Erythropoietin protects against local anesthetic myotoxicity during continuous regional analgesia.
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.
Nouette-Gaulain
Karine
K
Laboratoire de physiopathologie mitochondriale, Université Victor Segalen Bordeaux 2, Bordeaux, France. karine.nouette-gaulain@u-bordeaux2.fr
Bellance
Nadège
N
Prévost
Baptiste
B
Passerieux
Emilie
E
Pertuiset
Claire
C
Galbes
Olivier
O
Smolkova
Katarina
K
Masson
Françoise
F
Miraux
Sylvain
S
Delage
Jean-Paul
JP
Letellier
Thierry
T
Rossignol
Rodrigue
R
Capdevila
Xavier
X
Sztark
François
F
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
D000779:Anesthetics, Local; D011994:Recombinant Proteins; D004921:Erythropoietin