1. Recognition and Treatment of Local Anesthetic Systemic Toxicity (LAST) Brooke Bauer, M.D & Jeremy Dority, MD KSPAN 3/12/2016 Department of Anesthesiology University of Kentucky College of Medicine Lexington, KY An Equal Opportunity University

2. Disclosures The authors have no financial disclosures to report http://www.shutterstock.com/s/empty+pockets/search.html

3. Objectives https://sites.google.com/site/schoolstartinglater/visuals-and-statistics

4. Objectives Stay awake after lunch Understand background information about Local Anesthetic Systemic Toxicity (LAST) to become more familiar with the pathology and causation Recognize symptom presentation to raise suspicion of a diagnosis of LAST

5. Become comfortable with LAST treatment: Pharmacologic and supportive Utilize information from this presentation and your experience in an interactive question session Experience a LAST scenario through simulation Objectives

6. Be Interactive!

9. Case #1 38 y/o female s/p resection of mass at left cerebellopontine angle PMH: morbid obesity, anxiety, frequent PVCs s/p failed cardiac ablation, HTN, hypothyroidism 2mg versed, desflurane, succinylcholine, 250mcg fentanyl, remifentanil, low dose lidocaine infusion throughout IVF 3000mL, UOP 1500mL, EBL 25mL Myers, Rebecca & Dority, Jeremy. Altered Mental Status Following Craniotomy. GCC Presentation. UK Department of Anesthesiology.

10. Case #1 Patient agitated, moaning during PACU transport c/o head and back pain BP 174/93, HR 103 Given multiple 50 mcg fentanyl boluses without improvement in agitation and groaning Additionally received 2 mg hydromorphone, 4 mg morphine, 1mg lorazepam, 12.5mg meperidine BP 155/100 (HR 110), SpO 2 fell to 86% and she became minimally responsive. Nasal trumpet applied, started on nonrebreather; saturation rose to low 90s. TO BE CONTINUED… Myers, Rebecca & Dority, Jeremy. Altered Mental Status Following Craniotomy. GCC Presentation. UK Department of Anesthesiology.

11. Which is diagnosis is highest on your differential? A.LAST B.Hypercarbia C.Narcotic overdose D.Lack of pain control

13. Which was the first local anesthetic to be used medically? A.Lidocaine B.Prilocaine C.Cocaine D.Ropivacaine - Neal JM, Bernards CM, Butterworth JF et al, ASRA Practice Advisory on Local Anesthetic Systemic Toxicity. Regional Anesthesia and Pain Medicine. 35; 2:151-61. - https://en.wikipedia.org/wiki/Cocaine

14. History of Local Anesthetics Cocaine was introduced into medical practice in the 1880s & was the first local anesthetic to be used for medical purposes 1891 “Cocaine Poisoning” was published in Med Surg Rep - Neal JM, Bernards CM, Butterworth JF et al, ASRA Practice Advisory on Local Anesthetic Systemic Toxicity. Regional Anesthesia and Pain Medicine. 35; 2:151-61. - Mattison JB. Cocaine Poisoning. Med Surg Rep. 1891;115:645-50. - http://doctorspiller.com/Local_Anesthetics/local_anesthetics.htm

15. Local Anesthetic Mechanism https://www.netterimages.com/local-anesthetics-spinal-afferents-and-local-anesthetic-mechanisms-of-action-unlabeled-pharmacology-james-a-perkins-11123.html

16. Types of Local Anesthetic Esters: – Only one “i” – Procaine, benzocaine, chloroprocaine – Metabolized very quickly by esterases in the plasma Amides – 2 “i”s – Lidocaine, bupivacaine, ropivacaine – Metabolized by a much slower process in the liver - Boghdadly KE, Chin KJ. Local Anesthetic Systemic Toxicity: Continuing Professional Development. Can J Anesth 2016; 63:330-49. - https://upload.wikimedia.org/wikipedia/commons/3/3b/Struktur-Lokalanästhetika.png

17. Local Anesthetic Systemic Toxicity Rare life threatening complication due to – intra-arterial injection – intravenous injection – systemic absorption Affects Na Channels of highly vascular organs – Central nervous system – Cardiovascular system -Boghdadly KE, Chin KJ. Local Anesthetic Systemic Toxicity: Continuing Professional Development. Can J Anesth 2016; 63:330-49. -http://www.lookfordiagnosis.com/mesh_info.php?term=Injections%2C+Intra-Arterial&lang=1

18. Incidence 0.4 – 3.7 per 10,000 peripheral nerve blocks 1,2 0.7 – 1.8 per 10,000 epidurals 3,4 >1823 nerve blocks and epidurals performed by the acute pain service at UK in 2015; 2 presumed episodes of LAST 1.Liu SS, Ortolan S, Sandoval MV, et al. Cardiac arrest and seizures due to local anesthetic systemic toxicity after peripheral nerve blocks: should we still fear the reaper? Reg Anesth Pain Med. 2016;41:5-21. 2.Heinonen JA, Litonius E, Pitkanen M, Rosenberg PH. Incidence of severe local anaesthetic toxicity and adoption of lipid rescue in Finnish anaesthesia departments in 2011-2013. Acta Acaesthesiol Scand. 2015;59:1032-1037. 3.Auroy Y, Benhamou D, Bargues L, Ecoffey C, et al. Major complications of regional anesthesia in France: The SOS Regional Anesthesia Hotline Service. Anesthesiology 2002; 97:1274-80. 4.Brown DL, Ransom DM, Hall JA, Leicht CH, Schroeder DR, Offord KP. Regional anesthesia and local anesthetic-induced systemic toxicity: seizure frequency and accompanying cardiovascular changes. Anesth Analg 1995; 81:321-8.

19. - Gregorio GD, Neal JM, Rosenquist RW, Weinberg GL. Clinical Presentation of Local Anesthetic Systemic Toxicity: A Review of Published Cases, 1979 to 2009. Regional Anesthesia and Pain Medicine. 2010; 35:2 181-87.

20. CNS Toxicity Intracellular Na channels are blocked, inhibiting depolarization and preventing neuronal transmission 1 st Inhibitory pathways 2 nd Excitatory pathways -Boghdadly KE, Chin KJ. Local Anesthetic Systemic Toxicity: Continuing Professional Development. Can J Anesth 2016; 63:330-49. -Neal JM, Bernards CM, Butterworth JF, et al. ASRA Practice Advisory on Local Anesthetic Systemic Toxicity. Regional Anesthesia and Pain Medicine. 35; 2:152-61. -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: 181-7.

21. Which is the most commonly reported neurologic symptom during LAST? A.Dysarthria B.Seizure C.Drowsiness D.Loss of Consciousness - Gregorio GD, Neal JM, Rosenquist RW, Weinberg GL. Clinical Presentation of Local Anesthetic Systemic Toxicity: A Review of Published Cases, 1979 to 2009. Regional Anesthesia and Pain Medicine. 2010; 35:2 181-87.

22. CNS Toxicity - Gregorio GD, Neal JM, Rosenquist RW, Weinberg GL. Clinical Presentation of Local Anesthetic Systemic Toxicity: A Review of Published Cases, 1979 to 2009. Regional Anesthesia and Pain Medicine. 2010; 35:2 181-87.

23. CVS Toxicity Potassium and calcium channels are blocked, causing myocardial depression Conducting sodium channels are blocked, prolonging depolarization, which leads to arrhythmias – Avoid medications that slow this more! -Boghdadly KE, Chin KJ. Local Anesthetic Systemic Toxicity: Continuing Professional Development. Can J Anesth 2016; 63:330-49. -Neal JM, Bernards CM, Butterworth JF, et al. ASRA Practice Advisory on Local Anesthetic Systemic Toxicity. Regional Anesthesia and Pain Medicine. 35; 2:152-61.

24. CVS Toxicity - Gregorio GD, Neal JM, Rosenquist RW, Weinberg GL. Clinical Presentation of Local Anesthetic Systemic Toxicity: A Review of Published Cases, 1979 to 2009. Regional Anesthesia and Pain Medicine. 2010; 35:2 181-87.

25. Onset of Symptoms/Signs - Gregorio GD, Neal JM, Rosenquist RW, Weinberg GL. Clinical Presentation of Local Anesthetic Systemic Toxicity: A Review of Published Cases, 1979 to 2009. Regional Anesthesia and Pain Medicine. 2010; 35:2 181-87.

26. Which factor(s) increase risk of LAST? A.Extremes of age – metabolism/clearance reduced B.Cardiac dysfunction – prolonged circulation time C.Pregnancy – decreased protein binding D.Location of nerve block E.All of the above - Meunier JF, Goujard E, Dubousset AM, Samii K, Mazoit JX. Pharmacokinetics of bupivacaine after continuous epidural infusion in infants with an without biliary atresia. Anesthetiology 2001; 95: 87-95. - Rosenberg PH, Veering BT, Urmey WF. Maximum recommended doses of local anesthetics: a multifactoral concept. Reg Anesth Pain Med 2004; 29: 564-75. - Tsen LC, Tarshis J, Denson DD, Osanthanondh R, Datta S, Bader AM. Measurements of maternal protein binding of bupivacaine throughout pregnancy. Anesth Analg 199; 89: 965- 8.

27. Risk Factors Location of nerve block/LA injection 1.IV 2.Tracheal 3.Intercostal 4.Caudal epidural 5.Paracervical 6.Epidural 7.Brachial plexus 8.Sciatic 9.Subcutaneous Ranasinghe JS, Wahl KM, Harris EA, Lubarsky DA. Anesthesiology Board Review Third Edition. Pearls of Wisdom. 2002; p251.

28. Recommended Maximum Dosage - Boghdadly KE, Chin KJ. Local Anesthetic Systemic Toxicity: Continuing Professional Development. Can J Anesth 2016; 63:330-49.

29. … Continued Case #1 Lidocaine – Total: 800mg lidocaine  7.67mg/kg= 0.85mg/kg/hr – 9ml 0.5% ropivacaine for occipital nerve block Treatment – 1.5mL/kg 20% lipid emulsion with immediate resolution of symptoms – Agitation recurred at 25 minutes after rx – 2 nd bolus given and drip started at 0.25mL/kg/min with complete resolution Myers, Rebecca & Dority, Jeremy. Altered Mental Status Following Craniotomy. GCC Presentation. UK Department of Anesthesiology.

30. 20

31. http://www.berktree.com/baxter-healthcare-intralipid-20-iv-fat-emulsion-solution-50-each-model-2b6023.html

32. http://tywkiwdbi.blogspot.com/2010_11_01_archive.html Lipid Infusion Side Effects

33. Lipid Emulsion Mechanism Theories 1.“Lipid sink” 2.“Mass effect” 3.Ion channels Cave, Grant and Harvey, Martyn. Intravenous Lipid Emulsion as Antidote Beyond Local Anesthetic Toxicity: A Systematic Review. Academic Emergency Medicine. 2009; 16:9, 815-24.

34. - Di Gregorio G, Schwartz D, Ripper R, et al. Lipid emulsion is superior to vasopressin in a rodent model of resuscitation from toxin-induced cardiac arrest. Crit Care Med. 2009;37:993-99. - http://www.scielo.br/scielo.php?pid=S0102-35862003000600014&script=sci_arttext&tlng=en

35. Case #2 57yoM I&D left hand for chronic infection PMHx: CAD, MI 2007 s/p PCI, EF 20%, HTN, tachycardia, PVD s/p bilateral AKAs at groin, DM, CVA, Seizure disorder Uncomplicated supraclavicular block performed in pre-op holding area (10mL 0.5% Ropivacaine + 10mL 2% Lidocaine) VSS and denied any immediate symptoms following block Jerrod McCarty, Beril Abraham, Greg Rose, Shelly Ferrell. Local Anesthetic Toxicity After Supraclavicular Block. GCC. University of Kentucky Department of Anesthesia.

36. Case #2 After 15 minutes found to be minimally responsive; oriented and follows commands with stimulation then quickly returns to obtunded state Labored & tachypneic respirations - Supplemental O2 placed (poor SpO2 waveform 2/2 PVD) Glucose 121 CXR – Diaphragm in normal position Jerrod McCarty, Beril Abraham, Greg Rose, Shelly Ferrell. Local Anesthetic Toxicity After Supraclavicular Block. GCC. University of Kentucky Department of Anesthesia.

37. Case #2 Diagnosis : Hypercarbia vs LAST Given 1.5mL/kg intralipid & started infusion 0.25mL/kg/min Mental status improved after bolus and returned to baseline after 1 hour Adm overnight without further complication & DC’d next day Jerrod McCarty, Beril Abraham, Greg Rose, Shelly Ferrell. Local Anesthetic Toxicity After Supraclavicular Block. GCC. University of Kentucky Department of Anesthesia.

38. References Auroy Y, Benhamou D, Bargues L, Ecoffey C, et al. Major complications of regional anesthesia in France: The SOS Regional Anesthesia Hotline Service. Anesthesiology 2002; 97:1274-80. Boghdadly KE, Chin KJ. Local Anesthetic Systemic Toxicity: Continuing Professional Development. Can J Anesth 2016; 63:330-49. Brown DL, Ransom DM, Hall JA, Leicht CH, Schroeder DR, Offord KP. Regional anesthesia and local anesthetic- induced systemic toxicity: seizure frequency and accompanying cardiovascular changes. Anesth Analg 1995; 81:321-8. Cave, Grant and Harvey, Martyn. Intravenous Lipid Emulsion as Antidote Beyond Local Anesthetic Toxicity: A Systematic Review. Academic Emergency Medicine. 2009; 16:9, 815-24. Checklist for Treatment of Local Anesthetic Systemic Toxicity. American Society of Regional Anesthesia and Pain Medicine. Di Gregorio G, Schwartz D, Ripper R, et al. Lipid emulsion is superior to vasopressin in a rodent model of resuscitation from toxin-induced cardiac arrest. Crit Care Med. 2009;37:993-99. Gregorio GD, Neal JM, Rosenquist RW, Weinberg GL. Clinical Presentation of Local Anesthetic Systemic Toxicity: A Review of Published Cases, 1979 to 2009. Regional Anesthesia and Pain Medicine. 2010; 35:2 181-87. Heinonen JA, Litonius E, Pitkanen M, Rosenberg PH. Incidence of severe local anaesthetic toxicity and adoption of lipid rescue in Finnish anaesthesia departments in 2011-2013. Acta Acaesthesiol Scand. 2015;59:1032-1037. Liu SS, Ortolan S, Sandoval MV, et al. Cardiac arrest and seizures due to local anesthetic systemic toxicity after peripheral nerve blocks: should we still fear the reaper? Reg Anesth Pain Med. 2016;41:5-21. Mattison JB. Cocaine Poisoning. Med Surg Rep. 1891;115:645-50. McCarty J, Abraham B, Rose G, Ferrell S. Local Anesthetic Toxicity After Supraclavicular Block. GCC. University of Kentucky Department of Anesthesia. Meunier JF, Goujard E, Dubousset AM, Samii K, Mazoit JX. Pharmacokinetics of bupivacaine after continuous epidural infusion in infants with an without biliary atresia. Anesthetiology 2001; 95: 87-95. Myers, Rebecca & Dority, Jeremy. Altered Mental Status Following Craniotomy. GCC Presentation. UK Department of Anesthesiology. Neal JM, Bernards CM, Butterworth JF, et al. ASRA Practice Advisory on Local Anesthetic Systemic Toxicity. Regional Anesthesia and Pain Medicine. 35; 2:152-61. Ranasinghe JS, Wahl KM, Harris EA, Lubarsky DA. Anesthesiology Board Review Third Edition. Pearls of Wisdom. 2002; p251. Tsen LC, Tarshis J, Denson DD, Osanthanondh R, Datta S, Bader AM. Measurements of maternal protein binding of bupivacaine throughout pregnancy. Anesth Analg 199; 89: 965-8.

39. Visuals http://www.scielo.br/scielo.php?pid=S0102- 35862003000600014&script=sci_arttext&tlng=en http://tywkiwdbi.blogspot.com/2010_11_01_archive.html http://www.berktree.com/baxter-healthcare-intralipid-20-iv-fat-emulsion- solution-50-each-model-2b6023.html http://www.lookfordiagnosis.com/mesh_info.php?term=Injections%2C+Intra- Arterial&lang=1 https://upload.wikimedia.org/wikipedia/commons/3/3b/Struktur- Lokalanästhetika.png https://www.netterimages.com/local-anesthetics-spinal-afferents-and-local- anesthetic-mechanisms-of-action-unlabeled-pharmacology-james-a-perkins- 11123.html http://doctorspiller.com/Local_Anesthetics/local_anesthetics.htm https://en.wikipedia.org/wiki/Cocaine