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Local Anesthetics Toxicity and Management Gregory Pate, MD Department of Anesthesia Bremerton Naval Hospital.

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Presentation on theme: "Local Anesthetics Toxicity and Management Gregory Pate, MD Department of Anesthesia Bremerton Naval Hospital."— Presentation transcript:

1 Local Anesthetics Toxicity and Management Gregory Pate, MD Department of Anesthesia Bremerton Naval Hospital

2 Local Anesthetic Toxicity Topics Local Anesthetic Pharmacology Adverse Reactions to Local Anesthetics Types of Toxicity Acute Systemic Toxicity Management of Acute Systemic Toxicity

3 Basics: Local Anesthetic Pharm Amino esters and Amino amides Metabolism Protein binding Lipophilic- hydrophilic balance Hydrogen Ion concentration Katzung, Basic & clinical pharm, 10 th edition

4 Basics: Local Anesthetic Mechanism Active form of the local anesthetic Modulated receptor theory Other possible mechanisms of action Miller’s Anesthesia, 6 th edition

5 Local Anesthetic Toxicity Topics Local Anesthetic Pharmacology Adverse Reactions to Local Anesthetics Types of Toxicity Acute Systemic Toxicity Management of Acute Systemic Toxicity

6 Methemoglobinemia Prilocaine and Benzocaine Benzocaine sprays like Cetacaine EMLA cream which has prilocaine although this practice is still generally considered safe Seen with use of prilocaine in epidurals around at mg for adults Dapsone, antibiotics, nitrates, etc. Methemoglobin related to local anesthetics, Guay et al, 2009

7 Methemoglobinemia

8 Hypersensitivity Reactions IgE mediated vs Non-IgE mediated Perioperative anaphylaxis about 1:10,000 cases-NMBD, antibiotics, latex Does not take much allergen True allergy to amides very rare True allergy to esters like cocaine, procaine, chloroprocaine more common Anaphylaxis and Anesthesia, Dewachter, 2009

9 Features of Anaphylaxis Airway: stridor, hoarseness, laryngeal edema, dyspnea, cyanosis, bronchospasm, and obstruction Cardiac: tachycardia, hypotension, arrhythmia, cardiac arrest Neuro: dizzy, weak, syncopal, seizure Skin: flushing, erythema, pruritis, angioedema, maculopapular rash Diagnoss and Management of Anaphylaxis, CMAJ, 2003

10 Acute Anaphylaxis Acute Anaphylaxis Diagnoss and Management of Anaphylaxis, CMAJ, 2003

11 Biphasic Anaphylaxis Diagnoss and Management of Anaphylaxis, CMAJ, 2003

12 Local Anesthetic Toxicity Topics Local Anesthetic Pharmacology Adverse Reactions to Local Anesthestics Types of Toxicity Acute Systemic Toxicity Management of Acute Systemic Toxicity

13 Types of Local Anesthetic Toxicity LOCALIZED TOXICITY NeurotoxicityMyotoxicity SYSTEMIC TOXICITY CNS toxicity CVS toxicity

14 Neurotoxicity Dose/concentration Duration of nerve exposure Most common with continuous spinal anesthesia All amino amides/ amino esters can cause direct toxicity American Journal of Therapeutics, Cont Spinal Anesthesia, Moore, 2009

15 Myotoxicity Edema and necrosis after exposure to Lidocaine Normally limited and reversible Often reported in Ophthalmology Zink et al., 2005

16 Prevention of LA toxicity Dosing is a key factor in prevention Review Therapeutic Index

17 Local Anesthetic Toxicity Topics Local Anesthetic Pharmacology Adverse Reactions to Local Anesthetics Types of Toxicity Acute Systemic Toxicity Management of Acute Systemic Toxicity

18 LA toxicity - CNS Local Anesthetics readily cross the blood-brain barrier CNS toxicity is drug/dose dependent Clinical indicators of CNS toxicity Kreitzer, Journal of Clinical Anesthesia, 1996

19 Dose Dependent Systemic Effects Effects of Lidocaine by plasma concentration Effects of Lidocaine by plasma concentration CONC(mcg/mL) EFFECT CONC(mcg/mL) EFFECT 1–5 Analgesia 1–5 Analgesia 5–10 Lightheaded, Tinnitus, 5–10 Lightheaded, Tinnitus, Tongue numbness Tongue numbness 10–15 Seizure, LOC 10–15 Seizure, LOC 15–25 Coma, resp arrest 15–25 Coma, resp arrest >25 CV depression >25 CV depression Barash, 5 th pp464

20 Relative Potency for Toxicity (CVS:CNS) Toxicity ▪AGENT▪RELATIVE POTENCY FOR CNS TOXICITY ▪CVS:CNS Bupivacaine42 L-bupivacaine2.92 Etidocaine24.4 Lidocaine17.1 Mepivacaine Ropivacaine2.92 Barash, 5 th edition pp462

21 LA Toxicity - CVS Newer amino amide local anesthetics potential to cause CNS toxicity Indicators of CVS toxicity Mechanism of toxicity Albright, Anesthesiology,1979 Clarkson, Anesthesiology, 1985

22 Seizure 30% smaller dose for Bup than others 30% smaller dose for Bup than othersDysrhythmia (a) Bup 13.2 mg/kg (a) Bup 13.2 mg/kg (b) L-Bup 43.7mg/kg (b) L-Bup 43.7mg/kg (c) Rop 91.8 mg/kg (c) Rop 91.8 mg/kg Shigeo, Anesth Analg 2001

23 EKG in CVS Toxicity Kim, Canadian J of Anesthesia, 2003

24 Local Anesthetic Toxicity Topics Local Anesthetic Pharmacology Adverse Reactions to Local Anesthetics Types of Toxicity Acute Systemic Toxicity Management of Acute Systemic Toxicity

25 Early Options to Treat LA Toxicity Epinephrine and Atropine Shock, Shock, Shock Other ACLS MilrinoneVersedPropofolCPB

26 Early Options to Treat LA Toxicity Figure 1. Lethal dose-response curves for bupivacaine in the presence or absence of verapamil and nimodipine. B = bupivacaine, N + B = nimodipine 200 [micro sign]g/kg + bupivacaine, V + B = verapamil 150 [micro sign]g/kg + bupivacaine. Adsan, Anesth Analg, 1998

27 A FRESH IDEA Lipid Emulsions expand the list of options A Decade of research and a growing body of evidence and case reports The Rescue Kit Weinberg, LipidRescue.com, 2008

28 First To Benefit from Lipid Emulsion Promising experiments with LA toxicity and Lipid Emulsion resuscitation Success leads to expanded research Weinberg, Anesthesiology, 1998

29 Lipid Sink Hypothesis Lipid infusion Lipid phase Highly lipophilic amino amides Decreased unbound fraction Weinberg, Anesthesiology, 1998

30 GroupTreatment MAP mmHg HRPaO2PaCO2pH SalineBaseline 91 +/ / / / /-.04 SalineRecovery 10 +/-3 ASYS LipidBaseline 96 +/ / / / /-.02 LipidRecovery 93 +/ / / / /-.04 Studies with Lipid Emulsions in a Dog Model Weinberg et al, Lipid emulsion infusion rescues dogs, 2003

31 First Lipid Emulsion Resuscitation after Bupivacaine toxicity/arrest 20 min of advanced cardiac life support, a total of 3 mg epinephrine, given in divided doses, 2 mg atropine, 300 mg amiodarone, and 40 U arginine vasopressin were administered. In addition, monophasic defibrillation was used at escalating energy levels-200, 300, 360, and 360 J, according to the advanced cardiac life support protocol. Cardiac rhythms included ventricular tachycardia with a pulse, pulseless ventricular tachycardia that momentarily became ventricular fibrillation, and eventually asystole. The arrhythmias observed during most of the resuscitation period were pulseless ventricular tachycardia and asystole. Rosenblatt, Anesthesiology, 2006

32 Further Case Studies on LE LipidRescue lists several case reports of successful resuscitation with LE after CVS toxicity with life threatening rhythms or asystole. Inferior to randomized double-blinded trials but such investigations would clearly be unethical Not many case studies giving an account of an unsuccessful resuscitation effort with or without LE although we know such events have occurred Weinberg, Correspondence, 2008

33 Applications of Intralipid in ED Intralipid has been used to treat other types of drug overdose Case studies are on the Lipidrerscue.org website. Same lipid sink idea

34 The Big Question –Lipid Emulsions are NO SUBSTITUTE for ACLS. –Where do we insert lipid emulsion administration into the ACLS algorithm? –How is the drug given? Weinberg, correspondence, 2008

35 primum non nocere Risks of Lipid Emulsion Infusion: all < 1% Modulation of cytokine production by WBCs Altered inflammatory response Weakness, altered MS, seizures in children Fat emboli if lipid particles >5 microns in diameter Hyperlipedemia Pulmonary hypertension anaphylaxis especially if prepared from soybean oil (most likely adverse reaction with acute, short-term administration)

36 References Arthur GR: Alterations in the pharmacokinetic properties of amide local anesthetics following local anesthetic induced convulsions. Acta Anaesthesiol Scand 32:522, 1988 Barash P: Clinical Anesthesia, 5 th edition, chapter 17, 2006 Clarkson C: Mechanism for bupivacaine depression of cardiac conduction: fast block of sodium channels during the action potential with slow recovery from block during diastole. Anesthesiology 1985;62: Colin J: Intravenous ropivacaine bolus is a reliable marker of intravascular injection in premedicated healthy Volunteers. Canadian Journal of Anesthesia50: 8 / pp 795–800, 2003 Cotileas P: A Case Report. Cotileas P: Bupivacaine-Induced Myocardial Depression and Pulmonary Edema: A Case Report. Journal of Electrocardiology Vol. 33 No Katzung B: Basic & Clinical Pharmacology, 10th Edition, Chapter 26 Kim J: Continuous mixed venous oxygen saturation, not mean blood pressure, is associated with early bupivacaine cardiotoxicity in dogs. Canadian Journal of Anesthesia 50: (2003) Mather L: Acute Toxicity of LA: Underlying Pharmacokinetic and Pharmacodynamic Concepts, Regional Anesthesia and Pain Medicine, Vol 30, No. 6, 2005 Miller R: Miller’s Anesthesia, 6 th Edition, Chapter 14, 2005 Mischa J: The effects of Age on Neural Blockade and Hemodynamic Changes After Epidural Anesthesia with Ropivacaine. International Anesthesia Research Society, 94(5): , 2002 Morgan and Mikhail, 4 th edition, Chapter 14, 2006 Rosenberg H: maximum Recommended Doses of Local Anesthetics: A multifactorial Concept. American Society of Regional Anesthesia and Pain Medicine, 29 (6): , 2004 ScottD: EDITORIAL: “Maximum Recommended Doses” of Local Anesthetic Drugs. British Journal of Anesthesia Vol 63, No. 4, Shigeo O: Shigeo O: Systemic Toxicity and Resuscitation in Bupivacaine, Levobupivacaine, or Ropivacaine Infused Rats. Anesth Analg 2001;93:743–8) Weinberg G: Lipid emulsion infusion rescues dogs from Bupivacaine induced cardiac toxicity. Weinberg G: Lipid emulsion infusion rescues dogs from Bupivacaine induced cardiac toxicity. Regional Anesthesia and Pain Medicine, Vol 28, No 3 : , 2003 Weinberg G: Pretreatment or Resuscitation with a Lipid Infusion Shifts the Dose-Response to Bupivacaine- induced Asystole in Rats. Anesthesiology:Volume 88(4)April 1998pp Warren J: Reversal of Central Nervous System and Cardiac Toxicity After Local Anesthetic Intoxication by Lipid Emulsion Injection. International Anesthesia Research Society, Volume 106(5): , 2008 Yokoyama M: Effect of Vasoconstrictive Agents added to lidocaine on IV lidocaine-induced convulsions in rats. Anesthesiology 82:574,1995

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