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Toxicity of Local Anesthetics
A. Borgeat
Balgrist University Hospital, Zurich
Switzerland
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The fate of local anesthetics
Artery
Vein
97- 98%
LA
+/- 30%
Nerve
2-3%
Systemic resorption depends on local blood flow!
Heavner JE. Curr Opin Anaesthesiol 2007; 20:336-42. Review
Cox B et al. Best Pract Res Clin Anaesthesiol 2003; 17:111-36
Systemic Complications
Acute
CNS toxicity
Cardiotoxicity
CNS Toxicity
The key issue:
Understanding the physiopathology
Stage of CNS-Depression
Coma, Apnea, Depression, Hypotension
Convulsive Stage
General, tonic-clonic Seizures
Preconvulsive Stage
Tremor, Tinnitus, Nystagmus, clouding of
consciousness
First Stage
numbness, metalic flavour, dysgeusea
tachycardia
LA-Concentration
Systemic Toxicity - Clinical Symptoms
Regional anesthesia and seizures
(retrospective study)
Block
number
Caudal (adults)
Axillary
Interscalene
Supraclavicular
Epidural
1295
6620
659
253
16870
seizures
n (%)
9 (0.7)
8 (0.1)
5 (0.7)
2 (0.8)
2 (0.01)
Total incidence 0.1% (1/1000 blocks)
Brown et al.
Anesth Analg 1995;81:321,
Seizures after PNB
(prospective study)
Interscalene block
Supraclavicular block
Axillary block
Mid-humeral block
Psoas compartment block
Femoral block
Sciatic block
Popliteal block
Performed
Seizure
3‘459
1‘899
11‘024
7‘402
394
10‘309
8‘507
952
0
1
1
1
1
0
2
0
Auroy et al.
Anesthesiology 2002;97:1274,
Factors influencing CNS toxicity
• the concentration
• the speed of increase
„The higher the plasma level and
the faster it increases, the more
likely an adverse systemic response
is about to happen“.
• patient status (heart, liver, nutritional)
CNS Toxicity
LA concentration
(brain epilepsy)
threshold
time
Effect of pH and pCO2 on Toxicity
Alexander et al. Can J Anaesth 1987; 34:343,
Rendoing et al. Anesth Analg 1969;26,445,
Interaction Propofol - Remifentanil
I.V. ropi vs bupi 10 mg/min in volunteers: Mean
threshold plasma concentration for CNS toxicity
Arterial Plasma conc (mg/L)
Total
Free
Ropivacaine
4.3 (3.4-5.3)
0.55 (0.34-0.84)
Bupivacaine
4.0 (1.1-6.2)
0.30 (0.13-0.51)
Knudsen et al.
Br J Anaesth 1997;78:507
Is a recommended maximum
LA dose reliable ?
• No
• Site of injection
• Uncontrolled factors (quick reabsorption)
• Individual variations in PK/PD and
tolerability
instead: recommended effective dose,
be prepared for toxic reactions
Factors influencing toxicity
physico-chemical properties
local perfusion
vasoconstrictor adjuvants
chemical structure
intrinsic vasoactivity
cardio-vascular disease
liver disease
systemic absorption
renal dysfunction
„toxic“ dose of local anesthetics
injection site
protein binding
pregnancy
age
height and weight
individual pharmacodynamics
volume of distribution
metabolism/excretion
acidosis/temperature
drug interaction
Can we avoid intravascular injection
of LA ?
• IV injection is rare, except for deep block
• Slow administration
• Repeated aspiration
(cave deep block)
• Close verbal control with patient
• Watch out for progressive increase in
heart rate (with or without adrenaline)
CNS toxicity of LA
• Initial symptoms from organs with
large cortical representation
• Convulsion may be the first symptom
after IV (accidental) injection
– especially with bupivacaine -
Toxicity: when does it occur ?
Plasma concentration of total ropivacaine
Group 18mg/h
Group 12mg/h
mg/l
mg/l
Toxicity: when does it occur ?
Free fraction of ropivacaine
Group 12mg/h
%
Group 18mg/h
%
Toxicity: when does it occur ?
Plasma concentration of -1-glycoprotein
Group 12mg/h
mol/L
Group 18mg/h
mol/L
Booker et al
Br J Anaesth 1996;76:365,
male
female
Effect of age on the serum concentration of AAG
in 35 male and 33 female subjects
Veering et al.
Br J Clin Pharmac 1990;29:201,
CNS toxicity: Physiopathology
Normal
CNS activity
 LA
concentration
G
A
B
A
CNS toxicity: treatment
• Stop administration (if not too late!)
• Oxygen 100%
• Avoid acidosis
Therapy of systemic Toxicity
CNS depression  respiratory
depression
Acidosis pH;
pCO2 
cerebral
blood flow 
LA-H+
„ion trapping“
accumulation of LA
in the CNS
Plasma
protein-binding 
free [LA]  in
plasma
Alexander et al. Can J Anaesth 1987; 34:343,
Rendoing et al. Anesth Analg 1969;26,445,
CNS toxicity: treatment
• Stop administration (if not too late!)
• Oxygen 100%
• Avoid acidosis
• Anticonvulsant
CNS toxicity: treatment
• midazolam
• propofol
 CNS hyperexcitability successfully
blocked by both drugs
3.5 min
13.5 min
CNS Toxicity
• Systemic neurotoxicity can always
occur even in the best hands
• Treatment is usually easy and
successful
• Propofol possesses the best PK/PD
profile to treat (avoid) convulsion
Systemic toxicity of LA:
why the brain first ?
CNS
one system against another
cardiac
one or more receptors blocked
Cardiac Toxicity
The key issue:
Understanding the physiopathology
Cardiotoxicity
The most serious issue
when dealing with
local anesthetics
Systemic Toxicity - Clinical Symptoms
Stage of CNS-Depression
Coma, Apnea, Depression, Hypotension
Convulsive Stage
General, tonic-clonic Seizures
Preconvulsive Stage
Tremor, Tinnitus, Nystagmus, clouding of
consciousness
First Stage
numbness, metalic flavour, dysgeusea
tachycardia
LA-Concentration
direct cardiac depression
cardiac arrest
hypotension
ischemia
AV-dissociation
arrhythmia, bradycardia
ECG-widening
low output
indirect cardiac depression
hypertension, tachycardia, arrhythmia
Cardiotoxicity of local anesthetics
ADP
ATP
Sodium
Channel
Mitochondria
Calcium
Channel
Potassium
Channel
Local anesthetics :
physiochemical properties
Lidocaine
Mepivacaine
Bupivacaine
Levobupivacaine
Ropivacaine
pKa
Lipid
solubility
Protein
binding
7.8
7.7
2.9
0.8
64 %
77 %
8.1
27
95 %
8.1
14
94 %
Cardiotoxicity of LA :
effect on sodium channel
Affinity for Na+
channels
Lidoc
Ropiv
Bupiv
Fast in
Fast out
Fast in
Intermediate
out
Fast in
Slow out
1.4
1.9
10
5
Time constant for
recovery from Na+ 0.19
channel block (sec)
Arrhythmia threshold
(mmol/kg)
20
Reiz et al.
Acta Anaesth Scand 1989;33:93,
Cardiotoxicity of LA : effects on ATP
% Inhibition
100
*
40
0
Bupi
3mM
P < 0.05
Ropi
3mM
Sztark et al.
Anesthesiology 1998;88:1340,
cumulative doses (mg/kg)
Systemic Toxicity (Rat Model)
Bupivacaine
Levobupivacaine
Ropivacaine
~1:2
* p<0.05 vs. Bupivacaine
+ p<0.05 vs. Levobupivacaine
seizure
arrhythmia
asystolia
Ohmura S, et al.;
Anesth Analg 2001; 93:743-8
Systemic Toxicity (Rat Model)
Bupivacaine
n=11
Levobupivacaine
n=10
Ropivacaine*
n=11
Ohmura S, et al.;
Anesth Analg 2001; 93:743-8
Cardiotoxicity of LA : outcome
after cardiovascular collapse
%
Bupivacaine
Levo-Bupivacaine
50
Ropivacaine
Lidocaine
30
10
1
Groban et al.
Anesth Analg 2001;92:37
Cardiotoxicity of local anesthetics
g/ml
6.8
(C)
g/ml
4.0
1.6
2.2
6.3
4.2
3.1
L
R
LB
3.2
B
g/ml
5.8
L
5.0
3.3
L
R
LB
R
LB
B
3.6
B
Groban et al.
Reg Anesth Pain M 2002;27:460,
Cardiotoxicity: treatment
ropivacaine:
7 cases successfully treated with low
dose of epinephrine
bupivacaine:
mortality still around
5-10%
levobupivacaine: ?
Physiochemical properties of LA
implicated in cardiotoxicity
• lipid solubility
• size of the lateral chain
• stereoselectivity
Influence of stereoselectivity on cardiac toxicity
Mechanism
Effect
Remark
Affinity for the
Na+ channels
YesDecreased affinity
Arrhythmogenic
potential
Yes/No
Other mechanisms than
inhibition of conduction are
also implicated
Myocardial depression No
Lipid solubility and size of
the molecule are mainly
implicated
Mitochondrial energy
metabolism
No
Lipid solubility
is mainly implicated
Calcium homeostasis
No
Lipid solubility is mainly
implicated
Cardiotoxicity: treatment
• CV resuscitation
• Epinephrine
• Intralipid (bupivacaine)
Lipids for Local Anesthetics
Has the Silver Bullet been Identified?
Anaesthesia 2006;61:800,
RAPM 2008;33:178,
Anaesthesia 2007;62:516,
Dillane D et al. Can J Anesth 2010; 57:368-80
Recovery time after asystolia (sec)
Lipid-Studies on the isolated Heart
(n=5)
(n=5)
(n=5)
(n=5)
(n=5)
(n=5)
90% recovery
of heart rate
90% recovery
of cardiac product
Zausig Y, et al.
Anesth Analg 2009;109:1323
Lipid-Studies on the isolated Heart
no significant differences regarding starting points
•
prophylactic substitution of lipids:
significant duration till cardiac arrest for bupivacaine
no significant differences for ropivacaine and mepivacaine
Duration till cardiac arrest
[sec]
•
Lipidrescu® = lipid-sinks
time till cardiac arrest in sec
* p <0,05.
Zausig Y et. al.
German Anaesthesia Meeting 2010
Protocol:
Isolated rat hearts were perfused with or without intralipid
before administration of bupivacaine or mepivacaine
*p<0.05
Aumeier et al
Br J Anaesth 2013;112:735,
Protocol:
Newborn piglets received levobupivacaine until CV collapse
- Saline
- Intralipid alone
- Epinephrine alone
- Intralipid + epinephrine
De Queiroz et al
Br J Anaesth 2014;112:729,
Protocol: Infusion of bupivacaine till drop of blood pressure >50% of the initial value
epinephrine 3 ug/kg
intralipid 20% 2 ml/kg
intralipid 20% 4 ml/kg
Mauch J et al.
Paed Anaesth 2011; 21:1103,
Notably, ILE has been used effectively in treating overdose of many common prescription
medications (e.g. beta blockers, tricyclic antidepressants or calcium channel blockers) that
can be highly resistant to standard resuscitation measures. Identifying the precise
mechanism(s) underlying ILE holds the promise of improving its efficacy and providing an
effective, generic antidotal treatment for a range of life-threatening toxic drug overdoses.
However, the precise mechanisms of ILE are not well understood. The conventional
explanation involves partitioning of the offending toxin into the newly created lipemic
plasma phase, or 'lipid sink'. However, even this mechanism has not been tested rigorously
in vivo. Moreover, we have observed that key aspects of ILE cannot be explained by the
sink alone, indicating that other, less well-understood, mechanisms are also at play. We
believe that ILE also directly benefits cardiovascular function and have confirmed in
preliminary experiments that the infusion of lipid emulsion in the intact rat exerts positive
effecs on cardiac contractility and aortic blood flow. We hypothesize that this results in part
from direc, positive effects of fatty acid metabolism on cardiac function. Moreover, it is wellestablished tha tissue ischemia can cause intercellular endothelial gaps to expand, thereby
allowing liposomes to migrate into the myocardial interstitium. Such passive targeting of
lipid particles, essentially nano-medicine, will bypass the normal tissue barriers to diffusion
of drug away from cells and diminish the response time to lipid signal effectors. We
hypothesize that extravascular migration of lipid particles contributes to the overall efficacy
of ILE in reversing cardiac drug toxicity. W propose studies to test the metabolic effects of
ILE and transendothelial migration of lipid particles. Finally, we seek to improve the
translation of ILE to cocaine-related toxicity and longer-lasting overdoses such as calcium
channel blocker toxicity. Improved patient safety and outcomes from drug toxicity are the
over-arching goals of this project.
However, the precise mechanisms
of ILE are not well understood
Weinberg et al
National Inst of Health, 2015, abstract
Adverse Reactions of intralipid
1. Those more frequently encountered are due either to a) contamination of
the intravenous catheter and result in sepsis, or to b) vein irritation by
concurrently infused hypertonic solutions and may result in
thrombophlebitis. These adverse reactions are inseparable from the
hyperalimentation procedure with or without Intralipid®.
2. Less frequent reactions more directly related to Intralipid® are: a)
immediate or early adverse reactions, each of which has been reported to
occur in clinical trials, in an incidence of less than 1%: dyspnea, cyanosis,
allergic reactions, hyperlipemia, hypercoagulability, nausea, vomiting,
headache, flushing, increase in temperature, sweating, sleepiness, pain in
the chest and back, slight pressure over the eyes, dizziness, and irritation
at the site of infusion, and, rarely, thrombocytopenia in neonates; b)
delayed adverse reactions such as hepatomegaly, jaundice due to central
lobular cholestasis, splenomegaly, thrombocytopenia, leukopenia,
transient increases in liver function tests, and overloading syndrome (focal
seizures, fever, leukocytosis, hepatomegaly, splenomegaly and shock).
The deposition of a brown pigmentation in the reticuloendothelial system, the
so-called “intravenous fat pigment,” has been reported in patients infused with
Intralipid®. The causes and significance of this phenomenon are unknown.
Retrospective chart review in two academic medical
centers in the USA between 2005 and 2012
A total of nine patients were treated
Levine et al
J Med Toxicol 2014;10:10,
Lipid-Infusion
The Association of Anaesthetists of Great Britain & Ireland 2010
the Silver Bullet only
for lipophilic drugs!
Conclusions
„Poison in the hand of an expert is medicine,
medicine in the hand of a fool is poison
Giacomo Girolamo Casanova (1725-1798),