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Original Articles: Gastroenterology

Cisapride Use in Pediatric Patients With Intestinal Failure and Its Impact on Progression of Enteral Nutrition

Martinez, Andrea∗,†,‡; Belza, Christina∗,‡; Betts, Zachary; de Silva, Nicole; Avitzur, Yaron∗,†,‡; Wales, Paul W.∗,‡,§

Author Information
Journal of Pediatric Gastroenterology and Nutrition: January 2021 - Volume 72 - Issue 1 - p 43-48
doi: 10.1097/MPG.0000000000002868
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Abstract

What Is Known/What Is New

What Is Known

  • Gastrointestinal dysmotility is a common challenge in the management of pediatric intestinal failure and often results in prolonged time on parenteral nutrition.
  • First-line prokinetics such as domperidone and metoclopramide are not successful in a significant proportion 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 improving enteral feeding tolerance.
  • Cisapride can be considered when first-line dysmotility 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.

Intestinal failure (IF) is defined as the inability of the gastrointestinal (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 significant 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 introduced 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 subsequent 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 (50%) (7) and contributes substantially to the overall morbidity of this patient population. PN is a life-saving therapy; however, it carries multiple potential complications with prolonged exposure (4). Therefore, it is crucial to optimize strategies for the advancement of EN and PN weaning. Prokinetic agents have been used to overcome postoperative dysmotility and improve enteral tolerance. Herein we describe the use of prokinetics and the impact of cisapride on EN tolerance in children with PIF and its safety profile in a cohort of patients with PIF followed by a large intestinal rehabilitation program.

METHODS

We conducted a retrospective cohort study of all patients with PIF and prokinetic agent therapy who were managed by the Intestinal Rehabilitation Program at The Hospital for Sick Children between January 2008 and December 2015. Intestinal failure was defined as PN dependency >6 weeks after primary intestinal surgery or initial presentation in patients with a dysmotility disorder or mucosal enteropathy, and/or residual small bowel (SB) length of <25% expected for age at the time of the primary operation based on established norms (8). Patients were included if they had a primary diagnosis of IF and received therapy using a prokinetic. Prokinetic agents examined included domperidone, metoclopramide, and cisapride. Demographic characteristics were collected and included age, sex, gestational age, etiology of IF, and IF category (primary dysmotility, SBS). Residual intestinal anatomy was collected including SB and large bowel length (cm), percentage of expected based on established norms (8), presence or absence of an ostomy or ileocecal valve, and history of serial transverse enteroplasty procedure.

Cisapride was initiated after failure of other prokinetics (domperidone and metoclopramide) as per Health Canada regulations—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 prokinetic medication. Patients required a normal baseline electrocardiogram (ECG) without corrected QT interval (QTc) abnormality and no evidence of congenital heart disease before initiation of treatment. All patients receiving cisapride were approved through Health Canada's special access program based on the above criteria. Once cisapride was approved a starting dose of 0.2 to 0.3 mg · kg−1 · day−1 was initiated and the dose was titrated up to maximum of 1 mg · kg−1 · day−1 not to exceed 10 mg three times daily. Electrocardiogram was performed on every patient prescribed cisapride at baseline, 3 to 5 days after initiation of therapy and after every dose increase until final dose had been reached. Cisapride was discontinued if the QTc exceeded 450 ms.

Enteral tolerance was determined based on patient symptoms including gastric aspirates, episodes of vomiting, and volume of output from nasogastric and/or gastrostomy. As symptoms of dysmotility improved, we advanced feeds based on daily assessment of enteral tolerance from both a vomiting/gastric output perspective but also based on stool output. The PN was weaned based on tolerance of EN and weight gain. The determination of type of feed to provide was determined based on the patient's age. In infants, the first option was breast milk when available, but if this was not available, or a child demonstrated intolerance due to malabsorption, we progressed to a semielemental formula (Nutramigen A+). Older children were started on an age-appropriate diet with restriction of simple monosaccharides. Outcome measures included the percentage of overall kcal/kg/day delivered enterally before cisapride compared to 3 and 6 months postinitiation of treatment. We also assessed the proportion of patients achieving enteral autonomy, as well as, the rate of feed progression per day by calculating the percentage of EN tolerated in the 3 months before use of cisapride (percentage of EN at cisapride initiation minus EN 3 months prior divided by the number of days) versus the percentage of EN tolerated after initiation of cisapride (percentage of EN at 3 and 6 months after cisapride initiation minus percentage of EN at cisapride start divided by the number of days). Side effects were recorded to characterize safety of cisapride. QTc interval prolongation was defined as QTc interval >450 ms and cisapride was discontinued at any point when signs of prolonged QTc were detected.

Continuous variables were presented as means with standard deviations and categorical variables as frequencies and proportions. Student t test was used for continuous variables and chi-square or Fisher exact test for categorical variables. Statistical analysis was completed using IBM SPSS Statistics (version 23, Armonk, NY).

RESULTS

Overall, prokinetic therapy was employed in 61 of 106 patients with IF (57.5%). Table 1 compares patient characteristics between patients who received cisapride (29/61) versus other prokinetics (32/61). There was no statistical difference in patient characteristics between the groups. Etiologies of IF were similar between groups (P = 0.450). Necrotizing enterocolitis, intestinal atresia, gastroschisis, and Hirschsprung disease were the most common etiologies. Patients in both the cisapride and other prokinetic groups had similar percentage residual SB (69.4% ± 34.3% vs 61.2% ± 37.1%; P = 0.379) and percentage residual large bowel (75.4% ± 35.0% vs 75.4% ± 33.5%; P = 0.996). In addition, there was no statistical difference in the proportion of patients with an ostomy or who had resection of ileocecal valve between cisapride-treated patients and those who received other prokinetics.

TABLE 1 - Patient characteristics and intestinal anatomy of patients on cisapride compared to other first-line prokinetics
Cisapride (n = 29) Other prokinetic (n = 32) P
Sex, male (%) 12 (41.4) 16 (48.5) 0.575
GA, wk 34.1 (4.3) 33.5 (4.5) 0.606
Birth weight, g 2186 (903) 2053 (842) 0.580
Etiology 0.450
 NEC 4 (13.8) 10 (30.3)
 SB atresia 8 (27.6) 7 (21.2)
 Gastroschisis 11 (37.9) 10 (30.3
 Hirschsprung disease 1 (3.4) 2 (6.1)
 Other 5 (3.4) (17.2) 0
IF category 0.101
 SBS 15 (51.7) 23 (71.9)
 Dysmotility 14 (48.3) 8 (25.0)
Intestinal anatomy
 Percent residual SB, mean 69.4 (34.3) 61.2 (37.1) 0.379
 Percent residual LB, mean 75.4 (35.0) 75.4 (33.5) 0.996
 Stoma, yes (%) 6 (20.7) 14 (43.8) 0.055
 STEP procedure, yes (%) 3 (10.7) 6 (18.8) 0.612
 ICV resected, yes (%) 10 (34.5) 12 (37.5) 0.806
GA = gestational age; ICV = ileocecal valve; IF = intestinal failure; LB = large bowel; NEC = necrotizing enterocolitis; SB = small bowel; SBS = short bowel syndrome; STEP = serial transverse enteroplasty.
Other prokinetics indicate use of domperidone, metoclopramide, or both.

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 plateaued 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 significantly to 0.69%/day ± 0.31%/day (P < 0.001) (Fig. 1). Individual 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.

F1
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).
F2
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.
F3
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.

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 · kg−1 · day−1 with a mean dose in the cohort on cisapride of 0.81 mg · kg−1 · day−1 (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 secondary 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 prokinetics. Antroduodenal manometry and colonic manometry require 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 dysmotility 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 demonstrating 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).

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 (ranging 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 enteral tolerance after 7 weeks of therapy. In 2011, an open-label study by Raphael et al (n = 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 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 prucalopride. 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 experienced encouraging results, the small sample size makes it difficult to comment definitively on safety; therefore, potential risks associated 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 commencement of prokinetic therapy. They were also universally managed by an experienced multidisciplinary intestinal rehabilitation 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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Keywords:

cisapride; dysmotility; intestinal failure; pediatrics; prokinetics

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