Effects of cholinergic overstimulation on isoflurane potency and efficacy in cortical and spinal networks

In scenarios of terrorist attacks with organophosphorus compounds it appears likely that medical aid is required by victims not only suffering from the intoxication but also from physical trauma. These subjects may have to undergo surgical interventions, raising the need for anaesthesia. This prompts the question of how anaesthetic agents work in intoxicated patients. Organophosphates block acetylcholinesterase activity, thereby inducing excessive cholinergic overstimulation in the central nervous system. As the neocortex and spinal cord are important substrates for general anaesthetics, we investigated to what extent cholinergic overstimulation affects the potency and efficacy of the commonly used volatile anaesthetic isoflurane in depressing action potential activity of cortical and spinal neurons. We first quantified the effects of isoflurane in the absence of acetylcholine by performing extracellular voltage recordings in cultured tissue slices. Isoflurane induced a concentration-dependent decrease of neuronal activity in neocortical (EC(50)=0.43+/-0.08 MAC) and spinal slices (EC(50)=0.41+/-0.03 MAC). At concentrations above 1.5 MAC, the anaesthetic almost completely depressed action potential firing in both preparations. Next, we studied the effects of acetylcholine (10microM) in the absence of isoflurane. Acetylcholine approximately doubled spontaneous activity in neocortical and spinal slices. When applying isoflurane together with acetylcholine, different interactions between these agents were observed in neocortical and spinal networks. Acetylcholine significantly reduced both the potency and efficacy of the anaesthetic in neocortical (efficacy 83%; EC(50)=1.16+/-0.02 MAC) but not in spinal (efficacy 100%; EC(50)=0.41+/-0.04 MAC) slices. Our results indicate that cholinergic overstimulation increases the requirement for anaesthetic agents in patients suffering from organophosphorus poisoning via enhancing neuronal background activity of neocortical and spinal neurons and in addition via decreasing drug potency and efficacy in the cortex. Raising anaesthetic concentrations into a high-dose range may not be an appropriate alternative to compensate the increased excitability, since high concentrations of anaesthetics may worsen cardiac abnormalities and hemodynamic instability frequently observed in these patients.