Transcript Management of Local Anesthetic Toxicity

Local Anesthetics
Toxicity and Management
Gregory Pate, MD
Department of Anesthesia
Bremerton Naval Hospital
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,
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
Anesthetics
Types of Toxicity
Acute 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 Pharmacology
Adverse Reactions to Local Anesthestics
Types of Toxicity
Acute Systemic Toxicity
Management of Acute Systemic Toxicity
Types of Local Anesthetic Toxicity
LOCALIZED TOXICITY
Neurotoxicity
Myotoxicity
SYSTEMIC TOXICITY
CNS toxicity
CVS toxicity
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
Myotoxicity
Edema 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 Pharmacology
Adverse Reactions to Local Anesthetics
Types 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)
1–5
5–10
10–15
15–25
>25
Barash, 5th pp464
EFFECT
Analgesia
Lightheaded, Tinnitus,
Tongue numbness
Seizure, LOC
Coma, resp arrest
CV depression
Relative Potency for Toxicity
(CVS:CNS) Toxicity
▪AGENT
Bupivacaine
L-bupivacaine
Etidocaine
Lidocaine
Mepivacaine
Ropivacaine
Barash, 5th edition pp462
▪RELATIVE
POTENCY
FOR CNS
TOXICITY
▪CVS:CNS
4
2.9
2
1
1.4
2.9
2
2
4.4
7.1
7.1
2
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 Pharmacology
Adverse Reactions to Local Anesthetics
Types of Toxicity
Acute 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
Studies with Lipid Emulsions
in a Dog Model
Group
Treatment MAP
mmHg
HR
Saline
Baseline
122
236
+/-17 +/-69
ASYS
36
+/-2
7.38
128
+/-21
126
+/- 18
35
+/-2
36
+/-2
7.39
91
+/-12
Saline Recovery 10
+/-3
Lipid Baseline 96
+/-14
Lipid Recovery 93
+/-12
PaO2
228
+/- 63
212
+/-56
Weinberg et al, Lipid emulsion infusion rescues dogs, 2003
PaCO2 pH
+/-.04
+/-.02
7.35
+/- .04
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 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)
References
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induced convulsions. Acta Anaesthesiol Scand 32:522, 1988
Barash P: Clinical Anesthesia, 5th 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
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Morgan and Mikhail, 4th edition, Chapter 14, 2006
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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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