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Background Hypotensive states that require fast stabilisation of blood pressure can occur during anaesthesia. In 1963, the 20:1 mixture of cafedrine/theodrenaline (Akrinor®) was introduced in Germany for use in anaesthesia and emergency medicine in the first-line management of hypotensive states. Though on the market for many years, few pharmacodynamic data are available on this combination net beta-mimetic agent. Aim This study aimed to examine the drug combination in real-life clinical practice and recorded time to 10 % mean arterial blood pressure (MAP) increase and heart rate. Furthermore, potential factors that influence drug effectiveness under anaesthesia were assessed. Methods Data were collected within a standardised anaesthesia protocol. A total of 353 consecutive patients (female/male = 149/204) who received cafedrine/theodrenaline after a drop in MAP ≥ 5 % were included in the study. The time to 10 % increase in MAP, dosage of cafedrine/theodrenaline, volume loading, blood pressure and heart rate were monitored over time. Results Patients were a mean (standard deviation) of 64.4 ± 15.1 years old with a baseline MAP of 82 ± 14 mmHg, which dropped to a mean of 63 ± 10 mmHg during anaesthesia without gender differences. Cafedrine/theodrenaline (1.27 ± 1.0 mg/kg; 64 ± 50 µg/kg) significantly increased MAP (p

Between 1977 and 1986, 589 patients (age, 57 +/- 13 years; 464 men and 125 women) received amiodarone for ventricular fibrillation (VF; 147 patients), sustained (VT-S; 242 patients) or nonsustained (VT-NS; 80 patients) ventricular tachycardia, or supraventricular tachycardia (SVT; 120 patients). Mean left ventricular ejection fraction was 36 +/- 17%, with 23% in New York Heart Association functional class I, 49% in class II, 25% in class III, and 3% in class IV. Sixty-two percent had ischemic heart disease. Follow-up was 32 +/- 27 months (mean +/- SD). Life table analysis revealed that patients with VF, VT-S, and VT-NS had a cumulative incidence of sudden death of 9% at 1 year, increasing by about 3% per year. By years 2 and 5, the cumulative incidence of sudden death, VF, or VT-S recurrence was 26% and 38% and the percent of patients still taking amiodarone was 54% and 32%. For patients with SVT at years 2 and 5, the cumulative incidence of sudden death was 1% and 3%, and of sudden death or SVT recurrence the cumulative incidence was 20% and 29%. The percent of patients still taking amiodarone was 67% and 43%. Of 14 clinical variables assessed, New York Heart Association functional class was the best predictor of sudden death and arrhythmic failure and no other variable added independent predictive power. Older age and lower left ventricular ejection fraction were independent predictors of drug failure (sudden death or arrhythmic failure or need to discontinue amiodarone because of side effects). We conclude that despite its side effect profile, amiodarone is an effective and reasonably well-tolerated antiarrhythmic drug.

The site of ventricular stimulation is an important variable in the initiation of ventricular tachycardia (VT) by programmed ventricular stimulation. Among 169 patients studied consecutively, 17 (10%) had ventricular tachycardia induced by programmed electrical stimulation from the right ventricular outflow tract but not from the apex. Fourteen of these 17 patients had had prior myocardial infarction (12 had inferior, and two had both inferior and anterior myocardial infarction), two had a dilated cardiomyopathy, and one had a localized cardiomyopathy. Fourteen patients had echocardiograms suitable for analysis. Of these, 12 had posterior/inferior ventricular wall motion abnormalities located at the base of the heart. The ventricular effective refractory periods from the right ventricular outflow tract and right ventricular apex were 237 +/- 4 and 244 +/- 5 msec, respectively (p less than 0.05, mean +/- SEM). Induced VT had a cycle length of 229 +/- 4 msec and had the morphology of right bundle branch block in 12 patients, of left bundle branch block in three patients, and had both morphologies in two patients. In 14 patients the axis was superior. VT was initiated with two extrastimuli in 15 patients and with burst right ventricular pacing in two patients. Similar pacing techniques with identical pacing intervals did not induce VT at the right ventricular apex in 14 of these 17 patients. Further, among the 15 patients whose VT was induced at the right ventricular outflow tract with two extrastimuli, neither burst pacing (n = 13) nor two extrastimuli introduced at faster paced rates (n = 12) induced VT at the right ventricular apex.(ABSTRACT TRUNCATED AT 250 WORDS)

We followed 11 patients for 5 to 27 months (mean 14.9) after implantation of a permanent transvenous low-energy synchronized cardioverter to evaluate both long-term reproducibility of ventricular tachycardia (VT) induction via noninvasive programmed electrical stimulation with the cardioverter and efficacy of cardioversion. Induction and termination of VT were attempted at implantation and approximately every 3 months thereafter. All patients had coronary artery disease and were receiving antiarrhythmic drug therapy (amiodarone in eight). VT cycle length, morphology, and mode of induction were reproducible on multiple occasions in nine patients; clinical VT was induced inconsistently in two patients. Multiple VT episodes in five patients had one morphology, whereas two morphologies occurred in six patients. Synchronization of the shock within the QRS complex and right ventricular effective refractory periods determined via the cardioverter remained constant over the follow-up period. VT was terminated on every occasion in nine patients and on eight of nine occasions in one patient. Tachycardia was accelerated on three of five occasions in one patient. Consistently effective cardioversion energy (0.2 to 2.0 J) increased modestly in four patients. We conclude that patients with inducible monomorphic VT usually have sustained VT with similar characteristics inducible over a period of time and cardioversion and sensing functions of the cardioverter remain relatively stable over time.

We examined the influence of ventricular tachycardia (VT) cycle length and antiarrhythmic drugs on the frequency of VT termination and acceleration by single and double extrastimuli and right ventricular burst pacing. In 57 patients, 89 episodes of sustained VT (32 control, 57 drug) were induced by programmed electrical stimulation. Overall, 60 of 89 (67%) episodes of ventricular tachycardia were terminated by means of programmed electrical stimulation. In patients with relatively slow ventricular tachycardia (VT cycle length greater than or equal to 350 msec) pacing terminated 37 of 44 (84%) episodes but terminated only 24 of 45 (51%) episodes of more rapid VT (VT cycle length less than or equal to 349 msec, p less than 0.005). Pacing successfully terminated VT in nine of 49 (18%) episodes using a single extrastimulus, 22 of 52 (42%) episodes using double extrastimuli, and 40 of 66 (61%) episodes using burst right ventricular pacing. VT acceleration occurred in none of 49 attempts with a single extrastimulus, in eight of 52 (15%) attempts with double extrastimuli, and in 12 of 66 (18%) attempts using burst right ventricular pacing. During therapy, the frequency of either ventricular tachycardia termination or acceleration did not change regardless of the pacing termination method used. However, by prolonging the mean VT cycle length from 311.1 +/- 82.2 msec to 401.9 +/- 103.5 msec (p less than 0.01), drugs increased the overall frequency of VT termination. We conclude that: (1) pacing terminates VT more frequently if the VT cycle length is long and if right ventricular bursts are used, (2) burst right ventricular pacing increases the risk of VT acceleration, and (3) drugs increase the frequency of ventricular tachycardia termination by prolonging VT cycle length but do not affect frequency of VT acceleration.

Ventricular tachycardia induced by programmed electrical stimulation during amiodarone therapy often does not preclude a good clinical response. The purpose of this study was to determine whether use of discriminant analysis could distinguish patients who remained asymptomatic from those who subsequently developed symptomatic ventricular tachycardia or cardiac arrest. Studies were performed in 37 patients with sustained ventricular tachycardia who still had ventricular tachycardia induced during programmed electrical stimulation during amiodarone therapy. The mean follow-up time was 14.1 ± 1.3 months (± SEM). Twenty-three patients remained asymptomatic, whereas 14 patients had symptomatic recurrence of their ventricular tachycardia.In patients with recurrence of arrhythmia compared with asymptomatic patients, administration of amiodarone caused a longer ventricular effective refractory period (296 ± 8 versus 271 ± 7 ms, p < 0.05) and a greater change in corrected QT [QTc] interval (90 ± 18 versus 44 ± 9 ms, p < 0.02), but no difference in the decrease in premature ventricular complexes after treatment with amiodarone. During amiodarone therapy, nonbundle branch reentrant repetitive ventricular responses were induced by a single ventricular extrastimulus during sinus rhythm in 9 of 14 patients with recurrent arrhythmias compared with 2 of 21 asymptomatic patients (p = 0.001). Also, less aggressive pacing techniques were required to induce ventricular tachycardia in 9 of 14 symptomatic patients compared with 4 of 23 asymptomatic patients (p < 0.02). A discriminant analysis using the presence of nonbundle branch reentrant repetitive ventricular responses, change in method of ventricular tachycardia induction and either the change in QTcinterval or ventricular effective refractory period correctly identified clinical outcome in 90% of the patients, and all patients with recurrent arrhythmias were classified correctly. It is concluded that electrophysiologic testing during amiodarone therapy can provide data that identify patients who appear to be at risk for development of ventricular tachycardia after hospital discharge.

Oral encainide, varying from 75 to 300 mg/day (mean 174 mg/day), was administered to 52 patients with drug-resistant atrioventricular reciprocating tachycardia (AVRT) associated with the Wolff-Parkinson-White syndrome. Electrophysiologic studies were performed before and during drug treatment. Encainide resulted in anterograde accessory pathway block in 15 of 37 (41%) and retrograde accessory pathway block in 11 of 46 (24%) patients. In patients with residual accessory pathway conduction, encainide significantly prolonged the shortest pacing cycle length maintaining anterograde (261 +/- 26 to 404 +/- 85 ms) and retrograde (279 +/- 46 to 436 +/- 87 ms) accessory pathway conduction, as well as the anterograde accessory pathway effective refractory period (271 +/- 32 to 329 +/- 73 ms). AVRT could not be induced during encainide therapy in 20 of 49 patients (41%). In the remaining patients, AVRT cycle length increased (319 +/- 44 to 426 +/- 90 ms, p less than 0.001) due to prolongation of HV and ventriculoatrial intervals. During follow-up (mean 38.5 months), 30 patients continued to take the drug and 7 patients with favorable drug response subsequently elected to undergo surgical accessory pathway ablation (71% overall favorable response). Encainide was ineffective in 11 patients, was discontinued because of drug intolerance in 2 patients and exacerbated ventricular tachycardia in 2 patients. Lack of AVRT inducibility at encainide electrophysiologic study did not always predict recurrence-free follow-up. Encainide is an effective and well-tolerated drug to prevent recurrence of AVRT in patients with Wolff-Parkinson-White syndrome.

Sudden death has occurred in monkeys fed large doses of probucol, a cholesterol-lowering drug, given in combination with an atherogenic diet. These monkeys develop prolonged QT intervals and high serum levels of probucol. We investigated the effect of probucol on QT interval and the incidence of ventricular ectopy during a double-blind placebo-controlled study in 16 patients with less than 600 premature ventricular complexes (PVCs) per day and a corrected QT interval of less than 0.44 second. Seven patients received probucol and nine patients received placebo. Three 24-hour continuous ECG recordings were obtained prior to entry into the study and three additional recordings were obtained after 6 months of drug or placebo therapy. A 15-second ECG tracing was sampled from the continuous ECG recording every 30 minutes and, for the group, 15,000 QT intervals were measured permitting construction of QT versus R-R regression lines for each patient before and during therapy. Comparison of the regression lines revealed that the measured QT interval prolonged 20 +/- 18 msec during the awake state and 24 +/- 20 msec during sleep (mean + standard deviation) at matched heart rates in the seven patients receiving probucol (p less than 0.01). Using Bazett's formula to correct for rate, corrected QT interval prolonged 22 +/- 23 msec in the awake state and 20 +/- 18 msec in the asleep state (p less than 0.01). In probucol treated patients QT interval prolongation was directly related to increasing probucol plasma levels (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Natural history, structural substrate, electrocardiographic and electrophysiologic characteristics and therapy were evaluated in 18 patients who demonstrated repetitive ventricular tachycardia, defined as repeated episodes of ventricular tachycardia that had a uniform QRS configuration and normal sinus-conducted QRS complexes between the episodes of tachycardia. The patients were young (mean age 37 years) and frequently had a long history of arrhythmias before this evaluation; only two patients has a history of syncope and six were completely asymptomatic. Fourteen patients had no evidence of underlying structural heart disease, three had mitral valve prolapse and one had congestive cardiomyopathy. Episodes of ventricular tachycardia tended to occur in clusters over a 24 hour electrocardiographic recording period. Repetitive ventricular tachycardia was induced in two of nine patients by programmed electrical stimulation, and in seven patients incremental atrial and ventricular pacing suppressed spontaneous arrhythmia. In the one patient whose tachycardia was induced by incremental ventricular pacing there was an inverse relation between pacing cycle length and the interval from the last paced complex to the first complex of ventricular tachycardia, indicating there was overdrive suppression. At a follow-up time of 0.5 to 8 years no patient had died or had worsening of symptoms. Encainide completely eliminated episodes of ventricular tachycardia during acute treatment in five of six patients tested. Seven patients received no antiarrhythmic therapy and the arrhythmia appeared to have spontaneously resolved in four of these patients. Repetitive ventricular tachycardia appears to have distinct clinical and electrophysiologic characteristics. In this series the arrhythmia had a good prognosis and often required no treatment. The electrophysiologic features are consistent with a mechanism of automaticity.

Cibenzoline, a new antiarrhythmic agent, was tested in 26 patients who had symptomatic ventricular tachycardia (24 patients) or premature ventricular complexes (2 patients) unresponsive to conventional drugs. Cibenzoline was given orally every 8 hours to maximal doses of 65 mg in 2 patients, 81.25 mg in 22 patients and 97.5 mg in 2 patients. Cibenzoline abolished spontaneous episodes of ventricular tachycardia in 8 of 16 patients with ventricular tachycardia during a 72 hour control electrocardiographic recording, and 7 of 22 patients had greater than 83% decrease in premature ventricular complexes compared with control. The PR interval increased 14% (p < 0.001), QRS duration increased 17% (p < 0.001), QT interval did not change and mean ejection fraction in 10 patients did not change.Electrophysiologic studies were performed on 10 patients in the control period and during maximal cibenzoline dosage. Cibenzoline did not affect electrophysiologic properties of the atrium or atrioventricular (AV) node. It prolonged the ventricular effective (223 ± 16 to 241 ± 22 ms, p < 0.02) and functional (247 ± 18 to 264 ± 25 ms, p < 0.02) refractory periods. At control electrophysiologic studies, ventricular tachycardia was induced in 9 of 10 patients (mean cycle length 210 ± 31 ms). Cibenzoline therapy prevented ventricular tachycardia induction in two patients, and in the other seven patients the mean ventricular tachycardia cycle length increased from 210 to 260 ms. The one patient with no ventricular arrhythmia induced during the control study still had no arrhythmia induced while receiving cibenzoline. Among six patients receiving cibenzoline during follow-up, one patient died of recurrent myocardial infarction, two patients stopped taking cibenzoline because of recurrent veutricular tachycardia and three patients have continued taking cibenzoline for 10 ± 4 months with control of symptomatic arrhythmias.Thus, cibenzoliue suppressed ventricular tachycardia and premature veutricular complexes in some patients unresponsive to conventional drugs and was well tolerated. Cibenzoline significantly prolonged ventricular effective and functional refractory periods and had minimal negative hemodynamic effects.

This study examined the usefulness of programmed electrical stimulation in managing 83 patients who had ventricular tachycardia not due to coronary artery disease. Among 39 patients with a history of sustained ventricular tachycardia, programmed stimulation induced ventricular tachycardia in 14 of 14 patients with mitral valve prolapse or primary electrical disease (arrhythmias without evidence of structural heart disease) and in 13 of 25 with cardiomyopathy (total 27 of 39, 69 percent). Programmed stimulation induced nonsustained ventricular tachycardia in 15 (34 percent) of 44 patients with a history of nonsustained tachycardia (5 of 13 with mitral valve prolapse, 6 of 19 with primary electrical disease and 4 of 12 with cardiomyopathy). Seventy-three of the 83 patients were treated with antiarrhythmic drugs and then followed up for 14.4 ± 11.4 months (mean ± standard deviation). Drug therapy was determined with serial electrophysiologic testing in 31 patients. Twenty-four of these 31 patients had a history of sustained ventricular tachycardia, and drugs prevented induction of ventricular tachycardia in 9 (none of whom manifested symptomatic events) but did not prevent it in 15 (6 of whom had symptomatic events). Among seven patients with a history of nonsustained ventricular tachycardia, drugs prevented induction of ventricular tachycardia in five (none of whom had symptomatic events) and did not prevent it in two (none of whom had symptomatic events). Forty-two patients were treated using the results of noninvasive testing. Drugs suppressed spontaneous ventricular tachycardia in 15 of 15 patients with a history of sustained tachycardia (7 of whom had symptomatic events including one sudden death), and in 26 of 27 with a history of nonsustained tachycardia (6 of whom had symptomatic events including one sudden death). Thus, in patients with ventricular tachycardia unrelated to coronary artery disease: (1) programmed electrical stimulation induced ventricular tachycardia less often than in patients whose tachycardia was due to coronary artery disease; (2) programmed stimulation induced ventricular tachycardia less often in patients with a history of nonsustained versus sustained tachycardia; and (3) suppression of inducible ventricular tachycardia appeared to predict effective drug therapy but drug therapy predicted with noninvasive testing appeared to be unreliable.

Antiarrhythmic therapy in 506 consecutive patients undergoing 1,268 antiarrhythmic drug trials for ventricular tachycardia or ventricular fibrillation was reviewed for evidence of arrhythmogenic drug effect defined as the occurrence of a new form of ventricular tachyarrhythmia temporally associated with initiation of drug therapy or dosage increase. Arrhythmogenic effects occurred in 6.9% of patients and 3.4% of drug trials. This ranged from a high of 11.8% caused by encainide to none occurring with procainamide, tocainide or beta-adrenergic blocking drugs. The incidence of arrhythmogenesis was significantly greater in patients whose presenting arrhythmia was sustained ventricular tachycardia than it was in those who presented with nonsustained ventricular tachycardia or ventricular fibrillation (p = 0.02). Decreased systolic function measured echocardiographically at the base of the left ventricle was associated with an increased incidence of arrhythmogenic effects (p = 0.006) whereas global left ventricular ejection fraction was not. Age, gender, cardiac diagnosis, location of prior myocardial infarction and New York Heart Association functional class for heart failure were not related to the occurrence of drug-induced arrhythmias. These findings emphasize the need for in-hospital cardiac monitoring during initiation of antiarrhythmic drug therapy for ventricular tachyarrhythmias.

Induction of ventricular tachycardia (VT) at electrophysiologic study in patients taking amiodarone poorly predicts recurrence of VT. Consequently, a discriminant function was developed (using parameters based on retrospective data) that appeared to identify high-risk patients. These parameters included ventricular effective refractory period, corrected QT interval, initiation of a repetitive ventricular response and the mode of VT induction. In the present study these parameters were prospectively evaluated in 60 patients with coronary artery disease and sustained VT or ventricular fibrillation (VF), in whom VT was still induced at electrophysiologic study during amiodarone therapy. Thirteen patients had recurrent events (sudden death in 8 and sustained VT in 5) and 47 patients had no symptomatic arrhythmia recurrence (follow-up for 16 +/- 2 months, mean +/- standard error of the mean). The ventricular effective refractory period, corrected QT interval and presence of a repetitive ventricular response did not discriminate between patients with and without symptomatic arrhythmia recurrence. However, an easier mode of VT induction during amiodarone therapy versus control was highly predictive of arrhythmia recurrence: 9 of 13 (69%) recurrences were in this group. In contrast, only 4 of 44 (9%) patients who had either the same or harder mode of VT induction had a recurrent event. Overall, 9 of 16 (56%) patients with an easier mode of VT induction had a recurrence, including 6 of the 8 patients with subsequent sudden cardiac death. It is concluded that electrophysiologic testing during amiodarone therapy is useful to identify high-risk patients.

Un choc synchronise d'energie inferieure a 2 joules delivrea travers un catheter specialement concu a cet effet peut terminer une tachycardie ventriculaire soutenue chez le chien et l'homme. Une telle fonction est programee dans un boitier de 95 grammes, impiante sous anesthesie locale a la xylocaine, capable par ailleurs de stimulation VVI et d'effectuer des etudes electrophysiologiques. Sept patients ont recu ce boitier et J'experience initiale est rapportee. A synchronized shock of ≤2.0 joules delivered over a specially designed catheter electrode passed to the apex of the right ventricle effectively terminates sustained ventricular tachycardia in dogs and in patients. The capability has been engineered into a 95 gram device implanted using lidocaine anesthesia, which is also capable of VVI pacing and of performing programmed electrophysiologic studies. Seven patients have received the implant and the initial experience is described.

The purpose of these studies is to illustrate that the time of drug administration in experimental animals subjected to coronary artery occlusion is an important influence on the myocardial distribution of the drug as well as its electrophysiologic and arrhythmogenic effects. Also, because several drugs have active metabolites, some studies must be done after oral administration. Finally, electrophysiologic testing to determine drug efficacy may give misieading results with some drugs.

The effects of amiodarone on the pharmacokinetic and electrophysiologic properties of procainamide were examined in eight patients treated for recurrent ventricular arrhythmias who received intravenous procainamide, 6 to 15 mg/kg, at control and after 1 to 2 weeks of oral amiodarone treatment. Compared with control, procainamide plasma clearance decreased from 0.43 +/- 0.12 L/kg-hr to 0.33 +/- 0.12 L/kg-hr (P less than 0.01), plasma elimination half-life increased from 3.77 +/- 0.64 hours to 5.21 +/- 0.42 hours (P less than 0.01), and volume of distribution was unchanged from 2.31 +/- 0.74 L/kg to 2.47 +/- 0.90 L/kg during amiodarone treatment. As single agents, intravenous procainamide and oral amiodarone produced equivalent increases in QRS duration, rate-corrected QT interval, right ventricular effective refractory period, and cycle length of induced ventricular tachycardia. After the addition of intravenous procainamide to amiodarone the QRS duration, rate-corrected QT interval, and, in six of eight patients, ventricular tachycardia cycle length were significantly increased compared with control or either drug alone, suggesting additive electrophysiologic effect. However, acceleration of induced ventricular tachycardia occurred in one patient with combined treatment, suggesting a potential for adverse electrophysiologic interactions. These findings indicate that amiodarone has pharmacokinetic and electrophysiologic interactions with procainamide and suggest that the intravenous dose of procainamide be reduced by 20% to 30% during concurrent drug administration.

Parasympathetic blockade shortens the duration of the Q-T interval and ventricular effective refractory period independent of heart rate change. Since relative parasympathetic effect increases during sleep, it was determined whether sleep was associated with a change in the Q-T interval. Fifteen patients receiving no drugs underwent 3 to 6 days of continuous electrocardiographic recordings. Tracings were sampled every 30 minutes and recorded at a paper speed of 25 mm/s. This provided 12,000 Q-T and R-R intervals that were measured. Comparison of R-R intervals that had similar durations during sleep and awake states revealed that the duration of the Q-T interval was longer during sleep in all 15 patients (p less than 0.001). Eight patients had sufficient range of overlap of R-R intervals to compare linear regression lines of Q-T intervals recorded while awake with Q-T intervals recorded while asleep. The regression lines during sleep exhibited a mean intercept change of 38 +/- 37 ms and mean slope change of -0.021 +/- 0.040 ms when compared with the regression lines during the awake state. The difference in Q-T interval between awake and sleep states was 19 +/- 7 ms when calculated at a heart rate of 60 beats/min. These statistical comparisons of the relationship of the Q-T interval to R-R interval indicate that the Q-T interval is longer during sleep than during the awake state at the same heart rate. Prolongation of the Q-T interval during sleep may reflect increased vagal tone or sympathetic withdrawal. These changes in repolarization may be related to the diurnal variation of some ventricular arrhythmias.

Recent investigations have clarified some of the effects of the autonomic nervous system on duration and spatial distribution of the Q-T interval in humans. The use of atrial pacing to fix heart rate or 24-hour continuous electrocardiographic recording to develop a regression formula for individual patients has provided a means to interpret the effects of an intervention that alters both the heart rate and the Q-T interval. Drugs that affect Ihe autonomic nervous system can influence Q-T interval directly or by changing rate. Bazett's formula to correct for rate may be misleading after certain drug interventions. For example, the Q-T interval during sinus rhythm or afrial pacing and the ventricular effective refractory period shorten after atropine plus propranolol, but corrected Q-T interval using Bazetf's formula does not change. No change occurs in the Q-T interval during sinus rhythm or atrial pacing, or in ventricular effective refractory period after administration of propranolol although corrected Q-T interval using Bazett's formula markedly shortens. Q-T interval during sinus rhythm and atrial pacing and ventricular effective refractory period decrease after atropine but correct Q-T interval lengthens. To define further the relationship of the autonomic nervous system on the duration of the Q-T interval we studied the effects of sleep. Fifteen patients receiving no drugs underwent 3–6 days of continuous electrocardiography recordings. The duration of the Q-T interval was longer during sleep in all 15 patients independent of heart rate change. This prolongation of the Q-T interval during sleep may reflect increased parasympathetic tone or decreased sympathetic tone on the ventricle. Further investigation of the relation of the autonomic nervous system to ventricular depolarization and repolarization may delineate some of Ihe trigger mechanisms for the development of lethal ventricular arrhythmias in humans.

We have endeavored to relate known electrophysiologic mechanisms of arrhythmia development to clinically occurring arrhythmias, realizing that definitive conclusions can only be surmised at present. Arrhythmias that may be due to disorders of impulse formation include slow atrial, junctional, and ventricular escape rhythms, certain types of atrial tachycardias (such as those produced by digitalis), accelerated junctional (nonparoxysmal junctional tachycardia) and idioventricular rhythms, and parasystole. Arrhythmias that may be due to disorders of impulse conduction include flutter and fibrillation, atrioventricular nodal reentrant tachycardia, reciprocating tachycardias associated with an accessory pathway, sinus nodal reentry, some atrial tachycardias, and many ventricular tachycardias. Understanding the mechanism of the tachycardia, in some instances, helps direct rational therapeutic approaches.

Interest in amiodarone has increased because of its remarkable efficacy as an antiarrhythmic agent. The purpose of this report is to review what is known about the electrophysiologic actions, hemodynamic effects, pharmacokinetics, alterations of thyroid function, response to treatment of supraventricular and ventricular tachyarrhythmias and adverse effects of amiodarone. Understanding the actions of amiodarone and its metabolism will provide more intelligent use of the drug and minimize the development of side effects. The mechanism by which amiodarone suppresses cardiac arrhythmias is not known and may relate to prolongation of refractoriness in all cardiac tissues, suppression of automaticity in some fibers, minimal slowing of conduction in fast channel-dependent tissue, or to interactions with the autonomic nervous system, alterations in thyroid metabolism or other factors. Amiodarone exerts definite but fairly minor negative inotropic effects that may be offset by its vasodilator actions. Amiodarone has a reduced clearance rate, large volume of distribution, low bioavailability and a long half-life that may last 2 months in patients receiving short-term therapy. Therapeutic serum concentrations range between 1.0 and 3.5 micrograms/ml. The drug suppresses recurrences of cardiac tachyarrhythmias in a high percent of patients, in the range of 80% or more for most supraventricular tachycardias and in about 66% of patients with ventricular tachyarrhythmias, sometimes requiring addition of a second antiarrhythmic agent. Side effects, particularly when high doses are used, may limit amiodarone's usefulness and include skin, corneal, thyroid, pulmonary, neurologic, gastrointestinal and hepatic dysfunction. Aggravation of cardiac arrhythmias occurs but serious arrhythmias are caused in less than 5% of patients. Amiodarone affects the metabolism of many other drugs and care must be used to reduce doses of agents combined with amiodarone.

The electrophysiologic effects of oral encainide were assessed in 15 patients. Electrophysiologic studies were performed before and after 3 or more days of oral encainide therapy, 100 to 300 mg/day (mean 242 +/- 66). Patients received no other cardioactive drugs during this time. Encainide significantly (p less than 0.005) lengthened the following: A-H interval (74.5 +/- 21.5 to 105.5 +/- 39.1 ms, mean +/- standard deviation), the shortest atrial pacing cycle length maintaining 1:1 atrioventricular (A-V) nodal conduction (339.0 +/- 71.3 to 417.0 +/- 88.6 ms), H-V interval (47.5 +/- 7.8 to 67.1 +/- 12.9 ms), QRS interval (103.5 +/- 30.9 to 132.3 +/- 35.7 ms), right atrial (233.8 +/- 27.2 ms to 282.9 +/- 38.6 ms) and right ventricular (235.7 +/- 15.6 to 267.1 +/- 36.9 ms) effective refractory periods and Q-T interval (364.4 +/- 38.0 to 416.9 +/- 55.3 ms). The spontaneous sinus cycle length did not change significantly. In four patients who had accessory A-V muscle connections (two manifest, two concealed) encainide abolished anterograde conduction over the accessory pathway in two patients, and increased the retrograde effective refractory period and/or lengthened retrograde conduction time or blocked retrograde conduction in the accessory pathway, or all three variables, in all four patients. There was no correlation between the plasma encainide concentration obtained at the time of study and the magnitude of change in any electrophysiologic variable. It is concluded that (1) encainide depresses conduction in the A-V node, His-Purkinje system and accessory pathway, and increases refractoriness of the atrium, ventricle and accessory pathway, and (2) differences between these results and those of earlier studies using encainide in a single intravenous dose (which found no significant effects on A-V nodal conduction or atrial and ventricular refractoriness) may be explained in part by the effects of an active metabolite of encainide.

We retrospectively studied 28 patients with 38 episodes of newly occurring ventricular fibrillation during antiarrhythmic drug therapy. Twenty-six of these patients, who had ventricular fibrillation during single-drug therapy with quinidine, procainamide, or disopyramide, were compared with a control group of 62 patients who had been treated similarly for ventricular arrhythmias but did not have ventricular fibrillation during treatment. The median duration of therapy before ventricular fibrillation was three days. The left ventricular ejection fraction of the study group was lower than that of the control group (0.29 vs. 0.43; P less than 0.0001), and concomitant treatment with digitalis and diuretic agents was more common in the study group. The base-line QT interval (corrected for heart rate) was slightly longer in the study group than in the controls (0.47 vs. 0.44; P less than 0.005), although both groups had similar degrees of QT prolongation during drug therapy. Four of 13 patients (31 percent) who underwent multiple trials of antiarrhythmic drugs had recurrent episodes of ventricular fibrillation. Six patients died suddenly after a mean follow-up of 18 months--four who were receiving antiarrhythmic therapy and two who were not. We conclude that drug-associated ventricular fibrillation is an early event, that there may be an increased risk of its recurrence with subsequent trials of antiarrhythmic drugs, and that left ventricular dysfunction and concomitant therapy with digitalis and diuretic agents may predispose patients to this complication.

The relationship between plasma concentrations of cibenzoline and its antiarrhythmic effect was evaluated in patients receiving the drug orally as part of an ascending multiple dose efficacy and tolerance study. Twenty-five patients participated in a 3-day placebo period, 3 days of 32.5 mg cibenzoline every 6 hr, 3 days of 65 mg cibenzoline every 6 hr, 3 days of 81.25 mg cibenzoline every 6 hr, and 3 final placebo days. Arrhythmia frequency was monitored by 24-hr Holter monitoring and blood samples were drawn during and after dosing. Percent reduction in baseline premature ventricular complex (PVC) frequency for the 25 subjects demonstrated considerable interpatient variability in antiarrhythmic response. Cibenzoline plasma concentrations over 300 ng/ml were associated with some decrease in PVC frequency in virtually all cases. The relationship between plasma concentration and PVC frequency was studied more rigorously in eight of the 25 patients and that for ventricular couplet (VC) frequency was studied in six. For these analyses, PVC and VC frequency data were averaged over 6-hr intervals and plotted against trough cibenzoline concentrations. The data from each patient were fitted with a concentration-effect function (Hill equation) by means of least squares regression. With the exception of two extreme values, the concentration corresponding to 90% reduction in PVC frequency (C90) ranged from 215 to 405 ng/ml. In five of the six patients with arrhythmia in whom VC data were also evaluated, the individual C90 for VCs were considerably less than those for PVCs. The agreement between the observed concentration-response relationships and those predicted by curve-fitting the data suggests that the antiarrhythmic effect of cibenzoline is proportional to its plasma concentration, and that the Hill equation provides an accurate mathematic description of the concentration-response relationship. Clinical Pharmacology and Therapeutics (1984) 35, 307–316; doi:10.1038/clpt.1984.35

We performed electrophysiologic studies in 19 patients with accessory pathways before and during encainide therapy with a mean daily dose of 197 mg. Fourteen patients had manifest accessory atrioventricular connections, and five patients had concealed accessory atrioventricular connections. The patients had recurrent atrioventricular reentrant tachycardia for a mean of 15.8 years and had received a mean of 3.6 drug trials without successful suppression of recurrent arrhythmias. Encainide caused complete antegrade conduction block in the accessory pathway in eight of 14 patients with manifest accessory atrioventricular connections. The shortest atrial pacing cycle length maintaining 1:1 conduction over the accessory pathway at control study w3as 328 +/- 66 msec in patients in whom antegrade conduction block occurred, and it was 247 +/- 21 msec (p less than .01) in patients in whom conduction remained during encainide therapy. Retrograde conduction over accessory atrioventricular connections could be evaluated in 14 patients, and complete block occurred in seven patients during encainide therapy. There was no correlation between control retrograde effective refractory period or conduction of the accessory pathway and subsequent development of conduction block with encainide therapy. It should be noted that five patients who developed drug-related retrograde block over the accessory pathway had initial retrograde effective refractory periods for the accessory pathway less than 270 msec. Nineteen patients had atrioventricular reentrant tachycardia initiated at control electrophysiologic study. Encainide prevented induction of tachycardia in 10 patients, and in the other nine patients, cycle length of tachycardia increased during drug treatment from 313.9 +/- 53.1 to 418.3 +/- 80.9 msec (p less than .001), primarily due to an increase in ventriculoatrial conduction time from 162.2 +/- 43.8 to 238.3 +/- 87.9 msec (p less than .01). Fifteen patients continued encainide treatment for a mean of 18 months (range 7 to 38), and all but one patient remain asymptomatic. Encainide is well tolerated and prevents recurrence of reentrant tachycardia in patients with Wolff-Parkinson-White syndrome very effectively.

Propafenone was administered to 29 patients who had multiple episodes of recurrent ventricular tachycardia (VT) or ventricular fibrillation (VF) despite previous antiarrhythmic therapy. All patients had 24-hour continuous electrocardiographic recording and electrophysiologic study in a drug-free control state and while receiving maximum doses of propafenone. During propafenone treatment, the mean frequency of ventricular premature complexes (VPCs) decreased 74% (p less than 0.05). There was more than an 83% decrease in VPC frequency in 17 of 29 patients, and 11 patients had 99 to 100% decreases. Propafenone prevented VT induction at electrophysiologic study in 6 patients, whereas another 12 patients were judged to have satisfactory electrophysiologic responses on the basis of slower VT rates and absence of hemodynamic compromise during VT. After long-term treatment from 2 to 26 months, 9 patients continued propafenone without evidence of recurrent arrhythmia. Six of these 9 patients had not VT induction at electrophysiologic study while receiving propafenone. The decrease in VPC frequency produced by propafenone was a poor predictor of a successful electrophysiologic study and of long-term therapy. In conclusion, propafenone has potential as an effective antiarrhythmic agent, but better methods to stratify risk for recurrence of VT and VF are needed.

Drugs that affect the autonomic nervous system can influence the Q-T interval directly or by changing the heart rate. Bazett's formula to correct for rate may be misleading after certain drug interventions. This hypothesis was tested in 20 patients receiving both propranolol (0.15 mg/kg intravenously) and atropine (0.03 mg/kg intravenously). Six patients received propranolol first, 7 patients received atropine first, and 7 patients received atropine plus propranolol simultaneously. During control and after drug intervention, the Q-T interval was measured directly in sinus rhythm and during a fixed atrial paced rate, and was calculated using Bazett's formula. The ventricular effective refractory period was also determined in 6 patients after administration of atropine plus propranolol. The sinus cycle length (836 ± 156 to 648 ± 84 ms, mean ± standard deviation), measured Q-T interval (367 ± 26 to 329 ± 26 ms), and atrially paced Q-T interval (330 ± 28 to 315 ±27 ms) shortened after atropine plus propranolol (p

Electrophysiologic and hemodynamic effects of intravenous enoximone were studied in 15 male patients, mean age 62.2 years, with New York Heart Association classes II to IV congestive heart fallure (coronary artery disease in 10 and idlopathic dllated cardiomyopathy in five patients; mean ejection fraction, 0.19). All patients had spontaneous ventricular tachyarrhythmias: eight had sustained ventricular tachycardia (VT), one had ventricular fibrillation, and six had nonsustained VT. Hemodynamic and electrophysiologic parameters including VT induction were determined before and during an intravenous infusion of enoximone. The cardiac index increased (2.49 ± 0.89 to 2.96 ± 0.78), and the pulmonary capillary wedge pressure decreased (22.4 ± 13.2 to 10.0 ± 9.0) after enoximone per predefined protocol endpoints. There was a significant decrease in spontaneous sinus cycle length, corrected sinus nodal recovery time, AH interval during atrial pacing, shortest cycle length at which 1:1 atrioventricular nodal conduction occurred, and refractory periods of the atrium, ventricle, and atrioventricular node. Enoximone did not alter the cycle length of induced VT, and there was no consistent change in the number of extrastimuli required for VT induction. A baseline 24-hour ECG recording was obtained on 14 patients (while recelving a long-term antiarrhythmic drug regimen, if needed) and repeated after 1 week and 1 month of oral enoximone therapy. There was no significant increase in the number of premature ventricular complexes per hour or VT episodes per 24 hours after 1 week or 1 month of therapy with enoximone. However, if four patients who received amiodarone and may not yet have reached steady state were excluded from analysis, there was a significant increase in the frequency of premature ventricular complexes per hour 1 month after initiation of enoximone. We conclude that intravenous enoximone reduces pulmonary capillary wedge pressure and increases cardiac output in most patients. Intravenous enoximone in doses sufficlent to have hemodynamic effects shortens atrial, ventricular, and atrioventricular nodal refractoriness and decreases AV nodal conduction time but has no consistent effect on VT induction or VT cycle length. The frequency of spontaneous ventricular ectopy may increase in some patients after oral enoximone, but its clinical significance is undefined. Enoximone may be administered cautiously to patients with congestive heart fallure and preexisting ventricular tachyarrhythmias.

The pharmacokinetics of oral cibenzoline were studied in 30 arrhythmia patients as part of an ascending multiple-dose efficacy study. The elimination half-life of the drug following repetitive dosing ranged from 7.6 to 22.3 hours, with a harmonic mean of 12.3 hours (n = 24), and increased with age and decreasing renal function. The drug exhibited apparent dose proportional and linear pharmacokinetics over the range of doses studied. Multivariate analysis revealed that the patients' age and serum creatinine concentration accounted for 71% of the variability in the range of beta values (terminal elimination rate constant), and that 69.5% of the intersubject variability in the steady-state trough plasma concentrations could be accounted for by the patients' age, weight and serum creatinine concentration. These data suggest that, although there is some intersubject variability in the elimination and accumulation of cibenzoline, much of the variability can be explained by the patients' age, weight and renal function.

Three patients with drug-resistant atrioventricular (AV) nodal reentrant tachycardia and two patients with reciprocating tachycardia associated with nodoventricular pathways received oral encainide after a control drug-free electrophysiologic study. In one patient with AV nodal reentry, encainide prolonged anterograde AV nodal conduction, produced complete ventriculoatrial (VA) block, and prevented tachycardia induction. Encainide had no effect on AV or VA conduction in the second patient with AV nodal reentry, and tachycardia with similar cycle length was still induced. The third patient was not studied while receiving encainide, but spontaneous AV nodal reentrant tachycardia occurring multiple times daily was abolished. In both patients with nodoventricular pathways, anterograde AV nodal and VA conduction were prolonged by encainide and tachycardia was no longer inducible. Two patients with AV nodal reentry were given long-term encainide therapy and have been free of recurrent arrhythmias for 16 and 30 months. One patient with a nodoventricular pathway has been without arrhythmia recurrence after 73 months of encainide therapy; the other patient required addltion of propranolol to encainide because of recurrent tachycardia. We conclude that encainide can prolong anterograde AV nodal and VA conduction and prevent induced and spontaneous tachycardia in some patients with drug-resistant and highly symptomatic AV nodal or nodoventricular reentry.

The relationships between size of loading dose and drug concentration, size of maintenance dose and drug concentration, and pulmonary and cutaneous adverse side effects and drug dosage were examined in patients given amiodarone. Amiodarone and metabolite concentrations in plasma and red cell samples were measured by specific high-pressure liquid chromatography. During drug loading, a daily dose schedule of 1600 mg/day produced significantly higher drug concentrations than did a loading dose schedule of 800 mg/day. During maintenance therapy, amiodarone dosage correlated with drug concentrations but with a wide interpatient variability for any given dosage level. The ratio of desethylamiodarone to amiodarone remained relatively constant over different dosage or drug concentration ranges, but increased with duration of treatment, suggesting a time-dependent metabolic function that may be analogous to the time-dependent attainment of maximal antiarrhythmic effect. The occurrence of pulmonary toxicity from amiodarone was not related to duration of treatment or cumulative dose of drug, buy may relate to the magnitude of the maintenance dose of amiodarone. Blue skin discoloration occurred in 19 (36%) of 53 patients receiving amiodarone for longer than 17 months, and may relate to the cumulative dose.

Aprindine is a very effective antiarrhythmic agent with a narrow therapeutic-toxic ratio. It has been used successfully in treating patients who have both supraventricular and ventricular tachyarrhythmias. Aprindine slows conduction in all cardiac fibers and suppresses digitalis-induced after-depolarizations. Voltage-clamp studies indicate that aprindine, in higher doses, suppresses the slow inward current in frog atria. In the dog subjected to coronary artery occlusion, aprindine may be arrhythmogenic, antiarrhythmic, or have no effect on the development of arrhythmias, depending on the temporal relationship between time of administration and time of occlusion.

The purpose of this study was to test the efficacy, safety, and patient tolerance of transvenous cardioversion and defibrillation in patients who had recurrent ventricular tachyarrhythmias. In five of seven patients, a truncated exponential shock of 0.025 to 2.0 joules synchronized to the QRS complex terminated 47 episodes of recurrent sustained ventricular tachycardia (VT). Cardioversion threshold was less than or equal to 0.25 joule in three patients and 0.75 to 2.0 joules in two patients. Shocks of 0.75 joule and 2.0 joule failed to terminate VT in one patient each; higher energies were not tried because of hemodynamic decompensation. In one patient, a shock of 25 joules terminated ventricular fibrillation (VF) on three occasions, and in another patient a shock of 1.0 joule terminated atrial fibrillation on one occasion. Shocks less than or equal to 0.5 joule were well tolerated by the awake unsedated patient. One hundred forty of 141 synchronized shocks (including subthreshold shocks) produced no repetitive ventricular activity. In one seriously ill patient who had received multiple antiarrhythmic drugs and required balloon counterpulsation for hemodynamic support, on a single occasion each a synchronized transvenous shock and a synchronized conventional transthoracic shock produced ventricular flutter and ventricular fibrillation (VF), respectively. We conclude that synchronized transvenous cardioversion by a catheter electrode offers promise as a new therapeutic approach.

Noninvasive transcutaneous pacing has been used successfully in situations requiring emergent ventricular pacing,1–8 and has also been used to terminate ventricular (VT) or supraventricular tachycardia in some patients.9–13 Thus, transcutaneous pacing might logically be considered a suitable noninvasive substitute for endocardial pacing during programmed electrical stimulation studies. We therefore determined the following features of transcutaneous pacing using the Zoll noninvasive temporary pacemaker (Zoll NTP, ZMI Corp.): patient tolerance, which cardiac chambers were paced, the ventricular effective refractory period (ERP) compared with that determined by endocardial pacing and feasibility for programmed electrical stimulation in patients with ventricular tachyarrhythmias.

Eleven of 83 patients who had ventricular tachycardia (VT) and underwent serial electrophysiologic study (EPS) had a more severe VT induced while receiving a particular antiarrhythmic drug as compared to control study. For all patients only nonsustained VT was initiated during control study, while sustained VT occurred during drug testing with disopyramide (2 patients), quinidine (2 patients), amiodarone (4 patients), and encainide (7 patients), although spontaneous arrhythmias appeared well-controlled prior to repeat testing. Pacing techniques used to induce sustained VT were the same as those used in the control study in eight patients and "less aggressive" in three patients. Almost all episodes of sustained VT resulted in substantial hypotension, especially in patients who were taking encainide. Drugs associated with sustained VT increased the median tachycardia cycle length by 112 msec (p less than 0.005) but increased the median ventricular effective refractory period by only 30 msec (p less than 0.02). Assuming re-entry was responsible for VT, we postulate that drugs facilitated initiation of sustained VT by prolonging activation time but only minimally increasing refractoriness of the tachycardia circuit.

The clinical antiarrhythmic efficacy of amiodarone treatment was examined in 196 patients with recurrent ventricular tachycardia (VT) or ventricular fibrillation (VF) resistant to other antiarrhythmic drugs. Patients had received a mean of 4.4 +/- 1.9 unsuccessful drug trials over a mean of 15.2 months prior to amiodarone treatment of recurrent VF in 57 patients; recurrent, sustained VT in 95 patients; and recurrent, nonsustained VT in 44 patients. Amiodarone dosage during the first 2 to 4 weeks of treatment was 800 to 1600 mg/day. During long-term follow-up, amiodarone dosage was reduced to 200 to 600 mg/day, based on the control of arrhythmia and patient tolerance. Electrophysiologic studies were performed prior to and after 2 or more weeks of amiodarone treatment. After a mean follow-up of 16.2 +/- 13.0 months, 126 (64%) of 196 patients continued successful treatment with amiodarone. At electrophysiologic study, amiodarone prevented VT induction in 13 patients, and although VT was induced in 101 patients, 80 patients continued treatment for 14.2 months without recurrence of spontaneous VT. Amiodarone treatment was discontinued because of recurrent VT in 22 patients, sudden cardiac death in 15 patients, adverse effects in 12 patients, and noncardiac death in 21 patients. In nine patients, recurrent VT/VF appeared related to amiodarone-induced exacerbation of arrhythmia. Pulmonary toxicity occurred in seven patients, and 19 patients developed blue skin discoloration. Other adverse effects were usually dosage related. In summary, amiodarone was a highly effective antiarrhythmic drug, but at the dosages employed, the risk of significant adverse effects warrants careful surveillance during treatment.

The purpose of this study was to determine the effects of enhanced vagal tone on human right atrial refractoriness in 12 patients. A specially built neck collar connected to a vacuum source was placed around the patient's neck and enhanced vagal tone was produced during neck suction using intracollar negative pressures of 50 to 60 mm Hg. Refractory periods were determined with a catheter electrode positioned in the high right atrium near the sinus node. Induced neck suction increased the spontaneous sinus cycle length from 837 +/- 96 to 1.136 +/- 273 ms (p less than 0.001) and shortened the atrial effective refractory period from 241 +/- 24 to 230 +/- 20 ms (p less than 0.01) and the atrial functional refractory period from 272 +/- 32 to 262 +/- 29 ms (p less than 0.01). In 2 of 2 patients, collar-induced decreases in atrial refractoriness and increases in spontaneous cycle length were prevented after atropine (0.03 mg/kg) was given intravenously. It is concluded that enhanced vagal tone mediated through muscarinic receptors shortens atrial refractory periods in man.