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

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Local anestheticsystemic toxicity

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