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

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

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

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

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 500-600mg for adults
Dapsone, antibiotics, nitrates, etc.
Methemoglobin related to local anesthetics, Guay et al, 2009

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

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

Diagnoss and Management of
Anaphylaxis, CMAJ, 2003

Diagnoss and Management of
Anaphylaxis, CMAJ, 2003

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

LOCALIZED TOXICITY
Neurotoxicity
Myotoxicity
SYSTEMIC TOXICITY
CNS toxicity
CVS toxicity

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

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

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

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

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, 5 th pp464

Relative Potency for Toxicity
▪AGENT
(CVS:CNS) Toxicity
▪RELATIVE ▪CVS:CNS
POTENCY
FOR CNS
TOXICITY
Bupivacaine 4 2
L-bupivacaine
Etidocaine
Lidocaine
Mepivacaine
Ropivacaine
Barash, 5 th edition pp462
2.9
2
1
1.4
2.9
2
4.4
7.1
7.1
2

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

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

Kim, Canadian J of Anesthesia, 2003

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

Epinephrine and
Atropine
Shock, Shock,
Shock
Other ACLS
Milrinone
Versed
Propofol
CPB

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

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

Promising experiments with LA toxicity and Lipid
Emulsion resuscitation
Success leads to expanded research
Weinberg, Anesthesiology, 1998

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

Group Treatment MAP mmHg
HR PaO2 PaCO2 pH
Saline
Saline
Baseline 91
+/-12
Recovery 10
+/-3
Lipid Baseline 96
+/-14
Lipid Recovery 93
+/-12
122
+/-17
ASYS
128
+/-21
126
+/- 18
236
+/-69
228
+/- 63
212
+/-56
36
+/-2
35
+/-2
36
+/-2
7.38
+/-.04
7.39
+/-.02
7.35
+/- .04
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

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

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

– 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

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)

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;62:396-405.
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: 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, 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): 1325-1330, 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):564-575, 2004
ScottD
: 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 Bupivacaineinduced 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.
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