Acute Toxicity of Local Anesthetics: Underlying Pharmacokinetic and Pharmacodynamic Concepts

Abstract

The risk of accidental intravascular injection and consequent acute toxicity is ever-present with most neural blockade techniques. The severity of cardiovascular and central nervous system (respectively, CVS and CNS) toxicity is directly related to the local anesthetic potency, dose, and rate of administration. Nonetheless, although the anesthetic potency of ropivacaine and levobupivacaine is similar to that of bupivacaine, at usual clinical doses, ropivacaine and levobupivacaine are less likely than bupivacaine to cause convulsions or lethal dysrhythmias. Signs of CNS stimulation, ranging from tremors to convulsions and perhaps cardiac dysrhythmias, can be described in terms of a chaos-derived state change in which the local anesthetic appears to act as an initiator. Both CNS and CVS effects are rather poorly correlated with arterial drug concentrations but better correlated with concentrations in the respective regional venous drainage. Lung uptake reduces the maximum drug concentration by approximately 40%. Prolonging intravenous administration from 1 to 3 minutes results in a similar decrease in maximum concentration. This is an underlying tenet of dose fractionation, but the main advantage of dose fractionation is that the anesthesiologist is able to cease administration with less of the dose given if signs or symptoms of toxicity occur. Overall, it appears that the gains in safety from ropivacaine and levobupivacaine are due more to favorable pharmacodynamic enantioselectivity than to pharmacokinetic factors. This essay presents some pharmacokinetic aspects relevant to acute toxicity of local anesthetics, mainly using data from the authors' studies in a sheep model of simulated accidental intravenous administration.

Comparison of peri- and intraarticular analgesia with femoral nerve block after total knee arthroplasty: A randomized clinical trial

“…Ropivacaine is pharmacologically similar to bupivacaine but is associated with less cardiac and central nervous system toxicity, which allows patients to tolerate a larger dose (Mather et al 2005). The addition of epinephrine helps to reduce the toxicity of the local anesthetic by reducing the rate the drug is released into the circulation.…”

Lipid rescue: the use of lipid emulsions to treat local anaesthetic toxicity

“…The reasons elucidated for achieving better results with lipid were superior cardiac and metabolic function during and after resuscitation, 4 and adrenaline-induced aggravation of bupivacaine-related dysrhythmias. 4,15,72,73 However, rats treated with adrenaline showed a decline in haemodynamics after 10 minutes.…”

“…On the other hand, the addition of epinephrine may add confusion as to the cause of the dysrhythmias 83 and delay definitive therapy. The importance of dose fractionation has been emphasised, 73 because it provides an early warning system and an opportunity to terminate the local anaesthetic injection at the first sign of toxicity. Slower injection of local anaesthetic decreases the maximal blood concentration.…”

“…Prolonging the duration of an intravenous bolus of levobupivacaine from one to three minutes in sheep has been shown to reduce the peak plasma concentration by about 40%. 73 Nonetheless, whereas good technique will reduce the risk of toxicity it will not preclude it.…”

No change in impedance upon intravascular injection of D5W

“…[1][2][3][4][5] This possibility is of particular concern at the upper extremity since many of the nerve targets are located in highly vascular regions. Methods to minimize this risk include the use of slow incremental injection, the aspiration of syringes prior to injection of local anesthetic, and monitoring heart rate or T-wave amplitude changes following injection of a test dose of epinephrine.…”