Efficacy and tolerability of cisapride in children.

As gastro-oesophageal reflux disease (GORD) in infants and children is a motility disorder which differs in pathophysiology and clinical course from GORD in adults, prokinetics should be considered the drug of choice in certain circumstances. Indeed, cisapride may result in improvement of feeding tolerance in premature infants. Cisapride has a better tolerability profile than a 'wait-and-see-if-improvement-comes-spontaneously' policy or the other therapeutic options available. A careful and critical review of published data suggests that cisapride may have a QTc-prolonging effect. However, provided the precautions for cisapride administration are followed, the QTc-prolonging effect remains consistently without clinically relevant adverse effects. Correct dosage and avoidance of concurrent treatment with macrolides and/or azoles are the most relevant tolerability recommendations in children. Although there is a need for a prokinetic with better efficacy, cisapride is currently the prokinetic with the best benefit-to-risk ratio available. Thus, withdrawal of cisapride would result in a significantly increased risk for severe complications in infants and children with GORD or other gastrointestinal motility disorders such as chronic intestinal pseudo-obstruction, gastroparesis and feed intolerance in premature infants.

The effect of cisapride on the corrected QT interval and QT dispersion in premature infants.

BACKGROUND: Cisapride is used frequently in premature neonates as a gastrointestinal prokinetic drug. Concerns exist, however, about its safety because of its effect on the QT interval. Premature infants could be at higher risk for side effects because of their immaturity. This prospective study investigated the pharmacokinetics of cisapride and its effects on corrected QT interval (QTc) and QT dispersion in premature infants. METHODS: Electrocardiogram examination was performed just before and after 72 hours of treatment with cisapride (0.2 mg/kg per dose, four times daily) in 10 premature infants. Trough and anticipated peak plasma level of cisapride and norcisapride were quantified after 72 hours of treatment. Results were compared with a cohort of 41 term infants aged 0 to 3 months receiving cisapride treatment. RESULTS: The QTc interval increased significantly from 423 ms to 461 ms after 72 hours of treatment (P = 0.0007). No effect was seen on QT dispersion (44.3 ms vs. 45.9 ms). The change in QTc interval was inversely related to postnatal age (R2 = 0.52; P = 0.02), whereas there was no correlation with gestational age or plasma levels of cisapride or norcisapride. Trough and anticipated peak plasma levels of cisapride and norcisapride were significantly higher in the premature infants compared with the term infants aged 0 to 3 months (P < 0.001). CONCLUSIONS: Premature infants less than 1 month of age could be at higher risk for cardiac side effects of cisapride when used in the same dosage as in older infants. The daily dose should be reduced (0.1 mg/kg per dose, maximum four times daily), and the QTc interval should be monitored closely. The benefits and safety of cisapride in premature infants less than 1 month of age should be reconsidered.

Cisapride plasma levels and corrected QT interval in infants undergoing routine polysomnography.

BACKGROUND: Reported QTc prolongation associated with cardiac arrhythmia in a small number of children undergoing cisapride therapy and lack of pharmacokinetic correlation provided the impetus for this prospective study. The authors evaluated the relation between cisapride plasma concentrations, the electrocardiographic QT interval, and cardiac rhythm in infants undergoing routine 8-hour polysomnography. METHODS: A total of 211 infants were enrolled: 84 (17 born prematurely) undergoing cisapride therapy for at least 4 days for suspected gastroesophageal reflux and 127 controls (10 born prematurely), aged between 1 week and 13.5 months. Infants underwent continuous bipolar limb lead I recording during routine 8-hour polysomnography. QT intervals and heart rate were measured at hourly intervals. The morning after polysomnography, 12-lead electrocardiography was performed (1 hour after cisapride administration). Cisapride plasma concentrations were determined immediately before and 1 to 2 hours after administration. Serum electrolyte concentrations were measured. RESULTS: The administered cisapride dose ranged from 0.35 to 1.55 (mean, 0.81, median 0.79) mg. kg-1. d-1. Cisapride plasma concentrations were significantly higher in infants younger than 3 months of age. Cisapride-treated infants younger than 3 months of age had longer QTc intervals compared with age-matched controls. Heart rate was similar for cisapride-treated and control infants. No arrhythmia or atrioventricular conduction abnormalities were observed. CONCLUSIONS: At comparable doses of cisapride and comparable plasma concentrations, the QTc was significantly higher in infants younger than 3 months of age. This confirms age-dependent cisapride pharmacokinetics in the first 10 to 12 weeks strongly correlated with changes in body weight and may also suggest an altered ability of infants younger than 3 months of age to metabolize cisapride. The clinical significance and risk of the increased QTc interval is unclear. Cisapride should be judiciously prescribed in infants younger than the age of 3 months and electrocardiography should be performed before and during therapy.

Comparison of formulae for heart rate correction of QT interval in exercise ECGs from healthy children.

OBJECTIVE: To investigate the differences in four formulae for heart rate correction of the QT interval in serial ECG recordings in healthy children undergoing a graded exercise test. SUBJECTS: 54 healthy children, median age 9.9 years (range 5.05-14.9 years), subjected to graded physical exercise (on a bicycle ergometer or treadmill) until heart rate reached > 85% of expected maximum for age. DESIGN: ECG was recorded at baseline, at maximum exercise, and at one, two, four, and six minutes after exercise. For each stage, a 12 lead digital ECG was obtained and printed. In each ECG, QT and RR interval were measured (lead II), heart rate was calculated, and QTc values were obtained using the Bazett, Hodges, Fridericia, and Framingham formulae. A paired t test was used for comparison of QTc, QT, and RR interval at rest and peak exercise, and analysis of variance for all parameters for different stages for each formula. RESULTS: From peak exercise to two minutes recovery there was a delay in QT lengthening compared with RR lengthening, accounting for differences observed with the formulae after peak exercise. At peak exercise, the Bazett and Hodges formulae led to prolongation of QTc intervals (p < 0.001), while the Fridericia and Framingham formulae led to shortening of QTc intervals (p < 0.001) until four minutes of recovery. The Bazett QTc shortened significantly at one minute after peak exercise. CONCLUSIONS: The practical meaning of QT interval measurements depends on the correction formula used. In studies investigating repolarisation changes (for example, in the long QT syndromes, congenital heart defects, or in the evaluation of new drugs), the use of an ad hoc selected heart rate correction formula may bias the results in either direction. The Fridericia and Framingham QTc values at one minute recovery from exercise may be useful in the assessment of long QT syndromes.

Atrial flutter in the perinatal age group: diagnosis, management and outcome.

OBJECTIVES: The aim of this retrospective study was to evaluate perinatal atrial flutter (AF) and the efficacy of maternally administered antiarrhythmic agents, postpartum management and outcome. BACKGROUND: Perinatal AF is a potentially lethal arrhythmia, and management of this disorder is difficult and controversial. METHODS: Forty-five patients with documented AF were studied retrospectively. RESULTS: Atrial flutter was diagnosed prenatally in 44 fetuses and immediately postnatally in 1 neonate. Fetal hydrops was seen in 20 patients; 17 received maternal therapy, 2 were delivered and 1 was not treated because it had a severe nontreatable cardiac malformation. In the nonhydropic group of 24 patients, 18 were treated and the remaining 6 were delivered immediately. In the hydropic group, 10 received single-drug therapy (digoxin or sotalol) and 7 received multidrug therapy. In the nonhydropic group, 13 received a single drug (digoxin or sotalol) and 5 received multiple drugs. One patient with rapid 1:1 atrioventricular conduction (heart rate 480 beats/min) died in utero and another died due to a combination of severe hydrops because of the AF, sotalol medication, stenosis of the venous duct and hypoplastic placenta. Of the 43 live-born infants, 12 were in AF at birth. Electrical cardioversion was successful in eight of nine patients. No recurrences in AF have occurred beyond the neonatal period. Four patients with fetal flutter and hydrops showed significant neurological pathology immediately after birth. CONCLUSIONS: Fetal AF is a serious and threatening rhythm disorder, particularly when it causes hydrops, it may be associated with fetal death or neurological damage. Treatment is required and primarily aimed at reaching an adequate ventricular rate and preferably conversion to sinus rhythm. Digoxin failed in prevention of recurrence at time of delivery in a quarter of our patients, whereas with sotalol no recurrence of AF has been reported, suggesting that class III agents may be the future therapy. Once fetuses with AF survive without neurological pathology, their future is good and prophylaxis beyond the neonatal period is unnecessary.

Effects of cisapride on corrected QT interval, heart rate, and rhythm in infants undergoing polysomnography.

OBJECTIVE: To evaluate the effects of cisapride, a prokinetic gastrointestinal drug, on the electrocardiographic QT interval, heart rate, and rhythm in infants during routine 8-hour polysomnography. Reported electrocardiogram (ECG) and rhythm disturbances in a small number of patients with the use of cisapride provided the impetus for this prospective study. STUDY DESIGN: Two hundred fifty-two infants born at term were enrolled. Of these, 134 were on cisapride therapy for suspected gastroesophageal reflux and 118 were not on cisapride and served as controls. Cisapride-treated and control infants were from the outset divided into 3 age groups; group 1: under 3 months of age; group 2: between 3 and 6 months of age; and group 3: >6 months of age. Continuous ECG bipolar limb lead I recording, saturation monitoring, and electroencephalography were conducted. QT intervals and heart rate were measured at hourly intervals. RESULTS: Cisapride doses were: group 1 mean, 0.80 mg/kg/day (range: 0.38-1.55); group 2 mean, 0.80 mg/kg/day (range: 0. 23-1.38); and group 3 mean, 0.72 mg/kg/day (range: 0.32-1.41). Heart rate was higher in the younger infants, with a gradual decrease with age. No difference in heart rate was detected between the cisapride and control groups. The QTc interval in patients in group 1 was statistically longer than the controls, when applying both Bazett's and Hodges' formulae for QT correction. The other age groups did not differ. No arrhythmia or atrioventricular conduction abnormalities were observed. CONCLUSION: Infants under 3 months of age on cisapride treatment had significantly longer QTc intervals (with Bazett's formula, the 98th percentile was 504 ms in the cisapride group vs 447 ms in controls). The clinical significance and risk of the increased QTc interval in these infants are unclear and need further evaluation and risk stratification. Meanwhile, cisapride should be judiciously prescribed in infants <3 months of age.

Left-ventricular inflow obstruction due to a dilated coronary sinus mimicking Cor Triatriatum.

Persistence of the left superior vena cava with drainage to the coronary sinus is a common congenital anomaly. We report an infant with such a malformation associated with marked enlargement of the coronary sinus, which produced partial supramitral obstruction and consequently impairment to the left-ventricular inflow. The patient pre-sented with cardiac failure in infancy and features mimicking cor triatriatum. Surgical relief of the supramitral obstruction resulted in immediate reversal of the pulmonary hypertension, with clinical improvement. This rare entity, only once previously reported, is an unusual cause of pulmonary hypertension in infancy.

The role of cisapride in the treatment of pediatric gastroesophageal reflux. The European Society of Paediatric Gastroenterology, Hepatology and Nutrition.

BACKGROUND: Cisapride is a gastrointestinal prokinetic agent that is used worldwide in the treatment of gastrointestinal motility-related disorders in premature infants, full-term infants, and children. Efficacy data suggest that it is the most effective commercially available prokinetic drug. METHODS: Because of recent concerns about safety, a critical and in-depth analysis of all reported adverse events was performed and resulted in the conclusions and recommendations that follow. RESULTS: Cisapride should only be administered to patients in whom the use of prokinetics is justified according to current medical knowledge. If cisapride is given to pediatric patients who can be considered healthy except for their gastrointestinal motility disorder, and the maximum dose does not exceed 0.8 mg/kg per day in 3 to 4 administrations of 0.2 mg/kg (not exceeding 40 mg/d), no special safety procedures regarding potential cardiac adverse events are recommended. However, if cisapride is prescribed for patients who are known to be or are suspected of being at increased risk for drug-associated increases in QTc interval, certain precautions are advisable. Such patients include those:(1) with a previous history of cardiac dysrhythmias, (2) receiving drugs known to inhibit the metabolism of cisapride and/or adversely affect ventricular repolarisation, (3) with immaturity and/or disease causing reduced cytochrome P450 3A4 activity, or (4) with electrolyte disturbances. In such patients, ECG monitoring to quantitate the QTc interval should be used before initiation of therapy and after 3 days of treatment to ascertain whether a cisapride-induced cardiac adverse effect is present. CONCLUSIONS: With rare exceptions, the total daily dose of cisapride should not exceed 0.8 mg/kg divided into 3 or 4 approximately equally spaced doses. If higher doses than this are given, the precautions above are advisable. In any patient in whom a prolonged QTc interval is found, the dose of cisapride should be reduced or the drug discontinued until the ECG normalizes. If the QTc interval returns to normal after withdrawal of cisapride, and the administration of cisapride is considered to be justified because of its efficacy and absence of alternative treatment options, cisapride can be restarted at half dose with control of the QTc interval. Unfortunately, at present, normal ranges of QTc interval in children are unknown. However, a critical analysis of the literature suggests that a duration of less than 450 milliseconds can be considered to be within the normal range and greater than 470 milliseconds as outside it.

Tetralogy of Fallot with absent pulmonary valve. A continuing challenge.

Absent pulmonary valve syndrome (APVS); the combination of tetralogy of Fallot (TOF) with agenesis of the pulmonary valve, is a relatively rare cardiac malformation. Despite the anatomic similarity with classic TOF, the pathophysiology is strikingly different. Data on 10 patients (3 male, 7 female) with APVS, treated between January 1978 and December 1995, were retrospectively reviewed. During this period a total of 2920 children underwent correction of a variety of congenital cardiac anomalies, of which 246 patients (8%) had a correction for TOF. Two patients with APVS presented within the first four months of life with severe cardiorespiratory distress and required several operative procedures. The remaining eight patients had only mild to moderate respiratory and/or cardiac symptoms and elective intracardiac repair was performed on those between the ages of 10 months and 9.5 years. Associated cardiac anomalies seen in five patients included aberrant coronary artery, absent or interrupted left pulmonary artery, partial AVSD and aberrant azygos continuation. In those electively corrected, the strategies used were ventriculotomy (7), pulmonary homograft (3) and aneurysmorrhaphy (2). There were two deaths, one in each group of patients, as a result of progressive respiratory insufficiency and cardiac tamponade, respectively. The follow-up of the eight survivors ranged from 2 to 11 years (median 6.75). All have a normal effort tolerance; only one child is on digoxin therapy, and one child continues to suffer bronchospastis episodes. Our experience with infants with this lesion is limited but underlines the different approaches required, depending on the age of presentation.

Successful use of an intraosseous infusion in an 800 grams preterm infant.

An intravascular access line for the administration of life support drugs and volume expanders may be particularly difficult, especially in very small premature babies. We report on the successful use of an intraosseous accessline in an 800 grams preterm infant for the administration of drugs and fluid. The use and technique of an intraosseous access is an important emergency alternative which may be lifesaving, even in very preterm babies, when other methods fail.

Air travel and adults with cyanotic congenital heart disease.

BACKGROUND: Concern has been expressed that a reduction of partial oxygen pressure during flight in commercial aircraft may induce dangerous hypoxemia in patients with cyanotic congenital heart disease. METHODS AND RESULTS: To evaluate the validity of this concern, the transcutaneous SaO2 was measured in 12 adults with this type of heart disease and 27 control subjects during simulated commercial flights of 1.5 and 7 hours in a hypobaric chamber. Ten of those patients and 6 control subjects also were evaluated during two actual flights of approximately 2.5 hours in a DC-10 and an A-310, respectively. During the prolonged simulated and actual flights, the capillary blood pH, gases, and lactic acid were analyzed in the patients and during one of the actual flights also in the control subjects. During the simulated flights the SaO2 was at all times lower in the patients than in the control subjects. However, the maximal mean actual percentage decrease, as compared with sea level values, did not exceed 8.8% in either patients or control subjects. During the actual flights, this maximal decrease in the patients was 6%. In-flight reduction of the capillary PO2 was considerable in the control subjects but not in the patients. It is our hypothesis that the lack of a significant decrease of the PO2 in the patients might possibly be due to a high concentration of 2.3 diphosphoglycerate in the red cells. The flights had no influence on the capillary blood pH, PCO2, bicarbonate, or lactic acid levels in either patients or control subjects. CONCLUSIONS: Atmospheric pressure changes during commercial air travel do not appear to be detrimental to patients with cyanotic congenital heart disease.

Atrioventricular septal defect and type A postaxial polydactyly without other major associated anomalies: a specific association.

Four children are described, (three black and one white, two boys and two girls) with type A postaxial polydactyly. All four of them, in addition, had either a partial or complete atrioventricular septal defect (AVSD). None of these children had associated major malformations. Minor anomalies were observed (e.g., two patients with hypersegmentation of the sternal segments, one patient with undescended testes, one patient with hypoplastic lumbar vertebra, and one patient with a degree of craniofacial abnormality). Chromosome analysis was carried out for three of the four patients, and was normal in all of them. It is suggested that there is a specific association between type A postaxial polydactyly and the AVSD found in each of these patients. This picture does not conform to, but bears some resemblance to, the Ellis-van Creveld syndrome.

Pulmonary hypertension in infants with chronic lung disease: non-invasive evaluation and short term effect of oxygen treatment.

A total of 45 examinations on 30 premature infants with chronic lung disease (CLD) of prematurity were made using Doppler echocardiography. Pulmonary systolic time intervals and tricuspid regurgitant velocity were measured to assess the prevalence of pulmonary hypertension and short term responsiveness of the pulmonary circulation to oxygen. Twelve preterm infants matched for gestational age, served as controls. Tricuspid regurgitation (TR) was detected in 14 of the patients. Eleven of those with TR had pulmonary hypertension, of whom eight responded to oxygen treatment. Of the remaining three patients with 'fixed' pulmonary hypertension, one subsequently died. The detection of TR was the basis of the preferred method for measuring pulmonary artery pressure (Ppa) non-invasively, but the degree of correlation between the Ppa estimated from TR and pulmonary systolic time intervals was high (r = -0.84, p = 0.001). In the absence of TR, systolic time intervals are an effective way to monitor pulmonary artery pressure in infants with CLD. Without these measurements, it would have been impossible to predict which subjects had pulmonary hypertension, and which might respond to oxygen treatment.

Mid-term results of the modified Senning operation for cavopulmonary connection with autologous tissue.

UNLABELLED: The aim of this study was to determine the results and mid-term outcome of a modified Senning technique using autologous tissue for total cavopulmonary connection. The study involved 31 children, 8 with tricuspid atresia and 23 with complex congenital heart disease. In this operation, a flap of autologous atrial free wall tissue was used to tunnel inferior vena caval blood to the pulmonary arteries. An additional Damus-Kay-Stansel operation was required in 9 patients with subaortic obstruction. RESULTS: the early mortality rate was 16% (5 out of 31 patients) and there were four late deaths. COMPLICATIONS: Pleural effusions were encountered in 17 patients, of whom 4 had a concomitant pericardial effusion. Diaphragmatic paralysis was diagnosed in five patients, one of whom underwent surgical plication. Median hospital stay was 26 days. The 1- to 5-year actuarial survival was 68.6%. Follow-up ranged from 10 months to 7.1 years, mean 3.2 years. A serious atrial arrhythmia was diagnosed in one patient and another one died, possibly from rhythm disorders. Exercise tolerance and quality of life has improved in all but one of the survivors. Although follow-up is short, we have thus far witnessed a low incidence of hemodynamic and rhythm disturbances with this modification of the cavopulmonary connection.

Complication of intra-aortic balloon pumping in a pediatric patient.

A serious complication was seen following insertion of an intra-aortic balloon pump in the ascending aorta in a pediatric patient. The catheter initially coursed to the left subclavian artery from which it folded upon before finding its way in the descending aorta. We recommend that a suitably curved J-tip guidewire be used to guide the IABP balloons distal to the aortic arch into the descending aorta, so as to avoid potentially fatal complications.