pH-dependent effects of lidocaine on defibrillation energy requirements in dogs

D S Echt, E L Cato, D R Coxe
1989 Circulation  
Lidocaine increases the energy required for ventricular defibrillation in dogs. Because sodium channel-blocking agents that are weak bases have pH-dependent electrophysiologic effects, we investigated the pH dependence of lidocaine (pKa, 7.9) on internal defibrillation energy requirements in 28 dogs with atrial spring and left ventricular patch electrodes. Results of defibrillation testing were used to derive 50% and 90% successful energy requirements (ED50 and ED90) using logistic regression
more » ... d were compared with analysis of variance. Acidosis produced by hydrochloric acid infusion decreased the arterial pH from 7.40±0.05 (SD) to 7.18±0.03 (n=8, p<0.01), but no significant change in ED90 was observed (14±4 to 16+6 J). Lidocaine infusion to therapeutic levels (4.2+.07,ugIml) at normal pH (7.42+±0.02) increased ED90 from 13+3 to 17±3 J (n=6, p<0.05), and subsequent acidosis (pH 7.19±0.02, p<0.01) exacerbated this effect of lidocaine on ED90 (22±5 J, p<0.05). Alkalosis produced by respirator hyperventilation increased the arterial pH from 7.41±0.03 to 7.60±0.03 (n=8, p<0.01), with a fall in ED90 from 13±4 to 8±3 J (p<0.01). Lidocaine infusion to high levels (7.4±2 ,ug/ml) at normal pH (7.42±0.02) increased ED90 from 15±8 to 20+9 J (n =6, p <0.05), and subsequent alkalosis (pH 7.61+0.02,p <0.01) reversed the effect of lidocaine on ED90 (12+5 J, p <0.05). We conclude that in dogs, the increase in defibrillation energy requirements by lidocaine are enhanced by acidosis and reversed by alkalosis consistent with its sodium channel-blocking properties. These data provide further evidence in support of the hypothesized direct link between drug effects on defibrillation and drug effects on individual ion channels. (Circulation 1989;80:1003-1009 M any antiarrhythmic agents alter the energy required for successful ventricular V defibrillation in acute canine studies, and anecdotal and retrospective human data are also available.' The mechanism by which antiarrhythmic drugs affect defibrillation energy requirements is unknown. We have hypothesized that the electrophysiologic actions of antiarrhythmic drugs on ionic currents determine their effects on ventricular defibrillation.2 We and others2 6 have previously shown that lidocaine increases the energy required for ventricular defibrillation in dogs. Lidocaine is believed to suppress cardiac arrhythmias, at least in large part, by depressing the rapid inward sodium current.7 It has been shown in vitro that the extent of sodium current depression caused by lidocaine and similar drugs is dependent on many factors, including drug concentration, rate (frequency) and time at any rate (use), transmembrane potential, and pH.7 Several investigators have successfully applied these in vitro findings to demonstrate block of sodium channels by antiarrhythmic drugs in vivo.8-11 In the present study, we have taken advantage of the pH-dependent electrophysiologic effects of lidocaine to test our hypothesis that the mechanism by which lidocaine affects defibrillation energy requirements is determined by its actions on the fast inward sodium channel current. We first investigated the effects of acidosis and alkalosis alone on internal defibrillation energy requirements in acute canine experiments. We then investigated the modulation of lidocaine's effect on defibrillation energy requirements by acidosis and alkalosis in further experiments. Methods Surgical Preparation Acute studies were performed in adult mongrel dogs in accordance with the guiding principles of the American Physiologic Society. Under general by guest on July 22, 2018 Downloaded from
doi:10.1161/01.cir.80.4.1003 pmid:2791234 fatcat:ftoj2jggdbcxnijhkerviadjfm