The relationship between the effect of lidocaine and its plasma concentration has been well established; the therapeutic range of plasma levels has been reported as 1.2/xg/ml to 5.5/j.g/ml. The effects reported here are assumed to be related to the plasma level; however, no measurements of the plasma concentrations of lidocaine were made. From the pharmacokinetic model proposed by Rowland and co-workers, it is possible to estimate the plasma levels one might anticipate following the bolus and infusions of lidocaine administered in this investigation. Figure 4 shows a computer simulation of the plasma level of lidocaine vs time following both administration of a single 100-mg bolus and from the administration of a 100-mg bolus followed by a constant infusion of 2 mg/min. It can be seen that levels fall very rapidly following the initial bolus.
At three minutes following the single bolus, the plasma levels are approximately 2.1/xg/ml. The plasma levels of patients receiving a single bolus plus an infusion are seen to drop rapidly to a low level at about 20 minutes after administration of the bolus and then begin to rise again. The plasma level at 120 minutes is predicted to be 1.6/xg/ml. Without initiating an infusion, it can be seen that plasma levels are below the therapeutic range (0.9/ig/ ml) by 15 minutes following administration of the bolus alone.
This study demonstrates a negative inotropic effect of a 100-mg bolus of lidocaine injected into normal subjects, patients with angina, and patients with acute myocardial infarction. Consistent with the previously shown pharmacokinetic model, the negative inotropic effect of administration of lidocaine is manifested with therapeutic plasma levels. The maximum changes in the systolic time intervals occurred at approximately three minutes after injection, with values returning to baseline by 10 to 15 minutes. The significant negative inotropic effect was manifest by a prolongation of the PEPI and an increase in PEP/LVET. The PEP was not subdivided into isovolumic contraction time and electromechanical delay. The fact that the duration of the QRS complex was unchanged with administration of lidocaine makes unlikely the possibility that the changes in PEPI were related to an increase in the electromechanical delay.
The greatest change in the systolic time intervals following a 100-mg intravenously administered bolus of lidocaine occurred at three minutes. Consequently, the three-minute values will be employed hereafter. In Figure 1, it is seen that the effect on the systolic time intervals gradually returns to the baseline by 10 to 15 minutes after injection.
The PEP/LVET was prolonged significantly following administration of lidocaine in the patients with angina and in normal subjects. The ratio was not significantly changed in the patients with acute myocardial infarction (Table 1). Patients with acute myocardial infarction had the shortest initial QS2I and showed a significant lengthening of the QS2I. Significant lengthening of the QS2I was also observed in patients with angina and in normal subjects, but the lengthening was more profound in patients with acute myocardial infarction.
The PEPI was significantly lengthened by administration of lidocaine in all three groups. The LVET corrected for heart rate (LVETI) did not change significantly in the normal subjects or the group with angina but significantly lengthened in the group with acute myocardial infarction (Table 1). No changes in duration of the QRS complex were observed with administration of lidocaine.
Although lidocaine is a widely used antiarrhythmie drug, its effect on left ventricular performance is not well understood. Lidocaine has been shown to have a dose-dependent negative inotropic effect in isolated canine and human cardiac muscle and in experimental animals. In our laboratory, studies of dogs with experimentally produced acute myocardial infarction have shown that administration of lidocaine produces a significant negative inotropic effect manifest by a decrease in left ventricular dP/dt and in the acceleration of velocity of flow (dQ/dt) (unpublished data). We have also shown that ST-segment elevation in acute myocardial infarction was decreased significantly following administration of lidocaine. These findings are consistent with a significant negative inotropic effect; however, in clinical studies, few and often variable hemodynamic effects have been reported.
This study was therefore undertaken to evaluate the effect of administration of lidocaine on left ventricular performance as judged by systolic time intervals. To do so, we have studied patients with acute myocardial infarction, patients with chronic stable angina pectoris, and normal subjects. In addition, we have studied the effect of administering lidocaine produced by My Canadian Pharmacy before and after adrenergic blockade in normal subjects, since this is not an uncommonly employed therapeutic combination.