PEDIATRICS Vol. 106 No. 5 November 2000, pp. 1028-1030

Cisapride and QTc Interval in Children

Jaime Ramírez-Mayans, MD^*, Luis Martín Garrido-García, MD^*, Andrea Huerta-Tecanhuey, MD^*, Pedro Gutierrez-Castrellón, MD, PhD, Roberto Cervantes-Bustamante, MD^*, Norberto Mata-Rivera, MD^*, and Flora Zárate-Mondragón, MD^*

From the ^* Gastroenterology and Nutrition Department, and the  Clinical Research Department, Instituto Nacional de Pediatría, Tertiary Referral Center, Mexico City, Mexico.

	ABSTRACT

Top Abstract Methods Results Discussion References

Background.  Recent reports about cisapride have raised some concerns about the safety and efficacy of this medication in children. The aim of this study was to identify electrocardiographic changes and a predisposition to develop arrhythmias in children.

Methods.  Patients were divided in 2 groups: 1) 63 children (mean age: 29 months) who received cisapride (0.2 mg/kg/dose 3 times/day), and 2) 57 children (mean age: 27 months) who did not receive cisapride (they served as controls). Both groups did not have any associated disease. Electrocardiogram (EKG) was performed to children when they were included in the study. The QT interval was corrected using Bazett's formula. Twenty-four-hour Holter recording was performed in children with prolonged QT interval (PQTI). When PQTI was identified in group 1, cisapride was discontinued and a new EKG was performed.

Results.  Five children from group 1 and 6 from group 2 had PQTI. In 3 children with PQTI, the QTc interval returned to normal values when cisapride was discontinued. In children under 4 months of age, a statistical difference was found, with QTc interval being longer in group 2 (without cisapride) than in group 1. Holter recordings were normal in all children with PQTI.

Conclusion.  PQTI can be found in normal children with or without cisapride. In our study PQTI was not associated with any life-threatening event.  Key words:  electrocardiogram, arrhythmia.

Cisapride is a substituted benzamide that stimulates motor activity in all segments of the gastrointestinal tract. The drug enhances the release of acetylcholine from the myenteric plexus.¹ Cisapride has been on the Mexican market since 1988. Numerous overviews of its efficacy in children have been published.^2-8 These studies have shown that cisapride is beneficial for the treatment of infant regurgitation, esophagitis, chronic respiratory disease, functional dyspepsia, constipation, and fecal incontinence; other studies have demonstrated improvement in gastric emptying in premature infants and in neonates with postoperative ileus.^2-8

Recent reports showing that cisapride induces prolonged QT interval (PQTI) and potential cardiac arrhythmias have raised concerns about its use in children.^1,9 It is still unclear whether this happens with recommended or higher doses of cisapride or only when it is administrated in association with other drugs metabolized by the cytochrome P450A4. In children with electrolyte imbalance and cardiac dysfunction, cisapride should be deferred.^1,9 The aim of this study was to identify electrocardiographic changes and the predisposition to arrhythmias in children with gastroesophageal reflux treated with cisapride without any other associated diseases.

	METHODS

Top Abstract Methods Results Discussion References

We performed a standard electrocardiogram (EKG) with an HP Pagewriter Lxi (Hewlett Packard) in 120 children who were seen at the Gastroenterology and Nutrition Department of the Instituto Nacional de Pediatría SS (Mexico City, Mexico) a tertiary referral center, between September 1, 1998 and March 1999. The children (from 1 month to 18 years of age, any gender; Table 1) did not have evidence of any disease, such as cardiopathies, disrrhythmias, dehydration, or vomiting, and were without any other drug with metabolism at cytochrome P450. None of the study children were premature. One group of 63 children with gastroesophageal reflux arrived at the hospital for the first time and were already taking 0.20 mg/kg/dose of cisapride 3 times a day for at least 15 days. They were included in group I. Another group of 57 children seen in the hospital for other nonrelated problems, without cisapride or other oral treatment, served as controls (group II). All children were eating and had no diarrhea or vomiting when EKG was performed. Informed consent from parents in both groups was obtained. The QT interval was evaluated using Bazett's formula.¹⁰ PQTI was defined as a QTc interval 460 milliseconds. Analysis was stratified by age, the distribution was made considering the activity of the CYP450 enzyme. A second EKG was performed in children with PQTI from group I after discontinuation of cisapride for 15 days. The same pediatric cardiologist blinded to both groups interpreted the EKG. A 24-hour Holter recording was performed in children with PQTI in both groups when PQTI was found.

Statistical analysis was performed with SPSS, Version 8.0 for Windows (SPSS, Chicago, IL). Descriptive analysis was presented as the mean ± 1 standard deviation and median. Comparisons of data between the study and the control group were assessed with ², Student's t test, or Mann-Whitney U test according with unequal or equal variance. A P value <.05 was considered statistically significant.

	RESULTS

Top Abstract Methods Results Discussion References

The period of time on cisapride was 15 to 1825 days with a median of 60 days. There were 5 children with PQTI in group I: 3 returned to normal values after cisapride was discontinued, and the other 2 remained prolonged. In group II there were 6 children with PQTI. Holter recordings were made to 6 of the children, 3 in each group, and no arrhythmias were found. The remaining children had no Holter because they were lost to follow-up for some time. No family history consistent with congenital syndrome of prolonged QTc was found in any of these children. No statistical differences were found between both groups (P = 0.4). When the analysis was performed by groups of age, there was significant statistical difference in children <4 months of age (P = .04). The QTc interval was longer in group II than in group I (Table 2). In older children, PQTI frequencies and duration were similar between the 2 groups (Table 3). A significant statistical difference was found with a heart rate of 119 ± 24 bpm for group I and 130 ± 26 bpm for group II (P = .02). The heart rate for the different groups stratified by age identified a difference only in children <4 months of age (P = .006; Table 4). We found no clinical reason to support this difference.

	DISCUSSION

Top Abstract Methods Results Discussion References

Since the introduction of cisapride to the market, an estimated 140 000 000 courses of therapy have been prescribed.¹ The efficacy and safety of cisapride have been previously reported.^2-8 Although recent studies in children show that cisapride can increase the QT interval,^1-9,11,12 the clinical significance of a PQTI remains unclear.^13-15 It is not possible to predict how an individual will respond or when a child with PQTI will develop any kind of arrhythmias. There are 2 studies with special concern on cisapridethe study by Khongphattbanayothin et al¹ and the study by Hill et al.⁹ In the former, the patients had different diagnoses, such as history of prematurity, chronic lung disease, cerebral palsy, and congenital heart disease, which are risk factors that may contribute to PQTI. In the latter, there were only 2 patients with arrhythmias, and they were receiving macrolides at the same time.⁹

There are many drugs that have the ability to inhibit CYP4503A4, the most important enzyme responsible for the metabolism of numerous drugs including cisapride.^16,17 Lacroix et al demonstrated that CYP3A4 is present in the liver of infants from the first month of age and that it represents ~30% of the activity seen in adults.¹⁸ Levels of this enzyme seem to approach adult values between 6 to 12 months of age and may even exceed adult values between 1 to 4 years of age.¹⁹ In our study it seems that the cisapride effect was related to age. We found that in children <4 months of age, the prevalence of PQTI was greater in the control group than in the cisapride group, although with no statistical significance. In this age group, there was also another significant difference related to heart rate. The group without cisapride had higher heart rate and shorter QTc interval. We found no clinical explanation for this difference. However, it suggests that factors other than cisapride may be important. Currently, any drug that shares the same hepatic enzyme system, such as macrolides and the azole antifungals, are contraindicated for its simultaneous use.²⁰

In this study we found 3 patients in group I with PQTI that returned to normal values when cisapride was drawn. It is clear that cisapride prolonged the QTc interval, but we observed no clinical relevance, having normal Holter recording for these children. None of the children developed any clinical or subclinical evidence of arrhythmias according to Holter results. During the study, none of the children were receiving other medication or had any severe illness that could modify the QT interval.

Our findings suggest that PQTI can be found in normal children with or without cisapride. No association with arrhythmias was found. Although the sample size is small, no significant reflux is hoarseness.

	FOOTNOTES

Received for publication Nov 10, 1999; accepted Feb 28, 2000.

Reprint requests to (J.R.-M.) Instituto Nacional de Pediatría, Insurgentes Sur 3700-C, Insurgentes Cuicuilco, CP 04530, Mexico City, Mexico. E-mail: jramay1{at}yahoo.com

	ABBREVIATIONS

PQTI, prolonged QT interval; EKG, electrocardiogram.

	REFERENCES

Top Abstract Methods Results Discussion References

1. Khongphattbanayothin A, Lane J, Thomas D, Yen L, Chang D, Bubolz B Effects of cisapride on QT interval in children. J Pediatr 1998; 133:51-56 [CrossRef][Medline]
2. Cucchiara S Staiano A, Capuzzi C, Di Lorenzo C, Boccieri A, Auricchio S. Cisapride for gastroesophageal reflux and peptic oesophagitis. Arch Dis Child 1987; 62:454-457 [Abstract/Free Full Text]
3. Saye ZN, Forget PP, Geubelle F Effect of cisapride on gastroesophageal reflux in children with chronic bronchopulmonary disease: a double blind cross-over pH monitoring study. Pediatr Pulmonol 1987; 3:8-12 [Medline]
4. Halabi IM Cisapride in management of chronic pediatric constipation. J Pediatr Gastroenterol Nutr 1999; 28:199-202 [CrossRef][Medline]
5. Van Eygen M, Van Ravensteyns H Effect of cisapride on excessive regurgitation in infants. Clin Ther 1989; 11:669-677 [Medline]
6. Vandenplas Y, Deroy C, Sacre L Cisapride decreases prolonged episodes of reflux in infants. J Pediatr Gastroenterol Nutr 1991; 12:44-47 [Medline]
7. Lander A, Redkar R, Nicholls G, Cisapride reduces neonatal postoperative ileus: randomised placebo-controlled trial. Arch Dis Child 1997; 77:F119-F122
8. Enriquez A, Botisetty S Patole S, Garvey PA, Campbell PJ. Randomised controlled trial of cisapride in food intolerance in preterm infants. Arch Dis Child Fetal Neonatal Ed 1998; 79:F110-F113 [Abstract/Free Full Text]
9. Hill SL, Evangelista JK, Pizzi AM, Mobassaleh M, Fulton DR, Berul CI Proarrhythmia associated with cisapride in children. Pediatrics 1998; 101:1053-1056 [Abstract/Free Full Text]
10. Bazzet HC An analysis of the time relations of electrocardiograms. Heart. 1920; 7:353-367
11. Manji S, Lllyons H, Pieper D, Farooki Z Cisapride associated ECG changes in children. J Pediatr Gastroenterol Nutr 1999; 29:501
12. Shulman RJ, Boyle T, Colletti RB, The use of cisapride in children. J Pediatr Gastroenterol Nutr 1999; 28:529-533 [CrossRef][Medline]
13. Garson A Jr, Dick M II, Fournier A, The long QT syndrome in children: an international study of 287 patients. Circulation 1993; 87:1866-1872 [Abstract/Free Full Text]
14. Schwartz PJ, Strauba-Badiale M, Segantini A, Prolongation of the QT interval and the sudden infant death syndrome. N Engl J Med 1998; 338:1709-1714 [Abstract/Free Full Text]
15. Guyer B, Martin JA, Mac Dorman MF, Anderson RN, Strobino DM Annual summary of vital statistics1996. Pediatrics 1997; 100:905-918 [Abstract/Free Full Text]
16. Michalets EL Update: clinically significant citochrome p-450 drug interactions. Pharmacotherapy 1998; 18:84-112 [Medline]
17. Rendic S, Di Carlo F Human cytochrome p-450 enzymes: a status report summarizing their reactions, substrates, inducers and inhibitors. Drug Metab Rev 1997; 29:413-580 [Medline]
18. Lacroix D, Sonnier M, Moncion A, Cheron G, Cresteil T Expression of CYP3A in human liver: evidence that the shift between CYP3A7 and CYP3A4 occurs inmediately after birth. Eur J Biochem 1997; 247:625-634 [Medline]
19. Leeder JS, Kearns GL Pharmacogenetics in pediatrics: implications for practice. Pediatr Clin North Am 1997; 44:55-77 [CrossRef][Medline]
20. Vandenplas Y, Belli DC, Benatar A, The role of cisapride in the treatment of pediatric gastroesophageal reflux. J Pediatr Gastroenterol Nutr 1999; 28:518-528 [CrossRef][Medline]