Download 04 June 2015 - LAST Prevention and Treatment

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• CVS and CNS toxic side effects of LA are
relatively rare
• Potentially catastrophic complications of local
and RA.
• These reactions are in most cases readily
• We will review the risk factors, presentation,
and treatment of local anesthetic toxicity.
Mechanism of Local Anesthetic Toxicity
• In the plasma, all LAs are bound to proteins to
varying degrees, primarily to AAG and albumin.
• The long-duration LAs are bound by plasma proteins
to a greater extent than the less potent, shorter
duration LAs.
• Bupivacaine is ≈95% protein-bound.
• Intermediate-duration LAs have a smaller proteinbound fraction (60-70%).
• Protein binding helps to reduce the likelihood that
LAs in blood will enter brain or cardiac tissue causing
either CNS or cardiac toxicity
Mechanism of Local Anesthetic
Toxicity cont.
• LAs may bind a wide variety of channels and
enzymes in cardiac muscle and in the CNS.
• Lidocaine tends to produce vasodilation and
negative inotropy while rarely producing
• In contrast, bupivacaine has a greater
tendency to produce ventricular arrhythmias
in addition to vasodilation and negative
Routes for Entry of LA into the
Systemic Circulation
• There are three principal routes for entry of
local anesthetic into the blood:
1. Direct injection into an artery or vein
2. Absorption from a depot dose in other
tissues, and
3. Transcutaneous or transmucosal absorption.
Routes for Entry of LA into the
Systemic Circulation
Intravascular Injection
• Intravascular injection of LA agents is possible
with most RA techniques due to the proximity
of vascular structures to nervous tissue.
• E.g, accidental injection of LA into the epidural
venous plexus can occur when dosing an
epidural catheter, and injection into the
femoral artery or vein can occur during an
attempted femoral nerve block.
Routes for Entry of LA into the Systemic
Absorption from Tissues
• When LA is injected into perineural connective tissue
(as in a PNB) or the epidural space, the nerveblocking action is terminated by gradual absorption
from the nerve into the systemic circulation.
• Injecting a given dose of LA into highly vascular
tissue will lead to greater plasma drug
concentrations than placing the same dose of LA into
a poorly vascularized site.
• Epinephrine is effective in retarding the rate of
absorption of LA and reducing peak plasma levels of
Routes for Entry of LA into the
Systemic Circulation
Transcutaneous and Transmucosal Absorption
• LAs can be absorbed across cutaneous and
mucosal surfaces, most commonly in the oral,
nasal, and tracheo-bronchial mucosa
• Toxic blood concentrations are possible
following transcutaneous absorption of LA
creams or gels, particularly in small children.
Risk Factors for LA Toxicity
Route of Administration
• The location of LA injection affects its absorption
rate and peak plasma concentration.
• The LA dose may need to be reduced when it is
placed into an area with especially rapid
absorption, such as the airway or in intercostal
nerve blocks, as compared to sites with relatively
slow absorption, such as subcutaneous injections
or sciatic nerve blocks.
Risk Factors for LA Toxicity
Young Age
Infants have reduced concentrations of plasma
proteins to which LAs bind, such as AAG.
This leads to greater peak levels of free (unbound) LA
after single injections, such as caudal epidural blocks.
Infants also have a reduced capacity to metabolize LA
drugs, with lower plasma clearance rates than adults
This may lead to greater plasma levels when
continuous infusions of LAs are given.
Due to these factors, both bolus doses and infusion
rates of LAs should be reduced in infants
Risk Factors for LA Toxicity
Total Dose of LA Administered
• All other factors being equal, administering larger
doses of local anesthetic will lead to increased plasma
• Of note, it is the product of the concentration and the
volume of the local anesthetic solution that is
important, not either in isolation; plasma levels of local
anesthetic correlate with the total mass of drug given.
• For example, in most cases 20 ml of a 0.25%
ropivacaine solution and 10 ml of a 0.5% ropivacaine
solution will produce the same peak plasma
Risk Factors for LA Toxicity
Presence of Epinephrine
• Addition of epinephrine to LA solutions will
normally reduce the rate of absorption and
peak plasma levels.
• Epinephrine 1:400,000 to 1:200,000 is as
effective as more concentrated solutions,
while having a reduced risk of SEs such as
hypertension, tachycardia, and arrhythmias.
Risk Factors for LA Toxicity
Renal Dysfunction
• Patients with uremia have a hyperdynamic
circulatory state, and they have a more rapid
absorption of local anesthetic, with higher peak
plasma levels than in non-uremic patients.
• Partially offsetting this effect, uremic patients
have greater levels of AAG than non-uremic
• It is recommended that a dose reduction of 1020% be applied when administering LAs to
patients with renal dysfunction.
Risk Factors for LA Toxicity
Liver Dysfunction
Mild hepatic dysfunction appears to have a minimal effect
on LA levels.
In ESLD there is a significant reduced hepatic clearance
rates for LAs.
It is recommended that normal doses of LA may be used for
single-dose techniques in patients with liver dysfunction.
Continuous infusions must be significantly reduced in
patients with hepatic dysfunction due to their lower rate of
clearance of these drugs.
Dose reductions of 10-50% have been suggested based on
the severity of the hepatic dysfunction.
Risk Factors for LA Toxicity
Heart Failure
• Mild, well-controlled HF may not require any
reduction in local anesthetic dosing.
• In patients with severe heart failure, however,
clearance of local anesthetic drugs may be
substantially reduced due to decreased
hepatic blood flow and clearance.
Risk Factors for LA Toxicity
Pregnant patients have increased sensitivity to
LAs, allowing dose reductions.
They also have a reduced degree of protein
binding of LAs.
Because of the increased sensitivity and higher
risk of toxic effects, LA doses should be reduced
in pregnant patients.
Other factors, including the reduced spinal CSF
volume in pregnancy, lead to an exaggerated
spread of spinal and epidural local anesthetics.
Signs and Symptoms of LA Toxicity
CV Signs and Symptoms
• In general, cardiac signs of LA intoxication include:
 Transient hypertension and tachycardia (especially if
epinephrine is present)
 Hypotension
 Bradycardia
 Cardiac arrhythmias, including premature ventricular
contractions, ventricular tachycardia, ventricular
fibrillation, pulseless electrical activity, and cardiac
Signs and Symptoms of LA Toxicity
CNS Signs and Symptoms
After an accidental IV injection, LAs produce S&S of
CNS toxicity at lower doses and earlier than S&S of CV
However, the longer-acting LAs may produce toxicity in
the CNS and myocardium simultaneously, or CV toxicity
without any CNS SEs.
Early S&S: Perioral or tongue numbness or tingling,
altered or metallic taste sensation, lightheadedness or
vertigo, anxiety or panic, confusion, somnolence
Late s&s: Seizure activity (generally tonicclonic) ,
depressed LOC or coma, respiratory depression or
Treatment of Systemic LA Toxicity
• Rx for systemic LA toxicity should be guided by
the form of toxicity (CNS vs. CV vs. allergy) and
the LA agent used.
• In general, milder symptoms should be
treated with more conservative actions.
• Nevertheless, mild CNS symptoms may rapidly
progress into LA cardiotoxicity with
arrhythmias and cardiac arrest, and one
should frequently re-evaluate whether more
aggressive therapies are required.
Treatment of LA CNS Toxicity
• Mild-to-moderate S&S of LA toxicity (e.g.,
tinnitus, lightheadedness, tremulousness,
myoclonic jerks, or confusion) without seizure
activity or signs of cardiac toxicity, conservative
Rx (reassurance and mild sedation and anxiolysis
with benzodiazepines)
• Severe CNS S&S (Loss of consciousness or
seizures) standard resuscitation measures should
begin including ABCD.
• LA-induced seizures medications include
benzodiazepines, barbiturates, and propofol
Treatment of LA CV Toxicity:
• If unexplained ↓BP, ↓HR, or arrhythmias are
detected, Rx for suspected LACV toxicity should
begin without delay.
• Resuscitation may require prolonged and
extensive resuscitative efforts, particularly with
bupivacaine-induced toxicity, and may prove
• Rx may begin with standard ACLS methods, but
we recommend some minor changes to the
standard protocols
Treatment of LA CV Toxicity:
• We omit lidocaine from resuscitation due to its
potential to produce an additive effect with the
"intoxicating" LA agent.
• We suspect that amiodarone may be a better
choice for Rx of ventricular arrhythmias,
conclusive data are lacking
• Local anesthetic cardiac toxicity will often include
depressed contractility.
• One should avoid administering other negative
inotropes in LA CV toxicity which often include
depressed contractility.
Treatment of LA CV-toxicity: Lipid
• Infusion of a 20% lipid emulsion solution (such
as Intralipid™) appears to be an effective Rx
for severe LA cardiotoxicity.
• Boluses and short-term infusions of 20% lipid
emulsion have no important side effects.
• The mechanism by which 20% lipid emulsion
negates local anesthetic toxicity is not clear.
Treatment of LA Cardiotoxicity: CPB
• CV-toxicity associated with long-acting LA agents
toxicity can be quite refractory to standard ACLS
resuscitation methods.
• Resuscitation efforts may be prolonged, with some
patients potentially not responding to std drugs and
• When all other methods have failed, CPB for CP
support and to allow time for clearance of a
sufficient quantity of the LA from target tissues to
permit survival should be considered.
• There are case reports of successful resuscitations
using CPB after all other therapies have failed.