The Efficacy And Neurotoxicity Of Dexmedetomidine Administered Via The Epidural Route In Rats

Objective:α2-Adrenoceptor agonists administered into the intrathecal and epiduralspace have been found to be effective in the treatment of chronicpain.Moreover,it was shown that they increase the analgesic effects of localanaesthetics and provide sedation,anxiolysis and haemodynamic stability.Inthe1999,dexmedetomidine,a newly developed α2-adrenergic receptor agonistwith a1620:1ratio of α2:α1receptor binding,was first approved by theU.S.Food and Drug Administration for use in the intensive care unit as ashort-term intravenous sedative. The affinity of dexmedetomidine toα2-adrenoceptors is eight times greater than clonidine,it is expected thatdexmedetomidine could be advantageous in regional anaesthesia. After theintroduction of spinoaxial catheterization at the end of19th century,variousdrugs were either neurotoxic or potentially neurotoxic. In addition,preservatives added to drugs may be neurotoxic when injected spinoaxially.Establishing the safety of neuroaxial drugs is very important before thesedrugs are given to humans.Some anesthesiologists have applieddexmedetomidine intrathecally as an adjuvant to enhance the analgesicproperty of local anesthetics, however, the antinociception and theneurotoxicity on the nervous system of the dexmedetomidine were poorlyknown. The purpose of this prospective,randomized,double-blind study was toinvestigate whether dexmedetomidine have antinociception and neurotoxicitywhen it was administered via an epidural catheter in rats.Methods:Sixty rats weighing250-300g were planned to be included in thestudy.Before the placement of epidural catheter,10%Chloral hydrate wasadministered intraperitoneally.The catheter was inserted between T9and T10 intervertebral space and gently was advanced about1.5to2cm caudally.Caseswere excluded if blood or cerebrospinal fluid was aspirated.To confirm correctepidural placement of the catheter,0.15ml of2%lidocaine was administeredvia the epidural catheter after complete recovery from anesthesia;if the ratshowed transient hind-limb paralysis while the forelimbs retained normalmotor power,the catheter was regarded to be positioned in the epidural space.Ifsudden respiratory arrest was obervered during lidocaine injected, the testsolution was regarded to be injected either intrathecally or intravenously,andsuch cases were excluded from the study. After confirming correct epiduralcatheter placement, we examined gait, spinal deformity, and behavioralabnormalities for2days.If the rats showed abnormal findings during the2-dayobservation period, they were excluded from this study.The sixty rats whichcatheter place sucessessfully were divided into4grougs.Group N:Nacl0.9%0.3ml was administered through the epiduralcatheter.Group D:Dexmedetomidine(10μg/kg)0.3ml was administered throughthe epidural catheret.Group R:Ropivacaine0.75%0.3ml was administered through theepidural catherter.Group DR:Dexmedetomidine(10μg/kg) and Ropivacaine0.75%0.3mlwere administered through the epidural catheter.Pain threshold was performed at5,30,60,120and240min after epiduraldrug administration. Acute toxicity was evaluated3days after injection andchronic toxicity7and21days after injection. One examiner unware of thestudy details observed motor and sensory deficits. Pinch-toe testing was usedto evaluate motor and sensory deficits.Motor function was assessed using apreviously devised scoring system with some modification. Grades weredefined as follows: grade1:normal gait with no evidence of motorparesis;grade2:normal gait with slight hindpaw deformity, such as plantarflexion of toes; grade3:slight gait disturbance with motor weakness and/orinverted paw; and grade4:a prominent limping gait with a dropped hindpaw. The rats with a motor disturbance of grade2or above were considered to ahave motor defocit.At3,7,21days after injection, the animals were sacrificedand the lumbar segment of the spinal cord was removed for microscopicexamination. Calculate the abnormality rates of the neurons, the neuronsabnormality rates=abnormal neurons/the total number of neurons×100%;microscopic tissue analysis results were classified in8ways, namely as,dural hypertrophy, adhesion of meninges to surrounding tissues,localneuritis,meningeal inflammation, local myelopathy, myelin loss, andperipheral neuropathy.Results:1Evaluation of motor and sensory deficits in rats:All rats in group N,group D,group R and group DR responded normallyto pinch-toe testing and had a normal gait at each observation point,thedifference was not statistically significant (P>0.05).2comparent the pain threshold difference of each group:Basic pain threshold was not statistically significant (P>0.05);comparedwith the group N,the pain threshold difference of group D increased at5,30min after epidural injection,group R increased at5,30,60and120min, groupDR increased at5,30,60,120and240min after epidural injection(P<0.05);compared with group D, the pain threshold difference of group R increased at5,30,60and120min, group DR increased at30,60,120and240min afterepidural injection(P<0.05); compared with group R, the pain thresholddifference of group DR increased at30,60,120and240min after epiduralinjection(P<0.05).3Comparent the rate of abnormal neurons:Compared with group D and group R,the rate of abnormal neurons of thegroup DR increased at3and7days after epidural injection(P<0.05),while therate of abnormal neurons was not statistically significant at21days afterepidural injection(P>0.05); compared with21days,the rate of abnormalneurons of the group DR increased at3and7days after epiduralinjection(P<0.05);there were no statistically significant differences between the remaining groups(P>0.05).4Comparent the histological change of the spinal cords:No histological lesions on hematoxylin and eosin were observed ingroups N, D or R at any time; However, in group DR,spinal cords obtainedadhesion and meningeal inflammation after injection(P<0.05).Conclusions:1Epidural administration of dexmedetomidine increase the effect of analgesiainduced by ropivacaine and produce antinociception.2Dexmedetomidine administered epidurally to rats did not cause significantneurotoxicity.3Dexmedetomidine administered epidurally with ropivacaine can producetransient reversible toxicity to the spinal cord.