ORIGINAL ARTICLE: GASTROENTEROLOGY

Cisapride Use in Pediatric Patients With

Intestinal Failure and Its Impact on Progression
of Enteral Nutrition
yz
Andrea Martinez, zChristina Belza, Zachary Betts, Nicole de Silva,
yz
Yaron Avitzur, and z§Paul W. Wales

ABSTRACT

Objective: Gastrointestinal dysmotility is common in patients with pediatric What Is Known

intestinal failure (PIF), leading to delays in advancement of enteral nutrition
(EN). Few studies have been published regarding the safety and efficacy of
cisapride for improvement of enteral tolerance and ability to wean parenteral
nutrition. Our objective was to describe a single center experience on the use
of cisapride in patients with PIF.
Methods: Retrospective chart review of patients was performed.
Demographic, intestinal anatomy, and outcome data were collected.
Percentage of EN before initiation of cisapride, progression of EN at 3
and 6 months, and ability to wean parenteral nutrition after initiation of
cisapride were calculated.
Results: Prokinetics were used in 61 of 106 patients (56.6%); 29 of 60
patients (48.3%) failed to progress EN on other prokinetics and started on
cisapride. Before cisapride the progress of EN plateaued for a mean of 42.3
(standard deviation [SD] 60.2) days. The rate of feed progression was 0.14%
(SD 0.19)/day pre-cisapride and 0.69%/day (SD 0.31) after cisapride
initiation (P < 0.001). Percentage of EN improved significantly from
baseline to 3 months postinitiation (23.9% vs 79.4%, respectively;
P < 0.001). Electrocardiogram was performed on initiation of cisapride
and after every dose change. Medication was discontinued in 2 of 29 (6.8%).
Conclusion: This retrospective study suggests that cisapride may be
beneficial in PIF patients who fail to progress EN on first line
prokinetics. The most significant period of improvement occurs within
3 months of cisapride initiation. Cardiac side effects in our cohort were
lower than previously reported; however, cardiac monitoring is still
recommended.
Key Words: cisapride, dysmotility, intestinal failure, pediatrics,
prokinetics
(JPGN 2021;72: 43–48)
Received April 5, 2019; accepted June 14, 2020.
From the Group for Improvement of Intestinal Function and Treatment
(GIFT), the yDivision of Gastroenterology, Hepatology and Nutrition,
the zTransplant and Regenerative Medicine Centre, and the §Division of
General and Thoracic Surgery, The Hospital for Sick Children, Univer-
sity of Toronto, Toronto, Canada.
Address correspondence and reprint requests to Paul W. Wales, MD, The
Hospital for Sick Children, 555 University Ave, Rm 1526, Toronto,
Ontario, Canada M5G 1X8 (e-mail: paul.wales@sickkids.ca).
The authors report no conflicts of interest.
Copyright # 2020 by European Society for Pediatric Gastroenterology,
Hepatology, and Nutrition and North American Society for Pediatric
Gastroenterology, Hepatology, and Nutrition
DOI: 10.1097/MPG.0000000000002868
 Gastrointestinal dysmotility is a common challenge in
the management of pediatric intestinal failure and
often results in prolonged time on parenteral nutri-
tion.
 First-line prokinetics such as domperidone and meto-
clopramide are not successful in a significant propor-
tion of patient and carry a risk of side effects.
What Is New
 This retrospective study demonstrated that cisapride
under careful monitoring may be effective in improv-
ing enteral feeding tolerance.
 Cisapride can be considered when first-line dysmo-
tility therapy has failed in patients with intestinal
failure.
 Prolonged corrected QT interval after initiation was
noted in only 1 of 29 subjects, and this incidence was
less than that had been previously reported.
I ntestinal failure (IF) is defined as the inability of the gastroin-
testinal (GI) tract to absorb adequate fluids and nutrients to
sustain life (1). Intestinal failure encompasses a variety of diagnoses
including short bowel syndrome (SBS), primary intestinal motility
disorders, and mucosal enteropathies (1,2). There have been sig-
nificant improvements in the long-term survival of patients with IF
over the past 15 years that has led to increased time for patients to
achieve enteral autonomy. While new therapies have been intro-
duced to decrease the risk of complications (lipid management
strategies and various locking solutions) and aid in the achievement
of enteral autonomy (ie, Teduglutide) there continues to be a
population that develop significant dysmotility that hinders the
ability to wean parenteral nutrition (PN).
GI dysmotility is common in patients with pediatric intestinal
failure (PIF), leading to delays in advancement of enteral nutrition
(EN). Symptoms of dysmotility may include recurrent episodes of
abdominal distension, vomiting, abdominal or chest pain, feeding
intolerance, malabsorption, and bacterial overgrowth with subse-
quent systemic or central venous catheter infection related to
bacterial translocation (3). These symptoms contribute to the
inability to advance EN. Postoperative dysmotility is a common
problem in PIF and/or SBS secondary to necrotizing enterocolitis
(8%–12%) (4,5), gastroschisis (43%) (6,7), and intestinal atresia

JPGN  Volume 72, Number 1, January 2021 43

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Martinez et al JPGN  Volume 72, Number 1, January 2021

(50%) (7) and contributes substantially to the overall morbidity of enteral autonomy, as well as, the rate of feed progression per day by
this patient population. PN is a life-saving therapy; however, it calculating the percentage of EN tolerated in the 3 months before
carries multiple potential complications with prolonged exposure use of cisapride (percentage of EN at cisapride initiation minus EN
(4). Therefore, it is crucial to optimize strategies for the advance- 3 months prior divided by the number of days) versus the percentage
ment of EN and PN weaning. Prokinetic agents have been used to of EN tolerated after initiation of cisapride (percentage of EN at 3
overcome postoperative dysmotility and improve enteral tolerance. and 6 months after cisapride initiation minus percentage of EN at
Herein we describe the use of prokinetics and the impact of cisapride start divided by the number of days). Side effects were
cisapride on EN tolerance in children with PIF and its safety profile recorded to characterize safety of cisapride. QTc interval prolonga-
in a cohort of patients with PIF followed by a large intestinal tion was defined as QTc interval >450 ms and cisapride was
rehabilitation program. discontinued at any point when signs of prolonged QTc
were detected.
METHODS Continuous variables were presented as means with standard
We conducted a retrospective cohort study of all patients with deviations and categorical variables as frequencies and proportions.
PIF and prokinetic agent therapy who were managed by the Student t test was used for continuous variables and chi-square or
Intestinal Rehabilitation Program at The Hospital for Sick Children Fisher exact test for categorical variables. Statistical analysis was
between January 2008 and December 2015. Intestinal failure was completed using IBM SPSS Statistics (version 23, Armonk, NY).
defined as PN dependency >6 weeks after primary intestinal
surgery or initial presentation in patients with a dysmotility disorder RESULTS
or mucosal enteropathy, and/or residual small bowel (SB) length of Overall, prokinetic therapy was employed in 61 of 106
<25% expected for age at the time of the primary operation based patients with IF (57.5%). Table 1 compares patient characteristics
on established norms (8). Patients were included if they had a between patients who received cisapride (29/61) versus other
primary diagnosis of IF and received therapy using a prokinetic. prokinetics (32/61). There was no statistical difference in patient
Prokinetic agents examined included domperidone, metoclopra- characteristics between the groups. Etiologies of IF were similar
mide, and cisapride. Demographic characteristics were collected between groups (P ¼ 0.450). Necrotizing enterocolitis, intestinal
and included age, sex, gestational age, etiology of IF, and IF atresia, gastroschisis, and Hirschsprung disease were the most
category (primary dysmotility, SBS). Residual intestinal anatomy common etiologies. Patients in both the cisapride and other proki-
was collected including SB and large bowel length (cm), percentage netic groups had similar percentage residual SB (69.4%  34.3% vs
of expected based on established norms (8), presence or absence of 61.2%  37.1%; P ¼ 0.379) and percentage residual large bowel
an ostomy or ileocecal valve, and history of serial transverse (75.4%  35.0% vs 75.4%  33.5%; P ¼ 0.996). In addition, there
enteroplasty procedure. was no statistical difference in the proportion of patients with an
Cisapride was initiated after failure of other prokinetics ostomy or who had resection of ileocecal valve between cisapride-
(domperidone and metoclopramide) as per Health Canada regula- treated patients and those who received other prokinetics.
tions—persistence of dysmotility symptoms and inability to
advance enteral feeds. We defined failure of other prokinetics as
persistence of dysmotility symptoms and enteral feed intolerance
after minimum 2-week period of optimization of dosage of first-line TABLE 1. Patient characteristics and intestinal anatomy of patients on
prokinetic medication. Patients required a normal baseline electro- cisapride compared to other first-line prokinetics
cardiogram (ECG) without corrected QT interval (QTc) abnormal-
ity and no evidence of congenital heart disease before initiation of Other

treatment. All patients receiving cisapride were approved through Cisapride prokinetic
Health Canada’s special access program based on the above criteria. (n ¼ 29) (n ¼ 32) P
Once cisapride was approved a starting dose of 0.2 to
Sex, male (%) 12 (41.4) 16 (48.5) 0.575
0.3 mg  kg1  day1 was initiated and the dose was titrated up to
GA, wk 34.1 (4.3) 33.5 (4.5) 0.606
maximum of 1 mg  kg1  day1 not to exceed 10 mg three times
Birth weight, g 2186 (903) 2053 (842) 0.580
daily. Electrocardiogram was performed on every patient prescribed
Etiology 0.450
cisapride at baseline, 3 to 5 days after initiation of therapy and after
NEC 4 (13.8) 10 (30.3)
every dose increase until final dose had been reached. Cisapride was
SB atresia 8 (27.6) 7 (21.2)
discontinued if the QTc exceeded 450 ms.
Gastroschisis 11 (37.9) 10 (30.3
Enteral tolerance was determined based on patient symptoms
Hirschsprung disease 1 (3.4) 2 (6.1)
including gastric aspirates, episodes of vomiting, and volume of
Other 5 (3.4) (17.2) 0
output from nasogastric and/or gastrostomy. As symptoms of
IF category 0.101
dysmotility improved, we advanced feeds based on daily assess-
SBS 15 (51.7) 23 (71.9)
ment of enteral tolerance from both a vomiting/gastric output
Dysmotility 14 (48.3) 8 (25.0)
perspective but also based on stool output. The PN was weaned
Intestinal anatomy
based on tolerance of EN and weight gain. The determination of
Percent residual SB, mean 69.4 (34.3) 61.2 (37.1) 0.379
type of feed to provide was determined based on the patient’s age. In
Percent residual LB, mean 75.4 (35.0) 75.4 (33.5) 0.996
infants, the first option was breast milk when available, but if this
Stoma, yes (%) 6 (20.7) 14 (43.8) 0.055
was not available, or a child demonstrated intolerance due to
STEP procedure, yes (%) 3 (10.7) 6 (18.8) 0.612
malabsorption, we progressed to a semielemental formula (Nutra-
ICV resected, yes (%) 10 (34.5) 12 (37.5) 0.806
migen Aþ). Older children were started on an age-appropriate diet
with restriction of simple monosaccharides. Outcome measures GA ¼ gestational age; ICV ¼ ileocecal valve; IF ¼ intestinal failure; LB
included the percentage of overall kcal/kg/day delivered enterally ¼ large bowel; NEC ¼ necrotizing enterocolitis; SB ¼ small bowel; SBS ¼
before cisapride compared to 3 and 6 months postinitiation of short bowel syndrome; STEP ¼ serial transverse enteroplasty.

treatment. We also assessed the proportion of patients achieving Other prokinetics indicate use of domperidone, metoclopramide, or both.

44 www.jpgn.org

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JPGN  Volume 72, Number 1, January 2021
Twenty-nine patients received cisapride after failing to
respond to first-line prokinetics. Before initiation of cisapride the
progression of EN while receiving first-line prokinetics had pla-
teaued for a mean of 42.3 days (standard deviation 60.2). The mean
rate of advancement of EN volume pre cisapride was 0.14%/
day  0.19%/day and after cisapride initiation this improved sig-
nificantly to 0.69%/day  0.31%/day (P < 0.001) (Fig. 1). Individ-
ual patient trajectories at initiation and 3 to 6 months after initiation
are shown in Figure 2. The percentage of total kcal/kg/day supplied
by EN at baseline before initiation of cisapride was 23.1%. Three
months after initiation enteral tolerance had significantly improved
to 79.3% and 90.9% at 6 months. Both values were statistically
significant when compared to baseline (P < 0.001) (Fig. 3). Of the
29 patients, 22 (75%) weaned off PN by 6 months postinitiation
of cisapride.
The mean duration of cisapride therapy was 408 days (214–
741). Seventeen of 29 patients weaned off cisapride after a mean of
241 days (132–434). Of the 12 patients who remained on cisapride
the mean duration of treatment was 731 days (399–1267). The
maximum dose of cisapride was 1.10 mg  kg1  day1 with a mean
dose in the cohort on cisapride of 0.81 mg  kg1  day1 (0.20–
1.10). Cisapride treatment was prematurely terminated in 2 of 29
(6.8%) patients. One patient demonstrated a prolonged QTc interval
on ECG after initiating treatment. The other patient had cisapride
stopped as a precaution due to a diagnosis of cardiomegaly second-
ary to selenium deficiency. We did not encounter any other
side effects.
DISCUSSION
GI dysmotility is common in PIF, whether it’s postoperative
dysmotility or part of the pathophysiology of the underlying cause
of IF. In our experience the use of cisapride has mainly been in
infants and young children making the clinical signs and symptoms
the basis for diagnosis. For practical considerations, it is rare for
patients to receive formal motility testing before a trial of proki-
netics. Antroduodenal manometry and colonic manometry require
FIGURE 1. Rate of enteral nutrition progression per day pre- and post-cisapride. The mean rate of advancement per day of enteral nutrition
tolerated (expressed as a percentage) before the initiation of cisapride (0.14%/day  0.19%/day) and then 3 and 6 months after cisapride
initiation (0.69%/day  0.31%/day) (P < 0.001).
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Cisapride Use in IF and Its Impact on Progression of EN
endoscopic placement of catheters, and anal manometry requires
the patient to be cooperative. Nuclear medicine colonic motility is
also available, but not commonly performed. Therapeutic options
are limited and include medical management through the use of
prokinetics and in the appropriate setting, surgical interventions to
reduce bowel caliber via tapering and/or lengthening of the bowel to
improve motility, reduce bacterial overgrowth, and ultimately
optimize intestinal function (9). Despite poor level of evidence,
prokinetic agents have been used in an attempt to improve GI
motility in patients with IF.
Pharmaceutical options for the management of GI dysmo-
tility include agents such as domperidone, metoclopramide, and
cisapride; however, each carries its own risk of side effects.
Metoclopramide and domperidone are dopamine D2 receptor
antagonists with peripheral effects in the GI tract. Their most
common side effects include drowsiness, diarrhea, and depression,
whereas extrapyramidal symptoms and other serious neurological
side effects are less commonly witnessed (10). In February 2009,
the Food and Drug Administration issued a black box warning for
metoclopramide due to its association with the development of
tardive dyskinesia (11). Domperidone has been associated with an
increase in QT interval in several case reports and a recent study
demonstrated a proarrhythmic potential (12). In 1993, the Food and
Drug Administration approved the administration of cisapride for
adults with gastroesophageal reflux disease. Cisapride is a GI
prokinetic that facilitates or restores motility along the entire GI
tract. Cisapride differs from existing motility drugs by not demon-
strating dopamine-receptor enhancing properties at therapeutic
doses, avoiding the associated side effects. It is a selective serotonin
5-HT4 receptor agonist that belongs to a group of substitute
benzamides. The mechanism of action may be explained by the
enhancement of physiologic release of acetylcholine at the level of
the myenteric plexus (13). Cisapride has been used to treat GI
conditions in children including gastroesophageal reflux disease,
esophageal acid exposure in children with cystic fibrosis, functional
dyspepsia, constipation, postoperative ileus or delayed orocecal
transit and chronic intestinal pseudo-obstruction (14).
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Martinez et al
FIGURE 2. Individual patient progression of enteral intake after initiation of cisapride. Each individual patient’s trajectory is tracked based on
enteral intake at baseline when cisapride was initiated and then at 3 and 6 months post.
Cisapride was removed from the market in July 2000 after
reports of cardiac dysrhythmias in adults (15). Cardiac side effects
due to the benzamide structure are the main reason for its limited
access. Careful and critical review of published data suggests that
cisapride may have a QTc-prolonging effect, but correct dosage and
avoidance of concurrent treatment with macrolides and/or azoles
are the most relevant tolerability recommendations in children (16).
The effect of cisapride on cardiac events like prolonged QTc
interval and arrhythmias is related to dose and risk factors (17).
In 1998 Khongphatthanayothin et al (18) reported incidence of QTc
prolongation in 13% of 101 patients treated with cisapride but only
6% of these patients had no other risk factors such as drug
interactions and heart or renal disease. In 2003, a prospective study
evaluated the effects of cisapride on QTc interval in infants and
children. Electrocardiography was obtained for 175 children (rang-
ing in age from 1.5 months to 16.8 years), before and after 15 days
of treatment with cisapride (0.2 mg/kg/dose, 3–4 times/day). A
single post-treatment ECG was also obtained for 24 patients
(ranging in age from 1.5 month to 15.8 years). No statistically
significant differences were found between the mean QTc interval
before (0.390 [0.018 s]) and after treatment (0.391 [0.018 s]).
The QTc interval was never longer than 0.450 s in any of the
children (19).
Data on the safety and efficacy of cisapride use specifically
in patients with IF are scarce.
In 1986, Puntis et al (20) published the first case report of
cisapride use in a neonate with SBS, describing improvement of
46
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JPGN  Volume 72, Number 1, January 2021
enteral tolerance after 7 weeks of therapy. In 2011, an open-label
study by Raphael et al (n ¼ 10) reported a mean percentage of EN
increase by 2.9% for every month on cisapride (P < 0.0001). QTc
prolongation occurred in 20% of their cohort (21). Similar to the
findings by Puntis et al and Raphael et al, our patients demonstrated
a dramatic response in their enteral tolerance after initiation of
cisapride with enteral tolerance improving from 23% at baseline to
91% within 6 months of therapy. Of those patients, 75% had also
weaned from PN support by 6 months of therapy.
One of the main limitations to accessing cisapride is related
to the potential cardiac side effects due to the benzamide structure.
Cardiac side effects in our cohort was low with only 1 patient
demonstrating a prolonged QTc interval (3.4%) compared to 20%
observed by Raphael et al. Cardiac monitoring is, however, still
recommended and cisapride should not be initiated on any patient
with a prolonged QTc or history of cardiac arrhythmia. It should be
discontinued if QTc prolongation occurs while on cisapride and the
concomitant use of medications such as macrolides and azoles
should be avoided (16).
Although the risks associated with the use of cisapride were
low in our cohort of patients, it is not a benign medication and care
needs to be taken to determine the appropriate patient to consider
for its initiation. Despite the risks, the majority can be mitigated
with careful patient selection and serial monitoring. It is equally
important to highlight the benefit this medication may offer to
patients with severe dysmotility. Although many patients may
eventually show improvement of dysmotility symptoms, they will
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JPGN  Volume 72, Number 1, January 2021
FIGURE 3. Percentage of enteral intake at baseline and after 3 and 6 months after initiation of cisapride. The percentage of enteral nutrition
tolerated at baseline before initiation of cisapride was 23.1% and was increased after 3 months of therapy to 79.3% and further to 90.0% at
6 months after cisapride initiation.
likely require ongoing PN support until those symptoms abate.
Prolonged PN carries significant risks including intestinal failure
associated liver disease, vascular complications, renal disease, and
sepsis. The cumulative incidence of these complications is greater
than the reported risk of cisapride.
Prucalopride, a substituted benzamide with selective 5HT4-
agonist activity has been shown previously to improve symptoms in
patients with idiopathic constipation, accelerating both upper and
lower gut transit (22). In 2013, Winter et al (23) demonstrated an
apparent favorable efficacy and tolerability profile in children with
functional constipation after an 8-week treatment with prucalo-
pride. Emmanuel et al carried out a randomized, double-blind,
placebo-controlled, cross-over, multiple N of 1 study looking at the
efficacy of prucalopride in patients with chronic intestinal pseudo-
obstruction, and found that prucalopride relieved symptoms in
selected patients with chronic pseudo-obstruction (24). The role
of prucalopride in the setting of IF dysmotility, however, has not
been studied and remains unclear.
Although this is the largest cohort reported to evaluate the
use of cisapride in children with IF, this study has limitations that
need to be acknowledged. First, the retrospective design makes it
difficult to identify other confounders that may have contributed to
the success or failure of the cisapride. Second, although we experi-
enced encouraging results, the small sample size makes it difficult
to comment definitively on safety; therefore, potential risks associ-
ated with cisapride should not be minimized. It should also be
acknowledged that dysmotility may continue to improve regardless
of the intervention with prokinetics and the retrospective nature of
this study is unable to highlight those improvements. It is important
to consider; however, that these patients had demonstrated no
improvement in enteral tolerance for quite some time before
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Cisapride Use in IF and Its Impact on Progression of EN
commencement of prokinetic therapy. They were also universally
managed by an experienced multidisciplinary intestinal rehabilita-
tion that provides consistency to patient care.
In summary, cisapride in this retrospective patient cohort
appears to be effective in improving EN tolerance. It should be
considered when first-line therapy with other prokinetics such as
domperidone and metoclopramide at maximum recommended
dosages has failed to improve dysmotility symptoms and EN
tolerance in patients with IF. The monitoring of patients who meet
criteria for cisapride should include a baseline ECG to assess for
signs of prolonged QTc and then within 3 to 5 days after initiation
and any dose adjustment. Other medications that can result in
prolonged QTc should be avoided in patients on cisapride (ie,
macrolides and azoles). The most significant period of improved
EN intake occurred within 3 months of cisapride initiation.
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