Local Anesthetic-Induced Neurotoxicity

Abstract

This review summarizes current knowledge concerning incidence, risk factors, and mechanisms of perioperative nerve injury, with focus on local anesthetic-induced neurotoxicity. Perioperative nerve injury is a complex phenomenon and can be caused by a number of clinical factors. Anesthetic risk factors for perioperative nerve injury include regional block technique, patient risk factors, and local anesthetic-induced neurotoxicity. Surgery can lead to nerve damage by use of tourniquets or by direct mechanical stress on nerves, such as traction, transection, compression, contusion, ischemia, and stretching. Current literature suggests that the majority of perioperative nerve injuries are unrelated to regional anesthesia. Besides the blockade of sodium channels which is responsible for the anesthetic effect, systemic local anesthetics can have a positive influence on the inflammatory response and the hemostatic system in the perioperative period. However, next to these beneficial effects, local anesthetics exhibit time and dose-dependent toxicity to a variety of tissues, including nerves. There is equivocal experimental evidence that the toxicity varies among local anesthetics. Even though the precise order of events during local anesthetic-induced neurotoxicity is not clear, possible cellular mechanisms have been identified. These include the intrinsic caspase-pathway, PI3K-pathway, and MAPK-pathways. Further research will need to determine whether these pathways are non-specifically activated by local anesthetics, or whether there is a single common precipitating factor.

Keywords: adverse event; anesthetics; local; toxicity.

Figure 1

Schematic illustration of relevant intracellular signal transduction pathways of local anesthetic-induced toxicity. Signaling pathways and mediators that are conveying a toxicity-increasing effect are marked in red color, while those that are involved in protective mechanisms are highlighted green. Blue colored elements were proven not to be affected, while the role of non-highlighted (black) elements remains unclear or not investigated. Local anesthetic neurotoxicity can affect multiple signaling pathways and ultimately leads to the activations of mitochondrial signaling pathway of apoptosis, which is also referred to as the intrinsic pathway of apoptosis. This pathway involves mitochondrial injury and dysfunction, loss of mitochondrial membrane potential (ΔΨ_m), and the oligomerization of Bax protein in the outer mitochondrial membrane, which leads to the release of apoptosis-inducing mediators like cytochrome c. This leads to the formation of the apoptosome, which comprises caspase-9 and other factors. The apoptosome, in turn, activates the effector caspases 3 and 7 and therefore converges into a signaling cascade, which ultimately leads to specific nuclear DNA-fragmentation. Abbreviations: adenomatous polyposis coli tumor-suppressor gene (APC); alternate reading frame tumor suppressor protein (ARF); CCAAT-enhancer-binding protein homologous protein (CHOP); endoplasmatic reticulum (ER); extracellular-signal-regulated kinase (ERK); Fas-associated protein with Death Domain (FADD); focal adhesion kinase (FAK); mitogen-activated protein kinase (MAPK); reactive oxygen species (ROS); Smoothened protein (Smo) T-cell factor (TCF). This figure was prepared based on a previous figure by Hanahan and Weinberg [63] and a previously modified version (http://en.wikipedia.org/wiki/File:Signal_transduction_v1.png).