Amiodarone: Value of Programmed Electrical Stimulation and Holter Monitoring

The value of programmed electrical stimulation (PES) and Holter monitoring in the assessment of amiodarone efficacy was reviewed. Many physicians have been disturbed by the persistent inducibility of arrhythmias in patients treated with amiodarone, who nevertheless do very well during the follow-up period. Noninducibility was associated with a favorable prognosis among 366 VT patients. Eighty-eight (24%) were noninducible on amiodarone, and 10% of these had recurrences, vs 39% in patients who remained inducible. Further, increased difficulty of induction with PES or induction of a slower or better tolerated VT may indicate a favorable outlook, and add to the value of PES. Few papers rigorously employed Holter monitoring in the assessment of amiodarone. In general, suppression of previously frequent arrhythmias implies excellent protection for patients with benign arrhythmias and moderate protection with malignant arrhythmias. By Holter assessment in 186 VT patients, arrhythmias were suppressed in 114 (61%), and 18% of these had recurrences vs 50% in patients whose arrhythmias were not suppressed. Studies attempting to correlate the results of PES and Holter monitoring in the same patients are lacking and may prove useful.     

Studies in Phlebitis. II. Early Detection of Amiodarone-Induced Phlebitis in a Rabbit Model

Pharmaceutical Research -     

Quantitative image analysis of drug-induced lung fibrosis using laser scanning confocal microscopy.

Pulmonary fibrosis is a serious lung disorder that in certain cases may be difficult to quantify. It was our objective to evaluate the use of laser scanning confocal microscopy (LSCM) in quantifying fibrosis after exposure to amiodarone (AD) and bleomycin (BLM), two commonly used therapeutic drugs known to cause debilitating lung fibrosis in humans. Male F344 rats were intratracheally dosed with AD (6.25 mg/kg on days 0 and 2), BLM (0.25 and 1.0 mg/kg on day 0), or their respective vehicle controls. The right lung was assayed for hydroxyproline, a biochemical measure of collagen, at day 21 for the BLM groups and day 28 for the AD groups. The left lung was fixed, sectioned into blocks, dehydrated, stained with Lucifer yellow (LY, 0.1 mg/ml), and embedded in Spurr resin. The area of lung tissue stained by LY was quantified by LSCM. A fibrotic response in the AD and BLM groups was confirmed by histopathological assessment and a significant increase (p < 0.05) in total right lung hydroxyproline above control values. The area of connective tissue stained by LY of the two drug-treated groups appeared as bright linear bands in the alveolar septae and was significantly increased (p < 0.05) as measured by image analysis when compared with their respective controls. LSCM, with its advanced image analysis system, is an alternate method to quantify fibrotic lung disease. LSCM could be particularly useful when tissue quantity is limited, such as when tissue has been archived from previous studies, or when analyzing human lung biopsy samples for disease diagnosis, where biochemical analysis is difficult.     

Effect of mexiletine,amiodarone and disopyramide on the excitability and refractoriness of canine cardiac fibers: Possible relation to antiarrhythmic drug action and classification

Summary We tested the hypothesis of Campbell [1] that the effect of the sodium channel-blocking antiarrhythmic drugs on postrepolarization refractoriness i.e., relation between action potential duration (APD) and effective refractory period (ERP) is determined by the drug's effect on the recovery from V_max block. We studied the effects of two antiarrhythmic drugs with fast (mexiletine, amiodarone), and one with slow (disopyramide) kinetics of recovery from V_max block, at two different basic cycle lengths (BCL), on ERP/APD ratio in cardiac dog Purkinje and ventricular muscle fibers. ERP was measured using stimuli of 2 ms duration and 1.0 to 5.0 times diastolic threshold strength. The three drugs altered the kinetics of recovery from V_max block in the manner previously reported by us and other investigators. In both fiber types, mexiletine increased and the other two drugs did not change the ERP/APD ratio. We concluded that the magnitude of postrepolarization refractoriness could not be predicted from the kinetics of the V_max block. Also, the effect of the drug on the ERP/APD ratio could be altered by changes in the stimulus strength and the BCL.This study was supported in part by the Herman C. Krannert Fund; by Grants HL-06308 and HL-07182 from the National Heart, Lung, and Blood Institute of the National Institutes of Health; by the American Heart Association, Indiana Affiliate, and by the Veterans Administration.     

Chronic amiodarone effects on epicardial conduction and repolarization in the isolated porcine heart

Amiodarone is a potent antiarrhythmic agent with complex chronic effects, notably on repolarization and conduction, that are not fully understood. Its low arrhythmogenic potential has been related to a lack of increase in repolarization dispersion. Since its effects are not documented in pigs we conducted a mapping study of activation and repolarization in isolated perfused porcine hearts. Amio20 female pigs (n = 7) received amiodarone 20 mg/kg per day over 4 weeks while Amio50 female pigs (n = 7) received 50 mg/kg per day over 4 weeks. Concentrations of the drug encompassed values found in clinical studies. Then, activation patterns and activation-to-recovery intervals (ARI) were mapped epicardially from 128 unipolar electrograms in isolated perfused hearts in corroboration of epicardial action potential recordings. Mean ARI was longer in Amio20 experiments compared to the seven control hearts (325 +/- 11 ms vs 288 +/- 5 ms at 1,000 ms), whereas ARI dispersion was not different, being comprised between 7 and 11 ms and generating smooth gradients. In Amio50 experiments, mean ARI was further prolonged (390 +/- 10 ms at 1,500 ms) with an exaggerated reverse rate dependence concomitant with a depressant effect on the plateau of the action potential. Again, ARI dispersion did not differ from controls. Finally, the drug depressed the maximal rate of depolarization (Vmax) and slowed conduction in a rate dependent and concentration dependent fashion. In conclusion, chronic amiodarone induces Class I and Class III antiarrhythmic effects in ventricular porcine epicardium that are concentration dependent but does not affect dispersion of repolarization. This may partly explain its low arrhythmogenic potential.     

ECMO for cardiac rescue in a neonate with accidental amiodarone overdose

Intravenous (IV) amiodarone hydrochloride has proven to be a very effective antiarrhythmic treatment option for a variety of ventricular and supraventricular arrhythmias in adults and paediatric patients. Amiodarone is known to have significant side effects and these especially include profound hypotension in animals and adults, vasodilatation, negative inotropic effects, and significant bradycardia especially when administered intravenously. Special caution is warranted in patients with decreased contractility and end-stage heart failure. We present a case of accidental amiodarone overdose in a newborn treated for atrial flutter resulting in cardiovascular collapse. The patient could be rescued by rapid initiation of VA-ECMO treatment. The patient survived without neurological damage. This case study was supported by hospital funding.     

Effect of amiodarone on dispersion of atrial refractoriness and cycle length in patients with atrial fibrillation

INTRODUCTION: Amiodarone is effective in preventing the recurrence of atrial fibrillation (AF) after cardioversion (CV). Dispersion of atrial refractoriness may be relevant to the generation of AF. We designed a study to determine the electrophysiologic effects of amiodarone in patients with previous early recurrence of AF after CV. METHODS AND RESULTS: Fifteen patients with previous AF recurrence (without antiarrhythmic drugs) after CV (CV1) were selected for amiodarone therapy and repeat CV (CVamio). Prior to CV1, mean AF cycle length (AFCL) had been recorded at four atrial sites (right atrial appendage [RAA], distal coronary sinus [DCS], right atrial lateral wall [LAT], and interatrial septum [IAS]) and dispersion of AFCL had been calculated. These patients were treated with amiodarone and, prior to CVamio, AFCL was recorded at the four atrial sites as for CV1. Between CV1 and CVamio, AFCL increased at all atrial sites: 153 +/- 13 msec to 179 +/- 14 msec at RAA, 144 +/- 12 msec to 174 +/- 18 msec at DCS, 158 +/- 13 msec to 182 +/- 16 msec at LAT, and 161 +/- 18 msec to 181 +/- 17 msec at IAS. Dispersion of AFCL decreased from 24 +/- 10 msec at CV1 to 15 +/- 11 msec at CVamio (P = 0.01). The median time in sinus rhythm increased from 3.12 hours post CV1 to 28 days post CVamio, (P < 0.02). CONCLUSION: Amiodarone causes a reduction in the dispersion of AFCL. This action may be relevant to the beneficial effects of amiodarone in patients with AF.     

An evaluation of postoperative P-wave variables after cardiothoracic surgery

Postoperative atrial fibrillation is common after cardiac surgery. Prediction of which patients will develop postoperative atrial fibrillation would be clinically useful. Increased P-wave duration, suggesting atrial conduction delay and measured from preoperative electrocardiograms, predicts postoperative atrial fibrillation. However, postoperative P-wave duration has not been evaluated after cardiac surgery. In this study, we evaluated postoperative P-wave variables (maximum P-wave duration and P-wave dispersion) over 5 days in cardiac surgery patients receiving amiodarone, pacing or no atrial fibrillation prophylaxis. P-wave variables gradually shortened as time passed from surgery. Amiodarone did not shorten P-wave measurements throughout therapy, while pacing shortened P-waves in the immediate postoperative period; however, shortening was not sustained. P-waves did not differ between those who did and did not develop atrial fibrillation with amiodarone or pacing. Our findings suggest that atrial conduction delay resulting from cardiothoracic surgery tends to resolve over time and may not play a critical role in the etiology of postoperative atrial fibrillation.     

胺碘酮治疗老年人心律失常的疗效观察

目的:观察胺碘酮对老年人房颤和频发室性早搏的治疗效果,并与普罗帕酮进行疗效比较。方法:年龄≥60岁的频发室性早搏和房颤患者70例,分入胺碘酮组(Am组,36例)和普罗帕酮组(Pr组,34例)进行治疗,对频发室性早搏患者随访1个月,对房颤患者随访6～12个月。结果:两组频发室性早搏,有效率无显著差异;对房颤的转复胺碘酮优于普罗帕酮,但维持窦性心律方面两组有效率无显著差异;两组阵发性心房颤动转复率无显著差异,Pr组转复时间短于Am组(P0.05);Am组窦性心律的维持率高于Pr组(P0.05)。Am组4周时QTc,P-R间期显著延长(P0.05),左室射血分数(LVEF)无显著变化。Am组不良反应多于Pr组,因不良反应停药者多于Pr组。结论:胺碘酮对于老年人频发室性早搏及房颤疗效显著,对心功能影响小,致心律失常作用少见。     

A Short‐Term,Randomized, Double‐Blind,Parallel‐Group Study to Evaluate the Efficacy and Safety of Dronedarone versus Amiodarone in Patients with Persistent Atrial Fibrillation: The DIONYSOS Study

Dronedarone versus Amiodarone in Patients with AF. Introduction: We compared the efficacy and safety of amiodarone and dronedarone in patients with persistent atrial fibrillation (AF). Methods: Five hundred and four amiodarone‐naïve patients were randomized to receive dronedarone 400 mg bid (n = 249) or amiodarone 600 mg qd for 28 days then 200 mg qd (n = 255) for at least 6 months. Primary composite endpoint was recurrence of AF (including unsuccessful electrical cardioversion, no spontaneous conversion and no electrical cardioversion) or premature study discontinuation. Main safety endpoint (MSE) was occurrence of thyroid‐, hepatic‐, pulmonary‐, neurologic‐, skin‐, eye‐, or gastrointestinal‐specific events, or premature study drug discontinuation following an adverse event. Results: Median treatment duration was 7 months. The primary composite endpoint was 75.1 and 58.8% with dronedarone and amiodarone, respectively, at 12 months (hazard ratio [HR] 1.59; 95% confidence interval [CI] 1.28–1.98; P < 0.0001), mainly driven by AF recurrence with dronedarone compared with amiodarone (63.5 vs 42.0%). AF recurrence after successful cardioversion was 36.5 and 24.3% with dronedarone and amiodarone, respectively. Premature drug discontinuation tended to be less frequent with dronedarone (10.4 vs 13.3%). MSE was 39.3 and 44.5% with dronedarone and amiodarone, respectively, at 12 months (HR = 0.80; 95% CI 0.60–1.07; P = 0.129), and mainly driven by fewer thyroid, neurologic, skin, and ocular events in the dronedarone group. Conclusion: In this short‐term study, dronedarone was less effective than amiodarone in decreasing AF recurrence, but had a better safety profile, specifically with regard to thyroid and neurologic events and a lack of interaction with oral anticoagulants. (J Cardiovasc Electrophysiol, Vol. 21, pp. 597‐605, June 2010)