Dose-Dependent Electrophysiologic Effects of Amiodarone in the Immature Canine Heart ARTHUR S. PICKOFF, MD, SHARANJEET SINGH, MD, CELIA J. FLINN, MD, EDDA TORRES, MD, ALAN M. EZRIN, PhD, and HENRY GELBAND, MD, With the technical assistance of JUDITH KASSNER and CARLOS A. FLORES The electrophysiologlc effects of incremental doses of Intravenous amlodarone were studied In the Intact neonatal canine heart and were compared wlth the responses observed In the adult. Seven neonatal puppies aged 5 to 14 days, and 6 adult dogs were studied. Assessment of sinus and atrloventrlcular (AV) nodal function and atria1 and ventricular re- fractory periods was performed using standard HIS bundle recording techniques and programmed ex- trastlmulation before and after doses of 2.5,s and 10 mg/ki of Intravenous amlodarone. Amlodarone depressed sinus node cycle length, slnus node re- covery tlme and AV nodal conductIon in both groups. Atrlal and ventricular refractory periods were also prolonged In a dose-dependent fashion in both the neonatal and adult dogs. Although similar responses to amlodatone were observed in both groups, the Immature dogs were more sensltlve to amlodarone In prolongation of atrial refractory perlods and de- presslon of sinus node recovery time. The neonatal group, however, demonstrated more resistance to amlodarone-Induced depresslon of AV nodal con- duction. Thus, Intravenous amlodarone produces dose-dependent electrophysiologlc changes In the neonate similar to those In the adult, although the slgnlficant differences in drug sensltlvlty may be clinically Important. (Am J Cardlol 1983;52:621-625) Amiodarone has been proved effective in a wide variety of atria1 and ventricular arrhythmias in adults.‘-5 In children, this benzofuran derivative has been reported to be well tolerated and also very effective in treating cardiac arrhythmias.e Recent reports have suggested that in children, amiodarone may be particularly useful in treating atrial flutter7 and primary ventricular ar- rhythrhias.s However, the electrophysiologic effects of amiodarone in the immature heart have not been de- fined. Information available concerning the electro- physiologic effects of intravenous amiodarone has been from studies performed in the adult. In these studies, intravenous amiodarone has been shown to prolong atrioventricular (AV) nodal conduction time (that is, prolonged AH interval), although the effects on sinus node recovery time and atrial and ventricular refractory periods have been variable.g-13 The objective of this study is to define the electrophysiologic responses of the immature mammalian heart to incremental intravenous From the Division of Pediatric Cardiology, Department of Pediatrics, University of Miami School of Medicine. Miami, Florida. This study was supported in part by Clinical Investigator AwardH00881, andksearch Training Grant HL07438 from the National Heart, Lung, and Blood In- stitute. the National Institutes of Health. Bethesda. Meryland. and by a grant fnxn lhk Anmrican Heart Association of Greater Miami. hkruwlpt received March 14, 1983; revised manuscript received zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA May 9. 1983. accepted May 10,1983. Address for reprints: Arthur S. Pickoff, MD, Pediatric Cardiology, DepwlmM of PedMrks, uliwrsny Of MaInI, school of Medkine, P.O. Box 016820, Miami. Florida 33101. doses of amiodarone. These responses are compared with those observed in a group of mature animals to define developmentally determined differences in the response to amiodarone of the neonatal myocardium and specialized conduction system. Methods Two groups of dogs were studied: Group I included 7 neo- nates, aged 5 to 14 days, and Group II included 6 adults. All subjects were anesthetized with pentobarbital, 20 ta 30 mglkg, either intravenously (Group II) or intraperitoneally (Group I). All subjects underwent endotrachial intubation and were placed on an artificial ventilator with a tidal volume of 7 to 15 ml/kg. Surface electrocardiographic lead II and right femoral ar- tery blood pressure were monitored. Through a femoral transvenous cutdown, a No. 5 Elecath quadripolar electrical catheter (or No. 4 tripolar catheter in the neonates) was po- sitioned under fluoroscopic visual guidance to the high right atrium to record the atria1 electrogram and pacing. Through a left femoral approach in Group II or an external jugular vein approach in Group I, No. 5 tetrapolar and No. 4 tripolar electrophysiologic catheters, respectively, were advanced to the right ventricle apex. The His bundle electrogram was re- corded by introducing a No. 4 tripolar catheter into the right carotid artery and advancing the catheter to the right coronary cusp of the aorta. All intracardiac electrograms were amplified at a filter setting of 40 to 500 Hz (Electronics for Medicine DR-6) and recorded simultaneously with the surface elec- trocardiogram and femoral artery blood pressure on direct- writing paper (Kodak linagraph paper 2201, Eastman Kodak Company) at a paper speed of 100 mm/s. 621