Ernst A. Raeder

Side effects and complications of amiodarone therapy

To assess the incidence of adverse effects associated with long-term amiodarone therapy, we reviewed the records of 217 consecutive patients who were treated for refractory arrhythmia. After an average of 11.8 months of therapy, one or more side effects occurred in 113 patients (52%). These were considered clinically significant in 42 patients (19.3%), mandating discontinuation of amiodarone in 18 (8.3%). The untoward reactions requiring discontinuation of amiodarone included thyroid dysfunction, visual disturbances, pulmonary infiltrates, ataxia, cardiac conduction abnormalities, and drug interactions. The mild side effects included corneal microdeposits, skin rashes, and gastrointestinal symptoms. There was a weak correlation between blood levels of amiodarone, the daily dose, and the cumulative dose (r = 0.23, p = 0.015). Drug levels were higher in symptomatic patients (p less than 0.03), although they received lower doses of amiodarone. While amiodarone is associated with frequent side effects, they are generally mild and do not necessitate drug discontinuation. Careful monitoring of therapy is essential to detect the potentially serious adverse reactions which are encountered in nearly 20% of patients.

Spontaneous variability and circadian distribution of ectopic activity in patients with malignant ventricular arrhythmia.

Day to day variability of ventricular ectopic activity was analyzed in 45 patients with a history of malignant ventricular tachyarrhythmias who underwent two successive 24 h periods of ambulatory electrocardiographic (ECG) monitoring in the absence of antiarrhythmic drugs; 26 were male and 19 female, with a mean age of 56 years (range 15 to 76). The total number of single ventricular premature beats, couplets and ventricular tachycardia beats and runs on days 1 and 2 demonstrated a consistent overall correlation (r = 0.76 to 0.84). Individual variability was evaluated by regression analysis with determination of 95% confidence limits. The minimal decrease in arrhythmia density necessary to distinguish true drug effect from spontaneous variability was 64% for single ventricular premature beats, 83% for couplets, 90% for ventricular tachycardia runs and 93% for ventricular tachycardia beats. To meet the criteria for arrhythmia aggravation, the arrhythmia density had to increase by 400, 877, 1,500 and 2,400%, respectively. Multivariate analysis disclosed an inverse relation between day to day arrhythmia variability and baseline arrhythmia density and age. Variability was more pronounced in patients with coronary artery disease but was not influenced by the type of presenting arrhythmia or left ventricular function. The diurnal distribution of arrhythmias and heart rate followed a distinct circadian pattern. These data indicate that, despite good group reproducibility, spontaneous arrhythmia variability in individuals is substantial, necessitating standards to define both drug effect and arrhythmia aggravation.

Use of nonsustained ventricular tachycardia as a guide to antiarrhythmic drug therapy in patients with malignant ventricular arrhythmia

From a population of 260 patients with malignant ventricular arrhythmia (ventricular fibrillation or ventricular tachycardia with syncope) we identified 52 (20%) who had infrequent ventricular premature beats during exercise testing and 48 hours of ambulatory monitoring. These patients underwent invasive electrophysiologic study utilizing programmed premature stimulation with up to three extrastimuli at currents of twice and three times middiastolic threshold. The end point for testing was nonsustained ventricular tachycardia (NSVT), defined as 3 to 20 propagated responses resulting from the last premature stimulus. A multiple response was obtained in 45 patients consisting of reproducible NSVT in 36 and sustained ventricular tachycardia in nine. The 36 patients with NSVT underwent 540 electrophysiologic tests with 18 antiarrhythmic agents. Suppression of the repetitive response was achieved in 31 of the 36 patients (86.1%). After an average follow-up of 21 months, one of 31 patients in whom the repetitive response had been abolished had recurrent arrhythmia. This contrasted with recurrence in two of the five patients in whom NSVT was still provoked. During the extensive testing, ventricular fibrillation was not induced. Sustained ventricular tachycardia occurred in 27 of the 540 tests (5.0%), but cardioversion was required in only 12 (2.2%). We conclude that NSVT constitutes a safe electrophysiologic end point for selecting an effective antiarrhythmic program in patients who have experienced malignant ventricular arrhythmia but in whom monitoring and exercise testing are inadequate to guide therapy.

Predictors of antiarrhythmic drug efficacy in patients with malignant ventricular tachyarrhythmias

The relationship between arrhythmia density observed during ambulatory monitoring, left ventricular ejection fraction (EF), and response to antiarrhythmic drug therapy was evaluated in 94 patients presenting with ventricular fibrillation (VF) (n = 20) or ventricular tachycardia (VT) (n = 74). Following baseline studies, an average of 4.9 antiarrhythmic drugs were tested singly in each patient. Univariate and multivariate analyses revealed that the density of VT on baseline ambulatory monitoring and initial left ventricular EF were independent predictors of drug efficacy. The 45 patients with an EF less than or equal to 35% responded to 34 +/- 29% of drugs tested, whereas the 49 with an EF greater than 35% had arrhythmia suppression with 46 +/- 28% of agents (p less than 0.038). Patients exhibiting VT during greater than or equal to 50% of monitoring hours responded to 32 +/- 26% of drugs, whereas those with VT during less than 50% of hours showed arrhythmia suppression with 48 +/- 29% of antiarrhythmic agents tested (p = 0.009). During a mean follow-up period of 12.9 months, the annual sudden death mortality for all patients was 9.3%. However, 8 of the 55 patients responding to less than 50% of drugs tested died suddenly and 17 had recurrent VT. By contrast, only 1 of the 39 patients responding to greater than or equal to 50% of the antiarrhythmic drugs tested died suddenly and two experienced recurrent VT (p = 0.00005).(ABSTRACT TRUNCATED AT 250 WORDS)

Encainide for refractory ventricular tachyarrhythmia

Abstract Encainide, a new antiarrhythmic agent, was studied in 80 patients with sustained ventricular tachycardia or ventricular fibrillation. Drug efficacy was evaluated by ambulatory monitoring and exercise testing in 63 patients who had frequent or repetitive ventricular premature beats and by means of electrophysiologic testing in 17 patients who did not have significant arrhythmia during a 48-hour control period. Encainide was effective in 36 of 63 patients (57%) as judged by ambulatory monitoring and in 35 of 51 patients (69%) who had exercise tests while taking the drug. Overall, 34 patients (54%) responded to encainide when evaluated by both monitoring and exercise testing. The drug was effective in 7 of 16 patients (44%) who underwent electrophysiologic studies. Daily doses and blood levels of encainide were Comparable in responders and nonresponders. Toxicity occurred in 24 patients (30%) and included nausea, vomiting, headaches, lethargy, tremors and conduction disturbances. In 18 patients (23%) arrhythmia was aggravated. An increase in arrhythmia correlated with larger daily doses of encainide and higher serum blood levels of encainide and its metabolite OD-methyl-encainide, but did not correlate with QRS- or QT-interval widening. Of the 27 patients who were discharged on encainide, 23 were maintained on the drug for an average of 21 months (range 12 to 44). Three patients died suddenly. Thus, encainide is a useful agent for suppression of malignant ventricular arrhythmias. However, it has a high potential for worsening arrhythmias and careful evaluation by both monitoring and exercise testing is necessary to judge its effect.

Effect of hypokalemia on susceptibility to ventricular fibrillation in the normal and ischemic canine heart

To examine the impact of hypokalemia on cardiac electrical stability, the thresholds for repetitive extrasystole and ventricular fibrillation were determined before and after potassium depletion in 15 chloralose-anesthetized dogs. A reduction in serum potassium concentration from 3.6 to 2.1 mEq/L induced by hemodialysis decreased the repetitive extrasystole threshold by 30% and the ventricular fibrillation threshold by 25% (p less than 0.01). The increase in ventricular vulnerability following acute coronary occlusion was markedly augmented by concomitant potassium depletion. Thus, hypokalemia enhances the propensity for ventricular fibrillation in the normal as well as in the ischemic canine heart. These findings shed light on clinical observations of enhanced susceptibility to life-threatening arrhythmias during acute myocardial ischemia in hypokalemic patients.

Safety and efficacy of encainide for malignant ventricular arrhythmias

The antiarrhythmic effect of encainide was evaluated in 140 patients with documented symptomatic ventricular tachycardia or ventricular fibrillation refractory to conventional agents. In 102 patients with reproducible spontaneous arrhythmia, noninvasive methods, including ambulatory monitoring and exercise testing, were used to evaluate drug efficacy, while in the remaining 38 patients electrophysiologic testing was performed. Side effects necessitated drug discontinuation in 10 patients before noninvasive evaluation. Of the remaining 92 patients 44 (48%) responded to encainide. Of the 38 patients who underwent electrophysiologic study, 1 discontinued encainide because of side effects and in 4 patients the spontaneous occurrence of sustained ventricular tachycardia precluded repeat study. Of the remaining 33 patients, 10 (30%) were rendered noninducible with encainide. The drug was more effective in those with a left ventricular ejection fraction greater than 35% (p less than 0.03) and in those presenting with nonsustained ventricular tachycardia. Side effects were reported in 53 of 140 patients (38%) and were primarily nausea, vomiting, headaches and tremors. Aggravation of arrhythmia occurred in 4% of patients with a history of nonsustained arrhythmia and in 25% of those with a history of sustained ventricular tachycardia or ventricular fibrillation. Worsening of arrhythmia was not related to mean dose of drug, mean blood level or electrocardiographic changes; it was more likely to occur in patients with a markedly reduced left ventricular ejection fraction (average 32%) and in those with a history of sustained ventricular tachyarrhythmia (p less than 0.05). Long-term encainide therapy was continued in 48 patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Increased release of brain serotonin reduces vulnerability to ventricular fibrillation in the cat

Summary Brain serotoninergic neurons are known to participate in cardiovascular regulation. Administration of the serotonin precursor 5-l-hydroxytryptophan in conjunction with the monamine oxidase inhibitor phenelzine and the selective peripheral l-amino acid decarboxylase inhibitor carbidopa has been shown to raise the repetitive extrasystole threshold in the canine heart. The present investigation demonstrates that this drug regimen increases the cerebrospinal fluid concentration of serotonin and its major metabolite, 5-hydroxyindoleacetic acid, by 330 and 830%, respectively. By contrast, cerebrospinal fluid concentrations of norepinephrine and its major brain metabolite, 3-methoxy-4-hydroxyphenylethyleneglycol sulfate, and of dopamines metabolite, 3,4-dihydroxyphenylacetic acid, were not significantly altered. Concomitantly, the ventricular fibrillation threshold was elevated by 42% and the effective refractory period prolonged by 7%. Efferent sympathetic neural activity was suppressed in the normal heart (from 7.9 ± 1.3 to 3.9 ± 1.1 impulses/s). The surge in sympathetic activity associated with acute myocardial ischemia was markedly attenuated. These results indicate that enhancement of central serotoninergic neurotransmission can reduce the susceptibility to ventricular fibrillation mediated through a decline in sympathetic neural traffic to the heart.

Evaluation of aortocoronary venous bypass grafting for prevention of cardiac arrhythmias.

The influence of ACB on cardiac arrhythmias was examined in 27 patients. Eight-hour Holter monitoring was performed 8 days preoperatively and 100 days postoperatively. Arrhythmias were divided into 3 groups (Class I: NSR +/- occasional APBs; Class II: less than five unifocal VPBs per minute; Class II: more than five VPBs per minute, multifocal VPBs, VPBs in a row or VT). Preoperative classification disclosed that 13 patients (48.1 per cent) were in Class I, six patients (22.2 per cent) were in Class II, and eight patients (29.6 per cent) were in Class III. The corresponding values after surgery were 10 patients (37.0 per cent), 13 patients (48.1 per cent), and four patients (14.8 per cent). These differences were not statistically significant (p less than 0.1). In view of the tendency of arrhythmias of Class III to improve after ACB, we feel that further investigations in this area are needed. At the present time ventricular arrhythmias alone constitute no indication for bypass surgery.

Intrinsic sympathomimetic activity and the effects of beta-adrenergic blocking drugs on vulnerability to ventricular fibrillation

Beta-adrenergic blocking agents differ considerably in their effects on myocardial excitable properties. The possibility that intrinsic sympathomimetic activity might contribute to such differences has not been adequately explored. This study examined the influence of intrinsic sympathomimetic activity on the electrophysiologic effects of three agents with varying degrees of such activity. Intravenous propranolol (0.5 mg/kg), oxprenolol (0.5 mg/kg) and pindolol (0.05 mg/kg) were administered in 16 anesthetized dogs. The effects of the drugs on ventricular vulnerability were studied over a 2 hour period. Propranolol and oxprenolol raised the ventricular fibrillation threshold by 42 and 56%, respectively. In contrast, pindolol resulted in an elevation of only 25%. After depletion of endogenous norepinephrine stores using reserpine, pindolol led to a decrease of the ventricular fibrillation threshold, which was reversed by propranolol. These data indicate that intrinsic sympathomimetic activity of beta-adrenergic blocking agents substantially alters their ultimate effect on myocardial excitable properties.