Mexiletine for ventricular arrhythmias

Mexiletine, a new antiarrhythmic agent derived from lidocaine and available in oral form, was utilized in 108 patients with chronic and symptomatic ventricular arrhythmia. Recurrent ventricular tachycardia was present in 83 patients and considered refractory to antiarrhythmic therapy in 72. Twenty-five patients had at least one episode of ventricular fibrillation. There were four phases of study. Phase 0 consisted of 48 hours of ambulatory monitoring and exercise testing while the patient was taking no antiarrhythmic drugs. Phase 1 involved acute drug testing utilizing a single large dose of mexiletine (400 mg). Phase 2 involved 48 to 72 hours of mexiletine therapy during which 24 hour ambulatory monitoring and exercise testing were employed to evaluate drug efficacy. Phase 3 constituted long-term maintenance therapy in patients who demonstrated a good drug response without experiencing adverse effects.Eighty-eight patients underwent acute drug testing which included evaluation of mexiletine efficacy both at rest and with bicycle exercise. Suppression of ventricular ectopic activity was noted in 57 (65 percent) of 88 patients white sedentary and in 32 (58 percent) of 55 patients during exercise. Seventy-nine patients completed the phase 2 study; control of arrhythmia was demonstrated by monitoring in 51 of these (65.4 percent) and by exercise in 43 (66.2 percent) of 65 patients. Of the 65 patients undergoing both exercise and monitoring, 39 (60 percent) met criteria for drug efficacy with both methods. Results in phases 1 and 2 were concordant in 84.7 percent. Adverse effects occurred in 32 patients (29.6 percent); most commonly these were neurologic and gastrointestinal.Thirty-one patients have been taking mexiletine as their only antiarrhythmic drug (phase 3) for an average of 12.6 months (range 3 to 27) with continued suppression of arrhythmia. Thus mexiletine is effective and well tolerated in some patients having ventricular arrhythmia resistant to standard antiarrhythmic drugs.     

Therapy of coronary vasoconstriction in patients with coronary artery disease

Patients with obstructive coronary artery disease and stable, exertional angina respond to the alpha adrenergic stimulus of the cold pressor test with an inappropriate increase in coronary vascular resistance. The clinical significance of this abnormal response and its possible role in the pathogenesis of ischemic heart disease are discussed. Comparison of the anti-anginal agents currently in use of undergoing investigation suggests that the calcium antagonists may be the most effective therapy for coronary vasoconstriction. Nifedipine, 10 mg buccally, successfully prevented the increase in coronary vascular resistance during the cold pressor test in 10 of 10 patients, whereas the response in placebo-treated patients was unaltered. This dose of nifedipine was without effect on systemic hemodynamics or myocardial oxygen consumption, suggesting a selective antivasoconstrictor effect on the coronary vasculature.     

Effects of oral mexiletine on left and right ventricular function

Malignant ventricular arrhythmias often occur in patients with left ventricular (LV) dysfunction. Antiarrhythmic drugs may further impair LV function in these patients. Mexiletine, a lidocaine congener, is an effective antiarrhythmic drug, but when administered orally, its effect on LV and right ventricular (RV) function is unknown. To determine the hemodynamic effects of mexiletine, LV and RV ejection fraction (EF) were measured by radionuclide ventriculography in 10 patients with LV dysfunction (LVEF less than 50%). Symptom-limited exercise tests were also performed. Patients were studied before and during therapy with oral mexiletine. There was no significant change in LVEF (28% vs 27%) or RVEF (46% vs 41%). Also, heart rate at rest, exercise duration and peak heart rate during exercise were unchanged. Thus, in patients with LV dysfunction, oral mexiletine does not significantly affect LV or RV function.     

Quantification of pulmonary thallium-201 activity after upright exercise in normal persons: importance of peak heart rate and propranolol usage in defining normal values

Fifty-nine normal patients (34 angiographically normal and 25 clinically normal by Bayesian analysis) underwent thallium-201 imaging after maximal upright exercise. Lung activity was quantitated relative to myocardial activity and a lung/myocardial activity ratio was determined for each patient. Stepwise regression analysis was then used to examine the influence of patient clinical characteristics and exercise variables on the lung/myocardium ratio. Peak heart rate during exercise and propranolol usage both showed significant negative regression coefficients (p less than 0.001). No other patient data showed a significant relation. Using the regression equation and the estimated variance, a 95% confidence level upper limit of normal could be determined for a give peak heart rate and propranolol status. Sixty-one other patients were studied to validate the predicted upper limits of normal based on this model. None of the 27 patients without coronary artery disease had an elevated lung/myocardial ratio, compared with 1 of 8 with 1-vessel disease (difference not significant), 6 of 14 with 2-vessel disease (p less than 0.005), and 6 of 12 with 3-vessel disease (p less than 0.0001). Thus, lung activity on upright exercise thallium-201 studies can be quantitated relative to myocardial activity, and is inversely related to peak heart rate and propranolol use. Use of a regression analysis allows determination of a 95% confidence upper limit of normal to be anticipated in an individual patient.     

Heparin inhibits bovine testicular hyaluronidase activity in myocardium of dogs with coronary artery occlusion

Bovine testicular hyaluronidase (BTH) reduces experimental myocardial infarct size and ameliorates electrocardiographic signs of ischemia. This study was done to determine if heparin, an in vitro inhibitor of hyaluronidase activity, blocks the action of BTH in the myocardium of dogs after coronary artery occlusion. BTH was administered intravenously as 5,000 NF units/kg at 0.5 and 2.5 hours after coronary occlusion. Heparin was administered intravenously as a 150-unit/kg loading dose, followed by 10 units/kg per hour i.v., beginning 15 minutes before coronary occlusion. The area of myocardial ischemia at risk was assessed by a radiolabeled microsphere technique; the area that developed necrosis was assessed by a histochemical technique. In vivo activity of BTH was assessed by a colorimetric analysis of the BTH substrate, i.e., hyaluronic acid (HA), extracted from myocardial tissue. For biochemical analysis of HA, the heart was divided into anterior myocardium, which included ischemic tissue and posterior nonischemic myocardium. The myocardial HA content of dogs treated with BTH plus heparin (anterior, 3.44 +/- 0.40 micrograms HA/mg protein; posterior, 3.69 +/- 0.33 micrograms HA/mg protein) was not significantly different from control (anterior, 3.61 +/- 0.29 micrograms HA/mg protein; posterior, 3.55 +/- 0.23 micrograms HA/mg protein). In contrast, BTH lowered myocardial HA content (anterior, 2.16 +/- 0.21 micrograms HA/mg protein; posterior, 2.08 +/- 0.14 micrograms HA/mg protein) compared with either BTH plus heparin or control groups in both anterior myocardium (p = 0.006) and posterior myocardium (p = 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)     

Contaminated medication nebulizers in mechanical ventilator circuits. Source of bacterial aerosols

The contamination rates of medication nebulizers inserted into mechanical ventilator circuits were studied. Semiquantitative techniques were used to sample the reservoir fluid from in-line nebulizers during the first 24 hours after a circuit change. In the initial survey, high levels of contamination (organism concentrations above 10(3)/ml) were present in 13 (68 percent) of the 19 nebulizer reservoirs, and bacterial aerosols were produced by 10 (71 percent) of 14 nebulizers. Gram-negative bacilli were the predominant organisms isolated. Nebulizer contamination originated primarily from reflux of contaminated condensate in the ventilator circuit. When nebulizers were cleaned after each treatment, a reduced rate of contamination was found. Small bacterial aerosols (less than 3 microns in size) were produced in vitro after inoculation of nebulizers with gram-negative bacilli in concentrations isolated from in-use nebulizers. Contaminated in-line medication nebulizers generate small-particle bacterial aerosols that may increase the risk of ventilator-associated pneumonia and therefore should be cleaned or disinfected after each treatment rather than every 24 hours.     

Effect of beta blockade on plasma catecholamine levels during psychological and exercise stress

The effect of a single oral dose of 50 mg of metoprolol on plasma catecholamine levels was examined in 11 healthy young men. Subjects were studied during baseline at rest, postural challenge, psychological Stressors and graded maximal exercise testing. Metoprolol induced significant increases in plasma norepinephrine (NE) levels across most experimental conditions. Metoprolol did not have a consistent effect on plasma epinephrine levels. Because of wide interindividual variation in drug levels, the NE levels in subjects with high drug levels were compared with the NE levels in subjects who had negligible drug levels. NE levels were higher in subjects with higher drug levels.     

Correlates of reperfusion ventricular fibrillation in dogs

To elucidate determinants of reperfusion ventricular fibrillation (VF), regional myocardial blood flow, ATP, creatine phosphate (CP), heart rate and blood pressure were compared in 2 groups of anesthetized dogs: those that fibrillated spontaneously upon release of a 15-minute coronary artery occlusion (VF group, n = 8) and those that did not fibrillate when reperfused (No VF group, n = 27). Arterial pressure and heart rate before and during coronary artery occlusion were similar in both groups. Ischemie endo- and epicardial ATP values, measured at the end of the occlusion period, were reduced approximately 20% of nonischemic values in both groups. In contrast, CP (nmohmg protein^?1) within the ischemie zone was significantly lower in the VF group in both the epicardium (14.3 ± 1.6 in the VF group vs 22.8 ± 2.5 in the No VF group, p < 0.01) and the endocardium (9.0 ± 2.0 in the VF group vs 18.7 ± 1.8 in the No VF group, p < 0.01). Furthermore, epi- and endocardial regional myocardial blood flow in the center of the ischemic zone during occlusion was significantly lower in VF dogs than in No VF dogs. Epicardial flow was 0.06 ± 0.03 ml·min^?1·g^?1in VFdogsvs 0.44 ± 0.06 in No VF dogs (p < 0.001) and endocardial flow was 0.03 ± 0.02 ml·min^?1·g^?1 in VF dogs vs 0.23 ± 0.04 ·ml-min^?1·g^?1 in No VF dogs (p < 0.001). These data suggest that low levels of regional myocardial blood flow and CP during coronary artery occlusion are associated with an increased risk of VF on reperfusion. Thus, the severity of ischemia in the center of the ischemie zone may be a determinant of reperfusion VF.