Abstract
The current study was designed to investigate the mechanisms by which ropivacaine may act within the central nervous system (CNS) to produce cardiotoxicity. Eighty New Zealand rabbits were divided into four groups randomly. In Group 1, 20 rabbits received intracerebroventricular (icv) saline, and then received icv ropivacaine 30 min later. In Group 2, 20 rabbits received icv ropivacaine. Whenever dysrhythmias continued for more than 5 min, 0.1 ml saline was administered into the left cerebral ventricle. Ten minutes later, 0.1 ml midazolam was given into the left lateral ventricle. In Group 3, 20 rabbits received icv ropivacaine, and once the dysrhythmias developed, the inspired isoflurane concentration was increased from 0.75% to 1.50%. In Group 4, 20 animals received an intravenous (iv) phenylephrine infusion until dysrhythmias occurred. In Group 1, the rabbits did not develop dysrhythmias in response to icv saline, whereas dysrhythmias did develop in these animals after icv ropivacaine. In Group 2, icv saline had no effect on the dysrhythmias; however, icv midazolam terminated cardiac dysrhythmias. In Group 3, an increase in the concentration of the inspired isoflurane had no effect on dysrhythmias. In Group 4, icv midazolam had no effect on dysrhythmias in response to iv phenylephrine. Ropivacaine administered directly into the CNS is capable of producing cardiac dysrhythmias; midazolam terminated dysrhythmias presumably by potentiation of γ-aminobutyric acid (GABA) receptor activity. Our results suggest that ropivacaine produces some of its cardiotoxicity not only by the direct cardiotoxicity of the drug, but also by the CNS effects of ropivacaine.
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References
Ahmad, R., Beharry, K., Modanlou, H., 2000. Changes in cerebral venous prostanoids during midazolam-induced cerebrovascular hypotension in newborn piglets. Crit. Care Med., 28(7):2429–2436. [doi:10.1097/00003246-200007000-00040]
Asl, B.H., Hassanzadeh, K., Khezri, E., Mohammadi, S., 2008. Evaluation the effects of dextromethorphan and midazolam on morphine induced tolerance and dependence in mice. Pak. J. Biol. Sci., 11(13):1690–1695. [doi:10.3923/pjbs.2008.1690.1695]
Bilir, A., Yelken, B., Kaygisiz, Z., Senturk, Y., 2006. The effects of dopexamine in bupivacaine and ropivacaine induced cardiotoxicity in isolated rat heart. Saudi. Med. J., 27(8):1194–1198.
Copeland, S.E., Ladd, L.A., Gu, X.Q., Mather, L.E., 2008. The effects of general anesthesia on the central nervous and cardiovascular system toxicity of local anesthetics. Anesth. Analg., 106(5):1429–1439. [doi:10.1213/ane.0b013e31816d12af]
Dony, P., Dewinde, V., Vanderick, B., Cuignet, O., Gautier, P., Legrand, E., Lavand’homme, P., de Kock, M., 2000. The comparative toxicity of ropivacaine and bupivacaine at equipotent doses in rats. Anesth. Analg., 91(6): 1489–1492. [doi:10.1097/00000539-200012000-00036]
Greenblatt, E.P., Loeb, A.L., Longnecker, D.E., 1992. Endothelium-dependent circulatory control-a mechanism for the differing peripheral vascular effects of isoflurane versus halothane. Anesthesiology, 77(6): 1178–1185. [doi:10.1097/00000542-199212000-00020]
Guilhaumou, R., Boulamery, A., Deluca, B., Deturmeny, E., Bruguerolle, B., 2010. Effects of induced hyperthermia on pharmacokinetics of ropivacaine in rats. Fundam. Clin. Pharmacol., 24(4):463–468. [doi:10.1111/j.1472-8206.2009.00803.x]
Guinet, P., Estebe, J.P., Ratajczak-Enselme, M., Bansard, J.Y., Chevanne, F., Bec, D., Lecorre, P., Wodey, E., Ecoffey, C., 2009. Electrocardiographic and hemodynamic effects of intravenous infusion of bupivacaine, ropivacaine, levobupivacaine, and lidocaine in anesthetized ewes. Reg. Anesth. Pain Med., 34(1):17–23. [doi:10.1097/AAP.0b013e31819338e2]
Igarashi, A., Zadzilka, N., Shirahata, M., 2009. Benzodiazepines and GABA-GABAA receptor system in the cat carotid body. Adv. Exp. Med. Biol., 648(1):169–175. [doi:10.1007/978-90-481-2259-2_19]
Isaeva, E.V., 2008. Effects of isoflurane on hippocampal seizures at immature rats in vivo. Fiziol. Zh., 54(5):40–45.
Kanaya, N., Nakayama, M., Kobayashi, I., Fujita, S., Namiki, A., 1998. Effect of isoflurane on epinephrine-induced arrhythmias in ischemic-reperfused dog hearts. Res. Commun. Mol. Pathol. Pharmacol., 100(2):181–186.
Kimura, Y., Kamada, Y., Kimura, A., Orimo, K., 2007. Ropivacaine-induced toxicity with overdose suspected after axillary brachial plexus block. J. Anesth., 21(3): 413–416. [doi:10.1007/s00540-007-0518-x]
Kuthiala, G., Chaudhary, G., 2011. Ropivacaine: a review of its pharmacology and clinical use. Indian J. Anaesth., 55(2):104–110. [doi:10.4103/0019-5049.79875]
Ladd, L.A., Chang, D.H., Wilson, K.A., Copeland, S.E., Plummer, J.L., Mather, L.E., 2002. Effects of CNS site-directed carotid arterial infusions of bupivacaine, levobupivacaine, and ropivacaine in sheep. Anesthesiology, 97(2):418–428. [doi:10.1097/00000542-200208000-00020]
Lin, P.L., Fan, S.Z., Tsai, F.F., Tsai, M.C., Lin, C.H., Huang, C.H., 2007. Neurotoxicity of a novel local anesthetic agent, ropivacaine: the possible roles of bursts of potential and cytoplasmic second messenger. J. Formos. Med. Assoc., 106(10):815–825. [doi:10.1016/S0929-6646(08)60046-7]
Mather, L.E., 2010. The acute toxicity of local anesthetics. Expert Opin. Drug Metab. Toxicol., 6(11):1313–1332. [doi:10.1517/17425255.2010.514265]
Moore, D.C., 2009. Overextension of regional blocks: when is enough, enough? Reg. Anesth. Pain Med., 34(1):77–78. [doi:10.1097/AAP.0b013e318193406b]
Nishiyama, T., Tamai, H., Hanaoka, K., 2003. Serum and cerebrospinal fluid concentrations of midazolam after epidural administration in dogs. Anesth. Analg., 96(1): 159–162. [doi:10.1213/00000539-200301000-00032]
Novellas, R., Ruiz de Gopegui, R., Espada, Y., 2007. Effects of sedation with midazolam and butorphanol on resistive and pulsatility indices in healthy dogs. Vet. Radiol. Ultrasound, 48(3):276–280. [doi:10.1111/j.1740-8261.2007.00242.x]
Rodolà, F., Anastasi, F., Vergari, A., 2007. Ropivacaine induced acute neurotoxicity after epidural injection. Eur. Rev. Med. Pharmacol. Sci., 11(2):133–135.
Shen, X., Wang, F., Xu, S., Qian, Y., Liu, Y., Yuan, H., Zhao, Q., Feng, S., Guo, X., Xu, J., Yang, J., 2010. Is cardiolipin the target of local anesthetic cardiotoxicity? Rev. Bras. Anestesiol., 60(4):445–454.
Stehr, S.N., Christ, T., Rasche, B., Rasche, S., Wettwer, E., Deussen, A., Ravens, U., Koch, T., Hübler, M., 2007. The effects of levosimendan on myocardial function in ropivacaine toxicity in isolated guinea pig heart preparations. Anesth. Analg., 105(3):641–647. [doi:10.1213/01.ane.0000278146.15671.03]
Stewart, J., Kellett, N., Castro, D., 2003. The central nervous system and cardiovascular effects of levobupivacaine and ropivacaine in healthy volunteers. Anesth. Analg., 97(2): 412–416. [doi:10.1213/01.ANE.0000069506.68137.F2]
Tsibiribi, P., Bui-Xuan, C., Bui-Xuan, B., Tabib, A., Descotes, J., Chevalier, P., Gagnieu, M.C., Belkhiria, M., Timour, Q., 2006. The effects of ropivacaine at clinically relevant doses on myocardial ischemia in pigs. J. Anesth., 20(4): 341–343. [doi:10.1007/s00540-006-0429-2]
Udelsmann, A., Silva, W.A., Moraes, A.C., Dreyer, E., 2009. Hemodynamic effects of ropivacaine and levobupivacaine intravenous injection in swines. Acta Cir. Bras., 24(4):296–302. [doi:10.1590/S0102-86502009000400009]
Velly, A.B., Simon, N., Bedidjian, S., Bruguerolle, B., 2006. Effects of a seven-day continuous infusion of ropivacaine on circadian rhythms in the rat. Chronobiol. Int., 23(3): 683–693. [doi:10.1080/07420520600650570]
Wan, Q.X., Bo, Y.L., Li, H.B., Li, W.Z., 2010. Effects of mixture of lidocaine and ropivacaine at different concentrations on the central nervous system and cardiovascular toxicity in rats. Chin. Med. J. (Engl.), 123(1):79–83.
Wiktorowska, A., Owczarek, J., Orszulak-Michalak, D., 1999. The influence of lidocaine and verapamil on haemodynamic parameters after intravenous administration of midazolam in rabbits. Pharmacol. Res., 39(6):421–429. [doi:10.1006/phrs.1998.0464]
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Project (No. 2006K13-G7-4) supported by the Key Sci-Tech Research Project of Shaanxi Province, China
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Zhu, Ym., Yuan, Zy., Wu, H. et al. Midazolam in rabbits terminates dysrhythmias caused by intracerebroventricular ropivacaine. J. Zhejiang Univ. Sci. B 12, 668–676 (2011). https://doi.org/10.1631/jzus.B1000337
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DOI: https://doi.org/10.1631/jzus.B1000337
Key words
- Ropivacaine
- Cardiotoxicity
- Ventricular cerebrospinal fluid
- Central nervous system (CNS)
- Dysrhythmias
- Midazolam