The Journal of Pediatrics
Volume 153, Issue 5 , Pages 596-598, November 2008

Domperidone-Induced QT Prolongation: Add Another Drug to the List

  • Kathryn K. Collins, MD

      Affiliations

    • University of Colorado Denver, The Children's Hospital, Denver, Colorado
    • Corresponding Author InformationReprint requests: Kathryn K. Collins, MD, The Children's Hospital, Department of Cardiology/B100, 13123 E 16th Ave, Aurora, CO 80045
    • ,
  • Judith M. Sondheimer, MD

      Affiliations

    • Professor Emeritus, University of Colorado, Denver, Colorado

Article Outline

 

Drug-induced long QT syndrome is defined as “an excessive prolongation of the QT interval upon exposure to a drug, with reversion back to normal following removal of the drug.”1 QT prolongation places the patient at risk for torsades de pointes, a potentially fatal arrhythmia. The list of drugs with the potential to cause QT prolongation is long, and the number of patients exposed to these drugs is huge (http://www.torsades.org). The primary mechanism by which medications prolong the QT interval is through blockage of IKr, the rapid component of the delayed rectifier potassium current, which is encoded by KCNH2.1, 2, 3 Other mechanisms also have been described.1 In addition, familial or genetic components may contribute to the risk for drug-induced QT prolongation and torsades de pointes.1, 2, 3

See related articles, p 659 and p 663

In this issue of The Journal, Djeddi et al4 add another agent to the list of drugs that can cause QT prolongation. Although none of the patients in their study developed torsades de pointes, the degree of QT prolongation caused by domperidone, combined with previous reports of domperidone-induced QT changes,5, 6 make this medication suspect as a potential cause of adverse arrhythmic side effects.

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Lessons from Cisapride 

Cisapride is a prokinetic agent that was widely used in the 1980s and early 1990s for gastrointestinal disorders, especially gastroesophageal reflux. Although cisapride was initially considered safe, the marketing of this drug was stopped in 20002 after publication of multiple reports of QT prolongation, ventricular arrhythmia, and cardiac arrest in adults and children related to cisapride.7 In studies of children, cisapride was associated with a QTc prolongation of 10 to 15 msec, and 12% to 30% of reported cases involved a QTc exceeding the normal value of 440 msec.8, 9

Domperidone is a prokinetic agent that is chemically distinct from cisapride. As cisapride was being withdrawn from the market due to its malignant side effect profile, domperidone was becoming the preferred prokinetic agent in Europe. The drug was never approved for use by the US Food and Drug Administration, however. Domperidone's effect on cardiac repolarization involves the same mechanism as for cisapride and other medications known to prolong the QT interval—blockage of IKr.5 The few reported cardiac side effects of domperidone include arrhythmias during rapid intravenous infusion,10, 11 a single case report of oral domperidone causing QT prolongation,6 and a report of repolarization abnormalities in isolated guinea pig hearts.5 In the current study, Djeddi et al4 report QT prolongation in 31 infants taking oral domperidone. The mean QTc prolongation was 14 msec, similar to that seen for cisapride. Only 1 infant developed a QTc of longer than 450 msec, which returned to normal on discontinuation of the drug. None of the patients studied had a malignant arrhythmia.

The question is how much QTc prolongation is too much? In other words, what change in QTc or what absolute QTc puts a patient at risk for malignant arrhythmia? Unfortunately, drug-induced prolongation of QT appears to be an unpredictable phenomenon. Identifiable risk factors for drug-induced long QT syndrome include female sex, hypokalemia, bradycardia, concomitant administration of 2 drugs that prolong repolarization, and variants in different classes of genes that support a genetic predisposition.1 The risk of proarrhythmia may be determined not by the degree of QT prolongation, but rather by multiple genetic and environmental factors that combine to create the at-risk substrate.1 The risk of excessively prolonged QT and potential torsades de pointes is low when large populations are studied; however, the risk of fatal arrhythmia may be significantly higher in small groups of patients with a genetic predisposition.

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Screening Patients for QT Prolongation 

The screening of patients for drug-induced QT prolongation is a complex issue. Recent published guidelines have been interpreted by some as recommending electrocardiographic screening of all patients taking psychiatric medications that could potentially cause QT prolongation.12 These guidelines were met with a call for reevaluation based on the lack of scientific evidence supporting general screening of patients with no predisposing factors. A subsequent clarification of the guidelines has since been issued (http://www.aap.org/pressroom/aap-ahastatement.htm).

Based on their findings in a small group of patients, Djeddi et al4 recommend that “measurement of the QT interval be done before and after oral domperidone therapy.” Unfortunately, they fail to specify a recommended course of action after the screening electrocardiogram. Should domperidone be discontinued if the QTc is prolonged by more than14 msec even if the final QTc remains below the normal upper limit of 440 msec? Should the drug be stopped only if the QTc on therapy is longer than 440 msec, or should other factors also be taken into account in this calculation?13 It is worth repeating that the mean values and the 95% confidence intervals for QTc interval in the patients in Djeddi's study all fell below the normal value of 440 msec.4

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Is the Risk Worth the Benefit? 

The use of prokinetic agents to treat gastroesophageal reflux, whether physiological infant reflux or true gastrointestinal reflux disease, has decreased significantly in North America and in most European centers over the last 8 years. Side effects notwithstanding, physicians treating these disorders have recognized that prokinetic medications are not very effective in controlling symptoms, despite the fact that they improve the test results for reflux disease, such as esophageal pH, esophageal sphincter pressure, and gastric emptying time.14, 15, 16 There are legitimate indications for using domperidone in some disorders of gastrointestinal motility. With respect to gastroesophageal reflux disease, however, domperidone's lack of clinical efficacy appears to be similar to that of other prokinetics. Pritchard et al17 performed a meta-analysis of studies of domperidone used to treat gastroesophageal reflux disease in children. He found only 4 valid randomized controlled trials, none of which provided any robust evidence of domperidone's efficacy.

Djeddi et al4 have identified a potentially severe cardiac risk associated with domperidone therapy in infants. Other reported side effects include extrapyramidal symptoms,6, 17 oculogyric crisis,18 and hyperprolactinaemia.6 Although the cardiac risk is not yet predictable, the absence of compelling evidence of domperidone's efficacy in treating gastroesophageal reflux suggests that clinicians should err on the side of caution when prescribing domperidone for gastroesophageal reflux in children, especially healthy children with physiological gastroesophageal reflux.

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References 

  1. Kannankeril PJ. Understanding drug-induced torsades de pointes: a genetic stance. Expert Opin Drug Saf. 2008;7:231–239
  2. Gupta A, Lawrence AT, Krishnan K, Kavinsky CJ, Trohman RG. Current concepts in the mechanisms and management of drug-induced QT prolongation and torsade de pointes. Am Heart J. 2007;153:891–899
  3. Zeltser D, Justo D, Halkin A, Prokhorov V, Heller K, Viskin S. Torsade de pointes due to noncardiac drugs: most patients have easily identifiable risk factors. Medicine (Baltimore). 2003;82:282–290
  4. Djeddi D, Kongolo G, Lefaix C, Moundard J, Leke A. Effect of domperidone on QT interval in neonates. J Pediatr. 2008;153:663–666
  5. Drolet B, Rousseau G, Daleau P, Cardinal R, Turgeon J. Domperidone should not be considered a no-risk alternative to cisapride in the treatment of gastrointestinal motility disorders. Circulation. 2000;102:1883–1885
  6. Rocha CM, Barbosa MM. QT interval prolongation associated with the oral use of domperidone in an infant. Pediatr Cardiol. 2005;26:720–723
  7. Wysowski DK, Corken A, Gallo-Torres H, Talarico L, Rodriguez EM. Postmarketing reports of QT prolongation and ventricular arrhythmia in association with cisapride and Food and Drug Administration regulatory actions. Am J Gastroenterol. 2001;96:1698–1703
  8. Hill SL, Evangelista JK, Pizzi AM, Mobassaleh M, Fulton DR, Berul CI. Proarrhythmia associated with cisapride in children. Pediatrics. 1998;101:1053–1056
  9. Khongphatthanayothin 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
  10. Bruera E, Villamayor R, Roca E, Barugel M, Tronge J, Chacon R. Q-T interval prolongation and ventricular fibrillation with IV domperidone. Cancer Treat Rep. 1986;70:545–546
  11. Giaccone G, Bertetto O, Calciati A. Two sudden deaths during prophylactic antiemetic treatment with high doses of domperidone and methylprednisolone. Lancet. 1984;2(8415):1336–1337
  12. Vetter VL, Elia J, Erickson C, Berger S, Blum N, Uzark K, et al. Cardiovascular monitoring of children and adolescents with heart disease receiving stimulant drugs: a scientific statement from the American Heart Association Council on Cardiovascular Disease in the Young Congenital Cardiac Defects Committee and the Council on Cardiovascular Nursing. Circulation. 2008;117:2407–2423
  13. Chan A, Isbister GK, Kirkpatrick CM, Dufful SB. Drug-induced QT prolongation and torsades de pointes: evaluation of a QT nomogram. QJM. 2007;100:609–615
  14. Augood C, MacLennan S, Gilbert R, Logan S. Cisapride treatment for gastro-oesophageal reflux in children. Cochrane Database Syst Rev. 2003;(4):CD002300
  15. Craig WR, Hanlon-Dearman A, Sinclair C, Taback S, Moffatt M. Metoclopramide, thickened feedings, and positioning for gastro-oesophageal reflux in children under two years. Cochrane Database Syst Rev. 2004;(4):CD003502
  16. Dalby-Payne JR, Morris AM, Craig JC. Meta-analysis of randomized controlled trials on the benefits and risks of using cisapride for the treatment of gastroesophageal reflux in children. J Gastroenterol Hepatol. 2003;18:196–202
  17. Pritchard DS, Baber N, Stephenson T. Should domperidone be used for the treatment of gastro-oesophageal reflux in children? (Systematic review of randomized controlled trials in children aged 1 month to 11 years old). Br J Clin Pharmacol. 2005;59:725–729
  18. Shafrir Y, Levy Y, Ben-Amitai D, Nitzan M, Steinherz R. Oculogyric crisis due to domperidone therapy. Helv Paediatr Acta. 1985;40:95

PII: S0022-3476(08)00504-0

doi:10.1016/j.jpeds.2008.06.009

Refers to article:

  • Antiemetic Medications in Children with Presumed Infectious Gastroenteritis—Pharmacoepidemiology in Europe and Northern America , 02 October 2008

    Nicole Pfeil, Ulrike Uhlig, Karel Kostev, Rita Carius, Helmut Schröder, Wieland Kiess, Holm H. Uhlig
    The Journal of Pediatrics November 2008 (Vol. 153, Issue 5, Pages 659-662.e3)

  • Effect of Domperidone on QT Interval in Neonates , 01 July 2008

    Djamal Djeddi, Guy Kongolo, Charlotte Lefaix, Julie Mounard, André Léké
    The Journal of Pediatrics November 2008 (Vol. 153, Issue 5, Pages 663-666)

The Journal of Pediatrics
Volume 153, Issue 5 , Pages 596-598, November 2008

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