title: The influence of adjuvants used in regional anesthesia on lidocaine-induced neurotoxicity in vitro.
abstract: BACKGROUND
  Neurotoxic properties of local anesthetics can rarely lead to irreversible neuronal damage as in cauda equina syndrome. Clinically, local anesthetics are often combined with adjuvants to improve or prolong the anesthetic effect, whereas the impact of such adjuvants on lidocaine-induced apoptosis is unclear. Therefore, we investigated the influence of different adjuvants on the neurotoxicity of lidocaine.
  
  
  METHODS
  Human neuroblastoma cells and primary rat astrocytes were incubated for 24 hrs with lidocaine at a toxic concentration alone and in combination with morphine, sufentanil, clonidine, epinephrine, neostigmine, ketamine, and midazolam. Subsequently, the rates of cell death and early apoptosis were measured by flow cytometry in neuroblastoma cells, whereas astrocyte viability was analyzed by mitochondrial activity assay. In addition, isobolograms were calculated to describe the additive effects of lidocaine with ketamine or midazolam, respectively.
  
  
  RESULTS
  Coadministration of lidocaine with sufentanil, clonidine, epinephrine, and neostigmine did not alter the rates of cell death compared with cells treated with lidocaine alone. Morphine improved the viability of astrocytes only at concentrations beyond those occurring clinically. In contrast, coincubation of lidocaine with ketamine or midazolam led to significantly increased rates of cell death. The combined toxicity of ketamine and lidocaine was additive, whereas the combined toxicity of midazolam and lidocaine was subadditive.
  
  
  CONCLUSIONS
  Sufentanil, clonidine, epinephrine, and neostigmine do not influence the neurotoxicity of lidocaine in vitro. Morphine may have some cytoprotective effect at concentrations greater than those seen intrathecally in humans. In contrast, ketamine and midazolam increase the neurotoxicity of lidocaine in vitro, presumably by additive induction of mitochondrial apoptosis.
authors.affiliation: Departments of Anesthesiology, Heinrich-Heine-University, Düsseldorf, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Werdehausen
authors.forename: Sebastian
authors.initials: S
authors.lastname: Braun
authors.forename: Henning
authors.initials: H
authors.lastname: Hermanns
authors.forename: David
authors.initials: D
authors.lastname: Kremer
authors.forename: Patrick
authors.initials: P
authors.lastname: Küry
authors.forename: Markus W
authors.initials: MW
authors.lastname: Hollmann
authors.forename: Inge
authors.initials: I
authors.lastname: Bauer
authors.forename: Markus F
authors.initials: MF
authors.lastname: Stevens
mesh_terms: D000759:Adjuvants, Anesthesia / Q000008:administration & dosage / Q000633:toxicity*; D000765:Anesthesia, Conduction / Q000009:adverse effects; D000779:Anesthetics, Local / Q000008:administration & dosage / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001253:Astrocytes / Q000187:drug effects* / Q000473:pathology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004359:Drug Therapy, Combination; D006801:Humans; D008012:Lidocaine / Q000008:administration & dosage / Q000633:toxicity*; D009447:Neuroblastoma / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000759:Adjuvants, Anesthesia; D000779:Anesthetics, Local; D008012:Lidocaine