title: Local anesthetic Schwann cell toxicity is time and concentration dependent.
abstract: BACKGROUND
  Peripheral nerve blocks with local anesthetics (LAs) are commonly performed to provide surgical anesthesia or postoperative analgesia. Nerve injury resulting in persistent numbness or weakness is a potentially serious complication. Local anesthetics have previously been shown to damage neuronal and Schwann cells via several mechanisms. We sought to test the hypothesis that LAs are toxic to Schwann cells and that the degree of toxicity is directly related to the concentration of LA and duration of exposure. Intraneural injection of LAs has been shown to produce nerve injury. We sought to test the hypothesis that a prolonged extraneural infusion of LA can also produce injury.
  
  
  METHODS
  Schwann cells cultured from neonatal rat sciatic nerves were incubated with LAs at different concentrations (10, 100, 500, and 1000 μM), and each concentration was assessed for toxicity after 4, 24, 48 and 72 hours of exposure. Local anesthetics tested were lidocaine, mepivacaine, chloroprocaine, ropivacaine, and bupivacaine. Cell death was assessed by lactate dehydrogenase release measured by optical density.In a separate experiment, a microcatheter was placed along the sciatic nerves of Sprague-Dawley rats. Rats were randomly assigned to receive either 0.9% saline (n = 8) or bupivacaine (0.5%, n = 4; 0.75%, n = 4) via the perineural catheters for 72 hours. The rats were then killed, and their nerves sectioned and stained for analysis. Sections were stained for myelin and with an antimacrophage (CD68) antibody.
  
  
  RESULTS
  None of the LAs tested produced significant Schwann cell death at very low concentrations (10 μM, or 0.0003%) even after prolonged exposure. With prolonged exposure (48 or 72 hrs) to high concentrations (1000 μM, or 0.03%), all of the LAs tested produced significant Schwann cell death (increased lactate dehydrogenase release relative to control as measured by optical density, 0.384-0.974; all P values < 0.001). Only bupivacaine produced significant cell death (0.482, P < 0.001) after prolonged exposure to low concentrations (100 μM, or 0.003%). At intermediate concentrations (500 μM, or 0.015%), cell death was more widespread with bupivacaine (0.768, P < 0.001) and ropivacaine (0.675, P < 0.001) than the other agents (0.204-0.368; all P values < 0.001). Prolonged extraneural exposure of rat sciatic nerves to bupivacaine caused significant demyelination and infiltration of nerves with inflammatory cells.
  
  
  CONCLUSIONS
  Local anesthetics induce Schwann cell death in a time- and concentration-dependent manner. Bupivacaine and ropivacaine have greater toxicity at intermediate concentrations, and prolonged exposure to bupivacaine produces significant toxicity even at low concentrations. Brief exposure to high concentrations of bupivacaine damages Schwann cells. Prolonged extraneural infusion of bupivacaine results in nerve injury.
authors.affiliation: Department of Anesthesiology and Peri-Operative Medicine, Oregon Health and Sciences University, Portland, OR, USA.
authors.forename: Sufang
authors.initials: S
authors.lastname: Yang
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Abrahams
authors.forename: Patricia D
authors.initials: PD
authors.lastname: Hurn
authors.forename: Marjorie R
authors.initials: MR
authors.lastname: Grafe
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Kirsch
mesh_terms: D000779:Anesthetics, Local / Q000008:administration & dosage / Q000633:toxicity*; D000818:Animals; D000831:Animals, Newborn; D002417:Cattle; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012583:Schwann Cells / Q000187:drug effects* / Q000473:pathology; D013997:Time Factors
chemical_list: D000779:Anesthetics, Local