Local Anesthetics Toxicity and Management

Gregory Pate, MDDepartment of Anesthesia Bremerton Naval Hospital

Local Anesthetic Toxicity Topics

Local Anesthetic PharmacologyAdverse Reactions to Local AnestheticsTypes of ToxicityAcute Systemic Toxicity Management of Acute Systemic Toxicity

Basics: Local Anesthetic Pharm

Amino esters and Amino amidesMetabolismProtein bindingLipophilic-hydrophilic balanceHydrogen Ion concentration

Katzung, Basic & clinical pharm, 10th edition

Basics: Local Anesthetic Mechanism Active form of the local anestheticModulated receptor theoryOther possible mechanisms of action

Miller’s Anesthesia, 6th edition

Local Anesthetic Toxicity Topics

Local Anesthetic PharmacologyAdverse Reactions to Local AnestheticsTypes of ToxicityAcute Systemic Toxicity Management of Acute Systemic Toxicity

Methemoglobinemia

Prilocaine and BenzocaineBenzocaine sprays like CetacaineEMLA cream which has prilocaine although this practice is still generally considered safe Seen with use of prilocaine in epidurals around at 500-600mg for adults Dapsone, antibiotics, nitrates, etc.

Methemoglobin related to local anesthetics, Guay et al, 2009

Methemoglobinemia

Hypersensitivity Reactions

IgE mediated vs Non-IgE mediatedPerioperative anaphylaxis about 1:10,000 cases-NMBD, antibiotics, latex Does not take much allergenTrue allergy to amides very rareTrue allergy to esters like cocaine, procaine, chloroprocaine more common

Anaphylaxis and Anesthesia, Dewachter, 2009

Features of Anaphylaxis Airway: stridor, hoarseness, laryngeal edema, dyspnea, cyanosis, bronchospasm, and obstructionCardiac: tachycardia, hypotension, arrhythmia, cardiac arrest Neuro: dizzy, weak, syncopal, seizure Skin: flushing, erythema, pruritis, angioedema, maculopapular rash

Diagnoss and Management of Anaphylaxis, CMAJ, 2003

Acute Anaphylaxis

Diagnoss and Management of Anaphylaxis, CMAJ, 2003

Biphasic Anaphylaxis

Diagnoss and Management of Anaphylaxis, CMAJ, 2003

Local Anesthetic Toxicity Topics

Local Anesthetic PharmacologyAdverse Reactions to Local AnesthesticsTypes of ToxicityAcute Systemic Toxicity Management of Acute Systemic Toxicity

Types of Local Anesthetic Toxicity

LOCALIZED TOXICITYNeurotoxicityMyotoxicity

SYSTEMIC TOXICITYCNS toxicityCVS toxicity

NeurotoxicityDose/concentrationDuration of nerve exposureMost common with continuous spinal anesthesiaAll amino amides/ amino esters can cause direct toxicity

American Journal of Therapeutics, Cont Spinal Anesthesia, Moore, 2009

MyotoxicityEdema and necrosis after exposure to LidocaineNormally limited and reversibleOften reported in Ophthalmology

Zink et al., 2005

Prevention of LA toxicity

Dosing is a key factor in preventionReview Therapeutic Index

Local Anesthetic Toxicity Topics

Local Anesthetic PharmacologyAdverse Reactions to Local AnestheticsTypes of ToxicityAcute Systemic Toxicity Management of Acute Systemic Toxicity

LA toxicity - CNS

Local Anesthetics readily cross the blood-brain barrierCNS toxicity is drug/dose dependentClinical indicators of CNS toxicity

Kreitzer, Journal of Clinical Anesthesia, 1996

Dose Dependent Systemic Effects

Effects of Lidocaine by plasma concentration

CONC(mcg/mL) EFFECT 1–5 Analgesia 5–10 Lightheaded, Tinnitus, Tongue numbness 10–15 Seizure, LOC 15–25 Coma, resp arrest >25 CV depression

Barash, 5th pp464

Relative Potency for Toxicity (CVS:CNS) Toxicity

▪AGENT ▪RELATIVE POTENCY FOR CNS

TOXICITY

▪CVS:CNS

Bupivacaine 4 2L-bupivacaine 2.9 2Etidocaine 2 4.4Lidocaine 1 7.1Mepivacaine 1.4 7.1Ropivacaine 2.9 2

Barash, 5th edition pp462

LA Toxicity - CVS

Newer amino amide local anesthetics potential to cause CNS toxicityIndicators of CVS toxicityMechanism of toxicity

Albright, Anesthesiology,1979Clarkson, Anesthesiology, 1985

Seizure 30% smaller

dose for Bup than othersDysrhythmia

(a) Bup 13.2 mg/kg

(b) L-Bup 43.7mg/kg

(c) Rop 91.8 mg/kg

Shigeo, Anesth Analg 2001

EKG in CVS Toxicity

Kim, Canadian J of Anesthesia, 2003

Local Anesthetic Toxicity Topics

Local Anesthetic PharmacologyAdverse Reactions to Local AnestheticsTypes of ToxicityAcute Systemic Toxicity Management of Acute Systemic Toxicity

Early Options to Treat LA Toxicity

Epinephrine and AtropineShock, Shock, ShockOther ACLS MilrinoneVersed PropofolCPB

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

A FRESH IDEA

Lipid Emulsions expand the list of optionsA Decade of research and a growing body of evidence and case reportsThe Rescue Kit

Weinberg, LipidRescue.com, 2008

First To Benefit from Lipid Emulsion

Promising experiments with LA toxicity and Lipid Emulsion resuscitation Success leads to expanded research

Weinberg, Anesthesiology, 1998

Lipid Sink Hypothesis

Lipid infusionLipid phaseHighly lipophilic amino amidesDecreased unbound fraction

Weinberg, Anesthesiology, 1998

Group Treatment MAP mmHg

HR PaO2 PaCO2 pH

Saline Baseline 91 +/-12

122 +/-17

236 +/-69

36 +/-2

7.38 +/-.04

Saline Recovery 10 +/-3

ASYS

Lipid Baseline 96 +/-14

128 +/-21

228 +/- 63

35 +/-2

7.39 +/-.02

Lipid Recovery 93 +/-12

126 +/- 18

212 +/-56

36 +/-2

7.35 +/- .04

Studies with Lipid Emulsions in a Dog Model

Weinberg et al, Lipid emulsion infusion rescues dogs, 2003

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

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 unethicalNot 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

Applications of Intralipid in ED

Intralipid has been used to treat other types of drug overdoseCase studies are on the Lipidrerscue.org website.Same lipid sink idea

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

primum non nocere Risks of Lipid Emulsion Infusion: all < 1%

Modulation of cytokine production by WBCsAltered inflammatory responseWeakness, altered MS, seizures in childrenFat emboli if lipid particles >5 microns in diameterHyperlipedemiaPulmonary hypertension anaphylaxis especially if prepared from soybean oil (most likely adverse reaction with acute, short-term administration)

ReferencesArthur GR: Alterations in the pharmacokinetic properties of amide local anesthetics following local anesthetic induced convulsions. Acta Anaesthesiol Scand 32:522, 1988Barash P: Clinical Anesthesia, 5th edition, chapter 17, 2006 Clarkson C: Mechanism for bupivacaine depression of cardiac conduction: fast block of sodium channelsduring the action potential with slow recovery from block during diastole. Anesthesiology 1985;62:396-405.Colin J: Intravenous ropivacaine bolus is a reliable marker of intravascular injection in premedicated healthyVolunteers. Canadian Journal of Anesthesia50: 8 / pp 795–800, 2003Cotileas P: Bupivacaine-Induced Myocardial Depression and Pulmonary Edema: A Case Report. Journal of Electrocardiology Vol. 33 No. 3 2000 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 50:376-381 (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, 6th Edition, Chapter 14, 2005Mischa J: The effects of Age on Neural Blockade and Hemodynamic Changes After Epidural Anesthesia with Ropivacaine. International Anesthesia Research Society, 94(5): 1325-1330, 2002Morgan and Mikhail, 4th 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):564-575, 2004ScottD: EDITORIAL: “Maximum Recommended Doses” of Local Anesthetic Drugs. British Journal of Anesthesia Vol 63, No. 4, 1989.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. Regional Anesthesia and Pain Medicine, Vol 28, No 3 :198-202, 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 1071-1075 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):1578-1580, 2008 Yokoyama M: Effect of Vasoconstrictive Agents added to lidocaine on IV lidocaine-induced convulsions in rats. Anesthesiology 82:574,1995