This article provides a concise overview of local anesthetic systemic toxicity, its history, mechanisms, risk factors, prevention, clinical presentation, and treatment, with a special emphasis on issues specific to the geriatric population. The authors used MEDLINE, Scopus, and Google Scholar to search for original research articles (human and animal studies), registries data, case reports, review articles, and pertinent online publications using the combinations of the following search terms: local anesthetics, local anesthetic systemic toxicity, intralipid, lipid emulsion, Exparel, ultrasound-guidance, regional anesthesia, lidocaine, bupivacaine, ropivacaine, cocaine, procaine, tetracaine, levobupivacaine, liposomal bupivacaine, lignocaine. Local anesthetic systemic toxicity continues to occur despite the use of putatively less cardiotoxic formulations of local anesthetics and more common use of ultrasound guidance. The elderly appear to be at a disproportionately increased risk for toxicity owing to the presence of relevant comorbidities and decreased muscle mass. Examination of recent case reports involving patients over the age of 65 years demonstrates that inadvertent overdosing is responsible for some cases of local anesthetic systemic toxicity. Elderly patients are at increased risk of local anesthetic systemic toxicity. When considering use of local anesthetics in older patients, special attention should be paid to the presence of systemic disease and muscle wasting. The safety of regional anesthesia and multi-modal analgesia among these at-risk patients will be improved by educating physicians and staff to recognize and manage local anesthetic systemic toxicity.
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Redman M. Cocaine: what is the crack? A brief history of the use of cocaine as an anesthetic. Anesth Pain Med. 2011;1(2):95–7. https://doi.org/10.5812/kowsar.22287523.1890.
Calatayud J, Gonzalez A. History of the development and evolution of local anesthesia since the coca leaf. Anesthesiology. 2003;98(6):1503–8. https://doi.org/10.1097/00000542-200306000-00031.
Drasner K. Local anesthetic systemic toxicity: a historical perspective. Reg Anesth Pain Med. 2010;35(2):162–6. https://doi.org/10.1097/AAP.0b013e3181d2306c.
Ruetsch YA, Boni T, Borgeat A. From cocaine to ropivacaine: the history of local anesthetic drugs. Curr Top Med Chem. 2001;1(3):175–82.
Wolfe JW, Butterworth JF. Local anesthetic systemic toxicity: update on mechanisms and treatment. Curr Opin Anaesthesiol. 2011;24(5):561–6. https://doi.org/10.1097/ACO.0b013e32834a9394.
Bureau UC. Older Americans, Table 2; 2018. https://www.census.gov/newsroom/stories/2018/older-americans.html. Accessed 29 July 2019.
Gajdos C, Kile D, Hawn MT, Finlayson E, Henderson WG, Robinson TN. Advancing age and 30-day adverse outcomes after nonemergent general surgeries. J Am Geriatr Soc. 2013;61(9):1608–14. https://doi.org/10.1111/jgs.12401.
Fettiplace MR, Weinberg G. The mechanisms underlying lipid resuscitation therapy. Reg Anesth Pain Med. 2018;43(2):138–49. https://doi.org/10.1097/AAP.0000000000000719.
Vasques F, Behr AU, Weinberg G, Ori C, Di Gregorio G. A review of local anesthetic systemic toxicity cases since publication of the American Society of Regional Anesthesia recommendations: to whom it may concern. Reg Anesth Pain Med. 2015;40(6):698–705. https://doi.org/10.1097/AAP.0000000000000320.
Neal JM, Barrington MJ, Fettiplace MR, Gitman M, Memtsoudis SG, Morwald EE, et al. The Third American Society of Regional Anesthesia and Pain Medicine practice advisory on local anesthetic systemic toxicity: executive summary 2017. Reg Anesth Pain Med. 2018;43(2):113–23. https://doi.org/10.1097/AAP.0000000000000720.
Tunney RK Jr, Whyte K, DeAntonio HJ. Lidocaine toxicity in the setting of HeartMate II left ventricular assist device. J Clin Pharm Ther. 2018;43(5):733–6. https://doi.org/10.1111/jcpt.12717.
Hickey TR, Casimir M, Holt NF. Local anesthetic systemic toxicity after endovenous laser therapy. J Anaesthesiol Clin Pharmacol. 2018;34(3):401–2. https://doi.org/10.4103/joacp.JOACP_113_17.
Nelson M, Reens A, Reda L, Lee D. Profound prolonged bradycardia and hypotension after iterscalene brachial plexus block with bupivacaine. J Emerg Med. 2018;54(3):e41–3. https://doi.org/10.1016/j.jemermed.2017.12.004.
Monti M, Monti A, Borgognoni F, Vincentelli GM, Paoletti F. Treatment with lipid therapy to resuscitate a patient suffering from toxicity due to local anesthetics. Emerg Care J. 1820;2014(10):41–4.
Vadi MG, Patel N, Stiegler MP. Local anesthetic systemic toxicity after combined psoas compartment-sciatic nerve block: analysis of decision factors and diagnostic delay. Anesthesiology. 2014;120(4):987–96. https://doi.org/10.1097/ALN.0000000000000154.
Safety Committee of Japanese Society of Anesthesiologists. Practical guide for the management of systemic toxicity caused by local anesthetics. J Anesth. 2019;33(1):1–8. https://doi.org/10.1007/s00540-018-2542-4.
Rubin DS, Matsumoto MM, Weinberg G, Roth S. Local anesthetic systemic toxicity in total joint arthroplasty: incidence and risk factors in the United States from the national inpatient sample 1998–2013. Reg Anesth Pain Med. 2018;43(2):131–7. https://doi.org/10.1097/AAP.0000000000000684.
Beck L, Martin K. Hazards of paracervical block in obstetrics: a survey of 107 hospitals for women with a total of 32, 652 cases. Geburtshilfe Frauenheilkd. 1969;29(11):961–7.
Tsuchiya H, Mizogami M. R(+)-, Rac-, and S(−-bupivacaine stereostructure-specifically interact with membrane lipids at cardiotoxically relevant concentrations. Anesth Analg. 2012;114(2):310–2. https://doi.org/10.1213/ANE.0b013e31823ed410.
Onyuksel H, Sethi V, Weinberg GL, Dudeja PK, Rubinstein I. Bupivacaine, but not lidocaine, disrupts cardiolipin-containing small biomimetic unilamellar liposomes. Chem Biol Interact. 2007;169(3):154–9. https://doi.org/10.1016/j.cbi.2007.06.002.
Gitman M, Barrington MJ. Local anesthetic systemic toxicity: a review of recent case reports and registries. Reg Anesth Pain Med. 2018;43(2):124–30. https://doi.org/10.1097/AAP.0000000000000721.
Choi JW, Kim DK, Cho CK, Park SJ, Son YH. Trends in medical disputes involving anesthesia during July 2009–June 2018: an analysis of the Korean Society of Anesthesiologists database. Korean J Anesthesiol. 2019;72(2):156–63. https://doi.org/10.4097/kja.d.18.00198.
Weibel S, Jokinen J, Pace NL, Schnabel A, Hollmann MW, Hahnenkamp K, et al. Efficacy and safety of intravenous lidocaine for postoperative analgesia and recovery after surgery: a systematic review with trial sequential analysis. Br J Anaesth. 2016;116(6):770–83. https://doi.org/10.1093/bja/aew101.
Balocco AL, Van Zundert PGE, Gan SS, Gan TJ, Hadzic A. Extended release bupivacaine formulations for postoperative analgesia: an update. Curr Opin Anaesthesiol. 2018;31(5):636–42. https://doi.org/10.1097/ACO.0000000000000648.
Burbridge M, Jaffe RA. Exparel®: a new local anesthetic with special safety concerns. Anesth Analg. 2015;121(4):1113–4. https://doi.org/10.1213/ANE.0000000000000822.
US Food and Drug Administration. Label for Exparel; 2014. http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/022496s005lbl.pdf. Accessed 10 July 2019.
Aggarwal N. Local anesthetics systemic toxicity association with Exparel (bupivacaine liposome): a pharmacovigilance evaluation. Expert Opin Drug Saf. 2018;17(6):581–7. https://doi.org/10.1080/14740338.2017.1335304.
Smith EB, Kazarian GS, Maltenfort MG, Lonner JH, Sharkey PF, Good RP. Periarticular liposomal bupivacaine injection versus intra-articular bupivacaine infusion catheter for analgesia after total knee arthroplasty: a double-blinded, randomized controlled trial. J Bone Joint Surg Am. 2017;99(16):1337–44. https://doi.org/10.2106/JBJS.16.00571.
Liu SS, Ortolan S, Sandoval MV, Curren J, Fields KG, Memtsoudis SG, et al. Cardiac arrest and seizures caused by local anesthetic systemic toxicity after peripheral nerve blocks: should we still fear the reaper? Reg Anesth Pain Med. 2016;41(1):5–21. https://doi.org/10.1097/AAP.0000000000000329.
Barrington MJ, Kluger R. Ultrasound guidance reduces the risk of local anesthetic systemic toxicity following peripheral nerve blockade. Reg Anesth Pain Med. 2013;38(4):289–99. https://doi.org/10.1097/AAP.0b013e318292669b.
Morwald EE, Zubizarreta N, Cozowicz C, Poeran J, Memtsoudis SG. Incidence of local anesthetic systemic toxicity in orthopedic patients receiving peripheral nerve blocks. Reg Anesth Pain Med. 2017;42(4):442–5. https://doi.org/10.1097/AAP.0000000000000544.
Tucker GT, Mather LE. Clinical pharmacokinetics of local anaesthetics. Clin Pharmacokinet. 1979;4(4):241–78. https://doi.org/10.2165/00003088-197904040-00001.
Neal JM. Ultrasound-guided regional anesthesia and patient safety: update of an evidence-based analysis. Reg Anesth Pain Med. 2016;41(2):195–204. https://doi.org/10.1097/AAP.0000000000000295.
Barrington MJ, Uda Y. Did ultrasound fulfill the promise of safety in regional anesthesia? Curr Opin Anaesthesiol. 2018;31(5):649–55. https://doi.org/10.1097/ACO.0000000000000638.
Di Gregorio G, Neal JM, Rosenquist RW, Weinberg GL. Clinical presentation of local anesthetic systemic toxicity: a review of published cases, 1979 to 2009. Reg Anesth Pain Med. 2010;35(2):181–7.
Association of Anaesthetists of Great Britain and Ireland. Management of severe local anaesthetic toxicity 2 (A4 sheet and accompanying notes); 2010. https://www.aagbi.org/publications/publications-guidelines/M/R. Accessed 23 July 2016.
Fenten MG, Rohrbach A, Wymenga AB, Stienstra R. Systemic local anesthetic toxicity after local infiltration analgesia following a polyethylene tibial insert exchange: a case report. Reg Anesth Pain Med. 2014;39(3):264–5. https://doi.org/10.1097/AAP.0000000000000077.
Akimoto K, Yamauchi C, Fujimoto K, Kurahashi K. A case of delayed arousal after anesthesia due to aberrant epidural catheter placement in a blood vessel. Masui. 2014;63(7):814–6.
Gungor I, Akbas B, Kaya K, Celebi H, Tamer U. Sudden developing convulsion during interscalene block: does propofol anesthesia diminish plasma bupivacaine level? Agri. 2015;27(1):54–7. https://doi.org/10.5505/agri.2015.82160.
Gaies E, Jebabli N, Lakhal M, Klouz A, Salouage I, Trabelsi S. Delayed convulsion after lidocaine instillation for bronchoscopy. Rev Mal Respir. 2016;33(5):388–90. https://doi.org/10.1016/j.rmr.2015.09.010.
Corrections: Lipid rescue for treatment of delayed systemic ropivacaine toxicity from a continuous thoracic paravertebral block. BMJ Case Rep. 2017;2017. https://doi.org/10.1136/bcr-2016-215071corr1.
Bacon B, Silverton N, Katz M, Heath E, Bull DA, Harig J, et al. Local anesthetic systemic toxicity induced cardiac arrest after topicalization for transesophageal echocardiography and subsequent treatment with extracorporeal cardiopulmonary resuscitation. J Cardiothorac Vasc Anesth. 2019;33(1):162–5. https://doi.org/10.1053/j.jvca.2018.01.044.
LipidRescue™ Resuscitation. 20% Lipid emulsion for rescue from drug toxicity; 2019. http://lipidrescue.org. Accessed 13 June 2019.
Litz RJ, Roessel T, Heller AR, Stehr SN. Reversal of central nervous system and cardiac toxicity after local anesthetic intoxication by lipid emulsion injection. Anesth Analg. 2008;106(5):1575–7. https://doi.org/10.1213/ane.0b013e3181683dd7(table of contents).
Kane G, Hoehn S, Behrenbeck T, et al. Benzocaine-induced methemoglobinema based on the Mayo Clinic experience from 28478 transesophageal echocardiograms. Arch Intern Med. 2007;167(18):1977–82.
Bailey M, Corcoran T, Schug S, et al. Perioperative lidocaine infusions for the prevention of chronic postsurgical pain: a systematic review and meta-analysis of efficacy and safety. Pain. 2018;159(9):1696–704.
Weibel S, Jokinen J, Pace NL, et al. Efficacy and safety of intravenous lidocaine for postoperative analgesia and recovery after surgery: a systematic review with trial sequential analysis. BJA. 2016;116(6):770–83.
Gitman M, Fettiplace M, Weinberg G, et al. Local anesthetic systemic toxicity: a narrative literature review and clinical update on prevention, diagnosis, and management. Plast Reconstr Surg. 2019;144(3):783–95.
FDA: label for Exparel. http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/022496s005lbl/pdf.
Australian Medicines Handbook Pty Ltd. https://amhonline.amh.net.au.acs.hcn.com.au/?acc=36265.
Butterworth JF, Mackey DC, Wasnick JD. Local anesthetics. In: Butterworth JF, Mackey DC, Wasnick JD, editors. Morgan and Mikhail’s clinical anesthesiology. 5th ed. New York: McGraw-Hill Medical; 2013. p. 263–76.
Liu S, Lin Y. Local anesthetics. In: Barash PG, Cullen BF, Stoelting RK, et al., editors. Clinical anesthesia. 6th ed. Philadelphia: Lippincott Williams and Wilkins; 2009. p. 531–48.
Rosenberg PH, Veering BT, Urmey WF. Maximum recommended doses of local anesthetics: a multifactorial concept. Reg Anesth Pain Med. 2004;29:564–75.
Klein JA, Jeske DR. Estimated maximal safe dosages of tumescent lidocaine. Anesth Analg. 2016;122:1350–9.
Weinberg GL. Banning benzocaine: of bananas, bureaucrats, and blue men. Anesth Analg. 2009;108(3):699–701.
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Conflict of interest
Rachel Waldinger and Marina Gitman have no conflicts of interest that are directly relevant to the content of this article. Guy Weinberg is a shareholder and officer of ResQ Pharma, Inc.
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Waldinger, R., Weinberg, G. & Gitman, M. Local Anesthetic Toxicity in the Geriatric Population. Drugs Aging 37, 1–9 (2020) doi:10.1007/s40266-019-00718-0