A Cautionary Tale in Pediatric GERD Treatment
For decades, pediatricians struggled to help infants and children suffering from gastro-oesophageal reflux (GOR). Then came cisapride, a promising prokinetic agent that appeared to revolutionize treatment. At its peak, this medication was prescribed to an estimated 36 million children worldwide 1 , with some professional societies even endorsing it as a first-line treatment. Yet within years, it would become the center of a major pharmaceutical safety crisis, linked to fatal cardiac arrhythmias and sudden death in young patients 2 .
Gastro-oesophageal reflux (GOR) is the passage of gastric contents back into the oesophagus, a common and usually self-limiting condition in infants. A ring of smooth muscle called the lower oesophageal sphincter normally prevents this regurgitation, but when it relaxes inappropriately or when other factors like delayed stomach emptying occur, reflux results.
The peak incidence of reflux occurs at around four months of age, with most children outgrowing the condition by one to two years.
In a small percentage of infants, GOR leads to more serious problems classified as gastro-oesophageal reflux disease (GERD), which can include respiratory issues, feeding refusal, and failure to thrive.
| Common Symptoms | Potential Complications | Investigation Methods |
|---|---|---|
| Regurgitation | Respiratory problems | 24-hour esophageal pH monitoring |
| Vomiting | Oesophagitis | Upper GI endoscopy |
| Irritability | Failure to thrive | Oesophageal manometry |
| Back-arching | Sleep disturbance | Scintigraphy or sonography |
| Feeding refusal | Aspiration pneumonia | Histological examination |
Cisapride operated through a novel mechanism that distinguished it from earlier gastrointestinal medications. As a serotonin 5-HT4 receptor agonist, it worked primarily by enhancing the release of acetylcholine in the enteric nervous system—the complex network of neurons that governs gastrointestinal function.
Unlike some earlier prokinetic drugs, cisapride was noted for being largely devoid of central depressant or antidopaminergic effects, which meant it didn't cause the sedation or movement disorders associated with some other gastrointestinal medications.
The medication was typically administered 15-30 minutes before meals to ensure peak plasma levels coincided with food intake, maximizing its prokinetic effects when they were most needed. It was available in both tablet and suspension forms, with the latter being particularly important for pediatric use.
The medical community's initial enthusiasm for cisapride was tempered as rigorous clinical evidence accumulated. A Cochrane systematic review published in 2010 and updated in 2009 analyzed ten randomized controlled trials comparing cisapride with placebo or other non-surgical treatments for children with GOR 3 . The findings proved surprisingly ambiguous regarding the drug's actual benefits.
The review concluded that there was no statistically significant difference between cisapride and placebo for the key outcome of symptom improvement.
Despite this lack of clear symptom benefit, the medication did demonstrate measurable effects on physiological parameters. Cisapride significantly reduced the reflux index.
| Outcome Measure | Findings | Statistical Significance | Clinical Implications |
|---|---|---|---|
| Symptom improvement | No clear benefit over placebo | OR 0.34; 95% CI 0.10 to 1.19 | Limited evidence for symptomatic relief |
| Reflux index | Significant reduction | WMD -6.49; 95% CI -10.13 to -2.85 | Biological effect without clear symptom correlation |
| Adverse events | Mainly diarrhea, not statistically significant | OR 1.80; 95% CI 0.87 to 3.70 | Generally well-tolerated in studied populations |
| Other pH measures | No significant differences | P > 0.05 | Inconsistent effects on esophageal acidity parameters |
One particularly informative investigation was published in the Journal of Pediatric Gastroenterology and Nutrition in 1997 4 . This randomized, prospective, double-blind, placebo-controlled clinical trial—considered the gold standard in clinical research—was conducted across three study sites and provides a compelling case study in how cisapride was evaluated.
The study enrolled 45 infants aged 6 weeks to 2 years with daily regurgitant reflux. After a one-week baseline assessment period, participants were randomly assigned to receive either a 6-week course of cisapride suspension (0.2 mg/kg every 6 hours) or an identical-appearing placebo suspension.
The most dramatic chapter in the cisapride story began to unfold when reports emerged of serious cardiac adverse events associated with the medication. The drug was found to block the human ether-à-go-go-related gene (hERG) potassium channel in cardiac myocytes, which delayed repolarization of the heart muscle and prolonged the QT interval on electrocardiograms 5 .
This electrophysiological effect created a dangerous predisposition to torsades de pointes, a specific type of life-threatening ventricular arrhythmia that can degenerate into fatal cardiac arrest. By the year 2000, regulatory agencies worldwide had documented 175 reports of fatal cardiac arrhythmia or sudden death associated with cisapride use, including at least two deaths in children 6 .
Concomitant use with medications that inhibit cytochrome P450 3A4, the enzyme responsible for cisapride metabolism
Pre-existing cardiac conditions or family history of long QT syndrome
Electrolyte imbalances such as low potassium, calcium, or magnesium
Specific patient populations including those with severe dehydration, eating disorders, or significant kidney impairment
In July 2000, following intense regulatory pressure and accumulating safety reports, cisapride was voluntarily withdrawn from the U.S. market. Similar restrictions followed worldwide, with the drug either completely withdrawn or limited to specialized access programs supervised by pediatric gastroenterologists 7 .
The dramatic rise and fall of cisapride left an indelible mark on pediatric gastroenterology and drug safety monitoring. Its story highlights several critical lessons:
While cisapride demonstrated measurable effects on physiological parameters like esophageal acid exposure, these changes didn't reliably translate to meaningful symptom improvement for patients. This disconnect between laboratory measures and actual clinical benefit remains an important consideration in drug evaluation.
The cisapride experience accelerated the implementation of routine cardiac safety screening during drug development, particularly assessment of hERG channel interactions and QT interval prolongation potential. Today, comprehensive electrocardiographic evaluation is standard practice for new chemical entities.
It influenced treatment guidelines for pediatric GERD, with current recommendations emphasizing conservative measures like thickened feeds and positioning strategies over pharmacological interventions, especially for otherwise healthy infants.
"Scant evidence to support the efficacy of prokinetics and accumulating evidence for their significant negative side-effects both indicate they should not be used routinely to treat otherwise healthy infants with symptoms of GERD."
Finally, the cisapride story led to the development of safer prokinetic alternatives with more favorable cardiac safety profiles, such as mosapride and tegaserod, which were designed to provide similar gastrointestinal benefits without the dangerous arrhythmogenic potential.
The story of cisapride represents a pivotal moment in how we balance potential benefits against serious risks in pediatric pharmacotherapy. What began as enthusiasm for a promising prokinetic agent evolved into a cautionary tale about the importance of robust post-marketing surveillance and the limitations of basing treatment decisions solely on physiological measures rather than clinical outcomes.
While cisapride continues to have very limited specialized use under strict supervision in certain circumstances, and is still employed in veterinary medicine for conditions like megacolon in cats, its dramatic rise and fall permanently altered the landscape of pediatric gastroenterology. It serves as a powerful reminder that in medicine, even the most promising therapies must be evaluated with rigorous science and vigilant attention to potential harms—especially when treating our most vulnerable patients.