The seizure is typically of short duration and self-limiting Res

The seizure is typically of short duration and self-limiting. Respiratory arrest is common because of the lack of muscle control

associated with the seizure. Progression to hypoxia, cyanosis, and cardiac arrest may be rapid because of the Trichostatin A consequences of increased oxygen consumption of the tonic muscles and respiratory arrest [40]. Physiological changes such as acidosis and decrease of carbon dioxide tension may affect the CNS toxicity of local anesthetics [41]. There are a number of limitations to some published in vivo studies since they were performed in anesthetized animals with the complicating effects of anesthesia and surgery, and bupivacaine was Inhibitors,research,lifescience,medical administered at toxic doses which did Inhibitors,research,lifescience,medical not allow to evaluate the absolute CNS and/or CV effects. Although there is no generally agreed standard model of toxicity, whole-system models are generally considered more clinically

relevant than others. However, the data acquired are complicated by PK/PD interactions at different organ system, progressive (gradual) response, and intrinsic control mechanisms. As a result, the dose response may be discontinued and nonlinear [38]. CNS effects are generally assumed to precede CV toxicity; this notion was primarily derived from studies over the past several decades comparing doses causing disappearance of pulsative blood pressure and onset of convulsions effects in sheep [38]. This ratio was proposed as comparative measure Inhibitors,research,lifescience,medical of CV toxicity. It was suggested that the higher the ratio, the better the safety Inhibitors,research,lifescience,medical margin for a given compound. That is, the wider the safety margin between convulsions and CV collapse, the more time there may be for treatment intervention when early signs of toxicity arise. In a recent published report, the utility of site-directed delivery systems to differentiate between CNS and CV Inhibitors,research,lifescience,medical system effects has been emphasized [38]. The author questioned the “CNS hypothesis” of cardiotoxicity and commented that it may not be correct or, if it is, it may apply only to massive iv overdose and not be sensitive towards

the CNS site-selective doses used in close arterial models. In a CNS site-directed carotid arterial infusion studies, bupivacaine was found to be more potent toward direct CNS toxicity and indirect cardiac toxicity than levobupivacaine and ropivacaine; however, there was no remarkable difference Cell press between the agents in nonfatal arrhythmogenicity nor did it find fatal arrhythmias [35]. In site-directed coronary arterial infusion studies, direct cardiac effects of bupivacaine, levobupivacaine, and ropivacaine were reported in the sheep [33]. In such model, the time-course of myocardial depression was similar for bupivacaine, levobupivacaine, and ropivacaine in doses that cause no CVS effects in conscious sheep. All these drugs caused abrupt onset fatal dysrhythmias. In rabbits, the mean convulsive doses (3.6mg/kg, 0.18mg/kg/min) and mean lethal doses of bupivacaine (7.6mg/kg, ~0.

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