Neurotoxicity of Adjuvants Used in Perineural Anesthesia and Analgesia in Comparison With Ropivacaine

Abstract

Background and Objectives Clonidine, buprenorphine, dexamethasone, and midazolam (C,B,D,M) have been used to prolong perineural local anesthesia in the absence of data on the influence of these adjuvants on local anesthetic (LA)-induced neurotoxicity. Therefore, the impact of these adjuvants on ropivacaine (R)-induced death of isolated sensory neurons was assessed. Methods The trypan blue exclusion assay was used to assess death of sensory neurons isolated from adult male Sprague-Dawley rats. Drugs were applied, alone or in combination, for 2 or 24 hrs at 37°C. Results Neuronal viability was halved by 24 hr exposure to R (2.5 mg/mL), far exceeding the neurotoxicity of C, B, D, or M (at 2–100 times estimated clinical concentrations). Plain M at twice the estimated clinical concentration produced a small but significant increase in neurotoxicity at 24 hr. After 2 hr exposure, high concentrations of B, C, and M increased the neurotoxicity of R; the combination of R+M killed over 90% of neurons. Estimated clinical concentrations of C+B (plus 66 µg/mL D) had no influence on (i) R-induced neurotoxicity, (ii) the increased neurotoxicity associated with the combination of R+M, or (iii) the neurotoxicity associated with estimated clinical concentrations of M. There was dose-response neurotoxicity with 133 µg/mL D combined with R+C+B Conclusions Results with R re-affirm the need to identify ways to mitigate LA-induced neurotoxicity. While having no protective effect on R-induced neurotoxicity in vitro, future research with adjuvants should address if the C+B+D combination can enable reducing R concentrations needed to achieve equi-analgesia (and/or provide equal or superior duration, in preclinical in vivo models).

A systematic review and meta‐analysis of perineural dexamethasone for peripheral nerve blocks

“…Although caution is warranted, animal studies have provided encouraging results, concluding that neurological injury is absent [7,14,57]. During in-vitro studies, Ma et al demonstrated a potential protective effect of dexamethasone against local anaesthetic-induced cell injury [58] and a series of 2000 intrathecal injections of 8 mg dexamethasone for the treatment of post-traumatic visual disturbance in 200 patients failed to demonstrate any neurological sequelae [59].…”

Eficacia analgésica de una dosis única de dexametasona perineural en el bloqueo ecoguiado del nervio femoral en cirugía de prótesis total de rodilla

“… Por un lado, su efecto vasoconstrictor podría influir en el retraso de la absorción y eliminación del AL a nivel PN aumentando así la vida media de los AL y su poder de acción 35 .…”

“…Sin embargo, existen estudios en animales que sugieren una cierta toxicidad de la dexametasona, concretamente Williams et al 35 en un estudio realizado en ratas, observaron mayor toxicidad e hiperalgesia, cuando la concentración de la dexametasona aumentaba de 66 a 133 µg/ml y era utilizada conjuntamente con ropivacaína. La dosis utilizada en nuestro estudio ha sido de 400 µg/ml, que haciendo un cálculo en proporción al peso medio de cada especie, resultaría en una dosis muy inferior (1.71 µg/ml) a la registrada como peligrosa en el estudio de Williams.…”

“…Sin embargo, la dexametasona prolonga el efecto analgésico en bloqueos nerviosos del plexo braquial [22][23][24][25][26][27][28][29][30] y del nervio ciático 31,32 sin efectos secundarios. Esta propiedad parece ser debida a que por un lado, la dexametasona atenúa los mediadores de la respuesta inflamatoria producida por la cirugía, al disminuir la descarga neuronal ectópica e inhibir los canales de potasio dependientes de las fibras C-Nociceptivas [33][34][35][36] , y por otro lado a su poder de vasoconstricción 31 , disminuyendo por tanto la absorción de los AL.…”

Ultrasound and nerve stimulator guided peripheral nerve blocks of the upper and lower limbs

“…Kako bi se obezbedio što duži analgetski efekat, primenjivan je ili veći volumen ili koncentracija lokalnog anestetika, čime se povećava mogućnost za nastanak neželjnog motornog bloka ili toksičnog efekta lokalnog anestetika. Zbog toga se danas teži ka dodavanju lekova, ili sistemski ili perineuralno, kao i plasiranju katetera i kontinuiranoj administraciji lokalnog anestetika 67 . Tako je pokazan produžen efekat bloka perineuralnom primenom buprenorfina, klonidina, deksametazona, deksmedetomidina illi magnezijuma 68 , ali je i njihova sistemska primena kao rezultat imala gotovo identičan efekat na dužinu trajanja bloka, smanjujući rizik za nastanak oštećenja nerva 69 .…”