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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 anesthetic
Modulated receptor theory
Other possible mechanisms of action
Miller’s Anesthesia, 6th edition
Local Anesthetic Toxicity Topics
Local Anesthetic Pharmacology
Adverse Reactions to Local AnestheticsTypes of ToxicityAcute Systemic Toxicity Management of Acute Systemic Toxicity
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 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 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
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
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 TOXICITY
Neurotoxicity
Myotoxicity
SYSTEMIC TOXICITY
CNS toxicity
CVS toxicity
NeurotoxicityDose/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
MyotoxicityEdema and necrosis after exposure to Lidocaine
Normally limited and reversible
Often reported in Ophthalmology
Zink et al., 2005
Prevention of LA toxicity
Dosing is a key factor in prevention
Review Therapeutic Index
Local Anesthetic Toxicity Topics
Local Anesthetic PharmacologyAdverse Reactions to Local AnestheticsTypes of Toxicity
Acute Systemic Toxicity Management of Acute Systemic Toxicity
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
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 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
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 Atropine
Shock, Shock, Shock
Other ACLS
Milrinone
Versed
Propofol
CPB
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 options
A Decade of research and a growing body of evidence and case reports
The 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 infusion
Lipid phase
Highly lipophilic amino amides
Decreased 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 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
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
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)
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