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PEDIATRICS Vol. 107 No. 6 June 2001, pp. 1313-1316
,
, §, and
From the Divisions of * Pediatric Cardiology and Objective. No systematic study has
been performed to evaluate the effect of cisapride on the QT interval
in premature infants. Cisapride, which has recently been withdrawn by
the Food and Drug Administration and is no longer an approved therapy,
was commonly used for preterm infant care to improve the advance of
enteral feedings and to reduce reflux and associated apnea. Our aim was
to evaluate the effect of recommended doses of cisapride on the QT
interval in this population.
Study Design. Prospective blinded evaluation of
electrocardiogram for QT, JT, QTc, and JTc measurements in 25 preterm
infants before and after cisapride administration.
Results. Twelve of 25 infants (48%) developed
repolarization abnormalities with cisapride administration: 32% of the
infants (8/25) studied had QTc prolongation ( Conclusions. The QTc and JTc interval significantly
prolonged in preterm infants <32 weeks on the recommended dose of
cisapride therapy. A QTc Neonatal and
Development Medicine, Department of Pediatrics, Stanford University,
Stanford, California; § Netherlands Institute for Brain Research,
Amsterdam, The Netherlands; and the Leiden University School of
Medicine, Leiden, The Netherlands.
ABSTRACT
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Abstract
Methods
Results
Discussion
References
0.450 seconds), whereas
10/25 had JTc prolongation (0.360 seconds). Preterm infants <32
weeks significantly prolonged their QTc interval from 0.41 ± 0.02 to 0.44 ± 0.02. The QTc and/or JTc was prolonged in 54% of
infants receiving 0.1 mg/kg/dose and 42% receiving 0.2 mg/kg/dose.
0.450 seconds developed in 32% of infants
treated with cisapride, whereas the JTc prolonged in 40%. A
significant percentage of infants (54%) developed prolonged QTc
intervals at a dose of 0.1 mg/kg/dose. From these data we conclude that
there is a higher risk of prolongation of the QTc interval and risk of
arrhythmias with greater prematurity.
The use of oral gastrointestinal prokinetic agents to
improve gastric emptying and to treat clinical gastroesophageal reflux has become more common and accepted in newborn intensive care practices.1 The widespread use of cisapride, along with reports of potential cardiac toxicity and repolarization abnormalities, have recently culminated in the withdrawal of cisapride for clinical use in the United States.2,3
Cisapride is a prokinetic agent that is thought to enhance the release
of acetylcholine at the mesenteric plexus as its primary mechanism of
action for improvement of gastroesophageal reflux.4 Cisapride is also known to be a potent antagonist to the human ether a
go-go channel, which regulates the rapid delayed rectifier current
(Ikr), thereby prolonging action potential duration by prolonging
repolarization.5,6 Developmental aspects of this current
suggest that the role that Ikr plays in the action potential duration
may change from fetal life to adulthood.7-9 Wang and
associates9 have found that in the neonatal mouse heart,
Ikr plays a more prominent role in cardiac repolarization than it does
in the adult mouse heart. This change in channel physiology may be
relevant to the preterm and newborn infant in clinical practice.
Cisapride is metabolized through the cytochrome P450 system, the 3A4
isoform required for effective metabolism of cisapride seems to be less
developed in the preterm infant.10,11 This immaturity of
the 3A4 hepatic isoform has been hypothesized to be the mechanism for
decreased clearance of the drug and, thus, increased levels and
toxicity. Additionally, other drugs that inhibit this enzyme may also
contribute to increase serum levels of cisapride.12
Early studies reported cardiac side effects of cisapride in
adults13,14 and children.15-17 Bernardini
and colleagues18 suggest that preterm neonates may be at
an increased risk for cardiac repolarization abnormalities and
arrhythmias.
We hypothesized that repolarization abnormalities may be more frequent
in more premature infants receiving cisapride, because of the
immaturity of the cytochrome P450 system as well as a possible increased reliance on the rapid component of the delayed rectifier current. We, therefore, systematically studied preterm infants who were
receiving cisapride for the clinical management of reflux, to evaluate
the effect of such therapy on the QTc interval.
Participants
All infants with a gestational age of Exclusion criteria included family history of sudden infant death
syndrome or long QT syndrome, electrolyte abnormalities (including
calcium and magnesium) at time of study, congenital heart disease, and
renal or hepatic abnormalities.
This study was reviewed and approved by the Human Subjects
Institutional Review Board and Stanford University.
Cisapride Dose
Cisapride was started at an initial dose of 0.1 mg/kg every 6 hours. The dosage was increased if the postcisapride apnea/pH study
showed no decrease in gastroesophageal reflux. A maximum of 0.2 mg/kg/dose was used.
ECG Measurements
Standard 12-lead ECG was performed on all infants at paper speed
of 25 mm/second. RR, electrocardiographic wave complex, QT, and JT
intervals were measured manually. The JT interval, a measurement from
the end of the electrocardiographic wave complex to the end of the T
wave, was measured to account for any intraventricular conduction
delay.19 These measures were corrected for heart rate
using Bazett's formula. Measurements were made by 2 observers who were
blinded to the details of cisapride treatment. No interobserver
variability was seen using a Bland Altman test with a mean difference
from the average of 0.001 ± 0.02 seconds.20 The
longest QT interval was identified on each ECG. A QTc interval Statistics
All data are expressed as mean ± standard deviation.
Mann-Whitney rank test and Wilcoxon rank test were used to evaluate the effect of cisapride on the QTc and JTc intervals.
Participants
Twenty-five preterm infants (15 males) were studied. Gestational
age at birth was 29 ± 3 weeks (range: ECG Measurements
Pretherapy and during therapy measurements were performed an
average of 6 ± 7 days apart. RR, QTc, and JTc measurements for both groups before and during cisapride therapy are shown in Table
1. No difference in heart rate, QTc, or
JTc was noted between the 2 groups before therapy. However, when
comparing during cisapride measurements, the infants <32 weeks had a
significantly longer QTc (0.44 ± 0.02 seconds vs 0.42 ± 0.02 seconds; P = .02) and JTc (0.37 ± 0.03 seconds vs 0.35 ± 0.03 seconds; P = .05) than infants TABLE 1
METHODS
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Methods
Results
Discussion
References
34 weeks admitted to the
neonatal intensive care unit at the Lucile Salter Packard Children's
Hospital at Stanford from November 1998 to November 1999, who were
placed on cisapride for clinically diagnosed gastroesophageal reflux,
were included. A baseline electrocardiogram (ECG) was obtained 24 hours
before starting cisapride. Follow-up ECG was performed after at least 5 half-lives (30-60 hours) of cisapride therapy and a ECG was repeated 5 half-lives after each dosage increase. All infants were placed on
continuous bedside ECG monitoring, which is standard in the neonatal
intensive care unit during the entire hospitalization. When a prolonged
QTc was noted, it was reported and the recommendation to decrease or
discontinue cisapride was made.
0.45
seconds and JTc interval 0.36 seconds were considered abnormal.
RESULTS
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Abstract
Methods
Results
Discussion
References
27-34 weeks). Average postconceptional age at the time of study was 35 ± 3 weeks
(range: 29-41 weeks). Birth weight was 1.19 ± 0.40 kg (range:
0.61-2.26 kg). The infants were divided into 2 groups for analysis:
group A, gestational age 31 weeks (18 patients), group B, gestational age >31 weeks (7 patients).
32 weeks. Comparing before and during cisapride measurements for each group, the <32-week group significantly prolonged their QTc
and JTc, whereas the 32-week group did not.
Comparison of ECG Measurements Before and During Cisapride Therapy
Prolongation of QTc
Twelve of the 25 infants (48%) developed repolarization abnormalities (Table 2). Eight infants developed a long QTc interval, while 10 developed a prolonged JTc. Eleven of these infants were <32 weeks' gestation. Before and after cisapride QTc intervals for these children are shown in Fig 1.
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Cisapride Dose Versus QTc
Thirteen infants received 0.1 mg/kg/dose, whereas 12 were advanced
to 0.2 mg/kg/dose. No difference in postconceptional age was found
between the 2 dosing groups (35.4 ± 3.7 weeks vs 36.9 ± 2.9 weeks; P = not significant). Seven infants (53%)
receiving the lower dose prolonged their QTC or JTC above the cutoff
point (0.45 seconds and 0.36 msec, respectively), whereas 5 infants (42%) who received 0.2 mg/kg/dose developed a long QTc and/or JTc.
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DISCUSSION |
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Since the first reports of repolarization abnormalities and lethal arrhythmias in patients treated with cisapride, concern with the widespread use of the drug has grown.13-18 Because the drug is metabolized by the cytochrome P450 system, which is known to be immature in the preterm infant, these concerns have recently lead to the withdrawal of cisapride for clinical use in the United States. Recent molecular studies have shown that the drug is a potent antagonist of the rapid component of the delayed rectifier potassium current in cardiac cells and consequently acts on the heart as a class III antiarrhythmic.5,6 Recent studies of potassium channel development reveal significant differences in potassium currents when comparing fetal and adult animals.7-9 We hypothesize that the more preterm infants (<32 weeks) may have enhanced sensitivity to cisapride because they may be more dependent on the rapid component of the delayed rectifier potassium current channel and/or higher levels.
This study shows that there is a significant difference in preterm
infants with respect to repolarization abnormalities and cisapride. The
QTc and JTc significantly prolonged with cisapride therapy in infants
<32 weeks. Forty-eight percent had marked prolongation above the
accepted upper limits of normal for 1 or both repolarization indices.
Ninety-two percent were infants born under 32 weeks' gestation, which
is consistent with the hypothesis that the delayed development of
cytochrome P450 3A4 hepatic isoform (CYP3A4) may be an important
mechanism in repolarization abnormalities associated with
cisapride.10,11 These findings agree with the previous
study of Khongphatthanayothin et al17 who studied QT
interval in children between 17 days and 12.5 years of age. Thirteen
percent of children were found to have abnormal QT interval (0.44
seconds) after initiation of cisapride. Our data are also supported by
the study by Bernardini and colleagues18 who looked at
neonates receiving cisapride. They found prolongation of the QT
interval in 14% of infants, of which 86% were <33 weeks' gestational age. Bedu and colleagues21 also reported on
prolongation of QTc in 6 infants (1 term, 2 previously born premature,
and 3 preterm) by cisapride alone. These infants were receiving 1 to
1.6 mg/kg/day of the drug. However, Levine and colleagues22 showed no prolongation of QTc in children and
infants (including 10 preterm infants) after 1 month of low-dose cisapride therapy (0.8 mg/kg/day). It is interesting that the QTc
interval in these preterm infants was much shorter (~0.380 seconds)
compared with other studies including this one.
We were unable to establish a relationship between cisapride dose and QT interval, which may be attributable to the small number of patients included in the study and also attributable to the fact that we did not have blood levels. We did find that of the infants with QT prolongation, 58% were receiving what is considered low-dose cisapride therapy (<0.2 mg/kg/dose). Forty-two percent of the children on the recommended dose of cisapride (0.2 mg/kg/dose) developed QT prolongation. No study patient received cisapride in doses exceeding the recommended dose.
The arbitrary upper limits of normal for QTc reported for children is 0.45 seconds. To our knowledge, there are no data for a preterm infant population; therefore, we arbitrarily used this same limit in this study. There are also technical difficulties in determining the QT interval that should be acknowledged. The measurement of the QT can be difficult because the T wave often ends with a gentle slope or is followed by a poorly defined U wave.3 The QTc also does not take into account any intraventricular conduction abnormalities and may be falsely prolonged secondary to bundle branch delay. The JTc was established to account for such abnormalities; thus, JTc intervals were also measured.19 In our patients, when the QTc was abnormal, the JTc was abnormal as well.
We had no episodes of arrhythmias observed by bedside ECG monitoring in our patient population. There are several possible explanations for this. The infants were routinely on constant monitoring and there was a heightened awareness of their receiving cisapride therapy. Therefore, drugs that were known to interact with the cytochrome P450 system were not given. We also carefully screened for the possibility of long QT syndrome in this population by family history and baseline ECG. Finally, when an abnormal QT interval was found, the recommendation was made to discontinue or decrease the cisapride dose. Unfortunately, in the outpatient setting, these safety measures are less likely and usually not used, eg, constant ECG monitoring. Therefore, infants who are perhaps at less risk in the intensive care setting may be more vulnerable after discharge.
The QTc interval was significantly prolonged in preterm infants on appropriate dosage of cisapride eg, 0.1 mg/kg/dose 4 times daily. From these data, we conclude that cisapride has a greater effect on cardiac conduction and the QTc that is associated with the degree of prematurity. There was no correlation with the dose; however, blood levels were not performed and theoretically would be expected be higher because of immaturity of the CYP3A4 hepatic isoform and slower metabolism of cisapride with greater prematurity. The results of this study support the decision to withdraw cisapride from clinical use for the preterm infant because of potential for prolonged cardiac conduction and risk for arrhythmias. If an isoform of cisapride becomes available, which theoretically has no adverse effects on cardiac conduction, additional studies are needed to establish efficacy for the management of reflux, feeding intolerance, and apnea in the preterm infant.
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ACKNOWLEDGMENTS |
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This work was supported in part by Packard Children's Hospital Innovations in Care Grant and a medical student grant from the University of Leiden.
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FOOTNOTES |
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Received for publication Jun 6, 2000; accepted Sep 26, 2000.
Reprint requests to (A.D.) Division of Pediatric Cardiology, 750 Welch Rd, Suite 305, Palo Alto, CA 94303. E-mail: amdubin{at}leland.stanford.edu
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ABBREVIATIONS |
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ECG, electrocardiogram.
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REFERENCES |
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