We were struck by the title “Possible Mechanism of Irreversible Nerve Injury Caused by Local Anesthetics” that appeared recently in Anesthesiology.1Kitagawa et al.  1showed that “local anesthetics used clinically can form molecular aggregations at high concentrations, resulting in the appearance of detergent properties in these agents.” They concluded, “The mechanisms of irreversible neurologic injury induced by high concentrated local anesthetic seem likely to result from the detergent nature of local anesthetics.”

In 1994, we published results of in vitro  experiments regarding the irreversible conduction block associated with high concentrations of local anesthetics.2In that publication, we examined the changes in the compound resting potential (CRP) of the isolated frog sciatic nerve. The CRP, like the compound action potential (CAP), is an average of membrane potentials of all the fibers in the nerve bundle. The CRP became less negative (by 18 ± 2 mV, n = 3) when 5% lidocaine was placed in the drug exposure pool. The kinetics of this apparent depolarization consisted of a rapid phase of 5–10 mV in amplitude, occurring in less than 10 s, and a slow phase of 10–15 mV amplitude, taking 10–15 min to reach steady state. The CAP amplitude decreased to zero within 40 s of exposure to 5% lidocaine. On replacement of lidocaine by amphibian Ringer’s solution, this apparent depolarization reversed with a corresponding rapid and slow phase, and the CRP was restored to within 2–4 mV of its predrug value after a 2-h washout, although the CAP did not reappear. A similar depolarization of 24 ± 4 mV, consisting of rapid and slow phases, resulted when the nerve was exposed to 200 mm choline chloride dissolved in Ringer’s solution. In the choline chloride Ringer’s solution, however, the action potential amplitude only decreased by 58.8 ± 6.4% (n = 4) and recovered to within 3.2 ± 0.8% of the initial value after a 50-min wash in Ringer’s solution. It is likely that the rapid apparent depolarization is actually an ionic solution artifact resulting from the interaction of the silver–silver chloride electrode in the test pool with the increased [Cl] present in both 5% (185 mm) lidocaine hydrochloride and 200 mm choline chloride. The mechanism of the slow phase is unclear, but both phases of this depolarization seem to result from differences in the ionic composition and not tonicity, because exposure of two nerves to Ringer’s solution containing 400 mm dextrose (7.2%, equally hypertonic to the lidocaine) changed the CRP by less than 0.4 mV, accompanied by small reductions of the CAP (11% and 18%) that remained after 2 h of washing in Ringer’s solution. In contrast, if the nerve was intentionally lysed by 5% sodium lauryl sulfate (an ionic detergent) in Ringer’s solution, the CRP disappeared within 3 min (a permanent depolarization of 30–40 mV),3accompanied by an irretrievable loss of the action potential.

At first glance, the mechanism proposed by Kitagawa et al.  seems plausible. However, our data suggest that lysis of the nerve cell membrane resulting from a detergent action is not the mechanism for irreversible nerve injury that we observed in an isolated nerve preparation. It seems more likely that the local anesthetic injury that we observed resulted from a “wrecking” of the sodium conductance system (lack of CAP generation) in the face of preserved membrane structure, ionic gradients, and CRP.

* Boston University Medical School, Boston Medical Center, Boston, Massachusetts. donald.lambert@bmc.org

Kitagawa N, Oda M, Totoki T: Possible mechanism of irreversible nerve injury caused by local anesthetics: Detergent properties of local anesthetics and membrane disruption. Anesthesiology 2004; 100:962–7
Lambert LA, Lambert DH, Strichartz GR: Irreversible conduction block in isolated nerve by high concentrations of local anesthetics. Anesthesiology 1994; 80:1082–93
Rando TA, Wang GK, Strichartz GR: The interaction between the activator agents batrachotoxin and veratridine and the gating processes of neuronal sodium channels. Mol Pharmacol 1986; 29:467–77