Ed., November 1, 2007; 92(6): F468 - F472. [Abstract] [Full Text] [PDF]
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 S. R. Jadcherla and C. D. Rudolph Gastroesophageal Reflux in the Preterm Neonate NeoReviews, February 1, 2005; 6(2): e87 - e98. [Full Text] [PDF]
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