Unintentional intravascular administration of bupivacaine may cause local anesthetic systemic toxicity (LAST). Although many systems are affected in LAST, the cardiovascular effects can be life-threatening. Remifentanil is a selective, ultra-short-acting, µ-opioid receptor agonist opioid. This study assessed the effects of combined pretreatment with intravenous lipid emulsion (ILE) and remifentanil on the cardiotoxicity caused by bupivacaine in an experimental model of anesthetized rats. The rats were divided into three groups. Group B received a saline pretreatment plus a bupivacaine, group L received ILE pretreatment plus a bupivacaine, and in group R, remifentanil was infused intravenously, plus ILE pretreatment plus a bupivacaine. The electrocardiogram tracing, invasive arterial pressure, and heart rate (HR) of rats were monitored continuously. Arterial blood gas analysis was performed in all groups. Arterial blood gas analysis revealed that the baseline pH (7.38 ± 0.31, 7.39 ± 0.41, and 7.37 ± 0.02 for groups B, L, and R, respectively), PaO2 (198.5 ± 9.45, 196.1 ± 32.3, and 197.7 ± 9.25 mmHg, respectively), and PaCO2 (37.8 ± 4.91, 37.4 ± 4.85, and 36.9 ± 4.42 mmHg, respectively) were similar in the groups (p > 0.05). Time to first alteration in QRS complex, time to first arrhythmia, time to 25, 50, and 75% reductions in HR, time to 25, 50, and 75% reductions in MAP, and time to asystole were recorded. Widening of the QRS complex was found 41.8 ± 16.6, 88.5 ± 7.91, and 103.0 ± 15.7 s after initiating the bupivacaine infusion in groups B, L, and R, respectively. Time elapsed until 25% reduction in HR was found 136.5 ± 50.7, 284.7 ± 31.7, and 292.0 ± 46.0 s for groups B, L, and R, respectively, and that until 25% reduction in MAP was found 101.7 ± 14.3, 245.0 ± 36.6, and 237.6 ± 52.6 s, respectively. Arrhythmia was observed after 135.2 ± 27.4, 172.4 ± 18.1, and 176.2 ± 23.0 s in groups B, L, and R, respectively. Finally, asystole occurred after 553.6 ± 74.4, 766.7 ± 64.8, and 800.1 ± 94.7 s in groups B, L, and R, respectively. This finding indicates that the survival time of rats administered pretreatment with ILE plus remifentanil and those given ILE was observed to be longer. Additionally, this study found that intravenous lipid emulsion plus remifentanil pretreatment did not result in better durations in terms of formation of bupivacaine intoxication and asystole compared to lipid pretreatment alone.
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Price excludes VAT (USA)
Tax calculation will be finalised during checkout.
Groban, L. (2003). Central nervous system and cardiac effects from long-acting amide local anesthetic toxicity in the intact animal model. Regional Anesthesia and Pain Medicine, 28, 3–11.
Clarkson, C. W., & Hondeghem, L. M. (1985). Mechanism for bupivacaine depression of cardiac conduction: fast block of sodium channels during the action potential with slow recovery from block during diastole. Anesthesiology, 62, 396–405.
Litz, R. J., Roessel, T., Heller, A. R., & Stehr, S. N. (2008). Reversal of central nervous system and cardiac toxicity after local anesthetic intoxication by lipid emulsion injection. Anesthesia and Analgesia, 106, 1575–1577.
Oda, Y., & Ikeda, Y. (2013). Effect of lipid emulsion on the central nervous system and cardiac toxicity of bupivacaine and levobupivacaine in awake rats. Journal of Anesthesia, 27, 500–504.
Shirole, R. L., Shirole, N. L., & Saraf, M. N. (2015). In vitro relaxant and spasmolytic effects of essential oil of Pistacia integerrima Stewart ex Brandis Galls. Journal of Ethnopharmacology, 168, 61–65.
Nita, I. I., Hershfinkel, M., Lewis, E. C., & Sekler, I. (2015). A crosstalk between Na+ channels, Na+/K+ pump and mitochondrial Na+ transporters controls glucose-dependent cytosolic and mitochondrial Na+ signals. Cell Calcium, 57, 69–75.
Lynch, C., 3rd. (1986). Depression of myocardial contractility in vitro by bupivacaine, etidocaine, and lidocaine. Anesthesia and Analgesia, 65, 551–559.
Weinberg, G. L., VadeBoncouer, T., Ramaraju, G. A., Garcia-Amaro, M. F., & Cwik, M. J. (1998). Pretreatment or resuscitation with a lipid infusion shifts the dose–response to bupivacaine-induced asystole in rats. Anesthesiology, 88, 1071–1075.
Rosenblatt, M. A., Abel, M., Fischer, G. W., Itzkovich, C. J., & Eisenkraft, J. B. (2006). Successful use of a 20% lipid emulsion to resuscitate a patient after a presumed bupivacaine-related cardiac arrest. Anesthesiology, 105, 217–218.
ACMT. (2011). ACMT position statement: Interim guidance for the use of lipid resuscitation therapy. Journal of Medical Toxicology, 7(1), 81–82.
ASRA Checklist for treatment of local anesthetic systematic toxicity 2011Availlable from:https://www.asra.com/advisory-guidelines/article/3/checklist-for-treatment-of-local-anesthetic-systemic-toxicity. Accessed 29 December 2016.
Hayes, B. D., Gosselin, S., Calello, D. P., Nacca, N., Rollins, C. J., Abourbih, D., et al. (2016). Systematic review of clinical adverse events reported after acute intravenous lipid emulsion administration. Clinical Toxicology (Phila), 54, 365–404.
Hoegberg, L. C. G., Bania, T. C., Lavergne, V., Bailey, B., Turgeon, A. F., Thomas, S. H. L., et al. (2016). Systematic review of the effect of intravenous lipid emulsion therapy for local anesthetic toxicity. Clinical Toxicology (Phila), 54, 167–193.
Patel, S. S., & Spencer, C. M. (1996). Remifentanil. Drugs, 52, 417–427.
Peart, J. N., Gross, E. R., & Gross, G. J. (2005). Opioid-induced preconditioning: Recent advances and future perspectives. Vascular Pharmacology, 42, 211–218.
Yu, C. K., Li, Y. H., Wong, G. T., Wong, T. M., & Irwin, M. G. (2007). Remifentanil preconditioning confers delayed cardioprotection in the rat. British Journal of Anaesthesia, 99, 632–638.
Zhang, Y., Chen, Z.-W., Girwin, M., & Wong, T.-M. (2005). Remifentanil mimics cardioprotective effect of ischemic preconditioning via protein kinase C activation in open chest of rats. Acta Pharmacologica Sinica, 26, 546–550.
Hanci, V., Karakaya, K., Yurtlu, S., Hakimoglu, S., Can, M., Ayoglu, H., et al. (2009). Effects of dexmedetomidine pretreatment on bupivacaine cardiotoxicity in rats. Regional Anesthesia and Pain Medicine, 34, 565–568.
Yurtlu, D. A., & Kaya, K. (2013). Ropivacaine, articaine or combination of ropivacaine and articaine for epidural anesthesia in cesarean section: A randomized, prospective, double-blinded study. Brazilian Journal of Anesthesiology, 63, 85–91.
Faccenda, K. A., & Finucane, B. T. (2001). Complications of regional anaesthesia Incidence and prevention. Drug Safety, 24, 413–442.
Felice, K., & Schumann, H. (2008). Intravenous lipid emulsion for local anesthetic toxicity: A review of the literature. Journal of Medical Toxicology, 4, 184–191.
de La Coussaye, J. E., Eledjam, J. J., Brugada, J., & Sassine, A. (1993). Cardiotoxicity of local anesthetics. Cahiers d’Anesthesiologie, 41, 589–598.
Cave, G., Harvey, M., Willers, J., Uncles, D., Meek, T., Picard, J., et al. (2014). LIPAEMIC report: Results of clinical use of intravenous lipid emulsion in drug toxicity reported to an online lipid registry. Journal of Medical Toxicology, 10, 133–142.
Neal, J. M., Bernards, C. M., Butterworth, J. F. T., Di Gregorio, G., Drasner, K., Hejtmanek, M. R., et al. (2010). ASRA practice advisory on local anesthetic systemic toxicity. Regional Anesthesia and Pain Medicine, 35, 152–161.
Weinberg, G. L. (2010). Treatment of local anesthetic systemic toxicity (LAST). Regional Anesthesia and Pain Medicine, 35, 188–193.
Liu, P., Feldman, H. S., Covino, B. M., Giasi, R., & Covino, B. G. (1982). Acute cardiovascular toxicity of intravenous amide local anesthetics in anesthetized ventilated dogs. Anesthesia and Analgesia, 61, 317–322.
Cho, H. S., Lee, J. J., Chung, I. S., Shin, B. S., Kim, J. A., & Lee, K. H. (2000). Insulin reverses bupivacaine-induced cardiac depression in dogs. Anesthesia and Analgesia, 91, 1096–1102.
Vasques, F., Behr, A. U., Weinberg, G., Ori, C., & Di Gregorio, G. (2015). A review of local anesthetic systemic toxicity cases since publication of the american society of regional anesthesia recommendations: To whom it may concern. Regional Anesthesia and Pain Medicine, 40, 698–705.
Di Gregorio, G., Neal, J. M., Rosenquist, R. W., & Weinberg, G. L. (2010). Clinical presentation of local anesthetic systemic toxicity: A review of published cases, 1979 to 2009. Regional Anesthesia and Pain Medicine, 35, 181–187.
Kim, H. S., Cho, J. E., Hong, S. W., Kim, S. O., Shim, J. K., & Kwak, Y. L. (2010). Remifentanil protects myocardium through activation of anti-apoptotic pathways of survival in ischemia-reperfused rat heart. Physiological Research, 59, 347–356.
Wong, G. T. C., Li, R., Jiang, L. L., & Irwin, M. G. (2010). Remifentanil post-conditioning attenuates cardiac ischemia-reperfusion injury via kappa or delta opioid receptor activation. Acta Anaesthesiologica Scandinavica, 54, 510–518.
Zhang, Y., Irwin, M. G., Wong, T. M., Chen, M., & Cao, C. M. (2005). Remifentanil preconditioning confers cardioprotection via cardiac kappa- and delta-opioid receptors. Anesthesiology, 102, 371–378.
Tanaka, K., Kersten, J. R., & Riess, M. L. (2014). Opioid-induced cardioprotection. Current Pharmaceutical Design, 20(36), 5696–5705.
Glass, P. S., Gan, T. J., & Howell, S. (1999). A review of the pharmacokinetics and pharmacodynamics of remifentanil. Anesthesia and Analgesia, 89, 7–14.
Reid, J. E., & Mirakhur, R. K. (2000). Bradycardia after administration of remifentanil. British Journal of Anaesthesia, 84, 422–423.
Kurdi, O., Deleuze, A., Marret, E., & Bonnet, F. (2001). Asystole during anaesthetic induction with remifentanil and sevoflurane. British Journal of Anaesthesia, 87, 943.
The author(s) received no financial support for the research, authorship, and/or publication of this article.
Conflict of interest
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
About this article
Cite this article
Pişkin, Ö., Ayoğlu, H. Effects of Remifentanil Pretreatment on Bupivacaine Cardiotoxicity in Rats. Cardiovasc Toxicol 18, 56–62 (2018). https://doi.org/10.1007/s12012-017-9413-3