Erythropoietin Protects against Local Anesthetic Myotoxicity during Continuous Regional Analgesia

Abstract

The authors demonstrated a dose- and time-dependent protective effect of rhEPO against bupivacaine-induced myotoxicity in regional analgesia.

Time course of mitochondrial metabolism alterations to repeated injections of bupivacaine in rat muscle

“…This decrease in citrate synthase activity could be linked to the appearance of morphological signs of mitochondrial autophagy (mitophagy) induced by high doses ([5 mM) of bupivacaine. 4 This decrease following injections of high concentrations of bupivacaine in rat muscle could be closely associated with disjointed fibres, interstitial edema, infiltrating cells, 16 and a wide range of morphological fibre abnormalities ranging from absent, to focal, to moderate, to extreme. 15 The above discussed bupivacaine-induced mitochondrial inhibition showed a time dependency on the duration of bupivacaine exposure in psoas muscle.…”

“…19,20 Bupivacaine-induced myotoxicity is time-dependent for muscle fibres close to the nerve catheter and is concentration-dependent on mitochondria in vitro. 4,21 This finding suggests the need for clarifying analgesia protocols with optimal duration of protocol and probably optimal concentration of local anesthetic, as investigated for ropivacaine. 22 Chemical properties of local anesthetics are also important parameters for the occurrence of ultrastructural alterations in muscle, 18 but similar effects are not yet described in mitochondria toxicity in vivo.…”

“…3 2 and can be associated with rare but well-documented bupivacaineinduced myotoxicity. 4 Bupivacaine-induced myotoxicity is associated with alterations in mitochondrial metabolism, 5,6 as previously described in different experimental models ranging from isolated rat mitochondria to human myocytes in culture. Different effects can coexist, including 1) specific inhibition of mitochondrial respiratory chain complex I as observed in isolated mitochondria; 2) oxidative phosphorylation (OXPHOS) uncoupling; and 3) specific inhibition of the enzymatic mitochondrial activity, e.g., citrate synthase.…”

“…As a consequence of these bioenergetic alterations, bupivacaine impairs dimethyl thiazol diphenyl tetrazolium bromide reduction (and thus, decreases cell viability) in vitro, and this effect is a function of both duration of bupivacaine infusion and bupivacaine concentration. 4 In vivo, several drugs used in clinical practice exhibit a significant mitochondrial toxicity in a dose-and time-dependent manner. 7 However, little is known regarding the time dependency of the deleterious effect of the local anesthetics.…”

Nifedipine Versus Terbutaline for Tocolysis in External Cephalic Version

“…5 In a recent publication, a French group was able to show in a rat analgesia model and in a cell culture model of human skeletal myoblasts that bupivacaine had deleterious effects at concentrations required for postoperative analgesia; there was clear evidence of myotoxicity resulting from an inhibition of mitochondrial energy metabolism associated with a global inhibition of respiratory chain activity, a reduction in ATP synthesis, and a breakdown of mitochondrial membrane potential; all of which was partially prevented by co-administration of recombinant human erythropoietin. 6 In the study by Fanning et al, the effects of racemic bupivacaine and its S-enantiomer levobupivacaine were assessed in as far as they interfered with spontaneous contraction of isolated myometrial strips obtained from 8 nonlaboring term patients undergoing cesarean section. The working hypothesis was that these LAs might differ in blocking myometrial sodium and potassium currents (as observed in cardiac muscle cells) thus impinging on progress of labor as outcome.…”