Central Effects Index — a semiquantitative method for the assessment of CNS toxicity of local anaesthetic agents in sheep

Abstract

Local anaesthetic agents can cause central nervous system (CNS) and cardiovascular system toxicity. Whereas most previous work has described their behavioural CNS effects qualitatively (i.e., absence or presence of convulsions), we wished to describe their CNS effects more quantitatively. We hypothesised that early CNS excitatory or disinhibitory effects leading to convulsions represent a prodrome to the onset of chaotic dynamics in the form of a bifurcation in the chaotic map. We therefore used a chaotic map with a continuous scale to model their CNS effects. A Central Effects Index (CEI) was developed from our observation of behaviours before and after intravenous (iv) administration of local anaesthetic agents in graded doses to conscious sheep. These behaviours were ranked in severity, and modelled according to a logistic population growth equation using the onset of convulsive behaviour and death as point attractors. The behaviours, scaled to the maximum and area under the curve (AUC) CEI units, were then compared for intravenous doses of (±)- RS-bupivacaine and (−)-( S)-bupivacaine (or levobupivacaine), which is being evaluated as a substitute for (±)- RS-bupivacaine. (−)-( S)-bupivacaine produced smaller maximum and AUC CEI values at 75 and 100 mg doses, but equivalent values at 150 and 200 mg when the doses exceeded the convulsant threshold. It was concluded that the CEI provides a useful quantitative tool for evaluating these agents in subconvulsant doses, and that the CNS stimulatory potency of (−)-( S)-bupivacaine is less than that of (±)- RS-bupivacaine.