Anesthesiology 2002; 97:429 –35 © 2002 American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins, Inc. Intrathecal Ropivacaine in Rabbits: Pharmacodynamic and Neurotoxicologic Study Jean-Marc Malinovsky, M.D., Ph.D.,* Florence Charles, M.D.,* Marielle Baudrimont, M.D., Ph.D.,† Yann Péréon, M.D., Ph.D.,‡ Pascal Le Corre, Pharm.D, Ph.D.,§ Michel Pinaud, M.D., Dan Benhamou, M.D.** Background: Ropivacaine is available for spinal or intrathecal use in humans, although data on neurotoxicity after spinal injection are not yet available. The authors experimentally de- termined the relationship between doses of intrathecal ropiva- caine and spinal effects and local neurotoxic effects. Methods: Eighty rabbits equipped with an intrathecal lumbar catheter were studied. Sixty were randomly assigned to receive 0.2 ml of intrathecal solutions as a sole injection of: 0.2%, 0.75%, 1.0%, and 2.0% ropivacaine (doses from 0.4 – 4.0 mg; groups R 0.2 to R 2.0 ), 5.0% lidocaine (10 mg; group L), or 0.9% NaCl as control (group C). Twenty other rabbits received either repeated injections of 0.2 ml of 0.2% ropivacaine every 2 days during 2 weeks (total dose of 2.8 mg; group R INT ); or a continuous intrathecal infusion of 0.2% ropivacaine at the rate of 1.8 ml/h over 45 min (2.7 mg; group R CONT ). Injection rate was 30 s in all groups except RCONT. Time to onset, duration and extent of motor block, and variations of mean arterial blood pressure were recorded in all groups. Somatosensory evoked potentials were also recorded in group R CONT and R INT . Seven days after the last intrathecal injection spinal cord and nerves were sampled for histopathologic study. Results: In groups R 0.2 and R INT , the lowest dose of ropiva- caine induced a clinically visible spinal block in only 50% of rabbits, but SEPs recorded in group R INT were decreased by 70% in the lumbar dermatome. Complete motor block was observed with doses greater than 1.5 mg of ropivacaine (group R CONT and R 0.75 to R 2.0 ). Onset time was shorter and duration of block increased as doses of ropivacaine increased. Significant hypo- tension was observed only with 4.0 mg of ropivacaine (concen- tration of 2.0%). Complete paralysis and hypotension were observed with 5.0% lidocaine. No neurologic clinical lesion was observed in rabbits receiving saline or ropivacaine within the 7 days after the last intrathecal injection, and histopathologic study revealed no sign of neurotoxicity in these groups. In contrast, intrathecal lidocaine induced clinical and histopatho- logic changes. Conclusion: Ropivacaine induced dose-dependent spinal an- esthesia, and did not induce any neurotoxicologic lesion in this experimental animal model. LIDOCAINE has been shown to produce local neurotox- icity when intrathecally applied in humans 1,2 and ani- mals. 3 Several cases of cauda equina syndrome have also been reported after intended epidural anesthesia, lead- ing to the diagnosis of unexpected intrathecal insertion of the catheter. 4,5 Ropivacaine, which is routinely used epidurally, has been proposed for intrathecal use as an alternative to lidocaine. Ropivacaine is a pipecoloxylidid local anesthetic, which differs from bupivacaine by the presence of a propyl group on the aromatic ring instead of a butyl group and is used as a single enantiomer. With special regard to the cardiovascular 6 and central nervous systems 7,8 , ropivacaine offers more systemic safety. No local neurologic complication has been reported with this drug so far. However, the small number of patients included in human studies with intrathecal ropivacaine does not permit us to draw conclusions about its safe- ty. 9 –13 To date, there is no available published report about the local neurotoxicity of ropivacaine. To test the local neurotoxicity of intrathecal ropiva- caine in an experimental model, we first determined in rabbits the relationship between dose and motor and hemodynamic effects of ropivacaine, then we studied the clinical and histopathologic changes that ropivacaine might induce on the spinal cord and nerves of these animals. Materials and Methods Eighty albino New Zealand rabbits weighing 2.5–3.0 kg were included in the study, which was performed in accordance with French Ministry of Agriculture laws and guidelines for laboratory animal experiments, and ap- proved by our Institutional Animal Investigation Committee. The rabbits were chronically instrumented as follows: under general anesthesia and sterile conditions a lami- nectomy was performed at the caudal level to insert an intrathecal catheter. After dural incision, a 23-gauge cath- eter (Periquick®, Gamida Lab., Eaubonne, France) was gently inserted 7 cm cephalad into the intrathecal space to set the tip of the catheter at the L 6 level. The right position of the catheter was certified by cautious aspira- tion of cerebrospinal fluid (CSF). The system was tun- nelized and secured, and implanted subcutaneously on the back of the rabbit. The deadspace of the catheter was 0.15 ml. Then, an arterial catheter was inserted via the femoral artery and heparinized. After the intrathecal catheter had been inserted, rab- bits were housed individually in standard cages with free * Staff Anesthesiologist, Service d’ Anesthésie-Réanimation Chirurgicale et Laboratoire d’ Anesthésie, ‡ Assistant Professor, Laboratoire d’ Explorations Fonctionnelles,  Professor and Chair, Service d’ Anesthésie-Réanimation Chirur- gicale et Laboratoire d’ Anesthésie, Hôtel-Dieu, Nantes, France. † Assistant Pro- fessor, Service d’ Anatomopathologie, Hôpital Saint-Anne, Paris, France. § Assistant Professor, Laboratoire de Biopharmacie, Faculté de Pharmacie Rennes 1, Rennes, France. ** Professor and Chair, Département d’ Anesthésie-Réanimation, Hôpital de Bicêtre, Le Kremlin-Bicêtre, France. Received from the Service d’ Anesthésie-Réanimation, Chirurgicale, Hôtel- Dieu, Nantes Cedex, France. Supported by grants from the Groupement de Recherche en Anesthésie Clinique et Expérimentale-GRACE, Service d’ Anesthésie-Réanimation, University Hospital, Hôtel-Dieu, Nantes, France. Submitted for publication November 1, 2001. Accepted for publication March 14, 2002. Presented in part at the Annual Meeting of the American Society of Anesthesiologists, San Francisco, California, October 13–18, 2000. Address reprint requests to Dr. Malinovsky: Service d’ Anesthésie-Réanima- tion, Chirurgicale, Hôtel-Dieu, 44093 Nantes Cedex, France. Address electronic mail to: jeanmarc.malinovsky@chu-nantes.fr. Individual article reprints may be purchased through the Journal Web site, www.anesthesiology.org. Anesthesiology, V 97, No 2, Aug 2002 429 Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/97/2/429/652549/0000542-200208000-00021.pdf by guest on 13 August 2024