- Email: [email protected]
Domperidone-Induced QT Prolongation: Add Another Drug to the List
normalize these findings, suggesting that these changes are caused by, rather than a cause of, constipation. The protein calprotectin, found in neutrophils and monocytes, may be the more specific protein, if a true noninvasive biomarker is to be used in evaluating patients with persistent gastrointestinal complaints. In pediatric patients with undiagnosed gastrointestinal symptoms, elevated fecal calprotectin is an accurate maker of colorectal inflammation and thereby helpful in selecting patients who require colonoscopy to exclude inflammatory bowel disease. A previous study was conducted to determine whether ⬎50 g of fecal calprotectin per gram was predictive of colorectal inflammation and did not have bacterial gastroenteritis, celiac disease, or any other chronic inflammatory disease.10 Study results showed that children with colonoscopyproven colorectal inflammation have significantly higher levels of fecal calprotectin than did those without colorectal inflammation (median, 349 g/g vs 16.5 g/g; P ⬍ .001). Moreover, with an upper reference limit of 50 g/g, calprotectin testing had a sensitivity of 95%, specificity of 93%, positive predictive value of 95%, and negative predictive value of 93%. A separate study yielded somewhat less encouraging results, finding that fecal calprotectin can help distinguish organic causes of chronic diarrhea from IBS more effectively in children than in adults.11 Using a cutoff value of 50 g of calprotectin per gram of stool, in adults the test had a sensitivity of 64% and a specificity of 80% in detecting organic causes of gastrointestinal symptoms. Among the adult patients with levels ⬎50 g/g, the assay had 70% positive and 74% negative predictive values for identifying organic causes of diarrhea. Among children, the test was more accurate in ruling out organic causes, with a sensitivity of 70%, specificity of 93%, and positive predictive value of 56%. Despite these significant limitations and the missed opportunity to discuss the differences between the subsets of patients with IBS and FAP, Shulman et al3 should be congratulated. Their unique and original study with noninvasive techniques increases our understanding on subclinical inflammatory disease that exists in functional gastrointestinal disorders. The work here is increasingly important if we are to
augment our understanding of the pathophysiology and design effective interventions for FAP and IBS, which affect up to 20% of school aged children. Until recently, FAP, IBS, and other functional gastrointestinal disorders were believed to be “psychosocial disorders with physical symptoms.” This study serves as further evidence that these disorders are in reality “physical disorders” with organic disease and with associated local inflammation that may yet be completely understood. So perhaps when there is smoke, there may be fire. Nader N. Youssef, MD Maria E. Perez, DO Center for Pediatric Irritable Bowel & Motility Disorders Division of Pediatric Gastroenterology Goryeb Children’s Hospital at Atlantic Health Morristown, New Jersey
REFERENCES 1. Gershon MD, Tack J. The serotonin signaling system from basic understanding to drug development for functional GI disorders. Gastroenterology 2007;69:455-63. 2. Gwee KA, Collins SM, Read SW. Increased rectal mucosal expression of interleukin 1 beta in recently acquired post infectious irritable bowel syndrome. Gut 2003;52:523-6. 3. Shulman RJ, Eakin MN, Czyzewski DI, Jarrett M, Ou CN. Increased gastrointestinal permeability and gut inflammation in children with functional abdominal pain and irritable bowel syndrome. J Pediatr 2008;153:646-50. 4. Drossman D, Corazziari E, Thompson WG, Talley NJ, Whitehead WE, editors. Clinical Diagnostic Questionnaire for Pediatric Functional Gastrointestinal Disorders. Rome II The Functional Gastrointestinal Disorders 2000. p. 715-22. 5. Tibble J, Teahon K, Thjodleifsson B, Roseth A, Sigthorsson G, Bridger S, et al. A simple method for assessing intestinal inflammation in Crohn’s disease. Gut 2000;47:506-13. 6. Meling TR, Aabakken L, Roseth A, Osnes M. Fecal calprotectin shedding after short term treatment with non-steroidal anti-inflammatory drugs. Scand J Gastroenterol 1996;31:339-44. 7. Tibble JA, Sigthorsson G, Foster R, Scott D, Fagerhol MK, Roseth A, et al. High prevalence of NSAID enteropathy as shown by a simple fecal test. Gut 1999;45:362-6. 8. Somasundaram S, Hayllar H, Rafi S, Wrigglesworth JM, MacPherson AJS, Bjarnason I. The biochemical basis of non-steroidal anti-inflammatory drug-induced damage to the gastrointestinal tract: a review and a hypothesis. Scand J Gastroenterol 1995;30:289-99. 9. Khalif IL, Quigley EMM, Konovitch EA, Maximova ID. Alterations in the colonic flora and intestinal permeability and evidence of immune activation in chronic constipation. Digestive and Liver Disease 2005;35:839-48. 10. Fegerberg UL, Loof L, Lindholm J, Hansson LO, Finkel Y. Fecal calprotectin: a quantitative marker of colonic inflammation in children with inflammatory bowel disease. J Pedaitr Gastroenterol 2005;40:450-5. 11. Carroccio A, Iacono G, Cottone M, DiParma L, Cartabellotta F, Cavataio F, et al. Diagnostic accuracy of fecal calprotectin assay in distinguishing organic causes of chronic diarrhea from irritable bowel syndrome: a prospective study in adults and children. Clinical Chemistry 2003;49:861-7.
Domperidone-Induced QT Prolongation: Add Another Drug to the List
rug-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,
D 596
Editorials
which is encoded by KCNH2.1-3 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.1-3
See related articles, p 659 and p 663 Reprint requests: Kathryn K. Collins, MD, The Children’s Hospital, Department of Cardiology/B100, 13123 E 16th Ave, Aurora, CO 80045. E-mail: Collins.kathryn@ tchden.org. J Pediatr 2008;153:596-8 0022-3476/$ - see front matter Copyright © 2008 Mosby Inc. All rights reserved. 10.1016/j.jpeds.2008.06.009
The Journal of Pediatrics • November 2008
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.
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 Editorials
may be significantly higher in small groups of patients with a genetic predisposition.
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
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.14-16 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. 597
Kathryn K. Collins, MD University of Colorado Denver, The Children’s Hospital Denver, Colorado
Judith M. Sondheimer, MD Professor Emeritus, University of Colorado Denver, Colorado
REFERENCES 1. Kannankeril PJ. Understanding drug-induced torsades de pointes: a genetic stance. Expert Opin Drug Saf 2008;7:231-9. 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;153:891-9. 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;82:282-90. 4. Djeddi D, Kongolo G, Lefaix C, Moundard J, Leke A. Effect of domperidone on QT interval in neonates. J Pediatr 2008;153:663-6. 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;102:1883-5. 6. Rocha CM, Barbosa MM. QT interval prolongation associated with the oral use of domperidone in an infant. Pediatr Cardiol 2005;26:720-3. 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;96:1698-703. 8. Hill SL, Evangelista JK, Pizzi AM, Mobassaleh M, Fulton DR, Berul CI. Proarrhythmia associated with cisapride in children. Pediatrics 1998;101:1053-6.
598
Editorials
9. Khongphatthanayothin A, Lane J, Thomas D, Yen L, Chang D, Bubolz B. Effects of cisapride on QT interval in children. J Pediatr 1998;133:51-6. 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;70:545-6. 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):1336-7. 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;117:2407-23. 13. Chan A, Isbister GK, Kirkpatrick CM, Dufful SB. Drug-induced QT prolongation and torsades de pointes: evaluation of a QT nomogram. QJM 2007;100:609-15. 14. Augood C, MacLennan S, Gilbert R, Logan S. Cisapride treatment for gastrooesophageal 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;59:725-9. 18. Shafrir Y, Levy Y, Ben-Amitai D, Nitzan M, Steinherz R. Oculogyric crisis due to domperidone therapy. Helv Paediatr Acta 1985;40:95.
The Journal of Pediatrics • November 2008
augment our understanding of the pathophysiology and design effective interventions for FAP and IBS, which affect up to 20% of school aged children. Until recently, FAP, IBS, and other functional gastrointestinal disorders were believed to be “psychosocial disorders with physical symptoms.” This study serves as further evidence that these disorders are in reality “physical disorders” with organic disease and with associated local inflammation that may yet be completely understood. So perhaps when there is smoke, there may be fire. Nader N. Youssef, MD Maria E. Perez, DO Center for Pediatric Irritable Bowel & Motility Disorders Division of Pediatric Gastroenterology Goryeb Children’s Hospital at Atlantic Health Morristown, New Jersey
REFERENCES 1. Gershon MD, Tack J. The serotonin signaling system from basic understanding to drug development for functional GI disorders. Gastroenterology 2007;69:455-63. 2. Gwee KA, Collins SM, Read SW. Increased rectal mucosal expression of interleukin 1 beta in recently acquired post infectious irritable bowel syndrome. Gut 2003;52:523-6. 3. Shulman RJ, Eakin MN, Czyzewski DI, Jarrett M, Ou CN. Increased gastrointestinal permeability and gut inflammation in children with functional abdominal pain and irritable bowel syndrome. J Pediatr 2008;153:646-50. 4. Drossman D, Corazziari E, Thompson WG, Talley NJ, Whitehead WE, editors. Clinical Diagnostic Questionnaire for Pediatric Functional Gastrointestinal Disorders. Rome II The Functional Gastrointestinal Disorders 2000. p. 715-22. 5. Tibble J, Teahon K, Thjodleifsson B, Roseth A, Sigthorsson G, Bridger S, et al. A simple method for assessing intestinal inflammation in Crohn’s disease. Gut 2000;47:506-13. 6. Meling TR, Aabakken L, Roseth A, Osnes M. Fecal calprotectin shedding after short term treatment with non-steroidal anti-inflammatory drugs. Scand J Gastroenterol 1996;31:339-44. 7. Tibble JA, Sigthorsson G, Foster R, Scott D, Fagerhol MK, Roseth A, et al. High prevalence of NSAID enteropathy as shown by a simple fecal test. Gut 1999;45:362-6. 8. Somasundaram S, Hayllar H, Rafi S, Wrigglesworth JM, MacPherson AJS, Bjarnason I. The biochemical basis of non-steroidal anti-inflammatory drug-induced damage to the gastrointestinal tract: a review and a hypothesis. Scand J Gastroenterol 1995;30:289-99. 9. Khalif IL, Quigley EMM, Konovitch EA, Maximova ID. Alterations in the colonic flora and intestinal permeability and evidence of immune activation in chronic constipation. Digestive and Liver Disease 2005;35:839-48. 10. Fegerberg UL, Loof L, Lindholm J, Hansson LO, Finkel Y. Fecal calprotectin: a quantitative marker of colonic inflammation in children with inflammatory bowel disease. J Pedaitr Gastroenterol 2005;40:450-5. 11. Carroccio A, Iacono G, Cottone M, DiParma L, Cartabellotta F, Cavataio F, et al. Diagnostic accuracy of fecal calprotectin assay in distinguishing organic causes of chronic diarrhea from irritable bowel syndrome: a prospective study in adults and children. Clinical Chemistry 2003;49:861-7.
Domperidone-Induced QT Prolongation: Add Another Drug to the List
rug-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,
D 596
Editorials
which is encoded by KCNH2.1-3 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.1-3
See related articles, p 659 and p 663 Reprint requests: Kathryn K. Collins, MD, The Children’s Hospital, Department of Cardiology/B100, 13123 E 16th Ave, Aurora, CO 80045. E-mail: Collins.kathryn@ tchden.org. J Pediatr 2008;153:596-8 0022-3476/$ - see front matter Copyright © 2008 Mosby Inc. All rights reserved. 10.1016/j.jpeds.2008.06.009
The Journal of Pediatrics • November 2008
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.
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 Editorials
may be significantly higher in small groups of patients with a genetic predisposition.
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
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.14-16 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. 597
Kathryn K. Collins, MD University of Colorado Denver, The Children’s Hospital Denver, Colorado
Judith M. Sondheimer, MD Professor Emeritus, University of Colorado Denver, Colorado
REFERENCES 1. Kannankeril PJ. Understanding drug-induced torsades de pointes: a genetic stance. Expert Opin Drug Saf 2008;7:231-9. 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;153:891-9. 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;82:282-90. 4. Djeddi D, Kongolo G, Lefaix C, Moundard J, Leke A. Effect of domperidone on QT interval in neonates. J Pediatr 2008;153:663-6. 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;102:1883-5. 6. Rocha CM, Barbosa MM. QT interval prolongation associated with the oral use of domperidone in an infant. Pediatr Cardiol 2005;26:720-3. 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;96:1698-703. 8. Hill SL, Evangelista JK, Pizzi AM, Mobassaleh M, Fulton DR, Berul CI. Proarrhythmia associated with cisapride in children. Pediatrics 1998;101:1053-6.
598
Editorials
9. Khongphatthanayothin A, Lane J, Thomas D, Yen L, Chang D, Bubolz B. Effects of cisapride on QT interval in children. J Pediatr 1998;133:51-6. 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;70:545-6. 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):1336-7. 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;117:2407-23. 13. Chan A, Isbister GK, Kirkpatrick CM, Dufful SB. Drug-induced QT prolongation and torsades de pointes: evaluation of a QT nomogram. QJM 2007;100:609-15. 14. Augood C, MacLennan S, Gilbert R, Logan S. Cisapride treatment for gastrooesophageal 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;59:725-9. 18. Shafrir Y, Levy Y, Ben-Amitai D, Nitzan M, Steinherz R. Oculogyric crisis due to domperidone therapy. Helv Paediatr Acta 1985;40:95.
The Journal of Pediatrics • November 2008