Development and validation of a recirculatory physiological model of the myocardial concentrations of lignocaine after intravenous administration in sheep

A recirculatory physiological model of the determinants of the myocardial c oncentrations of lignocaine after intravenous administration was developed in sheep and validated with the intention of analysing and predicting the o utcome of altered dose regimens and various pathophysiological states on th e initial myocardial concentrations of lignocaine. The structure and parameters of the model were determined by hybrid modelli ng of the time-courses of the pulmonary artery, arterial and coronary sinus concentrations of lignocaine after the intravenous administration of 100mg of lignocaine over 5 min to 5 chronically instrumented sheep. The model ac counted for the determinants of the myocardial concentrations via compartme nts for venous mixing, the lung (a single-compartment model with a first-or der loss) and the heart (a single flow-limited compartment). Recirculation and the remainder of the body were represented as a single tissue pool with a clearance term. The distribution volume of the heart was 0.42 +/- 0.009 L, which gave a half-time of myocardium : blood equilibration of 2.37 min. The distribution volume of the lungs was 5.40 +/- 0.23 L, with an apparent first-order loss of 1.02 L min(-1) representing deep distribution or metabo lism. The validity of the model was tested by comparing the predictions of the model with the equivalent data collected in 6 sheep when lignocaine (89 mg) was administered via a complex dose regimen with a faster initial rate of infusion (39.1 mg min(-1)), declining exponentially to basal infusion r ate (7.02 mg min(-1)) over 8 min. The predictions of the model were in gene ral agreement with these data. It is concluded that the model was sufficient to account for the effect of altered dose regimens of lignocaine on the time-course of its myocardial co ncentrations.