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Local anesthetic systemic toxicity

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LA in CNS can have CV results. Interfere with resuscitation ... LA blood concentrations producing cardiac arrest in dogs: similar rank order as for potency ... – PowerPoint PPT presentation

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Title: Local anesthetic systemic toxicity


1
Local anestheticsystemic toxicity
  • John Butterworth, MD
  • Professor Head
  • Section on Cardiothoracic Anesthesiology
  • Wake Forest University School of Medicine
  • Winston-Salem, North Carolina

2
Local anestheticsystemic toxicity
  • History
  • Mechanisms
  • Patterns of LA toxicity
  • Summary

3
Early reports of LA mortality
  • AMA committee reviews 57 deaths from LAs Mayer
    et al JAMA 192482876-85 JAMA 1928901290-1
  • 3 deaths after 22,351 gastroscopies attributed to
    cocaine or tetracaine Schindler Am J Dig Dis
    19407293
  • 7 deaths in 39,278 uses of cocaine or tetracaine
    in North American otolaryngology clinics Ireland
    et al Laryngoscope 195161767-77

4
FDA and systemic toxicity from LAs
  • Cardiac arrest without prior CNS toxicity
    bupivacaine etidocaine (Albright, 1979)
  • Black box warning in package insert
  • Bupivacaine 1983
  • No black box warning
  • Ropivacaine 1997
  • Levobupivacaine 1999)

Horlocker Wedel. Reg Anesth Pain Med
200227562-7
5
Local anestheticsystemic toxicity
  • History
  • Mechanisms
  • Patterns of LA toxicity
  • Summary

6
LAs bind and inhibit many differing receptors and
channels
  • Channels
  • Na

Control
  • Control

QX222 0.5 mM
QX222
Anesthesiology 1990 72711-34
Hanck et al. J Gen Physiol 199410319-43
7
LAs bind and inhibit many differing receptors and
channels
  • Channels
  • Na
  • Ca (multiple types)
  • K

Ca oscillations in rat neonatal cardiomyocytes McC
aslin. Anesth Analg 2000 9182-8
8
LAs bind and inhibit many differing receptors and
channels
  • Channels
  • Na
  • Ca (multiple types)
  • K

Anesthesiology 1990 72711-34
9
LAs bind and inhibit many differing receptors and
channels
  • Channels
  • Na
  • Ca
  • K
  • Enzymes
  • Adenylyl cyclase

Anesthesiology 19937988-95
10
LAs bind and inhibit many differing receptors and
channels
  • Channels
  • Na
  • Ca (multiple types)
  • K
  • Enzymes
  • Adenylyl cyclase
  • Guanylyl cyclase
  • Lipases

Anesthesiology 1990 72711-34
11
LAs bind and inhibit many differing receptors and
channels
  • Channels
  • Na
  • Ca (multiple types)
  • K
  • Enzymes
  • Adenylyl cyclase
  • Guanylyl cyclase
  • Lipases
  • Receptors
  • Nicotinic acetylcholine
  • NMDA
  • ß2-adrenergic

Anesthesiology 1990 72711-34
12
LAs bind and inhibit many differing receptors and
channels
  • Channels
  • Na
  • Ca (multiple types)
  • K
  • Enzymes
  • Adenylyl cyclase
  • Guanylyl cyclase
  • Lipases
  • Receptors
  • Nicotinic acetylcholine
  • NMDA
  • ß2-adrenergic
  • Important for spinal, epidural, or systemic
    effects?

Anesthesiology 1990 72711-34
13
LAs bind and inhibit many differing receptors and
channels
  • Do not assume LA toxic side effects arise from Na
    channel inhibition!

Anesthesiology 1990 72711-34
14
Local anestheticsystemic toxicity
  • History
  • Mechanisms
  • Patterns of LA toxicity
  • Summary

15
Patterns of LA toxicity
  • CV system
  • CNS
  • Allergy
  • Treatment

16
Multiple LA actions on the cardiovascular system
  • Electrophysiologic
  • Bupivacaine vs. lidocaine faster binding,
    delayed unbinding from cardiac Na channels
  • Antiarrhythmic and proarrhythmic effects
  • Inhibit conduction system
  • Negative inotropic
  • Vascular
  • Vasoconstrict (low concentrations)
  • Vasodilate (high concentrations)
  • LA in CNS can have CV results
  • Interfere with resuscitation

17
LA blood concentrations producing cardiac arrest
in dogs similar rank order as for potency
µg/mL
Groban et al Anesth Analg 2000911103-11
18
Ventricular arrhythmias after supraconvulsant
(2x) doses of LAs
N
Feldman et al Anesth Analg 198969794-801
19
LA infusions, cardiac arrest resuscitation in
dogs
  • More inducible arrhythmias with B, LB than R, Li
  • More epi-induced VF (EpVF) death with B than R
    or Li
  • Continued epi often needed for Li (86) after
    arrest rarely with B

of animals
Groban. Anesth Analg 2000911103 Anesth Analg
20019237 RAPM 200227460
20
Bupivacaine more toxic thanlevo or ropivacaine
in rats
  • Rats infused LA at 2 mg/kg/min
  • Asystole treated with epi .01 mg/kg CPR
  • Resuscitation success SAP gt100 mmHg
  • B more potent than LB or R at sz, arr, asystole
  • Less epi needed for ropiv than bup or levo

Cumulative dose mg/kg
Ohmura. Anesth Analg 200193743-8
21
Is there one common mechanism for LA-induced
cardiac death?
  • Arrhythmias (bupivacaine)?
  • Left-ventricular depression (lidocaine)?
  • Resuscitation drug failure (bupivacaine)?
  • Mechanism probably depends on specific drug!

22
CNS toxicity from LAs
  • Progression of signs symptoms with ?LA
  • Vertigo
  • Tinnitus
  • Ominous feelings
  • Circumoral numbness
  • Garrulousness
  • Tremors
  • Myoclonic jerks
  • Convulsions
  • CNS depression
  • Convulsive LA dose inversely related to LA
    potency
  • Acidosis, hypercarbia ? convulsive dose
  • Pregnancy lowers dose but not concentration
    producing convulsions
  • CV toxicity requires greater LA doses and
    concentrations than CNS toxicity

23
CNS toxicity from LAs
  • Progression of signs symptoms with ?LA
  • Vertigo
  • Tinnitus
  • Ominous feelings
  • Circumoral numbness
  • Garrulousness
  • Tremors
  • Myoclonic jerks
  • Convulsions
  • CNS depression
  • Convulsive LA dose inversely related to LA
    potency
  • Acidosis, hypercarbia ? convulsive dose
  • Pregnancy lowers dose but not concentration
    producing convulsions
  • CV toxicity requires greater LA doses and
    concentrations than CNS toxicity

24
LA doses and blood concentrations producing
convulsions in sheep similar rank order as for
potency
Rutten. Anesth Analg 198969291-9
25
Allergy to LAs
  • Common misdiagnosis after accidental IV
    injections
  • True allergy more common with esters
    (particularly those related to PABA) than amides
  • Avoid PABA in sunscreens
  • Possible cross reaction between PABA and
    methylparaben (preservative in some amide LAs)

26
None of 90 patients referred for LA reactions
have allergy!
  • 0 of 90 reacted to 1100 LA dilutions!
  • Few respond to undiluted LA even among 14
    referred after anaphylactoid reactions
  • Thus, almost no patients had real LA allergy


1100 Undiluted
deShazo. J All Clin Immunol 197963387-94
27
Treatment of local anesthetic toxicity
  • Apparent allergy
  • Steroids
  • Histamine (H1) blockers
  • With severe reactions
  • Intravenous fluid
  • Epinephrine
  • CNS toxicity
  • Dont treat minor reactions
  • Seizures maintain airway, provide O2
  • Terminate seizure with thiopental, midazolam, or
    propofol
  • Intubate patients with full stomachs

28
Treatment of local anesthetic toxicity
  • Apparent allergy
  • Steroids
  • Histamine (H1) blockers
  • With severe reactions
  • Intravenous fluid
  • Epinephrine
  • CNS toxicity
  • Dont treat minor reactions
  • Seizures maintain airway, provide O2
  • Terminate seizure with thiopental, midazolam, or
    propofol
  • Intubate patients with full stomachs

29
Treatment of LA CV toxicity
  • Follow ACLS guidelines
  • Substitute amiodarone for lidocaine
  • Substitute vasopressin for epinephrine
  • Consider cardiopulmonary bypass or lipid infusion
    if standard drugs fail

30
Lipid emulsion counteracts bupivacaine cardiac
toxicity
  • Lipid pretreatment with increases toxic dose of
    bupivacaine
  • Animals not resuscitated using ACLS recovered
    when given lipid emulsion
  • Lipid may draw bupivacaine into plasma from
    binding site(s) in the heart
  • No human data

Weinberg. Anesthesiology 1998881071-5 Weinberg.
Reg Anesth Pain Med 200328198-202
31
Lipid emulsion vs. saline after bupivacaine in
rats
CPR
BUPI 15 mg/kg
CPR
CPR
Weinberg. Reg Anesth Pain Med 200227568-75
32
Lipid emulsion vs. saline after bupivacaine in
rats
BUPI 15 mg/kg
LIPID BOLUS
Weinberg. Reg Anesth Pain Med 200227568-75
33
Lipid emulsion counteracts bupivacaine cardiac
toxicity
  • Lipid pretreatment with increases toxic dose of
    bupivacaine
  • Animals not resuscitated using ACLS recovered
    when given lipid emulsion
  • Lipid may draw bupivacaine into plasma from
    binding site(s) in the heart
  • No human data

Weinberg. Anesthesiology 1998881071-5 Weinberg.
Reg Anesth Pain Med 200328198-202
34
Local anestheticsystemic toxicity
  • History
  • Mechanisms
  • Patterns of LA toxicity
  • Summary

35
Summary
  • LAs are not discriminating in selecting binding
    sites
  • CV toxicity
  • Electrophysiology vs inotropy
  • Specific agent
  • CNS toxicity
  • Allergy a rare event
  • Resuscitation we await the first reported use of
    lipid for resuscitation of a human

36
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37
Local anestheticsystemic toxicity
  • John Butterworth, MD
  • Professor Head
  • Section on Cardiothoracic Anesthesiology
  • Wake Forest University School of Medicine
  • Winston-Salem, North Carolina
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