title: Erythropoietin protects against local anesthetic myotoxicity during continuous regional analgesia.
abstract: BACKGROUND
  Local anesthetics offer the benefits of extended analgesia with greater patient satisfaction and faster rehabilitation compared with intravenous morphine. These benefits, however, can be offset by adverse iatrogenic muscle pain caused by bupivacaine. Here, the authors describe the mechanisms of local anesthetic-induced myotoxicity and a partial protective effect of recombinant human erythropoietin (rhEPO).
  
  
  METHODS
  The authors developed a rat analgesia model with femoral nerve catheter and a cell culture model of human skeletal muscle myoblasts to study local anesthetic effects. Rats were randomly assigned to four different groups: daily intraperitoneal injection with 5,000 U/kg rhEPO or saline coupled to a perineural catheter injection with 1 ml/kg bupivacaine, 0.25%, or saline. In psoas rat muscle, oxygen consumption rates were measured using a Clark-type electrode in saponin-skinned fibers. Mitochondrial adenosine triphosphate synthesis rates were determined by bioluminescence. Enzymatic activity of mitochondrial respiratory chain complexes was measured on tissue homogenates using spectrophotometric procedures, and mitochondrial morphology was analyzed by transmission electron microscopy. In addition, the interaction between bupivacaine and rhEPO was investigated on human skeletal muscle myoblasts by fluorescence microscopy using mitotracker green and using the lipophilic cation JC-1.
  
  
  RESULTS
  Bupivacaine caused impairment of mitochondrial structure and bioenergetics in rats. Human myoblasts treated with bupivacaine showed a dose-dependent decrease in mitochondrial membrane potential associated with unusual morphologies. Impairment of mitochondrial bioenergetics was prevented partially by the use of rhEPO coadministered with bupivacaine.
  
  
  CONCLUSIONS
  The authors demonstrated a dose- and time-dependent protective effect of rhEPO against bupivacaine-induced myotoxicity in regional analgesia.
authors.affiliation: Laboratoire de physiopathologie mitochondriale, Université Victor Segalen Bordeaux 2, Bordeaux, France. karine.nouette-gaulain@u-bordeaux2.fr
authors.forename: Karine
authors.initials: K
authors.lastname: Nouette-Gaulain
authors.forename: Nadège
authors.initials: N
authors.lastname: Bellance
authors.forename: Baptiste
authors.initials: B
authors.lastname: Prévost
authors.forename: Emilie
authors.initials: E
authors.lastname: Passerieux
authors.forename: Claire
authors.initials: C
authors.lastname: Pertuiset
authors.forename: Olivier
authors.initials: O
authors.lastname: Galbes
authors.forename: Katarina
authors.initials: K
authors.lastname: Smolkova
authors.forename: Françoise
authors.initials: F
authors.lastname: Masson
authors.forename: Sylvain
authors.initials: S
authors.lastname: Miraux
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Delage
authors.forename: Thierry
authors.initials: T
authors.lastname: Letellier
authors.forename: Rodrigue
authors.initials: R
authors.lastname: Rossignol
authors.forename: Xavier
authors.initials: X
authors.lastname: Capdevila
authors.forename: François
authors.initials: F
authors.lastname: Sztark
mesh_terms: D000765:Anesthesia, Conduction / Q000009:adverse effects*; D000779:Anesthetics, Local / Q000008:administration & dosage / Q000009:adverse effects*; D000818:Animals; D002478:Cells, Cultured; D004921:Erythropoietin / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000473:pathology; D010149:Postoperative Pain / Q000139:chemically induced* / Q000517:prevention & control*; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins
chemical_list: D000779:Anesthetics, Local; D011994:Recombinant Proteins; D004921:Erythropoietin