Letters to the Editor

Indian Pediatrics 2001; 38: 108-110

Cisapride Use in Preterms

We read with interest the recently published study on prophylactic use of Cisapride on feed intolerance and gastric empying in preterm neonates(1). The authors must be compli-mented for doing an objective, randomized double blind study on normal preterm neonates, probably first of its kind from the Indian subcontinent.

However, we need certain clarifications. Firstly, it is not clear from the study whether the placebo used in the study contained the same base as in Cisapride preparation as any difference in composition will have a bearing on the final outcome. Secondly, was the drug administered at the time of feeding or some time before feeding, since the peak level of cisapride is effected if taken with food(2). Lastly, while undergoing nuclear scan study, was Tc99 phytate administered at a fixed time in each baby to minimize the effect of circadian rhythm?

There are only few double blind studies on the use of cisapride in preterm neonates(3,4). In one such study(3), the time taken to tolerate full enteral feeds was unaltered by Cisapride as compared to placebo, but large gastric residua did seem to be significantly reduced. The author concluded that its use may be appropriate in neonates with significant gastric stasis or regurgitation. Contrary to this, in a recent study(4). Cisapride used for clinically diagnosed cases of gastroesophageal reflux (GER) and feed intolerance didn’t demonstrate any benefit; rather it worsened the GER as reaffirmed the current study. One plausible explanation for the ineffectiveness of Cisapride on preterm neonates could be its action on intestinal receptors. Cisapride acts by stimula-tion of 6-Hydroxytyptamine (5-HT4) intesti-nal receptors. It has been suggeted on basis of animal model that 5 HT4 receptors have differing affinities for Cisapride(5). Hence, stimulation of high affinity receptors seemed to increase gastrointestinal motor activity while that of low receptors had the opposite effect. It is quite possible that in the gastrointestinal tract of the preterm neonates, only low affinity receptors have developed sufficiently to be stimulated by Cisapride. Alternatively, the dose of Cisapride used in the current study (within the quoted recommended ranges) may have been too high for the babies and may have resulted in stimulation of low affinity receptors.

We as neonatologists and pediatricians working in nursery, are routinely using Cisapride for feed intolerance and GER in preterm neonates and we are not sure how many of us are using it under cardiac monitoring. In view of the conflicting reports of benefit of Cisapride in preterm neonates, we feel that it should not be used in normal preterm neonates and we fully agree with the authors that multicentric trials are necessary betore it can be prescribed in preterm neonates for feed intolerance and GER. Moreover, in UK, the Medicines Control Agency has stated that Cisapride is contraindicated in neonates born before 36 weeks of gestation until they are 3 months of age due to its fatal side effects(3). So are we really justified in using cisapride in preterm neonates?

Srikanta Basu,
Durlabh S. Bishnoi,
Department of Pediatrics,
Government Medical College,
Chandigarh 160 047, India.

1. Reddy PS, Deorari AK, Bal CS, Paul VK, Singh M.A. double-blind placebo controlled study on prophylactic use of cisapride on feed intolerance and gastric emptying in pre- term neonates. Indian Pediatr 2000; 37: 837-844.

2. Brunton LL. Agents affecting gastrointestinal water flux and motility; emesis and antiemetics; bile acids and pancreatic enzymes. In: Goodman and Gillman’s: The Pharmacological Basis of Therapeutics, 9th edn. Eds. Hardman JG, Limbird LE, Molinoff PB, Ruddon RW. New York, Mc Graw Hill, 1996; pp 817-937.

3. Enriquez A, Bolisetty S, Patole S, Garvey PA, Campbell PJ. Randomized controlled trial of Cisapride in feed intolerance in preterm infants. Arch Dis Child 1998; 79: F 110-F113.

4. Mc Clure RJ, Kristensen JH, Grauaug A. Randomized controlled trial of Cisapride in preterm infants. Arch Dis Child 1999; 80: F 174-F177.

5. Chen HT, Goh MH, Pan S. The effect and mechanism of prokinetic action of Cisapride on gastrointestinal smooth muscle. Gastroentero-logy Japonica 1993; 28: 218-223.

We agree that till now there are conflicting reports of efficay of Cisapride in preterm neonates. But if we consider all randomized controlled studies published till now, (includ-ing ours) only one study has shown a beneficial effect(1). All other have shown either no effect(2,3) or negative effect(4). Thus, we believe that efficacy for which we are using Cisapride in neonates is of doubtful nature.

We obtained the drug and placebo from a pharmaceutical company, who provided the placebo with the same base without the drug. The drug was administered along with feeds in all babies at 8 hourly intervals. The nuclear scan was performed in all babies at a fixed time slot in the afternoon (3.00-6.00 p.m.). The drug or placebo was administered approximately two hours prior to nuclear scan (the timing of peak level of Cisapride).

Safety of Cisapride in neonates is not yet settled. There are serious concerns and conflicting views(5,6). Not surprisingly FDA has withdrawn the drug from the US market. Cisapride can be associated with serious side-effects if used inappropriately especially in preterm neonates. Thus Cisapride should be used, if at all, judiciously and under close monitoring(7).

A.K. Dorari,
P.S. Reddy,
V.K. Paul,
Department of Pediatrics,
All India Institute of Medical Sciences,
Ansari Nagar, New Delhi 110 029, India.

1. Lander A, Redkar R, Nicholls G, Lawson A, Choudhury SA, Corkery JJ et al. Cisapride reduces neonatal postoperative ileus: Random-ized placebo controlled trial. Arch Dis Child 1997; 77: F 119-F22.

2. Reddy PS, Deorari AK, Bal CS, Paul VK, Singh M. A double-blind placebo controlled study on prophylactic use of cisapride on feed intolerance and gastric emptying in preterm neonates. Indian Pediatr 2000; 37: 837-844.

3. Enriquez A, Bolisetty S, Patole S, Garvey PA, Campbell PJ. Randomized controlled trial of cisapride in feed intolerance in preterm infants. Arch Dis Child 1998; 79: F110-F113.

4. McClure RJ, Kristensen JH, Grauaug A. Randomized controlled trial of cisapride in preterm infants. Arch Dis Child 1999; 80: F174-F117.

5. Khoshoo V. Edell D, Clarke R. Effects of cisapride on the QT interval in infants with gastroesophageal reflux. Pediatrics 2000, 105: E24.

6. Vandenplas Y. Randomized controlled trial of cisapride in preterm infants. Arch Dis Child 2000; 83: F75.

7. Markiwicz M, Vandenplas Y. Should Cisapride have been "blacklisted"? Arch Dis Child 2000; 82: F3-F4.