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Biomedical subjects

R A Winkle

Publications and source records attributed to R A Winkle.

At least 73 records · Page 4Linked to original sources
PubMed1983

Clinical factors predicting successful electrophysiologic-pharmacologic study in patients with ventricular tachycardia.

Data from 142 patients who had sustained ventricular tachycardia or ventricular fibrillation were analyzed to determine if clinical variables predict response to antiarrhythmic drugs at electrophysiologic study. Effective antiarrhythmic drugs were identified for 43 patients (30%). Ten of 25 variables analyzed were univariate predictors of drug response at the probability (p) level of less than 0.05. Stepwise logistic regression identified three variables independently predictive of drug response: fewer coronary arteries with 70% or greater stenosis (p less than 0.001), female sex (p less than 0.002) and fewer episodes of arrhythmia (p less than 0.03). A function incorporating these three variables was constructed to predict the probability of drug response, and ranges of the predictor function corresponding to high, intermediate and low probabilities of drug response were identified. Response rates in the high (greater than 50%), intermediate and low (less than 10%) probability ranges were 28 (58%) of 48, 10 (27%) of 37 and 5 (9%) of 57, respectively. Thus 40% of the patients who had a less than 10% likelihood of benefit from electrophysiologic-pharmacologic study were classified into the low probability range. When the predictor function was applied prospectively to 25 additional patients, response rates in the three probability ranges were 3 (50%) of 6, 1 (12%) of 8 and 0 (0%) of 11. These data show that analysis of clinical variables can be used to estimate the probability of benefit from electrophysiologic-pharmacologic study.

Anti-Arrhythmia Agents↗
PubMed1983

Lorcainide disposition kinetics in arrhythmia patients.

Lorcainide disposition kinetics were studied after intravenous and oral administration to patients with ventricular arrhythmias. After intravenous doses ranging from 100 to 200 mg, blood samples were drawn and plasma was analyzed for lorcainide concentration by high-pressure liquid chromatography. A three-compartment model was used to fit the data. The model-independent calculated values for clearance, steady-state volume of distribution, and terminal half-life were 14.4 +/- 3.28 ml/min/kg, 6.33 +/- 2.23 l/kg, and 7.8 +/- 2.2 hr. After nine doses of oral lorcainide (100 mg every 12 hr) blood samples were drawn and analyzed for lorcainide and its active metabolite, norlorcainide. The lorcainide and norlorcainide half-lifes were 9.6 +/- 2.8 and 26.8 +/- 8.2 hr. Mean steady-state level of norlorcainide was 2.2 +/- 0.9 times the level of lorcainide. The data suggest that the clearance of lorcainide decreases with time during long-term dosing.

Administration, Oral↗
PubMed1983

The implantable defibrillator in ventricular arrhythmias.

The most common cause of sudden cardiac death appears to be electrical instability that culminates in ventricular fibrillation. The implantable defibrillator, a self-contained diagnostic-therapeutic system, provides automatic detection and correction of malignant ventricular tachyarrhythmias. Principles involved in its development are reviewed, as are initial clinical results.

Animals↗
PubMed1983

Amiodarone: clinical efficacy and toxicity in 96 patients with recurrent, drug-refractory arrhythmias.

Ninety-six patients with recurrent, drug-refractory tachyarrhythmias were treated with amiodarone for 8.0 +/- 7.5 months (range 1 day to 27 months): 77 for recurrent ventricular tachycardia or ventricular fibrillation (VT/VF), two for complex ventricular ectopy, and 17 for supraventricular tachyarrhythmias. The actuarial incidence of successful amiodarone therapy was 52 +/- 7% at 12 months and 28 +/- 9% at 24 months for patients with VT/VF. Neither patient with complex ventricular ectopy was successfully treated. Among the patients with supraventricular tachyarrhythmias, 64.7% were successfully treated for 7.7 +/- 7.6 months (range 1 to 22 months). Amiodarone toxicity occurred in 66 of 91 patients (72.5%) treated for more than 1 week. Fourteen patients had therapy-limiting toxicity. Of these 14, six had pulmonary toxicity, four had arrhythmia exacerbation, one had hepatitis, one had renal toxicity, one had rash, and one had erythema nodosum. The actuarial incidence of therapy-limiting side effects was 27 +/- 7% at 15 months. We conclude that amiodarone is useful in the treatment of refractory tachyarrhythmias but that the rate of efficacy in VT/VF is lower and the incidence of significant toxicity is higher than has been generally appreciated.

Adult↗
PubMed1983

Comparison of the electrophysiologic effects of intravenous and oral lorcainide in patients with recurrent ventricular tachycardia.

The electrophysiologic effects of intravenous lorcainide (2.2 mg/kg) in 10 patients were compared with the electrophysiologic effects of oral lorcainide (mean dose 400 mg/day for 8 days) in 11 patients, all with recurrent ventricular tachycardia that could be induced with programmed stimulation. Intravenous and oral lorcainide resulted in similar prolongation of the QRS, QT, and HV intervals, but only oral lorcainide resulted in prolongation of the AH interval and atrial and ventricular effective refractory periods. After both oral and intravenous lorcainide, ventricular tachycardia could still be induced, but the arrhythmia was slower and better tolerated hemodynamically. The mean plasma lorcainide level during a maintenance intravenous infusion was 1254 +/- 662 ng/ml compared with a lorcainide level of 562 +/- 41 ng/ml and a norlorcainide level of 1212 +/- 653 ng/ml after oral dosing. No norlorcainide was detected in plasma after intravenous lorcainide. These data suggest that the short-term electrophysiologic effects of intravenous lorcainide may be different from those of short-term therapy with the oral drug. These differences should be considered during short-term studies of lorcainide.

Administration, Oral↗
PubMed1983

Prognostic significance of the number of induced ventricular complexes during assessment of therapy for ventricular tachyarrhythmias.

We analyzed 255 long-term trials of antiarrhythmic therapy, each of which had been evaluated at electrophysiologic study, to identify the maximum number of induced ventricular complexes consistent with the long-term efficacy of antiarrhythmic therapy. All patients had spontaneous and inducible sustained ventricular tachycardia or ventricular fibrillation. The incidence of therapeutic efficacy at 1 month and throughout follow-up was similar for trials in which zero, one, two, three, four, five, six to 10, and 11 to 15 complexes were induced, but significantly lower (p less than .001) for trials in which 16 or more complexes were induced. The cumulative incidence of efficacy at 1 year was 75 +/- 5% for 0 to 5 induced complexes, 72 +/- 11% for six to 10 complexes, 83 +/- 15% for 11 to 15 complexes, 42 +/- 10% for 16 complexes to 15 sec, and 48 +/- 6% for sustained ventricular tachycardia. At 1 year, the incidence of "sudden death-free" survival was higher for patients in trials that prevented initiation of sustained ventricular tachycardia than for those in trials that permitted initiation of sustained ventricular tachycardia (91 +/- 3% vs 75 +/- 6%; p = .01). The duration of the arrhythmia induced at therapy assessment was in the range of 11 to 20 complexes for only 4% of trials. Antiarrhythmic therapy is likely to be effective if as many as 15 complexes are induced at therapy assessment. The best cutoff, between 11 and 20 complexes, is difficult to identify because of the small fraction of trials in this range. Patients in whom initiation of sustained ventricular tachycardia is not prevented are at high risk for arrhythmia recurrence and sudden death.

Adult↗
PubMed1983

Clinical pharmacology of propafenone.

We determined the efficacy, pharmacokinetics, and plasma concentration-response relationships of propafenone, a promising new antiarrhythmic drug. Thirteen patients with frequent and complex ventricular premature beats were studied after receiving four increasing doses, during drug washout and during a randomized double-blind placebo-controlled trial, to evaluate the optimal dose in each patient. A nonlinear relationship was found between propafenone dose and steady-state mean concentration with a 10-fold increase in drug concentration as dose increased threefold from 300 to 900 mg/day. There was great intersubject variability in elimination half-life (mean 6 hr, range 2.4 to 11.8), steady-state mean concentration on 900 mg/day of propafenone (mean 1008 ng/ml, range 482 to 1812), and "therapeutic" plasma concentration (mean 588 ng/ml, range 64 to 1044). The interaction of these three parameters in individual patients determined the duration of the antiarrhythmic action of propafenone during washout (mean 11.5 hr, range 4 to 22). There was a greater than 90% reduction of ventricular premature beats in 10 subjects during dose ranging and in seven during double-blind crossover. Side effects requiring discontinuation of the drug occurred in three patients and included apparent worsening of arrhythmias in two. We conclude that propafenone effectively suppresses ventricular arrhythmias and that nonlinear drug accumulation and intersubject variability in elimination of half-life, steady-state mean plasma concentration, and therapeutic concentration indicate a need for individual therapy.

Adult↗
PubMed1983

Mortality in patients with implanted automatic defibrillators.

Fifty-two patients who survived several arrhythmic cardiac arrests had implantation of an automatic defibrillator along with additional cardiovascular surgery as indicated. The mean follow-up was 14.4 months and the longest was 3 years. In the hospital, the implanted devices identified and reverted 82 episodes of spontaneous and 81 of 99 episodes of induced malignant tachyarrhythmias. There were 62 automatic resuscitations in 17 patients outside the hospital. Twelve patients died; four of the deaths were not witnessed. These deaths represent a 22.9% total and 8.5% sudden-death 1-year mortality rate. Because the expected 1-year mortality in patients without the automatic defibrillator was calculated to be 48%, there was an estimated 52% decrease in anticipated total deaths. The automatic implantable defibrillator can identify and correct potentially lethal ventricular tachyarrhythmias, leading to a substantial increase in 1-year survival in properly selected high-risk patients.

Adolescent↗
PubMed1982

Acute hemodynamic effects of intravenous encainide in patients with heart disease.

Encainide, a new antiarrhythmic drug, was given intravenously (0.9 mg/kg) to 18 patients over 15 minutes to evaluate the hemodynamic effects. Hemodynamics and drug plasma concentrations were measured during and 30 minutes postdrug infusions. Encainide infusion was associated with a decrease in cardiac index from 2.6 +/- 0.7 to 2.4 +/- 0.7 L/min/m2 (p less than .05), a significant decrease in stroke work index and left ventricular end-diastolic pressure, and with a rise in systemic vascular resistance. There was no change in systemic or pulmonary arterial pressure, left ventricular dp/dt, or pulmonary vascular resistance. The patients were studied 30 to 60 minutes after cardiac angiography. Comparison of hemodynamic values obtained preangiography with those obtained postangiography (before, during, and after drug infusion) strongly suggests that many of the observed effects were due to radiographic contrast media (initial osmotic volume loading and subsequent diuresis). We conclude that if encainide has any significant hemodynamic effects after intravenous use, it is a modest decrease in cardiac output, possibly as a result of decreased left ventricular filling pressure.

Adult↗
PubMed1982

Randomized double-blind placebo controlled crossover trial documenting oral lorcainide efficacy in suppression of symptomatic ventricular tachyarrhythmias.

Lorcainide, a new antiarrhythmic drug, was given to 10 patients with frequent (greater than 1/min) premature ventricular contractions (PVCs) on a baseline 24-hour Holter monitor. Each patient received lorcainide, 100 mg twice daily, and an identical placebo, in a randomized double-blind crossover trial, with 1 week in each treatment period. Before the trial and at the end of each period, routine laboratory, clinical evaluation, 12-lead ECG's, and 24-hour ambulatory ECG recordings were performed. Trough drug plasma concentration measurements were done at the end of each treatment period. All patients had reduction in PVCs, comparing drug to placebo, averaging 82.3 +/- 19.7% (mean +/- SD, p less than 0.01 by Wilcoxin ranked sum), and there was also significant decrease in the number of ventricular pairs and runs. Levels of the major metabolite, norlorcainide, ranged from 34 to 254 ng/ml (mean 160 ng/ml) and exceeded those for lorcainide, range 6 to 169 ng/ml (mean 79 ng/ml). Prolongation of PR, QRS, and QTc intervals was evident during drug therapy, as was decrease in heart rate, but these changes were minimal. The major adverse effect noted was sleep disturbance, which was often initially severe, but improved during the week of therapy.

Administration, Oral↗
PubMed1982

Decreased incidence of antiarrhythmic drug efficacy at electrophysiologic study associated with the use of a third extrastimulus.

Drug trials during electrophysiologic study were performed in 166 patients with sustained ventricular tachycardia (VT) or ventricular fibrillation. In the first 21 patients (group I), a maximum of two extrastimuli was used. In 145 subsequent patients (group II), drug efficacy was assessed using three extrastimuli if one or two failed to induce VT. The incidence of acute drug efficacy was 15 of 21 (71%) in group I, but only 44 of 145 (30%) in group II (p less than 0.01). To assess the influence of the third extrastimulus on the differing incidence of acute drug efficacy, we examined the 69 group II patients whose VT was initially induced by one or two extrastimuli. Acutely effective agents were identified for 19 of these 69 patients using up to three extrastimuli to define efficacy. In 24 of te 50 patients for whom no effective drug could be found, VT was induced with one or two extrastimuli during all drug trials. In the remaining 26 patients VT could be induced after drug administration only with use of three extrastimuli. If efficacy had been defined using a maximum of two extrastimuli, these 26 patients would have been considered responsive to drug testing. Overall, 45 to 69 (65%) rather than 19 of 69 (28%) would have had a favorable response (p less than 0.001). Fourteen group I patients and 17 group II patients in whom VT was initially induced by one or two extrastimuli received chronic therapy with agents predicted effective during acute drug trials. At 18 months, the cumulative percent of patients free of arrhythmia recurrence by actuarial analysis was 79 +/- 14% in group I and 80 +/- 14% in group II (NS). Use of three extrastimuli during drug trials is associated with a lower incidence of acute drug efficacy. Limited data suggest that prophylaxis against VT induction by three, rather than two, extrastimuli may not be a stronger predictor of chronic efficacy in patients whose VT is initially induced by one or two extrastimuli. Further study is needed to identify optimal pacing methods for antiarrhythmic drug assessment.

Anti-Arrhythmia Agents↗
PubMed1982

Programmed ventricular stimulation in predicting vulnerability to ventricular arrhythmias and their response to antiarrhythmic therapy.

In predicting vulnerability to ventricular arrhythmias and their response to antiarrhythmic therapy, several factors and questions need to be considered, including the following. (1) Ventricular tachycardia (VT) can be induced in most patients who have recurrent sustained VT. (2) Because induced VT can often be pace terminated, termination by pacing should be attempted before cardioversion is applied. (3) Acutely effective antiarrhythmic agents are no longer being found for the majority of patients undergoing electrophysiologic-pharmacologic study in our series. (4) Specific VT-induction programs affect both the inducibility of VT and acute efficacy of drugs at electrophysiologic study; this point requires examination. (5) Arrhythmia-induction studies may not product high yield in patients with clinical ventricular fibrillation or unsustained VT. (6) It is as yet unclear whether some drugs, such as amiodarone, can be accurately evaluated by using arrhythmia-induction techniques. (7) Induction of the repetitive ventricular response by V2 stimulation is not a useful method for antiarrhythmic drug selection in patients with recurrent ventricular tachyarrhythmias. (8) Adequate data do not yet exist to identify either the ECG-monitoring technique or the arrhythmia-induction technique as the preferred method for selecting antiarrhythmic drugs for chronic therapy of patients with recurrent ventricular tachyarrhythmias. A study to compare the accuracies of the two techniques is both feasible and needed.

Amiodarone↗
PubMed1982

Frequency response characteristics of ambulatory ECG monitoring systems and their implications for ST segment analysis.

Because of the increasing interest in using ambulatory ECG monitoring equipment to study cardiac ischemia, we examined the frequency response characteristics and the reproducibility of a standard ST segment shift for equipment from eight manufacturers. Output/input amplitude versus frequency response curves, derived from input sine waves, were compared with American Heart Association (AHA) standards. Low- and high-frequency cutoffs (-3dB) were examined as well as flat response within the pass band. A new test based on Fourier analysis provided evaluation of phase shift versus frequency response and a more detailed analysis of the amplitude versus frequency response. By using a modified ECG simulator, flat-line ST segment depression from 0 to 10 mm (in 1 mm increments) was input to two or three recording devices for each manufacturer. The outputs from the scanners were evaluated for the amount of ST depression and the quality of the waveform reproduction. No system met all AHA standards for frequency response. Each system also had varying amounts of phase shift which could potentially distort the ECG signal. Although some manufacturers' equipment gave faithful reproductions of the simulated ST segment depression, others did not. We conclude that additional investigation is necessary to determine the clinical implications of our findings and to establish better standards for low- and high-frequency cutoffs, flat response within pass band, and phase shift for ambulatory ECG monitoring equipment.

American Heart Association↗
PubMed1982

Relative efficacy of blind left ventricular aneurysm resection for the treatment of recurrent ventricular tachycardia.

Coronary arterial bypass grafting and left ventricular aneurysm resection and the two combined have been reported effective in control of refractory ventricular tachyarrhythmias; 82 percent of a pool of 127 patients (from 22 reports) survived after surgery. However, the follow-up period in this group is short and the extent of medical therapy is not well defined. Actuarial analysis of results of conventional left ventricular aneurysm resection in 32 Stanford patients with well documented ventricular tachyarrhythmias shows an arrhythmia recurrence rate of 50 +/- 9 percent (mean +/- standard error of the mean) during the postoperative hospitalization. In contrast, after 10 months only 11 +/- 9 percent of 18 patients who underwent myocardial resection guided by intraoperative electrical activation sequence mapping experienced arrhythmia recurrence. These data demonstrate that simple left ventricular aneurysm resection is less effective in preventing ventricular tachyarrhythmias than originally believed. Preliminary data suggest that surgery of the left ventricle guided by intraoperative mapping may provide more effective control of ventricular tachyarrhythmias. However, intraoperative mapping has many technical and interpretive problems. Investigations are needed to determine the roles of conventional and new operative approaches to treatment of medically refractory ventricular tachyarrhythmias.

Aged↗
PubMed1982

Metabolite cumulation during long-term oral encainide administration.

Cumulation of encainide and its major metabolites, O-demethylencainide (ODE), 3-methoxy-ODE (MODE), and N-demethylencainide (NDE) was examined in patients with frequent complex ventricular ectopy. After 6 mo on encainide patients were admitted to Stanford University Hospital and the drug was discontinued for 24 hr. During this time blood samples were drawn to characterize the cumulation and disposition of the drug and metabolites. The mean steady-state concentrations of encainide, ODE, and MODE were 56.3, 214.6, and 184.6 ng/ml after doses ranging from 100 to 250 mg/day. The concentration ratios of ODE/encainide and MODE/encainide were 5.02 +/- 2.61 and 5.15 +/- 4.13. NDE was detected in the plasma of only one patient. Elimination half lifes of encainide and ODE were 1.16 +/- 0.5 and 11.41 +/- 9.58 hr. MODE disappeared slowly and at 24 hr the plasma concentration was still 59.8 +/- 39.9% of its mean steady-state concentration. Our data indicate that the metabolites of encainide cumulate in the plasma of patients on long-term oral therapy and must be considered when evaluating its clinical efficacy.

Administration, Oral↗
PubMed1982

Surgery for ventricular tachycardia: efficacy of left ventricular aneurysm resection compared with operation guided by electrical activation mapping.

Sixty-five patients underwent surgery for recurrent ventricular tachyarrhythmias. The 32 patients in group 1 underwent simple left ventricular aneurysm resection. The 33 patients in group 2 underwent myocardial resection or incision guided by intraoperative mapping of the electrical activation sequence. The clinical, hemodynamic and angiographic characteristics of the two groups were similar. Although actuarial survival in the two groups was similar through 24 months, late attrition in group 1 patients has left only 21 +/- 13% (+/- SEM) alive by life-table analysis at 94 months. Arrhythmia recurrence has been greater in group 1 than in group 2. In group 1, 50 +/- 9% of patients at risk at 3 months had recurrences by actuarial analysis. In group 2, only 13 +/- 6% at 1 month, 17 +/- 7% at 3 months and 29 +/- 9% at 24 months relapsed. Death was caused by ventricular tachyarrhythmias in 12 of the 17 patients (71%) who died in group 1, but only three of 12 (25%) who died in group 2. We conclude that surgery of the left ventricle, guided and modified by intraoperative mapping of the electrical activation sequence, frequently eliminates ventricular tachyarrhythmias and may be more effective than blind resection of left ventricular aneurysm.

Electrocardiography↗