REGIONAL ANAESTHESIA

Systemic toxic effects of Learning objectives

local anaesthetics After reading this article, you should:
Christina Beecroft C be able to recognize the early signs and symptoms of local
anaesthetic toxicity
Gillian Davies C understand how to reduce systemic local anaesthetic
absorption
C have knowledge of the recommended management of severe
Abstract local anaesthetic toxicity and be aware of lipid-rescue
Systemic toxicity from local anaesthetic agent use is a rare, but potentially guidelines.
life-threatening, complication. It most commonly occurs with inadvertent
intravascular injection. High plasma levels of local anaesthetic lead to
central nervous system and cardiovascular toxicity. Treatment of toxicity
Factors affecting toxicity
is mainly supportive; however, there is now evidence for the use of
lipid emulsions in the management of severe local anaesthetic toxicity. The most common causes of systemic toxicity are direct
intravascular injection and delayed absorption from a tissue
Keywords Bupivacaine; levobupivacaine; lidocaine; lipid emulsion; depot of drug. The recent National Audit Project Report of the
toxicity Royal College of Anaesthetists reported six cases where local
anaesthetic intended for epidural infusion was administered
intravenously. In five of these six cases, the infusion was
connected by a non-anaesthetist,1 highlighting the impor-
tance of education and vigilance for all staff involved. Other
factors affecting plasma concentration of the drug after
Local anaesthetic agents produce a reversible block of the injection are dependent on the administered dose, the rate of
transmission of peripheral nerve impulses, causing a temporary absorption, distribution to other tissues and the rate of
loss of sensation in a specific area of the body. Systemic toxicity metabolism.
from local anaesthetic injection is a rare, but potentially life-
threatening, risk of its use. Absorption
Absorption from the site of injection will be more rapid in
Mechanism of action of local anaesthetic agents vascular areas, causing a more rapid increase in plasma
concentration (Figure 1). The addition of vasoconstrictors,
Local anaesthetics block membrane depolarization in all excit-
commonly epinephrine, to the local anaesthetic solution
able tissues. The drugs have both hydrophilic and hydrophobic
decreases absorption and enables the use of higher doses.
properties and, as a result, cross cell membranes quickly in their
Intravenous regional anaesthesia can prove fatal if the tourniquet
unionized form. They then dissociate into the ionized, active
is deflated before sufficient drug has diffused from the vascular
form before interacting with voltage-gated sodium channels,
system to become fixed in the tissues. Additionally, failure of the
blocking them to reduce inward sodium current and prevent
tourniquet can result in a large dose rapidly entering the systemic
depolarization. As well as sodium channels, local anaesthetics
circulation, causing toxicity.
bind ligand-gated channels and other proteins in the cytosol and
cell or organelle membranes.

Mechanism of toxicity of local anaesthetic agents Rate of absorption of local anaesthetic from site
Toxicity results if significant amounts of local anaesthetic drug of injection
reach other electrically active tissues, such as that found in
cardiac muscle and the central nervous system. In these tissues,
local anaesthetics produce the same membrane-stabilizing effects
Intercostal
as on peripheral nerves, resulting in progressive depression of
function. Caudal
Epidural
Highest
Brachial plexus
systemic
Christina Beecroft FRCA FDS RCS is a locum Consultant Anaesthetist at Spinal concentrations
Ninewells Hospital, and Medical School, Dundee, UK. Her main interest Subcutaneous
is regional anaesthesia and she has completed a six-month training
fellowship in this specialty. Conflicts of interest: none declared. Lowest systemic
concentrations
Gillian Davies FRCA is a Specialty Registrar in Anaesthesia at Ninewells
Hospital, Dundee, UK. Conflicts of interest: none declared. Figure 1

ANAESTHESIA AND INTENSIVE CARE MEDICINE 11:3 98 2010 Elsevier Ltd. All rights reserved.
 REGIONAL ANAESTHESIA

Distribution translocase by mass action.3 However, it may simply act as

Local anaesthetics are distributed to and absorbed by organs with a circulating lipid sink, drawing local anaesthetic out of the plasma.
a high blood supply, such as the heart, brain, lungs and liver. Tissue
with a low blood supply, for example muscle and fat, equilibrate Prevention of toxicity
more slowly. Adipose tissue has a high affinity for local
Awareness of the risk and subsequent development of toxicity
anaesthetics.
when using local anaesthetic agents is crucial. Avoidance of
Metabolism accidental intravascular injection is an important factor in the
The esters, with the exception of cocaine, are hydrolysed rapidly prevention of toxicity; careful aspiration is essential before and
by plasma cholinesterases, resulting in a short elimination half- during injection, and whenever the needle is moved. Aspiration
life. Amides are metabolized in the liver by amidases, a much should be performed gently to avoid collapsing small vessels.
slower process. Reduced hepatic blood flow or hepatic dysfunc- However, negative aspiration is not an absolute guarantee, and
tion can lead to decreased amide metabolism. vigilance should be maintained during and after injection. The
use of ultrasound-guided nerve block insertion may also reduce
Features of systemic toxicity the risk as blood vessels can be visualized and avoided. The local
anaesthetic should be injected slowly whilst closely observing
Toxicity results from a high plasma concentration of local and questioning the patient. Larger volumes of solution are
anaesthetic agent. Acidosis, hypoxia and hypercarbia all poten- divided into 5 ml aliquots with aspiration between each.
tiate the sequelae of local anaesthetic toxicity. Epinephrine added to the local anaesthetic solution will produce
an increase in heart rate if injected intravascularly. However, this
Central nervous system toxicity does not guarantee against subsequent needle or catheter
Local anaesthetics cross the bloodebrain barrier rapidly, and migration. A sound working knowledge of local anatomy is
produce a biphasic effect on the central nervous system. Initially, required to minimize intravascular needle placement, and
excitatory phenomena develop, due to depression of the cortical caution taken in areas where a small intravascular dose of
inhibitory pathways. This manifests as peri-oral tingling and solution can produce major effects such as carotid or vertebral
numbness, tinnitus, dizziness, tremors, visual disturbance, and artery puncture with blocks of the head and neck. Recommended
confusion, progressing to grand-mal convulsions. This phase of maximum doses for local anaesthetic agents as quoted by
excitation is then followed by central nervous system depression manufacturer data sheets should be followed (Table 1). As stated
leading to coma and respiratory arrest. However, there may be earlier, the site of administration of the injection is equally
no early signs, with convulsions and subsequent cardiac arrest important with regards to tissue vascularity, and hence absorp-
the first indications of toxicity. tion of local anaesthetic.
There are advantages in using the enantio-pure preparation of
Cardiac toxicity
local anaesthetic agent, and both bupivacaine and ropivacaine
Cardiac toxicity is related to the action of local anaesthetics on the
are available as enantio-pure preparations. Levobupivacaine has
cardiac action potential, and their membrane-stabilizing effects.
two important advantageous properties over racemic bupivi-
Local anaesthetics block cardiac sodium channels and decrease
caine2: (1) the dose required to produce myocardial depression is
the maximum rise of Phase 0 of the cardiac action potential leading
higher with levobupivacaine, (2) and convulsions are triggered at
to a serious, evolving cardiac conduction defect. Electrocardio-
higher doses. Ropivacaine, available as the S-enantiomer only,
graph (ECG) changes include prolonged PR and QRS intervals and
has an improved toxicity profile when compared to bupivacaine.4
a prolonged refractory period. Bupivacaine dissociates much more
Potential disadvantages include slower onset of action, shorter
slowly2 than lidocaine from sodium channels, accounting for its
duration and lower potency compared with equivalent doses of
greater cardiac toxicity, with decreased automaticity and, poten-
bupivacaine.4
tially, tachyarrhythymias. The effect on sodium channels is
stereospecific; the sinister or levo () stereoisomer of bupivacaine
Management of local anaesthetic toxicity
has a lower binding affinity than the rectus or dextro () stereo-
isomer. This accounts for the improved safety profile of levobu- The management of local anaesthetic toxicity is mainly
pivacaine and ropivacaine (ropivacaine is in the form of the S- supportive, and is summarized in Box 1.
enantiomer only). Local anaesthetics also have a non-selective
action on calcium and potassium channels, reducing current
amplitude. Maximum recommended doses of local anaesthetics in
As well as ion-channels, one carrier protein in the heart of mg/kg
particular importance is carnitine acylcarnitine translocase. This
protein has a predilection for fatty acids, ketone bodies and lactate, Plain solution Solution with epinephrine
and the translocase contributes to the passage of the acyl CoA Lidocaine 3 7
constituents of the longer fatty acids across the mitochondrial Prilocaine 6 9
membrane to the site of their oxidation. If inhibited by local Bupivacaine 2 2.5
anaesthetics then fatty acids will not be fully oxidized, and the Levobupivacaine 2.5e3 2.5e3
hearts adenosine triphosphate supply will become exhausted. Ropivacaine 3e4 3e4
Reversal of this mechanism may be the basis of lipid-rescue therapy;
the fat from the lipid rescue overwhelms the inhibition of the Table 1

ANAESTHESIA AND INTENSIVE CARE MEDICINE 11:3 99 2010 Elsevier Ltd. All rights reserved.
 REGIONAL ANAESTHESIA

Lipid rescue
Treatment of local anaesthetic toxicity Early animal work by Weinberg et al.5,6 highlighted the role of
lipid emulsion in the management of severe local anaesthetic
C Injection or infusion of the local anaesthetic agent should be toxicity. As large trials of this treatment are impossible, the
stopped immediately. evidence for use both in the peri-arrest and cardiac arrest
C If the patient is showing mild symptoms, they should be situation is largely based on case reports, but these have so far
reassured and continuously monitored until they improve. been very encouraging.7e9 Guidelines for the management of
Preparations should be made in case the toxicity progresses. severe local anaesthetic toxicity and treatment with lipid
C Adequate oxygenation and ventilation should be maintained, and emulsion have been produced by The Association of Anaes-
respiratory acidosis avoided, as this will potentiate the toxicity. thetists of Great Britain and Ireland (AAGBI). Suggested doses,
C Adequate intravascular volume should be maintained; vaso- taken from the guideline, are provided in Box 2. Cardiopul-
pressors and/or vagolytics may be required. monary resuscitation should be continued throughout treat-
C If the conscious level is deteriorating or convulsions develop, ment with lipid emulsion, and recovery from local anaesthetic
the patient will require maintenance of the airway; this may induced cardiac arrest may take over 1 hour. The AAGBI
necessitate tracheal intubation. 100% oxygen should be suggests that Intralipid 20% 1000 ml should be immediately
administered and adequate ventilation ensured. available in all areas where potentially cardiotoxic doses of
C For convulsant activity thiopental, propofol or a benzodiaze- local anaesthetics are used. A
pine can be administered in small incremental doses. Suxa-
methonium may be required to facilitate tracheal intubation
and secure the airway.
REFERENCES
C For cardiac arrest associated with local anaesthetic toxicity,
1 Major complications of central neuraxial block in the United Kingdom;
cardiopulmonary resuscitation should be commenced using stan-
The 3rd National Audit Project of the Royal College of Anaesthetists,
dard protocols. Cardiac arrhythmias should be managed according
January 2009.
to standard protocols, but they may be refractory to conventional
2 Peck TE, Hill SA, Williams M. Pharmacology for anaesthesia and
treatment. Consideration should be given to cardiopulmonary
intensive care. 2nd edn. Cambridge University Press, 2006.
bypass, if available, or treatment with lipid emulsion.
3 Picard J, Meek T. Lipid emulsion to treat overdose of local anaesthetic:
the gift of the glob. Anaesthesia 2006; 61: 107e9.
Box 1 4 McClure JH. Ropivacaine. Br J Anaesth 1996; 76: 300e7.
5 Weinberg GL, VadeBoncouer T, Ramaraju GA, Garcia-Amaro MF,
Cwik MJ. Pretreatment or resuscitation with a lipid infusion shifts the
The Association of Anaesthetists of Great Britain and doseeresponse to bupivacaine-induced asystole in rats. Anaesthesi-
Ireland guidelines for treatment of cardiac arrest with ology 1998; 88: 1071e5.
lipid emulsion 6 Weinberg G, Ripper R, Feinstein DL, Hoffman W. Lipid emulsion infu-
sion rescues dogs from bupivacaine-induced cardiac toxicity. Reg
Treatment of cardiac arrest with lipid emulsion (approximate Anaesth Pain Med 2003; 28: 198e202.
doses given in red for 70 kg patient): 7 Rosenblatt MA, Abel M, Fischer GW, Itzkovich CJ, Eisenkraft JB.
C Give an intravenous bolus injection of Intralipid Successful use of a 20% lipid emulsion to resuscitate a patient after
20% 1.5 ml/kg over 1 min presumed bupivacaine-related cardiac arrest. Anaesthesiology 2006;
B Give a bolus of 100 ml 105: 217e8.
8 Litz RJ, Popp M, Stehr SN, Koch T. Successful resuscitation of a patient
C Continue cardiopulmonary resuscitation with ropivacaine-induced asystole after axillary plexus block using
C Start an intravenous infusion of Intralipid 20% lipid infusion. Anaesthesia 2006; 61: 800e1.
at 0.25 ml/kg/min 9 Foxall G, McCahon R, Lamb J, Hardman JG, Bedforth NM. Levo-
B Give at a rate of 400 ml over 20 min
bupivacaine-induced seizures and cardiovascular collapse treated
C Repeat the bolus injection twice at 5-min intervals if an with intralipid. Anaesthesia 2007; 62: 516e8.
adequate circulation has not been restored
FURTHER READING
B Give two further boluses of 100 ml at 5-min intervals
Association of Anaesthetists of Great Britain and Ireland e Management of
C After another 5 min, increase the rate to 0.5 ml/kg/min if an Severe Local Anaesthetic Toxicity 2 (2010), www.aagbi.org/publications/
adequate circulation has not been restored guidelines/docs/la_toxicity_2010.pdf (accessed 27th January 2010).
B Give at a rate of 400 ml over 10 min Patient Safety alert 21 (28th March 2007) e safer practice with epidural
injections and infusions, www.npsa.nhs.uk.
C Continue infusion until a stable and adequate circulation has
Wildsmith JAW, Kendall J. Local anaesthetic agents. In: Aitkenhead AR,
been restored
Rowbotham DJ, Smith G, eds. Textbook of anaesthesia. 4th edn.
Elsevier Limited. 2001, www.lipidrescue.org.
Box 2

ANAESTHESIA AND INTENSIVE CARE MEDICINE 11:3 100 2010 Elsevier Ltd. All rights reserved.