Frequency-Dependent Block in Humans?

Abstract

In Response: We concur with Stevens that, as our study demonstrated, a frequency- dependent action of local anesthetics is unlikely to be a mechanism at work in stimulation-induced (i.e., muscular exercise) reductions in latency of onset of sensory or motor block following peripheral nerve injections in humans.1,2 In fact, frequency-dependent block (use-dependent; phasic block) is likely to be limited clinically in humans to cardiac tissue exposed to critical concentrations of tertiary local anesthetics. Experimentally, sodium conductance decreases with repetitive neural stimulation. Invitro studies in mammalian peripheral nerves and in cardiac tissue have demonstrated that the intensity or depth of impulse blockade increased as the rate of stimulation increased.3,4 In reptilian sciatic nerve, a marked reduction in the height of the tenth action potential when compared with the first has been shown after exposure to local anesthetics. This phenomenon was dependent upon the agent used and the frequency of stimulation,5 and was maximal as early as the third, and as late as the twentieth impulse. All tertiary local anesthetic agents demonstrated this effect at a stimulation frequency of 40 Hz.6 Being highly lipid soluble, bupivacaine is a logical choice for studying frequency-dependent block in humans.1 While greater lipid solubility has been associated with increased repetitive stimulation requirements to reach maximal blocking effects compared with less lipid-soluble drugs such as lidocaine,3 much greater degrees of frequency-dependent cumulative block occur after bupivacaine than after lidocaine at lower stimulation frequencies.6 Frequency-dependent block persists for as long as the train of neural impulses that drives depolarization continues, and is ideally studied in a contracting heart responding to spontaneous nodal activity. Since the tonic impulse traffic in peripheral nerves differs from that observed in the heart, even when employing 5 min of continual muscular exercise as was done in our study,1 it is logical that, as Stevens noted, the enhancement of local anesthetic action by employing a frequency-dependent block vanishes within seconds after peripheral nerve blocks.2 With the recent renewed attention being given to cardiac toxicity of local anesthetics, however, there continues to be a necessity to study frequency-dependent block induced by local anesthetic drugs applied to contracting muscle. Frequency-dependent block is likely responsible for the observed cardiac toxicity of bupivacaine, its resistance to conventional pharmacological treatments, and its propagation for extended periods of time while cardiac activity persists. Frequency-dependent block is thus not necessarily species-dependent, but more appropriately should be characterized as being organ or system-dependent. Kenneth D. Candido, MD Department of Anesthesiology University of Illinois College of Medicine Chicago, IL [email protected] Kenneth D. Langen, MD Michael King, MD Guido Marra, MD Department of Orthopaedic Surgery Loyola University Medical Center Maywood, IL Alon P. Winnie, MD Northwestern University/Feinberg School of Medicine Chicago, IL