- Email: [email protected]
Effect of Domperidone on QT Interval in Neonates
Effect of Domperidone on QT Interval in Neonates DJAMAL DJEDDI, MD, GUY KONGOLO, MD, PHD, CHARLOTTE LEFAIX, MD, JULIE MOUNARD, MD,
AND
ANDRÉ LÉKÉ, MD, PHD
Objectives
To determine whether oral domperidone is associated with QT interval prolongation and ventricular arrhythmia and to identify factors that can influence these effects. Study design An electrocardiogram was performed before and after oral administration of domperidone in 31 neonates or infants classified into 3 groups according to gestational age. Results Oral domperidone is associated with QTc prolongation except in infants with a gestational age less than 32 weeks of amenorrhea (P < .005). Mean QTc prolongation was 14 msec. On univariate analysis, oral domperidone-induced QTc prolongation was correlated with gestational age, birth weight, and elevated serum potassium. On multivariate analysis, after adjustment for gestational age, serum potassium was the only factor independently associated with interval QT prolongation during treatment. No ventricular arrhythmias were observed. Conclusions This study shows a significant association between oral domperidone therapy and QTc prolongation. Two risk factors were identified: advanced gestational age and serum potassium at the upper limit of normal. It is recommended that measurement of the QT interval be done before and after oral domperidone therapy. (J Pediatr 2008;153:663-6)
omperidone is a prokinetic widely prescribed in adults and children with gastrointestinal disorders, especially gastroesophageal reflux. Domperidone has been increasingly used because cisapride has been shown to induce QT prolongation and ventricular arrhythmias.1-4 The QT interval corresponds to the time required for ventricular repolarization.5 The QT interval depends on heart rate and must therefore be corrected by measuring the R-R interval (QTc). Long QT can have serious repercussions: ventricular tachycardia, torsades de pointe, and fatal ventricular fibrillation.6 The objectives of our study were (1) to determine whether oral domperidone is associated with QTc prolongation; (2) to determine whether this prolongation exceeds physiologic limits or can even induce ventricular arrhythmias (torsades de pointe); and (3) to identify factors that may influence the effect of oral domperidone on the QTc interval.
D
METHODS This study was conducted in neonates and infants, regardless of their gestational age (GA), admitted to a neonatology unit of Amiens University Hospital (France) between May 2005 and May 2006. All infants requiring oral domperidone regardless of the indication were included. To comply with precautions similar to those recommended by the French Agency for the Safety of Health Products for cisapride, a prolonged ECG was performed in these infants before and after starting treatment. Routine laboratory measures (serum potassium, serum calcium, serum phosphorus, serum magnesium, and serum proteins) were recorded. See editorial, p 596 and Exclusion criteria were patients with congenital long QT, arrhythmias or conducrelated article, p 659 tion disorders; treatments able to prolong the QT interval or inhibit cytochrome P4503A4; preexisting metabolic disorders able to prolong the QT interval (hypokalemia ⬍3.5 From the Department of Pediatrics, School mmol/L), hypocalcemia (⬍2.2 mmol/L), and serum creatinine (⬎1 mg/dL). The infants’ Hospital of Amiens, Amiens, France. feeding habits were not modified and all infants received feeds quantitatively and qualiThe authors declare no conflict of interest. tatively adapted to their age. Submitted for publication Sep 21, 2007; last Three groups of infants were defined according to GA to take into account revision received Apr 2, 2008; accepted May 7, 2008. variations in the distribution of fluid compartments, hepatic maturation of cytochrome Reprint requests: Dr. Djamal Djeddi, CHU P450, renal maturation and glomerular filtration; group A: GA ⱖ37 weeks of amenorrhea Nord, Department of Pediatrics, Place Vic(WA); group B: 32 ⱕ GA ⬍37 WA; group C: GA ⬍32 WA. All ECGs were performed tor Pauchet, 80000 Amiens, France. E-mail: [email protected]. with the same apparatus (M11771A, Agilent Technologies; Palo Alto, California). ⌬QTc GA
Variation of the QTc interval Gestational age
WA
Weeks of amenorrhea
0022-3476/$ - see front matter Copyright © 2008 Mosby Inc. All rights reserved. 10.1016/j.jpeds.2008.05.013
663
Table. Demographic data n ⴝ 31
Mean ⴞ SD
Median (Min-Max)
Group A n ⴝ 13
Group B nⴝ7
Group C n ⴝ 11
Age, d GA, wk BW (g) BL (cm) BHC (cm) Current weight (g)
17.6 ⫾ 12.4 34.2 ⫾ 5.5 2150 ⫾ 1083 42.2 ⫾ 6.9 30.1 ⫾ 4.4 2264.5 ⫾ 1006.4
14 (2-42) 33 (25-42) 1830 (504-3930) 42 (27-52) 31 (20-36.5) 2285 (740-3800)
10.1 ⫾ 6.4 40.1 ⫾ 1.2 3221.5 ⫾ 493.1 48.9 ⫾ 2.5 34.1 ⫾ 1.5 3238 ⫾ 388
28.3 ⫾ 15.4 32.9 ⫾ 1.1 1694.9 ⫾ 853.2 39.1 ⫾ 5.7 28.00 ⫾ 4 2032 ⫾ 733
19.5 ⫾ 10.8 28.3 ⫾ 2 1174.5 ⫾ 329.5 36.41 ⫾ 3.8 26.73 ⫾ 3.2 1262 ⫾ 399
GA, Gestational age; BW, birth weight; BL, birth length; BHC, birth head circumference. Group A: GA ⱖ 37 WA, Group B: 32 ⱕ GA ⬍ 37 WA, Group C: GA ⬍ 32 WA.
The QT interval was measured according to the method of Surawicz7,8 on lead II of the ECG recording. Three different measurements were performed for each ECG recording by a single operator to avoid interobserver variability. The QT interval was corrected for heart rate by the formula of Bazett7 and the mean of the 3 QTc intervals was then determined. A QTc interval ⬎450 msec was considered to be pathologic in infants under the age of 6 months.7 When the QTc interval was ⬎450 msec on the second ECG, treatment with oral domperidone was stopped immediately. A third ECG was recorded 48 hours after stopping treatment to ensure return to normal of the QTc interval.
Statistics All variables are described as mean ⫾ SD or by the median (minimum-maximum) for variables with a non-normal distribution. Quantitative variables were compared between groups by analysis of variance. The limit of significance was set at P ⬍ .05. Statistical calculations were performed on Statistica software version 7.00 (StatSoft Inc; Tulsa, Oklahoma).
RESULTS The indication for domperidone therapy was gastroesophageal reflux in every case (Table). Domperidone was administered orally (1 mg/mL oral suspension) in 3 or 4 divided doses, 15 to 20 minutes before feeds. The mean daily dosage was 1.3 ⫾ 0.7 mg/kg/day. Two infants accidentally received doses higher than the therapeutic range (⬎2.4 mg/ kg/day), but neither of them developed QTc prolongation. The first ECG was systematically performed before starting domperidone therapy, usually several hours before the first dose. The second ECG was performed an average of 2.5 ⫾ 1.5 days after starting treatment (median, 2 days; minimum, 1 day, maximum: 10 days). Only 1 infant required more than 2 ECG examinations to ensure return to normal of the QTc interval which had become pathologic (450 msec) 48 hours after an oral dose of domperidone (⌬QTc, 45 msec). This treatment was stopped immediately. Successive ECGs confirmed reduction of the QTc interval (429 msec 72 hours after discontinuation of domperidone and 410 msec 1 week after stopping domperidone). This patient, who did not present any electrolyte disorder or any particular disease, did not develop any cardiac arrhythmia. 664
Djeddi et al
The QTc interval (msec) was prolonged during oral domperidone therapy (P ⬍ .01): pretreatment, 373.2 ⫾ 4.8; during treatment, 387.2 ⫾ 5.1. The mean variation of the QTc interval (⌬QTc) was 14 msec over a mean duration of 60 hours. The value of the QTc interval (msec) was significantly different between the GA groups (P ⬍ .05): group A: 364.8 ⫾ 6.8; group B: 398 ⫾ 9.3; and group C: 377.9 ⫾ 7.4 (Figure). ⌬QTc also varied according to GA group (P ⬍ .05): mean ⌬QTc (msec) during treatment was 19.1 ⫾ 23.7 in group A, 26 ⫾ 14.4 in group B and ⫺2.9 ⫾ 20.4 in group C (Figure). The QTc interval was prolonged by more than 12 msec in 48.4% of these patients. After elimination of aberrant values (values situated outside of the ⫾ 2 SD interval), univariate analysis showed that oral domperidone-induced QTc prolongation was correlated with GA, birth weight, and serum potassium. The effect of serum phosphorus was borderline significant (P ⫽ .05). The dosage of oral domperidone was found to be inversely correlated with ⌬QTc, which appeared to be somewhat paradoxical. More thorough analysis of the data identified 2 aberrant cases, in which the dosage used differed by more than 2 SD from the cloud of points of dosages used in this population. This inverse correlation between the dosage of oral domperidone and ⌬QTc was no longer observed after exclusion of these 2 cases. Serum calcium, serum magnesium or serum protein did not influence ⌬QTc. On multivariate analysis, after adjustment for GA, serum potassium was the only factor independently associated with ⌬QTc during domperidone therapy (regression coefficient, 1.73; P ⬍ .01). The “birth weight” variable was not entered into the multivariate model to avoid redundant data due to the strong correlation (correlation coefficient ⫽ 0.92 ⫾ 0.07, P ⬍ .001) between birth weight and GA.
DISCUSSION This study reports QTc prolongation induced by oral domperidone; there have been a few isolated cases.9 The ⌬QTc observed in this study was higher than the physiologic prolongation reported in the literature that is observed up until the 4th month of life and then declines. Schwartz et al reported a ⌬QTc of 12 msec between the 4th day of life and The Journal of Pediatrics • November 2008
Figure. Analysis of QTc interval during domperidone therapy according to the various GA groups.
the end of the 2nd month and Alimurung et al10 reported a value of 24 msec between the end of the 1st months and the end of the 4th month. Several cases of QTc prolongation and ventricular tachyarrhythmia related to intravenous domperidone have been reported in the literature and in the case of rapid injection.11-13 This QTc prolongation can be explained by the pharmacologic properties of domperidone. Domperidone (like cisapride) at usual dosages induces reversible prolongation of ventricular repolarization due to Ikr potassium channel blockade (similar to that induced by class III antiarrhythmics).14 In vitro data suggest that concomitant administration of drugs that inhibit cytochrome P450-3A4 can induce elevation of plasma domperidone concentrations. One study showed that almost all patients with druginduced torsades de pointe presented one or more concomitant risk factors (hypokalemia, female sex, drug interaction, etc).15 Not all drugs responsible for torsades de pointe are powerful Ikr blocking agents, and Ikr blockade is not systematically associated with torsades de pointe.16 The small sample size of our cohort could account for the absence of torsades de pointe, which is a serious but rare adverse event. Various studies suggest that a ⌬QTc ⬍30 msec does not have any clinical consequences, but that a prolongation ⬎60 msec induces a potential risk of torsades de pointe.17 Nine of our patients (29%) had a ⌬QTc ⬎30 msec, but none of our patients had a ⌬QTc ⬎60 msec, which could explain the absence of any cases of cardiac arrhythmia. Plasma concentrations increase as a function of the dose of oral domperidone. At equivalent doses, the oral and rectal forms of domperidone have the same bioavailability.18 The capacity of this molecule to prolong the QTc interval therefore concerns the intravenous and oral routes, as well as the rectal route. A study has shown the absence of accumulation of oral domperidone: the plasma peak at 90 minutes after 2 weeks of oral administration of 30 mg/day was the same as that after Effect of Domperidone on QT Interval in Neonates
the first dose (21 ng/mL versus 18 ng/mL).19 Consequently, in the context of surveillance of patients treated by oral domperidone, a late ECG (several weeks after starting treatment) would not be any more informative and an ECG performed during the first 48 hours of treatment appears to be sufficient. Elevated serum potassium, even in the range of physiologic values, was significantly and independently associated with significant QTc prolongation. The early effect of moderate hyperkalemia is to increase myocyte excitability by raising the resting membrane potential. Hyperkalemia has a profound effect on phases 2 and 3 of the action potential. A significant reduction of the QTc interval has been reported in a context of hyperkalemia in patients with congenital long QT but not in healthy control subjects.20 In the present study, GA was significantly associated with QT interval prolongation during domperidone therapy. QTc and ⌬QTc values during oral domperidone therapy differed between the various GA groups: oral domperidone had a significant impact on the QTc interval in groups A and B but not in group C (⬍32 WA). However, studies on cisapride in premature infants suggest that the effect of cisapride on cardiac conduction and QTc is correlated with the degree of prematurity.21,22 Since 2002, cisapride is no longer recommended in premature infants. In severely premature infants (⬍32 WA), first-line prescription of oral domperidone can be considered to replace cisapride for the treatment of gastroesophageal reflux.
REFERENCES 1. Tahiri C. Prépulsid et allongement de l’espace QT. J Pédiatr Puériculture 1998;11:422-8. 2. Lupoglazoff JM, Bedu A, Faure C, Denjoy I, Casasoprana A, Cézard JP, et al. Allongement de l’espace QT sous cisapride chez le nouveau-né et le nourrisson. Arch Pédiatr 1997;4:509-14. 3. Hanson R, Browne G, Fasher B, Mcaskill M, Moroney P, Hawker R. Cisaprideinduced prolonged QT interval: too much of a good thing! J Pediatr 1997;130:164-6. 4. Wysowski D, Bacsanyi J. Cisapride and fatal arrhythmia. N Engl J Med 1996;335:4. 5. Abildskov JA. The prolonged QT interval. Ann Rev Med 1979;30:171-9. 6. Alimurung M, Joseph L, Graige E, Massell BF. The Q-T interval in normal infants and children. Circulation 1950;1:1329-37. 7. Lepeschkin E, Surawicz B. The measurement of the QT interval of the Electrocardiogram. Circulation 1952;6:378-88. 8. Savelieva I, Yi G, Guo X, Hnatkova K, Malik M. Agreement and reproducibility of automatic versus manual measurement of QT interval and QT dispersion. Am J Cardiol 1998;81:471-7. 9. Rocha C, Barbosa M. QT interval prolongation associated with the oral use of Dompéridone in an infant. Pediatr Cardiol 2005;26:720-3. 10. Morganroth J. Relations of QTc prolongation on electrocardiogram to torsades de pointes: definitions and mechanisms. Am J Cardiol 1993;72:10B-13B. 11. Bruera E, Villamayor R, Roca E, Barugel M, Tronge J, Chacon R. QT interval prolongation and ventricular fibrillation with IV domperidone. Cancer Treat Rep 1986;70:545-6. 12. Quinn N, Parkes D, Jackson G, Upward J. Cardiotoxicity of domperidone. Lancet 1985;2:724. 13. Wang SH, Lin CY, Huang TY, Wu WS, Chen CC, Tsai SH. QT interval effects of cisapride in the clinical setting. Inter J Cardiol 2001;80:179-83. 14. 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.
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15. Zeltser D, Justo D, Halkin A, Prokhorov V, Heller K, Viskin S. Torsade de pointes due to noncardiac drugs. Medicine 2003;82:282-90. 16. Yang T, Snyders D, Roden D. Drug block of Ikr: model systems and relevance to human arrhythmias. J Cardiovasc Pharmacol 2001;38:737-44. 17. Committee for Proprietary Medicinal Products. The Assessment of the potential for QT interval prolongation by non-cardiovascular medicinal products 1997;986-96. 18. Heykants J, Hendriks R, Meuldermans W, Michiels M, Scheygrond H, Reyntjens H. On the pharmacokinetics of domperidone in animals and man, IV: the pharmacokinetics of intravenous domperidone and its bioavailability in man following intramuscular, oral and rectal administration. Eur J Drug Metab Pharmacokinet 1981;61:61-70.
19. Huizing G, Brouwers JR, Westhuis P. Plasma drug concentration and prolactin release after acute and subchronic oral administration of domperidone and metoclopramide: the serum concentration of drugs 1980:271-7. 20. Compton SJ, Lux RL, Ramsey MR, Strelich KR, Sanguinetti MC, Green LS, et al. Genetically defined therapy of inherited long-QT syndrome: correction of abnormal repolarization by potassium. Circulation 1996;94:1018-22. 21. Dubin A, Kikkert M, Mirmiran M, Ariagno R. Cisapride associated with QTc prolongation in very low birth weight preterm infants. Pediatrics 2001;107:1313-6. 22. Zamora SA, Belli DC, Friedli B, Jaeggi E. 24-hours electrocardiogram before and during cisapride treatment in neonates and infants. Biol Neonate 2004;85:229-36.
50 Years Ago in The Journal of Pediatrics ADENOVIRUS
PNEUMONIA
Blattner RJ. J Pediatr 1958;53:631-3
It is now known that the spectrum of disease manifestations of human adenovirus infection can be quite variable, depending on the serotype. Blattner described an outbreak of adenovirus pneumonia that occurred in France in 1955. At that time, only 18 serotypes of adenovirus were known. Today, more than 52 serotypes have been identified, and the disease spectrum extends from asymptomatic infection through pharyngoconjunctival fever, pneumonia, epidemic keratoconjunctivitis, acute hemorrhagic cystitis, gastroenteritis, meningoencephalitis, hepatitis, myocarditis, and lifethreatening disseminated disease. Severe or even fatal infections can occur in immunocompromised persons. Advances in molecular biology have enhanced our understanding of this virus. To allow easy and rapid identification, serotypes are classified into subgroups or species (A to G) according to genomic DNA sequence, tissue tropism, and other biological properties. Quantitative polymerase chain reaction technology has become the state-of-the-art approach to providing early diagnosis, tracking the course of infection, and monitoring response to treatment. For adenoviral disease in recipients of bone marrow transplantation, treatment with cidofovir (a selective viral DNA synthesis inhibitor) has decreased viremia and produced concomitant clinical improvement in case series. Oral adenovirus vaccine (Ad4 and Ad7), which is no longer manufactured, had been used in military populations for decades to prevent adenovirus infection. The vaccine was demonstrated to be safe, and with increasing incidence and severity of adenovirus infection, interest in an adenovirus vaccine has been rekindled. The past 50 years have seen the development of rapid molecular assays for early detection of adenovirus in clinical settings. These assays allow for further research aimed at discovering new antiviral agents and type-specific vaccines that hopefully will substantially decrease adenovirus-associated morbidity and mortality in vulnerable populations. Frankie Wai Tsoi Cheng, MD Albert Li, MD Department of Pediatrics The Chinese University of Hong Kong Hong Kong, China 10.1016/j.jpeds.2008.05.006
666
Djeddi et al
The Journal of Pediatrics • November 2008
AND
ANDRÉ LÉKÉ, MD, PHD
Objectives
To determine whether oral domperidone is associated with QT interval prolongation and ventricular arrhythmia and to identify factors that can influence these effects. Study design An electrocardiogram was performed before and after oral administration of domperidone in 31 neonates or infants classified into 3 groups according to gestational age. Results Oral domperidone is associated with QTc prolongation except in infants with a gestational age less than 32 weeks of amenorrhea (P < .005). Mean QTc prolongation was 14 msec. On univariate analysis, oral domperidone-induced QTc prolongation was correlated with gestational age, birth weight, and elevated serum potassium. On multivariate analysis, after adjustment for gestational age, serum potassium was the only factor independently associated with interval QT prolongation during treatment. No ventricular arrhythmias were observed. Conclusions This study shows a significant association between oral domperidone therapy and QTc prolongation. Two risk factors were identified: advanced gestational age and serum potassium at the upper limit of normal. It is recommended that measurement of the QT interval be done before and after oral domperidone therapy. (J Pediatr 2008;153:663-6)
omperidone is a prokinetic widely prescribed in adults and children with gastrointestinal disorders, especially gastroesophageal reflux. Domperidone has been increasingly used because cisapride has been shown to induce QT prolongation and ventricular arrhythmias.1-4 The QT interval corresponds to the time required for ventricular repolarization.5 The QT interval depends on heart rate and must therefore be corrected by measuring the R-R interval (QTc). Long QT can have serious repercussions: ventricular tachycardia, torsades de pointe, and fatal ventricular fibrillation.6 The objectives of our study were (1) to determine whether oral domperidone is associated with QTc prolongation; (2) to determine whether this prolongation exceeds physiologic limits or can even induce ventricular arrhythmias (torsades de pointe); and (3) to identify factors that may influence the effect of oral domperidone on the QTc interval.
D
METHODS This study was conducted in neonates and infants, regardless of their gestational age (GA), admitted to a neonatology unit of Amiens University Hospital (France) between May 2005 and May 2006. All infants requiring oral domperidone regardless of the indication were included. To comply with precautions similar to those recommended by the French Agency for the Safety of Health Products for cisapride, a prolonged ECG was performed in these infants before and after starting treatment. Routine laboratory measures (serum potassium, serum calcium, serum phosphorus, serum magnesium, and serum proteins) were recorded. See editorial, p 596 and Exclusion criteria were patients with congenital long QT, arrhythmias or conducrelated article, p 659 tion disorders; treatments able to prolong the QT interval or inhibit cytochrome P4503A4; preexisting metabolic disorders able to prolong the QT interval (hypokalemia ⬍3.5 From the Department of Pediatrics, School mmol/L), hypocalcemia (⬍2.2 mmol/L), and serum creatinine (⬎1 mg/dL). The infants’ Hospital of Amiens, Amiens, France. feeding habits were not modified and all infants received feeds quantitatively and qualiThe authors declare no conflict of interest. tatively adapted to their age. Submitted for publication Sep 21, 2007; last Three groups of infants were defined according to GA to take into account revision received Apr 2, 2008; accepted May 7, 2008. variations in the distribution of fluid compartments, hepatic maturation of cytochrome Reprint requests: Dr. Djamal Djeddi, CHU P450, renal maturation and glomerular filtration; group A: GA ⱖ37 weeks of amenorrhea Nord, Department of Pediatrics, Place Vic(WA); group B: 32 ⱕ GA ⬍37 WA; group C: GA ⬍32 WA. All ECGs were performed tor Pauchet, 80000 Amiens, France. E-mail: [email protected]. with the same apparatus (M11771A, Agilent Technologies; Palo Alto, California). ⌬QTc GA
Variation of the QTc interval Gestational age
WA
Weeks of amenorrhea
0022-3476/$ - see front matter Copyright © 2008 Mosby Inc. All rights reserved. 10.1016/j.jpeds.2008.05.013
663
Table. Demographic data n ⴝ 31
Mean ⴞ SD
Median (Min-Max)
Group A n ⴝ 13
Group B nⴝ7
Group C n ⴝ 11
Age, d GA, wk BW (g) BL (cm) BHC (cm) Current weight (g)
17.6 ⫾ 12.4 34.2 ⫾ 5.5 2150 ⫾ 1083 42.2 ⫾ 6.9 30.1 ⫾ 4.4 2264.5 ⫾ 1006.4
14 (2-42) 33 (25-42) 1830 (504-3930) 42 (27-52) 31 (20-36.5) 2285 (740-3800)
10.1 ⫾ 6.4 40.1 ⫾ 1.2 3221.5 ⫾ 493.1 48.9 ⫾ 2.5 34.1 ⫾ 1.5 3238 ⫾ 388
28.3 ⫾ 15.4 32.9 ⫾ 1.1 1694.9 ⫾ 853.2 39.1 ⫾ 5.7 28.00 ⫾ 4 2032 ⫾ 733
19.5 ⫾ 10.8 28.3 ⫾ 2 1174.5 ⫾ 329.5 36.41 ⫾ 3.8 26.73 ⫾ 3.2 1262 ⫾ 399
GA, Gestational age; BW, birth weight; BL, birth length; BHC, birth head circumference. Group A: GA ⱖ 37 WA, Group B: 32 ⱕ GA ⬍ 37 WA, Group C: GA ⬍ 32 WA.
The QT interval was measured according to the method of Surawicz7,8 on lead II of the ECG recording. Three different measurements were performed for each ECG recording by a single operator to avoid interobserver variability. The QT interval was corrected for heart rate by the formula of Bazett7 and the mean of the 3 QTc intervals was then determined. A QTc interval ⬎450 msec was considered to be pathologic in infants under the age of 6 months.7 When the QTc interval was ⬎450 msec on the second ECG, treatment with oral domperidone was stopped immediately. A third ECG was recorded 48 hours after stopping treatment to ensure return to normal of the QTc interval.
Statistics All variables are described as mean ⫾ SD or by the median (minimum-maximum) for variables with a non-normal distribution. Quantitative variables were compared between groups by analysis of variance. The limit of significance was set at P ⬍ .05. Statistical calculations were performed on Statistica software version 7.00 (StatSoft Inc; Tulsa, Oklahoma).
RESULTS The indication for domperidone therapy was gastroesophageal reflux in every case (Table). Domperidone was administered orally (1 mg/mL oral suspension) in 3 or 4 divided doses, 15 to 20 minutes before feeds. The mean daily dosage was 1.3 ⫾ 0.7 mg/kg/day. Two infants accidentally received doses higher than the therapeutic range (⬎2.4 mg/ kg/day), but neither of them developed QTc prolongation. The first ECG was systematically performed before starting domperidone therapy, usually several hours before the first dose. The second ECG was performed an average of 2.5 ⫾ 1.5 days after starting treatment (median, 2 days; minimum, 1 day, maximum: 10 days). Only 1 infant required more than 2 ECG examinations to ensure return to normal of the QTc interval which had become pathologic (450 msec) 48 hours after an oral dose of domperidone (⌬QTc, 45 msec). This treatment was stopped immediately. Successive ECGs confirmed reduction of the QTc interval (429 msec 72 hours after discontinuation of domperidone and 410 msec 1 week after stopping domperidone). This patient, who did not present any electrolyte disorder or any particular disease, did not develop any cardiac arrhythmia. 664
Djeddi et al
The QTc interval (msec) was prolonged during oral domperidone therapy (P ⬍ .01): pretreatment, 373.2 ⫾ 4.8; during treatment, 387.2 ⫾ 5.1. The mean variation of the QTc interval (⌬QTc) was 14 msec over a mean duration of 60 hours. The value of the QTc interval (msec) was significantly different between the GA groups (P ⬍ .05): group A: 364.8 ⫾ 6.8; group B: 398 ⫾ 9.3; and group C: 377.9 ⫾ 7.4 (Figure). ⌬QTc also varied according to GA group (P ⬍ .05): mean ⌬QTc (msec) during treatment was 19.1 ⫾ 23.7 in group A, 26 ⫾ 14.4 in group B and ⫺2.9 ⫾ 20.4 in group C (Figure). The QTc interval was prolonged by more than 12 msec in 48.4% of these patients. After elimination of aberrant values (values situated outside of the ⫾ 2 SD interval), univariate analysis showed that oral domperidone-induced QTc prolongation was correlated with GA, birth weight, and serum potassium. The effect of serum phosphorus was borderline significant (P ⫽ .05). The dosage of oral domperidone was found to be inversely correlated with ⌬QTc, which appeared to be somewhat paradoxical. More thorough analysis of the data identified 2 aberrant cases, in which the dosage used differed by more than 2 SD from the cloud of points of dosages used in this population. This inverse correlation between the dosage of oral domperidone and ⌬QTc was no longer observed after exclusion of these 2 cases. Serum calcium, serum magnesium or serum protein did not influence ⌬QTc. On multivariate analysis, after adjustment for GA, serum potassium was the only factor independently associated with ⌬QTc during domperidone therapy (regression coefficient, 1.73; P ⬍ .01). The “birth weight” variable was not entered into the multivariate model to avoid redundant data due to the strong correlation (correlation coefficient ⫽ 0.92 ⫾ 0.07, P ⬍ .001) between birth weight and GA.
DISCUSSION This study reports QTc prolongation induced by oral domperidone; there have been a few isolated cases.9 The ⌬QTc observed in this study was higher than the physiologic prolongation reported in the literature that is observed up until the 4th month of life and then declines. Schwartz et al reported a ⌬QTc of 12 msec between the 4th day of life and The Journal of Pediatrics • November 2008
Figure. Analysis of QTc interval during domperidone therapy according to the various GA groups.
the end of the 2nd month and Alimurung et al10 reported a value of 24 msec between the end of the 1st months and the end of the 4th month. Several cases of QTc prolongation and ventricular tachyarrhythmia related to intravenous domperidone have been reported in the literature and in the case of rapid injection.11-13 This QTc prolongation can be explained by the pharmacologic properties of domperidone. Domperidone (like cisapride) at usual dosages induces reversible prolongation of ventricular repolarization due to Ikr potassium channel blockade (similar to that induced by class III antiarrhythmics).14 In vitro data suggest that concomitant administration of drugs that inhibit cytochrome P450-3A4 can induce elevation of plasma domperidone concentrations. One study showed that almost all patients with druginduced torsades de pointe presented one or more concomitant risk factors (hypokalemia, female sex, drug interaction, etc).15 Not all drugs responsible for torsades de pointe are powerful Ikr blocking agents, and Ikr blockade is not systematically associated with torsades de pointe.16 The small sample size of our cohort could account for the absence of torsades de pointe, which is a serious but rare adverse event. Various studies suggest that a ⌬QTc ⬍30 msec does not have any clinical consequences, but that a prolongation ⬎60 msec induces a potential risk of torsades de pointe.17 Nine of our patients (29%) had a ⌬QTc ⬎30 msec, but none of our patients had a ⌬QTc ⬎60 msec, which could explain the absence of any cases of cardiac arrhythmia. Plasma concentrations increase as a function of the dose of oral domperidone. At equivalent doses, the oral and rectal forms of domperidone have the same bioavailability.18 The capacity of this molecule to prolong the QTc interval therefore concerns the intravenous and oral routes, as well as the rectal route. A study has shown the absence of accumulation of oral domperidone: the plasma peak at 90 minutes after 2 weeks of oral administration of 30 mg/day was the same as that after Effect of Domperidone on QT Interval in Neonates
the first dose (21 ng/mL versus 18 ng/mL).19 Consequently, in the context of surveillance of patients treated by oral domperidone, a late ECG (several weeks after starting treatment) would not be any more informative and an ECG performed during the first 48 hours of treatment appears to be sufficient. Elevated serum potassium, even in the range of physiologic values, was significantly and independently associated with significant QTc prolongation. The early effect of moderate hyperkalemia is to increase myocyte excitability by raising the resting membrane potential. Hyperkalemia has a profound effect on phases 2 and 3 of the action potential. A significant reduction of the QTc interval has been reported in a context of hyperkalemia in patients with congenital long QT but not in healthy control subjects.20 In the present study, GA was significantly associated with QT interval prolongation during domperidone therapy. QTc and ⌬QTc values during oral domperidone therapy differed between the various GA groups: oral domperidone had a significant impact on the QTc interval in groups A and B but not in group C (⬍32 WA). However, studies on cisapride in premature infants suggest that the effect of cisapride on cardiac conduction and QTc is correlated with the degree of prematurity.21,22 Since 2002, cisapride is no longer recommended in premature infants. In severely premature infants (⬍32 WA), first-line prescription of oral domperidone can be considered to replace cisapride for the treatment of gastroesophageal reflux.
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15. Zeltser D, Justo D, Halkin A, Prokhorov V, Heller K, Viskin S. Torsade de pointes due to noncardiac drugs. Medicine 2003;82:282-90. 16. Yang T, Snyders D, Roden D. Drug block of Ikr: model systems and relevance to human arrhythmias. J Cardiovasc Pharmacol 2001;38:737-44. 17. Committee for Proprietary Medicinal Products. The Assessment of the potential for QT interval prolongation by non-cardiovascular medicinal products 1997;986-96. 18. Heykants J, Hendriks R, Meuldermans W, Michiels M, Scheygrond H, Reyntjens H. On the pharmacokinetics of domperidone in animals and man, IV: the pharmacokinetics of intravenous domperidone and its bioavailability in man following intramuscular, oral and rectal administration. Eur J Drug Metab Pharmacokinet 1981;61:61-70.
19. Huizing G, Brouwers JR, Westhuis P. Plasma drug concentration and prolactin release after acute and subchronic oral administration of domperidone and metoclopramide: the serum concentration of drugs 1980:271-7. 20. Compton SJ, Lux RL, Ramsey MR, Strelich KR, Sanguinetti MC, Green LS, et al. Genetically defined therapy of inherited long-QT syndrome: correction of abnormal repolarization by potassium. Circulation 1996;94:1018-22. 21. Dubin A, Kikkert M, Mirmiran M, Ariagno R. Cisapride associated with QTc prolongation in very low birth weight preterm infants. Pediatrics 2001;107:1313-6. 22. Zamora SA, Belli DC, Friedli B, Jaeggi E. 24-hours electrocardiogram before and during cisapride treatment in neonates and infants. Biol Neonate 2004;85:229-36.
50 Years Ago in The Journal of Pediatrics ADENOVIRUS
PNEUMONIA
Blattner RJ. J Pediatr 1958;53:631-3
It is now known that the spectrum of disease manifestations of human adenovirus infection can be quite variable, depending on the serotype. Blattner described an outbreak of adenovirus pneumonia that occurred in France in 1955. At that time, only 18 serotypes of adenovirus were known. Today, more than 52 serotypes have been identified, and the disease spectrum extends from asymptomatic infection through pharyngoconjunctival fever, pneumonia, epidemic keratoconjunctivitis, acute hemorrhagic cystitis, gastroenteritis, meningoencephalitis, hepatitis, myocarditis, and lifethreatening disseminated disease. Severe or even fatal infections can occur in immunocompromised persons. Advances in molecular biology have enhanced our understanding of this virus. To allow easy and rapid identification, serotypes are classified into subgroups or species (A to G) according to genomic DNA sequence, tissue tropism, and other biological properties. Quantitative polymerase chain reaction technology has become the state-of-the-art approach to providing early diagnosis, tracking the course of infection, and monitoring response to treatment. For adenoviral disease in recipients of bone marrow transplantation, treatment with cidofovir (a selective viral DNA synthesis inhibitor) has decreased viremia and produced concomitant clinical improvement in case series. Oral adenovirus vaccine (Ad4 and Ad7), which is no longer manufactured, had been used in military populations for decades to prevent adenovirus infection. The vaccine was demonstrated to be safe, and with increasing incidence and severity of adenovirus infection, interest in an adenovirus vaccine has been rekindled. The past 50 years have seen the development of rapid molecular assays for early detection of adenovirus in clinical settings. These assays allow for further research aimed at discovering new antiviral agents and type-specific vaccines that hopefully will substantially decrease adenovirus-associated morbidity and mortality in vulnerable populations. Frankie Wai Tsoi Cheng, MD Albert Li, MD Department of Pediatrics The Chinese University of Hong Kong Hong Kong, China 10.1016/j.jpeds.2008.05.006
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The Journal of Pediatrics • November 2008