Cisapride, a Prokinetic Agent Used in Adults

Effects of Cisapride on Corrected QT Interval, Heart Rate, and Rhythm in Infants Undergoing Polysomnography

Avram Benatar, MBChB, FCP(SA), FRCPCH*; Arjen Feenstra, MD‡; Tine Decraene, MD*; and Yvan Vandenplas, MD, PhD‡

ABSTRACT. Objective. To evaluate the effects of isapride, a prokinetic agent used in adults and cisapride, a prokinetic gastrointestinal drug, on the elec- children with gastrointestinal motility disor- trocardiographic QT interval, heart rate, and rhythm in ders, has been reported in some patients to infants during routine 8-hour polysomnography. Re- C increase the QT interval on the electrocardiogram ported electrocardiogram (ECG) and rhythm distur- (ECG).1–3 Prolongation of the electrocardiographic bances in a small number of patients with the use of 4–6 7 cisapride provided the impetus for this prospective QT interval may be either congenital or acquired. study. Acquired prolongation of the QT interval can be Study Design. Two hundred fifty-two infants born at caused by electrolyte disturbances (commonly hypo- term were enrolled. Of these, 134 were on cisapride ther- kalemia and hypocalcemia), hypothermia, central apy for suspected gastroesophageal reflux and 118 were nervous system injury, malnutrition, organophos- not on cisapride and served as controls. Cisapride-treated phate poisoning, and medication. Medications that and control infants were from the outset divided into 3 have been implicated include tricyclic antidepres- age groups; group 1: under 3 months of age; group 2: sants, macrolide antibiotics, phenothiazines, and an- between 3 and 6 months of age; and group 3: >6 months 7 of age. Continuous ECG bipolar limb lead I recording, tiarrhythmic agents. saturation monitoring, and electroencephalography were The QT interval on the ECG represents the period conducted. QT intervals and heart rate were measured at from the beginning of depolarization (QRS complex) hourly intervals. to the end of repolarization (T wave) of the ventri- Results. Cisapride doses were: group 1 mean, 0.80 cles. There are at least 5 different genes responsible mg/kg/day (range: 0.38–1.55); group 2 mean, 0.80 mg/kg/ for the various congenital forms of long QT syn- day (range: 0.23–1.38); and group 3 mean, 0.72 mg/kg/day drome, and it is now clear that several different ion (range: 0.32–1.41). Heart rate was higher in the younger channels play a role in cardiac repolarization, and infants, with a gradual decrease with age. No difference defects in any one of these ion channel genes can in heart rate was detected between the cisapride and 8 control groups. The QTc interval in patients in group 1 result in a long QT syndrome. Channel types in- was statistically longer than the controls, when applying clude the voltage-gated potassium channel, out- both Bazett’s and Hodges’ formulae for QT correction. wardly rectifying potassium channel, and the volt- The other age groups did not differ. No arrhythmia or age-gated sodium channel.7 The QT interval varies atrioventricular conduction abnormalities were ob- with heart rate, lengthening at slower rates and served. shortening at faster rates.9 The QT interval corrected Conclusion. Infants under 3 months of age on cisa- for heart rate, the QTc, may be obtained by a number pride treatment had significantly longer QTc intervals of formulae, one of which is Bazett’s formula.10 Nor- (with Bazett’s formula, the 98th percentile was 504 ms in mal ranges for the QTc Bazett in children have been the cisapride group vs 447 ms in controls). The clinical ϳ significance and risk of the increased QTc interval in published; the mean value of QTc remains at 400 these infants are unclear and need further evaluation and ms throughout all age groups. In 95% of the children, risk stratification. Meanwhile, cisapride should be judi- the QTc is Ͻ450 ms, and in 98% Ͻ480 ms with the ciously prescribed in infants <3 months of age. exception of the first days of life, when the values are Pediatrics 2000;106(6). URL: http://www.pediatrics.org/ slightly higher.9 From other data on normal infants,11 cgi/content/full/106/6/e85; QT interval, QTc, cisapride, taking 3 standard deviations from the mean QTc as heart rate, heart rhythm, infants. the upper normal limit of normal, on the fourth day of life the value is 451 ms; at 2 months, 454 ms; at 4 ABBREVIATIONS. ECG, electrocardiogram; CYP, cytochrome months, 451 ms; and at 6 months, 442 ms. P-450. Delayed cardiac repolarization, as reflected by QT prolongation on the ECG, can predispose to the occurrence of arrhythmia. Such a proarhythmic effect From the Departments of *Pediatric Cardiology and ‡Pediatric Gastroen- terology, Academisch Ziekenhuis, Free University of Brussels, Brussels, can degenerate into the potentially fatal polymor- Belgium. phous ventricular tachycardia, torsade de pointes, or Received for publication Mar 28, 2000; accepted Jul 10, 2000. even ventricular fibrillation. Cisapride can prolong Reprint requests to (A.B.) Department of Pediatric Cardiology, Academic the QT interval by blocking the rapid component of Hospital, Free University of Brussels, 101 Laarbeeklaan, 1090, Brussels, the delayed rectifying Kϩ current in the myocardi- Belgium. E-mail: [email protected] 12 PEDIATRICS (ISSN 0031 4005). Copyright © 2000 by the American Acad- um. Effects of cisapride on cardiac rhythm have emy of Pediatrics. been documented in adults and more recently in http://www.pediatrics.org/cgi/content/full/106/6/Downloaded from www.aappublications.org/newse85 by PEDIATRICS guest on September Vol. 30, 106 2021 No. 6 December 2000 1of5 children.1–3,13,14 Two publications in 199715,16 ad- Parameters recorded continuously during the 8-hour nocturnal dress the issue of cisapride-associated QTc lengthen- polysomnography (Morpheus pediatric vs 7.3 Medatec BVBA) were stored on optical disk for subsequent retrieval and analysis. ing in premature neonates. Cisapride, like many Parameters recorded included: thoracic movement, abdominal other drugs, is metabolized by the cytochrome P-450 movement, nasal air flow by thermistor, oxygen saturation using 3A4 enzyme system.17 The immature cytochrome pulse oximetry (Radiometer Copenhagen, Denmark), bilateral P-450 3A4 capacity reported in neonates, particularly electromyography of eye muscles to detect rapid eye movement premature infants, may predispose to high plasma sleep, electromyography of jaw muscles, and electroencephalography (2 channels). One channel was used for continuous record- concentrations of the drug or its metabolites. In ad- ing of the bipolar ECG, lead I (between the right and left arm). The dition, concurrent use of cytochrome P-450 3A4 in- parameters were analyzed thoroughly for episodes of desatura- hibitors may also result in increased plasma levels of tion, apneas (central or obstructive), and seizure disorder. Patients cisapride.18,19 displaying any of these events were excluded from the study. The stored ECG recordings were retrieved from the optical disk We set out to test the hypothesis of the extent and and digitized on screen. The QT and R-R intervals were measured significance of the effects of cisapride on cardiac blinded in 3 consecutive heart cycles with calipers at approxi- rhythm and myocardial repolarization in infants. mately hourly intervals (10, 60, 120, 180, 240, 300, 360, and 420 Given this background, the aim of our prospective minutes) and averaged. Measurement at a fixed time interval was study was twofold: 1) to assess the effects of cisa- performed to obtain standardized QT interval measurements after cisapride administration. The mean of 3 R-R intervals and the pride on QTc interval and heart rate during an mean of 3 QT intervals were used. Thus, the QT interval calculated 8-hour polysomnographic examination in infants on was an average of 24 cycles. Alteration of the scale of the P-QRS cisapride therapy, compared with age- and sex- complex permitted accurate measurement of the end of the T matched controls; and 2) to determine the incidence wave. To avoid interobserver variability, one blinded investigator performed all ECG measurements. The QT interval was corrected of arrhythmia during this 8-hour period. for the heart rate with the use of 2 formulae 1) Bazett’s formula,10 QTcB ϭ QT/͌R-R, and 2) Hodges’ formula,24 QTcH ϭ QT ϩ 1.75 METHODS (rate Ϫ 60). The 8-hour recordings were screened for rhythm During a 24-month period, we prospectively enrolled 252 in- disorders. fants (born at term), admitted for routine polysomnographic The protocol was approved by the medical ethics committee of study, a cardiorespiratory and neurological screening test rou- the Academic Hospital of the Free University of Brussels. In- tinely practiced in Belgium for many years.20 It is estimated that formed consent was given by the parents. 25% to 30% of all infants in Belgium undergo a routine polysomnographic study (H. Devlieger, personal communication, 1994). None of the enrolled infants had an episode or history of an acute Statistics life-threatening event, were receiving diuretic or methylxanthine Descriptive statistics were calculated for age, weight, QTcB, therapy, or had any previous bowel surgery. The study protocol and QTcH. Variables are expressed as mean Ϯ standard deviation permitted infants to be studied on only one occasion to obviate or median and range. Analysis of variance and posthoc Bonfer- bias. Demographic data as well as a complete medical history roni-Dunn and Scheffe F test at a significance level of 1% were were obtained at the time of admission. A thorough physical used to compare the 3 age groups for QT interval, QTcB, QTcH, as examination was conducted before commencing the polysomno- well as heart rate. A P value of Ͻ.0001 was accepted as significant. graphic recording. Infants on cisapride for a minimum of 4 days to ensure a steady-state cisapride plasma level21 were compared with a control group not receiving cisapride. Cisapride was pre- RESULTS scribed for suspected gastroesophageal reflux. Criteria for exclu- The demographic data of the patients are pre- sion from the study included a family history of arrhythmia or sented in Table 1. sudden death, a history of acute life-threatening event, bundle Cisapride doses for the different age groups were branch block on ECG, use of other medications known to prolong the QT interval on ECG or inhibit cytochrome P-450 3A4, meta- as follows: group 1, mean: 0.80 mg/kg/day (range: bolic or central nervous system disorder, apneas, and/or desatu- 0.38–1.55 mg/kg/day and median: 0.78 mg/kg/ ration (Ͻ93%). Blood electrolyte levels were not quantified. Bottle- day); group 2, mean 0.80 mg/kg/day (range: 0.23– fed infants were receiving infant formulae with adequate calcium, 1.38 mg/kg/day and median: 0.80 mg/kg/day); and potassium, and sodium content. The infants were divided into 3 age groups at the time of group 3; mean 0.72 mg/kg/day (range: 0.32–1.41 enrollment; group 1: Ͻ3 months of age; group 2: between 3 and 6 mg/kg/day and median: 0.77 mg/kg/day). Fre- months; and group 3: Ͼ6 months of age. The infants were divided quency of administration varied from twice to 4 into 3 age groups for the following reasons: 1) the body fluid times daily. compartments undergo a significant change in the first year of life Heart rate (Table 2) was, as expected, higher in the resulting in changes in the volume of distribution,22 and thus possibly plasma and tissue drug concentrations; 2) the hepatic younger infants, showing a gradual decrease with cytochrome P-450 3A4 enzyme system undergoes a maturation increasing age for both the cisapride and control process and may, therefore, not have the full capacity of ade- patients. There was no statistical difference between quately metabolizing cisapride in younger infants; 3) renal matu- the heart rate of those receiving cisapride and con- rity and glomerular filtration may play a role in the excretion of drugs23; 4) binding of cisapride to the myocardium may be age-/ trols in each of the different age groups. Results of maturity-dependent; and 5) heart rate is inversely proportional to the QT and corrected QT intervals are shown in age.9 The chosen age cutoff of 3, 6, and above 6 months was Table 3 and show a significant prolongation of QTc arbitrary and primarily based on fluid compartment changes in in the group Ͻ3 months of age. For both Bazett’s and 22 the first year of life. Hodges’ formulae, a significant difference in QTc Cisapride was administered between 40 and 60 minutes before the commencement of the polysomnographic recording and was was found in the cisapride patients, compared with immediately followed by a feed. Once the infant fell asleep, re- the controls for those younger than 3 months (group cording was begun. Infants on an 8- or 12-hour schedule did not 1; P Ͻ .001). However, in infants older than 3 months receive cisapride during the 8-hour recording. Infants on a 6-hour (groups 2 and 3), there were no significant differ- schedule were given cisapride only if they awakened for a feed at the appropriate time. In the event of an awakening, the polysom- ences in QTc interval. nographic recording was temporarily stopped and recommenced Using Bazett’s formula, the 98th percentile QTc once the infant fell asleep again. values for the controls were as follows; 447 ms for

2of5 CISAPRIDE EFFECTSDownloaded ON from QTc, www.aappublications.org/news HEART RATE AND RHYTHM by guest on INSeptember INFANTS 30, 2021 TABLE 1. Demographic Data Cisapride (n ϭ 134) Controls (n ϭ 118) Mean Median Mean Median Age (weeks) Group 1 n ϭ 64 8 (3–12) n ϭ 55 9 (4–12) 8.4 Ϯ 2.12 8.7 Ϯ 1.18 Group 2 n ϭ 35 18 (13–24) n ϭ 32 19.5 (13–24) 18.2 Ϯ 3.1 18.7 Ϯ 3.3 Group 3 n ϭ 35 36 (26–58) n ϭ 31 37 (25–125) 37.4 Ϯ 9.4 43.1 Ϯ 20.3 Weight (kg) Group 1 n ϭ 64 4.81 (3.1–6.64) n ϭ 55 5.08 (3.5–6.7) 4.89 Ϯ .69 5.07 Ϯ 0.68 Group 2 n ϭ 35 6.2 (4–9) n ϭ 32 6.57 (3.08–9) 6.24 Ϯ 1.3 6.37 Ϯ 1.4 Group 3 n ϭ 35 7.9 (5.27–13) n ϭ 31 8.7 (6.2–12.7) 8.15 Ϯ 1.6 8.75 Ϯ 1.6 Parentheses ϭ range; Ϯϭstandard deviation; group 1 ϭ 0 to 3 months; group 2 ϭ 3 to 6 months; group 3 ϭϾ6 months of age.

TABLE 2. Heart Rate by Age Group percentile QTc values for the cisapride-treated Heart Rate Cisapride (n ϭ 134) Controls (n ϭ 118) groups were: 467 ms, 433 ms, and 426 ms, respectively. Group 1 n ϭ 64 131 Ϯ 10 n ϭ 55 132 Ϯ 9.8 Group 2 n ϭ 35 122 Ϯ 11.3 n ϭ 32 122.5 Ϯ 11.4 The 8-hour recording was scanned for arrhythmia. Group 3 n ϭ 35 114 Ϯ 11.4 n ϭ 31 117.7 Ϯ 12.2 No abnormality of atrioventricular conduction or evidence of ventricular ectopy was identified. Mean heart rate in beats per minute, Ϯϭstandard deviation; group 1 ϭϽ3 months; group 2 ϭ 3 to 6 months; group 3 ϭϾ6 We chose to discontinue cisapride therapy in those months of age. patients with a QTc Bazett’s formula value equal to or beyond 480 ms (98 percentile for QTc Bazett, 9 TABLE 3. QT and QTC intervals Davignon et al ). Cisapride (n ϭ 134) Controls (n ϭ 118) DISCUSSION QT interval We conducted this study to determine whether Group 1 n ϭ 64 309.5 Ϯ 16.4 n ϭ 55 284.9 Ϯ 15.9* cisapride, a prokinetic drug commonly used in in- ϭ Ϯ ϭ Ϯ Group 2 n 35 301.0 22.4 n 32 293.0 18.0 fants, had any significant effect on the QT interval, Group 3 n ϭ 35 304.0 Ϯ 17.8 n ϭ 31 294.0 Ϯ 201.1 Bazett† heart rate, and rhythm when used at the recom- Group 1 n ϭ 64 455.5 Ϯ 18.7 n ϭ 55 420.3 Ϯ 18.2* mended doses. Because all children were on cisa- Group 2 n ϭ 35 427.0 Ϯ 22.0 n ϭ 32 415.7 Ϯ 21.0 pride before entering the study, baseline QT data are Group 3 n ϭ 35 416.8 Ϯ 18.6 n ϭ 31 408.0 Ϯ 18.8 not available. We deliberately excluded patients tak- Hodges‡ Group 1 n ϭ 64 434.6 Ϯ 14.89 n ϭ 55 411.1 Ϯ 14.6* ing other medication that may affect the metabolism Group 2 n ϭ 35 410.2 Ϯ 15.3 n ϭ 32 402.4 Ϯ 17.0 of cisapride and may lead to potential toxic plasma Group 3 n ϭ 35 399.0 Ϯ 15.8 n ϭ 31 395.0 Ϯ 11.4 levels. From the outset, we divided the patients into Ϯϭstandard deviation; group 1 ϭϽ3 months; group 2 ϭ 3to6 3 age groups, because the pharmocokinetics, matu- months; group 3 ϭϾ6 months of age. rity of hepatic enzymes, and total body water content * P Ͻ .001. and volume of distribution within the body compart- † Bazett values in milliseconds. ments change considerably during the first year of ‡ Hodges values in milliseconds. life.22 Maturation or changes in the cardiac channels with age may, theoretically, also play a role. The group 1, 453 ms for group 2, and 439 ms for group 3. results of this study showed a statistically significant The corresponding 98th percentile QTc values for the prolongation of the uncorrected QT and QTc interval cisapride treated groups were: 504 ms; 458 ms; and in infants under 3 months of age receiving cisapride. 451 ms, respectively. Thirty of the 64 group 1 cisa- However, this prolongation of QTc interval was not pride patients (46.9%) had a QTc Bazett’s formula associated with the occurrence of rhythm disorders. value beyond 455 ms.11 Of these 30 infants, 2 had a Correction of the QT interval for heart rate remains QTc value Ͼ480 ms and in another 2 infants the QTc a complex and controversial area. Bazett’s formula10 value was Ͼ500 ms (505 ms and 507 ms). Two of the is commonly used to correct the QT interval; how- group 2 cisapride patients had a QTc Bazett’s for- ever, this formula overcorrects at extreme heart rates. mula value above 455 ms (457 ms in both) and none As a result, normal infants with relatively elevated in the cisapride group 3 patients. In the controls, 1 heart rates tend to have a long QTc interval when infant in group 1 had a QTc Bazett’s formula value corrected using Bazett’s formula. In contrast, the for- Ͼ455 ms (491 ms), 1 in group 2 (466 ms), and none in mula of Hodges et al24 is linear. For this reason we group 3. chose to use both Bazett’s and Hodges’ formulae to For the Hodges’ formula, the 98th percentile QTc evaluate the QT interval. We chose to measure the values for the controls were: 432.4 ms in group 1, 438 QT intervals during an 8-hour nocturnal period to ms in group 2, and 423 ms in group 3. The 98th obtain a meaningful trend of the QT interval during

Downloaded from www.aappublications.org/newshttp://www.pediatrics.org/cgi/content/full/106/6/ by guest on September 30, 2021 e85 3of5 steady-state plasma concentrations of the drug. In The relationship between the QTc interval and risk addition, this permitted an evaluation of heart rate of ventricular dysrhythmia if the interval is mildly and detection of arrhythmia over a reasonably long prolonged is not known. Using Bazett’s formula, the period of time. risk is unknown between 440 and 500 ms. At Ͼ500 The ability of cisapride to prolong cardiac repolar- ms, there is a higher risk and at Ͼ600 ms there is a ization is a potentially serious adverse effect and in very high risk of fatal outcome.34 A value of 440 ms infants younger than 3 months, cisapride seems to marks the limit of the top 2.5% range within the prolong cardiac repolarization. Excessive QT prolon- population. The risk of arrhythmia associated with a gation may be proarhythmic and degenerate into QTc of 500 ms attributable to cisapride effects on the potentially fatal ventricular arrhythmia, such as tor- rapid potassium-delayed rectifier current may not be sades de pointes. Cisapride, a noncardiac drug, may the same as that attributable to a congenital abnor- at high serum levels have an adverse effect on car- mality of one of the potassium or sodium channels, diac Kϩ channels. Single cardiac myocyte experi- or that caused by amiodarone or sotalol. Other fac- ments have demonstrated block of the delayed rec- tors are used to increase the predictive value of the 16 tifier potassium channel (IKr), while in whole-heart risk of a prolonged QTc interval (family history, T experiments, increased action potential duration and wave profile, and history of syncope).34,35 The risk after depolarizations were seen.16,25,26 These associated with a drug-induced prolonged QTc in- changes, related to the cisapride concentration, can terval is unknown. It is not possible to predict how result in prolongation of the QTc interval.27 an individual will respond. In our study, the 98th In addition, there are a number of substances ca- percentile QTc value for infants under 3 months of pable of increasing cisapride plasma concentrations age receiving cisapride therapy with Bazett’s for- by inhibiting metabolism by cytochrome P-450 3A4. mula was 504 ms, decreasing substantially beyond For this reason, all patients taking drugs metabolized that age. Extrapolating to the prolonged QTc syn- by cytochrome P-450 3A4 or drugs known to prolong drome, our children under 3 months of age are at a QTc in combination with cisapride were excluded value of unknown risk. from our study. The hepatic cytochrome P-450 3A4 Several studies and case reports have now corrob- enzyme is quantitatively the most important cyto- orated the findings of QT prolongation during cisa- chrome P-450 (CYP) isoform and is responsible for pride therapy in children.1,3,13–15,36,37 Our data are the metabolism of numerous drugs, including cisa- consistent with the published reports, and highlight pride. The cytochromes P-450 are a superfamily of the potential for increased QT prolongation in the haem proteins and consist of the subfamilies CYP1A, youngest age group, those less than 3 months. The CYP2B, CYP2C, CYP2D, and CYP3A.28 The CYP3A clinical significance of the increased QTc interval subfamily comprises up to 40% of the total cyto- observed in these patients and ours is unclear. In chrome P-450 content present in both the adult hu- experimental studies cisapride prolongs cardiac re- man liver and small intestine29 and consists of at polarization (QT interval) without altering depolar- least 3 isoforms in humans (ie, CYP3A4, CYP3A5, ization.25 Although symptomatic arrhythmia related and CYP3A7) capable of metabolizing numerous to cisapride appear to occur infrequently, a pro- drugs and endogenous substrates. Shortly after birth, longed QTc interval in the very young infants is a shift in activity from CYP3A7 to CYP3A4 begins to potentially of concern. Increased QT dispersion has occur.30,31 been advocated by some authors to be a good marker Lacroix et al30 demonstrated that the extent of of an increased risk of ventricular arrhythmia in catalytically active CYP3A4 present in the liver of adult patients with heart disease,26 while other au- infants at 1 month of postnatal age was ϳ30% of thors have found QT dispersion not to be a reliable adult activity. Levels of CYP3A4 activity in infants marker for arrhythmic risk in children with idio- seem to approach adult values by ϳ6 to 12 months of pathic ventricular arrhythmia and structurally nor- age. Furthermore, CYP3A4 is characterized by sub- mal hearts.38 We could not measure QT dispersion in stantial intersubject variability in both hepatic en- this study, because this necessitates the recording of zyme content and constitutive activity.32 Gotschall et 12 electrocardiographic leads. In the study by Hill al32 provided in vitro evidence using human hepatic and associates,37 only 3 of 35 children on cisapride microsomes and heterologously expressed human therapy had an increased QT dispersion. Further cytochromes P-450 that CYP3A4 is responsible for studies on QT dispersion in infants on cisapride ther- catalyzing the biotransformation of cisapride to its apy are required before definite conclusions can be major metabolite, norcisapride. Norcisapride has no made regarding its usefulness as a risk marker for intrinsic activity on myocardial conduction.33 ventricular arrhythmia. Immaturity of cytochrome P-450 3A4 may result in poor clearance of cisapride and may be related to the effect on QTc in infants under 3 months of age ob- CONCLUSION served in our study. Administration of cisapride The use of cisapride in infants older than 3 months with any drug that inhibits CYP3A4 such as the of age is not associated with significantly longer QT macrolide antibiotics (erythromycin and clarithro- intervals, compared with controls. However, infants mycin) and the azole antifungal agents (ketocon- younger than 3 months of age on cisapride have a azole, fluconazole, miconazole, and itraconazole) has significantly longer QT interval than that of the con- the capacity to inhibit cisapride biotransformation trol group. The QTc duration in infants under 3 and, thus, increase cisapride plasma concentration. months of age suggests a pro-arrhythmic effect, and

4of5 CISAPRIDE EFFECTSDownloaded ON from QTc, www.aappublications.org/news HEART RATE AND RHYTHM by guest on INSeptember INFANTS 30, 2021 judicious use of cisapride in this age group is re- 19. Shulman RJ, Boyle T, Coletti RB, et al. The use of cisapride in children. quired. J Pediatr Gastroenterol Nutr. 1999;28:529–533 20. Vandenplas Y, Goyvaerts H, Helven R, Sacre´L. Gastroesophageal reflux, in 509 healthy infants screened for risk of sudden infant death ACKNOWLEDGMENT syndrome. Pediatrics. 1991;88:834–840 We thank R. Kerstens, MSc (Janssen Research Foundation) for 21. Rowland M. In: Melmon R, Morelli H, eds. Clincial Pharmacology. New the biostatistical support. York, NY: Macmillan; 1972:53 22. Winters RW. Water and electrolyte regulation. In: Winters RW, ed. The REFERENCES Body Fluids in Pediatrics. Boston, MA: Little, Brown and Company; 1973 1. Wysowski DK, Bacsanyi J. Cisapride and fatal arrhythmia. N Engl J Med. 23. 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