PEDIATRICS Vol. 105 No. 2
February 2000,
p. e24
ELECTRONIC ARTICLE:
Effect of Cisapride on the QT Interval in Infants With
Gastroesophageal Reflux
Vikram Khoshoo, MD, PhD,
Dean Edell, MD, MPH, and
Robert Clarke, MD
From West Jefferson Medical Center, New Orleans, Louisiana.
 |
ABSTRACT |
Objective. We prospectively studied
the effect of cisapride per se on QT interval in young infants (3-6
months) with gastroesophageal reflux (GER) in a controlled
setting.
Study Design. The infants diagnosed with GER and deemed to
require therapy with cisapride were divided into 2 groups. Group A
comprised infants with GER who underwent an electrocardiogram (ECG)
before initiation of therapy with cisapride in the dose of 1 mg per kg per 24 hours, divided into 3 doses. They were reweighed after 7 to 10 days, and the dose was adjusted for their new weight. A repeat ECG was
performed after ~2 weeks (12-18 days) of therapy. The QT interval
was measured in each ECG and then the corrected QT interval was
calculated by Bazett's formula. Group B comprised infants with GER who
had already been on therapy with cisapride for over 1 month. All
infants in group B received cisapride in an approximate dose of 1 mg
per kg per 24 hours (.8-1.1 mg/kg/24 hours) given in 3 divided doses.
They underwent only 1 ECG, ie, at 1 to 4 months after initiation of
therapy. The measurement of the actual dose of cisapride was
demonstrated to every parent and a marked measuring syringe was
provided. The following categories of infants were not included: those
with any underlying cardiopulmonary, renal, or hepatic problem; those
with a history of apnea; those using a macrolide antibiotic or azole
antifungal at any stage during the study; and infants hospitalized for
any reason during the course of the study.
Results. Cisapride therapy in the dose of 1 mg/kg/day
frequently resulted in a slight increase in the QT interval
(pretreatment: 390 ± 18 milliseconds; posttreatment: 400 ± 20 milliseconds) but the increase was still below the accepted upper
limit of 440 milliseconds and not statistically significant.
Even with prolonged therapy, the pattern of change in QT interval was
similar to that with therapy for 2 weeks. Overall, 2 of 100 (2%)
infants developed a prolongation of corrected QT interval beyond the
normal range (456 and 486 milliseconds). Neither infant had evidence of
any arrhythmia or conduction defect on ECG. No additional factor could be identified in either infant to explain prolongation of the QT
interval.
Conclusion. Our experience suggests that cautious
cisapride therapy in young infants in a modest dose does not result in
arrhythmias or conduction defects. We recommend that: 1) the dose of
cisapride in infants be <1.2 mg/kg/day and preferably between .8 and 1 mg/kg/day; 2) the right measure of the dose be actually demonstrated to
the parents; and 3) parents be provided a list of drug interactions with cisapride. One should think twice before denying the use of an
effective drug simply because of the need for closer monitoring and
extra time spent for parent education.
Key words:
cisapride,
gastroesophageal reflux,
corrected QT interval,
arrhythmia.
Gastroesophageal reflux (GER) is a common problem during
infancy. Promotility agents like cisapride are widely used to alleviate symptomatology of GER. Recently some concern has been expressed regarding the safety of using cisapride in children and adults. The
major concern has been the association of cisapride with prolongation of QT interval, which may result in ventricular
arrhythmia.1-3 In most of these cases, the common
denominator has been circumstances resulting in increased serum level
of cisapride either from overdose or concomitant use of drugs that
inhibit cisapride metabolism or independently prolong QT
interval.2,4 We prospectively studied the effect of
cisapride per se on QT interval in young infants with GER in a
controlled setting.
| |
METHODS |
The infants diagnosed with GER and deemed to require therapy
with cisapride were divided into 2 groups. Group A comprised of infants
with GER who underwent an electrocardiogram (ECG) before initiation of
therapy with cisapride in the dose of 1 mg per kg per 24 hours, divided
into 3 doses. They were reweighed after 7 to 10 days and the dose was
adjusted for their new weight. A repeat ECG was performed after ~2
weeks (12-18 days) of therapy. The QT interval was measured in each
ECG and then the corrected QT interval was calculated by Bazett's
formula.5 Group B comprised of infants with GER who had
already been on therapy with cisapride for over 1 month. All infants in
group B received cisapride in an approximate dose of 1 mg per kg per 24 hours (.8-1.1 mg/kg/24 hours) given in 3 divided doses. They underwent
only 1 ECG, ie, at 1 to 4 months after initiation of therapy. All
infants were managed by 1 of the 3 authors. The same pediatric
cardiologist who was unaware of the treatment status read all ECGs. The
measurement of the actual dose of cisapride was demonstrated to every
parent and a marked measuring syringe was provided.
The following categories of infants were not included: those with any
underlying cardiopulmonary, renal or hepatic problem; those with
history of apnea; those using a macrolide antibiotic or azole
antifungal at any stage during the study; and infants hospitalized for
any reason during the course of the study.
| |
RESULTS |
Table 1 shows that cisapride therapy in the dose
of 1 mg/kg/day frequently resulted in a slight increase in the QT interval, but the increase was still below the accepted upper limit of
440 milliseconds and not statistically significant (P > .05; paired t test). Even with prolonged therapy, the
pattern of change in QT interval was similar to that with therapy for 2 weeks (P > .05). Overall, 2 of 100 (2%) infants
developed a prolongation of QT interval beyond the normal range (456 and 486 milliseconds). Neither infant had evidence of any arrhythmia or conduction defect on ECG. No additional factor could be identified in
either infant to explain prolongation of the QT interval.
| |
DISCUSSION |
Our experience suggests that cautious cisapride therapy in young
infants in a modest dose does not result in arrhythmias or conduction
defects.
Lewin et al1 reported a 2-month-old expremature infant
with prolonged QT interval and 2:1 atrioventricular conduction while
being on cisapride in the dose of 1.2 mg/kg/day. The infant was
concomitantly on caffeine, ferrous sulfate, and ranitidine, none of
which have been associated with a prolongation of QT interval. However,
the infant was breastfed and the mother was on miconazole suppositories. Miconazole is an inhibitor of cytochrome P450 3A4 and
although there is minimal systemic absorption of vaginal miconazole, it
raises the possibility of a drug interaction. Hill et al2 reported 11 children with prolonged QT interval while being on cisapride therapy, of whom 2 developed torsades de pointes ventricular tachycardia. Both of these children were concomitantly on macrolide antibiotics. Lupoglazoff et al4 reported 7 small infants (age: 14-79 days; weight: 1.2- 4 kg; 6 of 7 were premature) with prolonged QT interval without arrhythmia while being on a large dose of
cisapride (1-1.7 mg/kg/day). The QT interval returned to normal within
48 hours after the dose was reduced to a more modest dose of .8 mg/kg/day. This fits in nicely with the findings of a large study by
Levine et al6 involving 30 premature infants, none of whom
had any evidence of prolongation of QT interval or arrhythmia when
cisapride was given in the dose of .8 mg/kg/day.
Several features of our prospective study need to be highlighted: 1)
study patients were full-term, small infants over 3 months of age, in
the age group in which GER is most prevalent, cisapride most often
prescribed, and cytochrome P450 3A4 levels are below adult
levels,7 so risk of toxicity is high; 2) patients had an
established, reliable history and a narrow age range making the group
homogenous; 3) patients served as their own controls, a method which
offers a better comparison than using normal healthy controls as has
been previously reported; 4) cisapride was given in a modest dose with
very close follow-up and frequent monitoring and adjustment of dose; 5)
all clinical conditions that could potentially increase the toxicity of
cisapride were excluded. None of the drugs that prolong QT interval
were given (ie, quinidine, sotalol, and procainamide). None of the
drugs that inhibit cytochrome P450 3A4, thus increasing serum levels of
cisapride, were concomitantly given (ie, ketoconazole, itraconazole,
fluconazole, miconazole, troleandomycin, erythromycin, clarithromycin,
ritonavir, indinavir, nefazodone, amitryptaline, astemizole,
thioridazine, and haloperidol). Under such conditions, cisapride was
not associated with any ventricular arrhythmia. Our findings support
the opinion expressed in the consensus statement by the North American
Society for Pediatric Gastroenterology and Nutrition, and this study
responds to their recommendation for collecting more data on this
issue.8
Finally, we would like to make the following recommendations: 1) the
dose of cisapride in infants be <1.2 mg/kg/day and preferably between
.8 and 1 mg/kg/day; 2) the right measure of the dose be actually
demonstrated to the parents; and 3) parents be provided a list of drug
interactions with cisapride. One should think twice before denying the
use of an effective drug simply because of the need for closer
monitoring and extra time spent for parent education.
| |
ACKNOWLEDGMENTS |
We thank Dana Allemand, Diana Buras, Becky Falgout, and Mona
Hernandez for consoling all young infants and patiently performing so
many ECGs.
| |
FOOTNOTES |
Received for publication Jul 26, 1999; accepted Sep 17, 1999.
Reprint requests (V.K.) 4709 Butternut Pl, Midland, MI 48640. E-mail: vkhoshoo{at}earthlink.net
| |
ABBREVIATIONS |
GER, gastroesophageal reflux;
ECG, electrocardiogram.
| |
REFERENCES |
-
Lewin M,
Bryant R,
Fenrich A,
Grifka R
Cisapride induced long QT interval.
J Pediatr
1996;
128:279-281 [CrossRef][Medline]
-
Hill S,
Evangelista J,
Pizzi AM,
Mobbassaleh M,
Fulton D,
Berul C
Proarrhythmia associated with cisapride in children.
Pediatrics
1998;
101:1053-1056 [Abstract/Free Full Text]
-
Bran S,
Murray W,
Hirscg I,
Palmer J
Long QT syndrome during high-dose cisapride.
Arch Intern Med
1995;
155:765-768 [Abstract]
-
Lupoglazoff JM,
Bedu A,
Faure C,
Long QT syndrome under cisapride in neonates and infants.
Arch Pediatr
1997;
4:509-514 [CrossRef][Medline]
-
Bazett HC
An analysis of the time relation of electrocardiogram.
Heart
1920;
7:353-370
-
Levine A, Fogelman R, Sirota L, Zangen Z, Shamir R, Dinari G. QT interval in children and infants receiving cisapride. Pediatrics. 1998; 101(3). URL: http://www.pediatrics.org/cgi/content/full/101/3/e9
-
Leeder JS,
Kearns GL
Pharmacogenetics in pediatrics: implications for practice.
Pediatr Clin North Am
1997;
44:55-77 [CrossRef][Medline]
-
Shulman RJ,
Boyle JT,
Coletti RB,
The use of cisapride in children.
J Pediatr Gastroenterol Nutr
1999;
28:529-533 [CrossRef][Medline]
Pediatrics (ISSN 0031 4005). Copyright ©2000 by the American Academy of Pediatrics
Top
Abstract
Methods
