title: Epinephrine increases the extracellular lidocaine concentration in the brain: a possible mechanism for increased central nervous system toxicity.
abstract: BACKGROUND
  Local anesthetics exert central nervous system (CNS) toxicity by inhibiting intracerebral neuronal activity, while epinephrine augments the CNS toxicity of intravenously administered local anesthetics. Viewed together, increases of extracellular concentrations of local anesthetics in the brain may be directly associated with increased CNS toxicity. The authors examined the hypothesis that epinephrine enhances the CNS toxicity of lidocaine by increasing the extracellular concentration in the brain.
  
  
  METHODS
  An awake, spontaneously breathing rat model was used. Twenty male Sprague-Dawley rats received an intravenous infusion of lidocaine (3 mg x kg x min; group C) or lidocaine with epinephrine (3 mg x kg x min and 2 microg x kg x min, respectively; group E) for 10 min (n = 10 in each group). Effects of epinephrine on the convulsive dose and concentrations of total (protein-bound and unbound) and unbound lidocaine in plasma were examined. Concentrations of extracellular lidocaine in the cerebral nucleus accumbens were quantitatively determined by a microdialysis method.
  
  
  RESULTS
  The convulsive dose of lidocaine was significantly lower in group E than in group C (22.4 +/- 5.5 vs. 27.9 +/- 3.1 mg/kg, respectively; P < 0.05). Overall concentrations and area under the plasma concentration-versus-time curve of unbound lidocaine in group E were significantly higher than those in group C. Concentrations of extracellular lidocaine in the nucleus accumbens in group E were comparable to those of unbound fraction in plasma and were also significantly higher than those in group C.
  
  
  CONCLUSIONS
  Concomitant administration of epinephrine significantly enhanced the CNS toxicity of intravenously administered lidocaine. Increased extracellular concentration in the brain would be related to this mechanism.
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Graduate School of Medicine, Osaka City University, Osaka, Japan.
authors.forename: Ryota
authors.initials: R
authors.lastname: Takahashi
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Oda
authors.forename: Katsuaki
authors.initials: K
authors.lastname: Tanaka
authors.forename: Hisayo O
authors.initials: HO
authors.lastname: Morishima
authors.forename: Koki
authors.initials: K
authors.lastname: Inoue
authors.forename: Akira
authors.initials: A
authors.lastname: Asada
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism*; D002490:Central Nervous System / Q000187:drug effects; D004357:Drug Synergism; D004837:Epinephrine / Q000008:administration & dosage / Q000494:pharmacology*; D045604:Extracellular Fluid / Q000187:drug effects / Q000378:metabolism; D007262:Infusions, Intravenous; D008012:Lidocaine / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000139:chemically induced
chemical_list: D008012:Lidocaine; D004837:Epinephrine