Pharmacokinetics of esmolol in children.

The pharmacokinetics and concentration-response relationships of intravenous esmolol were investigated in 20 children undergoing indicated cardiac electrophysiologic testing. A loading dose of 600 micrograms/kg was infused for 2 minutes. An infusion of esmolol was initiated and dosage was titrated until beta-blockade occurred. Serial esmolol blood samples were obtained for pharmacokinetic analysis. Non-compartmental pharmacokinetic analysis of the data revealed the following parameter estimates (mean +/- SD): volume of distribution at steady state, 2.0 +/- 1.4 L/kg; total body clearance, 321.2 +/- 238.8 ml/kg/min; and terminal elimination half-life, 4.5 +/- 2.1 minutes. There was a significant correlation between mean esmolol concentrations and mean percentage of reductions of mean arterial pressures and heart rates at each sample time (p less than 0.001). The doses of esmolol required for beta-blockade (mean +/- SD, 535 +/- 180 micrograms/kg/min) in children were considerably higher than those typically used in adults. Esmolol should prove useful in children in the acute management of cardiac arrhythmias and hypertension.

Pharmacokinetics and pharmacodynamics of atenolol in children.

The pharmacokinetics and pharmacodynamics of intravenous atenolol were studied in 10 children during cardiac electrophysiologic studies. The intravenous pharmacokinetic data were best described by a two-compartment model and revealed the following (mean +/- SD): total body clearance, 0.15 +/- 0.06 L/hr/kg; volume of the central compartment 0.33 +/- 0.06 L/kg; volume of distribution at steady state, 0.83 +/- 0.15 L/kg; distributive elimination half-life, 0.29 +/- 0.08 hour; and terminal elimination half-life, 4.56 +/- 1.05 hours. The data suggest that children have a slightly shorter terminal elimination half-life than that of adults. Pharmacodynamic data showed a significantly (p less than 0.01) increased sinus cycle length and an increase in His to ventricle conduction time (p less than 0.05). Further studies are necessary to determine the optimal oral dose and dosing frequency of atenolol and to access the response of children to long-term treatment.

Long QT syndrome associated with syndactyly identified in females.

The identification of female children with this syndrome is evidence that this disorder is not X-linked in inheritance. Possible inheritance modes still include autosomal recessive or, more likely, a de novo mutation, given the absence of family history in any of the patients. Children of both sexes with syndactyly should be screened with an electrocardiogram for this syndrome. Female children with this syndrome may have an increased risk of sudden death similar to male children.

New antiarrhythmic agents in pediatrics.

This article reviews recent developments in the pharmacologic management of arrhythmias in children and provides specific information about six newer antiarrhythmic agents. With the current increase in recognition, frequency, and complexity of rhythm disturbances in children, pediatricians can expect to encounter children on these antiarrhythmic medications in their practices with increasing frequency.

The longitudinal time course of QTc in early infancy. Preliminary results of a prospective sudden infant death syndrome surveillance program.

Eleven hundred one healthy neonates in Charleston County, SC, were enrolled in a prospective, serial measurement sudden infant death syndrome/QT surveillance program. Automated computer-enhanced ECGs were recorded at 1 day of age in the hospital nursery and again at 1 week and 1, 2, and 3 months in the participant's home. At 1 year, the families were contacted by phone or mail and questioned as to the health of the child. Validation studies demonstrated the computer-enhanced ECGs to be 96% accurate, whereas traditional ECG recording and measurement was 94% accurate. No systematic differences in the QTc according to race and sex were observed. There were parallel longitudinal time courses for each race and sex group with a significant (P less than .001) shortening of the QTc at 1 week. There was no evidence of tracking of the QTc during the first 3 months of life. In conclusion, (1) automated, enhanced ECG QTc intervals are superior to traditional electrocardiography while retaining the advantages of automation; (2) there is a significant shortening of the QTc during the first month of life; and (3) a home follow-up sudden infant death syndrome surveillance program is feasible and produces accurate, reliable information.

Atenolol in children with ventricular arrhythmias.

Twenty children and adolescents treated orally with atenolol for chronic paroxysmal ventricular tachycardia (n = 10) or Long QT Syndrome (n = 10) over a 5 year period were retrospectively evaluated to ascertain the efficacy of arrhythmia suppression, the effective dosage, the cardiovascular effects, and the incidence of adverse effects. Patients with paroxysmal ventricular tachycardia were classified by their response to exercise or catecholamines. Atenolol was effective in each patient (n = 5) whose tachycardia was precipitated or exacerbated by exercise or catecholamines when the patient was receiving a dosage of approximately 1.7 mg/kg/day. In those patients (n = 4) in whom exercise or catecholamines either suppressed or had no effect on the tachycardia, none were effectively treated in spite of receiving comparable dosages. Three of these four patients also had structural abnormalities or myocardial dysfunction. Atenolol was effective in treating 4 of 10 patients with long QT syndrome with a dosage of approximately 1.5 mg/kg/day. Six ineffectively treated patients received similar dosages, and four required either additional medication or surgical sympathectomy for persistent syncope. The other two patients died suddenly. Cardiovascular side effects included bradycardia in three patients and hypotension in one. Noncardiovascular effects included mild fatigue (four patients) headache (two), sleep disturbance (two), and difficulty concentrating (one). The medication was discontinued because of side effects in two patients. Atenolol is more likely to be effective in the suppression of paroxysmal ventricular tachycardia in children if the tachycardia is exacerbated by exercise or catecholamines and if the heart is otherwise normal.

Cardiovascular and antiarrhythmic effects of esmolol in children.

This prospective study evaluated the cardiovascular and antiarrhythmic effects of esmolol, an intravenous beta-blocker with an extremely short half-life. Twenty patients (aged 2 to 16 years) underwent diagnostic electrophysiologic studies at rest and during beta-blockade induced with esmolol. An initial dose of 600 micrograms/kg was infused for 2 minutes and followed by an infusion of 200 micrograms/kg per minute. The dosage was increased by 50 to 100 micrograms/kg per minute every 5 to 10 minutes until a reduction of greater than 10% in either heart rate or mean blood pressure was seen. The dosage required to achieve beta-blockade ranged from 300 to 1000 micrograms/kg per minute (mean 550 micrograms/kg per minute). Electrophysiologic effects included a decrease in the rate of sinoatrial node discharge and delay in conduction through the atrioventricular node. There was no effect on His-Purkinje conduction. Atrial and ventricular effective refractory periods were unchanged. In six patients with supraventricular tachycardia, esmolol prevented induction of tachycardia in four and slowed the rate of the tachycardia in two. In four patients with ventricular tachycardia, clinical findings were improved in three and unchanged in one. Heart rate and blood pressure returned to near baseline values 10 minutes after the esmolol infusion was stopped. Adverse ventricular electrophysiologic effects were observed in two patients with biopsy evidence of myocarditis. No other adverse effects were seen. We conclude that the effects of esmolol in children are similar to those of other beta-blockers and that it is useful in the evaluation and management of pediatric tachyarrhythmias. The weight-adjusted dosage required to induce beta-blockade in children is larger than the adult dosage, and the effects of esmolol dissipate rapidly.

The acute effects of flecainide in the swine heart failing from incessant supraventricular tachycardia.

The acute hemodynamic and electrophysiologic effects of flecainide in tachycardia-induced ventricular dysfunction were investigated using an animal model. Seven swine were initially (CON) evaluated by echocardiography and then by right heart catheterization and provocative electrical ventricular stimulation both before and after treatment with intravenous flecainide. Rapid atrial pacing at 210 to 240 beats/min (SVT) was then employed for 2 to 4 weeks until echocardiographic evidence of left ventricular dysfunction developed. Immediately upon termination of pacing, the above studies were repeated both before and after treatment with flecainide. Significant (p less than 0.0001) pacing-related hemodynamic effects on the cardiac output (CON:3.0 L/min versus SVT:1.6 L/min), right ventricular ejection fraction (CON:55% versus SVT:17%), and pulmonary wedge pressure (CON:8 mm Hg versus SVT:22 mm Hg) were observed. Pacing-related electrophysiologic effects included increases in the PR interval (CON:94 msec versus SVT:119 msec, p less than 0.001) and QTc interval (CON:418 msec versus SVT:450 msec, p = 0.016). With serum flecainide concentrations in the human therapeutic range, no significant effect on hemodynamic or electrophysiologic parameters in either the normal or failing heart were detected. Nonsustained ventricular tachycardia induced prior to pacing in one animal and after pacing in another animal was seen before but not following use of flecainide. No acute proarrhythmic effects were observed. In summary, intravenous flecainide had no significant acute adverse hemodynamic, electrophysiologic, or proarrhythmic effects in an animal model of tachycardia-induced ventricular dysfunction.