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Review article

Local anesthetic systemic toxicity (LAST) e Should we not be

concerned?

Lt Col Rakhee Goyal a,*, Col R.N. Shukla b

a
Classified Specialist (Anaesthesia and Critical Care), Command Hospital (SC), Pune 411040, India
b
Senior Advisor & HOD, (Anaesthesia and Critical Care), Command Hospital (SC), Pune 411040, India

article info abstract

Article history: Local anesthetics are one of the most commonly used drugs in the field of medicine. Yet
Received 3 November 2011 little is known about the systemic toxicity that can occur with their overdose. In the last
Accepted 24 February 2012 few years, a lot of research has taken place understanding the etiology of the Local
Available online 17 July 2012 anesthetics systemic toxicity (LAST) and the role of lipid emulsion in treating it. There is
a need to increase the awareness about LAST and establish a protocol to treat any serious
Keywords: neuro or cardiotoxicity.
Local anesthetics systemic toxicity ª 2012, Armed Forces Medical Services (AFMS). All rights reserved.
(LAST)
Lipid emulsion
Bupivacaine
Lignocaine

Introduction toxicity (LAST) and the acceptance of lipid emulsion as an

antidote to LA poisoning. There is a non-commercial educa-
Local anesthetics (LA) are one of the most commonly used tional website dedicated to the use of intravenous (iv) lipid to
drugs in the field of medicine. Anesthesiologists love them, treat this drug overdose http://www.lipidrescue.org. It was
surgeons use them and physicians like them to make some of initiated by Guy Weinberg and it reports all the cases of LAST
their procedures easier. Though the recommended safe doses treated by lipid emulsion. Besides, there is information on the
are always known to the users, severe neuro and cardiotox- etiology of LAST, mechanism of action of lipid emulsion and
icity consequent to unintended intravascular injection or various other aspects. The Council of the Association of
delayed tissue uptake are not unknown in clinical practice. Anaesthetists of Great Britain and Ireland was the first in the
Are we really aware of or concerned about this systemic world to acknowledge and establish a guidance document on
toxicity of local anesthetics? Are we adequately prepared to the use of lipid to treat local anesthetic intoxication in 2007
treat it? The time has come when these questions need (updated in 2010).1
a definite answer. American Society of Regional Anesthesia (ASRA) Practice
The last few years have witnessed a worldwide recognition Advisory2 in 2010, also published guidelines which assimi-
of the existence or possibility of local anesthetics systemic lates and summarizes current knowledge regarding the

* Corresponding author. Tel.: þ91 7798225637 (mobile), 6134 (O), þ02024272188 (R).
E-mail address: [email protected] (R. Goyal).
0377-1237/$ e see front matter ª 2012, Armed Forces Medical Services (AFMS). All rights reserved.
http://dx.doi.org/10.1016/j.mjafi.2012.02.011
372 m e d i c a l j o u r n a l a r m e d f o r c e s i n d i a 6 8 ( 2 0 1 2 ) 3 7 1 e3 7 5

prevention, diagnosis, and treatment of this potentially fatal detection of toxicity, and adequacy of treatment. In most of
complication. the cases, it is usually a combination of more than one of these
factors which contributes to a severe response.
Drug doses have to be reduced in the neonates and young
History infants because of their immature liver and renal function and
decreased plasma protein concentration. The elderly may
Mild to severe toxic effects of LA have been known since the have poor organ function affecting the metabolism of LA.
very time cocaine, the first LA was used in 1880s.3 Since then, There may also be a need to alter LA doses in epidural infu-
there have been several published reports in the literature4,5 sions in obstetric cases because of several hormonal and
which confirm their association with seizures and respira- mechanical factors.14
tory depression. A lot of research has taken place in the field of It is a common practice to combine one long acting LA with
pharmacology with an aim to discover drugs in this category another LA with faster onset like bupivacaine with lignocaine.
which are safer for clinical use. Bupivacaine, one of the most However, it should be strictly noted that their toxicity is
common long acting LA used, was introduced in the 1960s but additive and therefore, the individual recommended doses
had the most serious concerns of systemic toxicity associated (usually 2e3 mg/kg, 5 mg/kg and 7 mg/kg for bupivacaine,
with its overdose. This led to the development and marketing lignocaine and lignocaine with adrenaline respectively for
of its safer and less cardiotoxic enantiomers ropivacaine and most peripheral nerve blocks) are no longer safe.15
levobupivacaine in the late 1980s but LAST continued to be The site of injection of LA plays a major role in the inci-
reported even with them.5 It was more than ten years later dence of LAST. Some of the regional nerve blocks are vulner-
that some animal studies indicated that lipid emulsion may be able to iv injection of the drug because of their close proximity
useful in successful resuscitation following overwhelming to blood vessels. The commonest are intercostal blocks
doses of LA.6 Controlled trials in humans were not possible to followed by epidural and brachial blocks. The incidence is
prove the hypothesis. However, the first case of successful use approximately 1:10,000 for epidurals and 1:1000 for peripheral
of 20% lipid emulsion in refractory cardiac toxicity was re- nerve blocks (www.lipidrescue.org). Considering how
ported in 20067 and since then there have been many more common and frequent these blocks are, it is very important
such reports supporting the hypothesis.8e12 that care should be taken while performing them, and
adequate monitoring and resuscitation measures should be
What is the mechanism of action of local anesthetics and available to treat any untoward toxicity.16 It is best not to
how does LAST happen? administer more than one block in order to avoid any
overdose.
Chemically, LA have hydrophilic and hydrophobic moieties
that are separated by an intermediate ester or amide linkage.
The hydrophilic moiety is either a tertiary or a secondary Features of LAST
amine and the hydrophobic moiety is aromatic. The type of
linkage between the two determines many of the pharmaco- With absorption of LA and their increasing plasma concen-
logical properties. Hydrophobicity on one hand increases the tration, there is stimulation of the central nervous system
duration and potency of the drugs while on the other hand (CNS) followed by depression. As the LA is absorbed further,
decreases the therapeutic index making them prone to there may be tremors, restlessness followed by tonic-clonic
toxicity.13 pKa, lipid solubility and molecular size are the other convulsions due to selective depression of inhibitory
factors that also affect the pharmacological action of LA. The neurons. With faster and greater absorption, it may directly
commonly used LA, lignocaine and bupivacaine, are both cause loss of consciousness with respiratory depression
amides but differ largely in their hydrophobicity (366:3420). following sudden depression of all neuronal activity.13
Lignocaine is less potent but has a faster onset though shorter LA may target the myocardium where it may decrease the
duration of action than bupivacaine. electrical excitability, conduction rate, and force of contrac-
LA reversibly block the action potentials responsible for tion resulting in severe ventricular arrhythmias and myocar-
nerve conduction by binding to a specific receptor site within dial depression. There may be a sudden cardiovascular
the pore of the Naþ channels in nerves, thereby blocking the collapse with sinus bradycardia, conduction blocks, asystole
ion movement. They also block conduction in nerve axons in or ventricular tachyarrhythmias (mainly re-entry type).
the peripheral nervous system and interfere with the function Bupivacaine is more cardiotoxic than equi-effective doses of
of all organs in which conduction or transmission of impulses lignocaine. Although both the drugs block sodium channels
occurs. Thus, they may also have clinical effects on the central rapidly during systole, it is bupivacaine which dissociates
nervous system (CNS), the autonomic ganglia, the neuro- more slowly during diastole. Therefore, at the end of diastole
muscular junction, and all types of muscle in the event of there are still a large number of these channels which are
overdose. blocked making the cardiotoxicity more cumulative and more
A variety of factors come into play when LA are injected, potent. The dose of bupivacaine required for irreversible
which is why LAST does not occur in most cases. The inci- cardiovascular collapse compared to that required for CNS
dence and severity is affected by individual patient risk toxicity is lower than that of lignocaine (CC:CNS ratio 2.0:7.1
factors, concurrent illness and medications, site and tech- for the two LA).17 Moreover, bupivacaine cardiotoxicity may be
nique of drug use, specific type of local anesthetic compound, difficult to treat and may worsen in the presence of hypox-
total local anesthetic dose (concentration  volume), time of emia, hypercarbia or acidosis.13 Commercially available
 m e d i c a l j o u r n a l a r m e d f o r c e s i n d i a 6 8 ( 2 0 1 2 ) 3 7 1 e3 7 5 373

bupivacaine is a racemic mixture of (R)- and (S)-stereoisomers. a benzodiazepine, thiopental or propofol in small incremental
Ropivacaine and levobupivacaine are single (S)-stereoisomers doses. It is recommended to monitor the cardiovascular status
formulated with an aim to decrease the cardiotoxicity (former throughout the resuscitation and take blood samples for
has a propyl group compared to a butyl group on the piperi- analysis, if feasible.
dine ring in the latter). The reversal of Naþ channel blockade Treatment of cardiac arrest e Cardiopulmonary resusci-
appears to be faster and negative inotropy lesser with tation (CPR) should be started and arrhythmias should be
ropivacaine.18e20 Groban et al has shown that the doses managed using standard protocols (they may be very refrac-
required to induce cardiovascular collapse were greater for tory to treatment and lignocaine should not be used to treat
lignocaine than ropivacaine, levobupivacaine and bupiva- them) in cases of circulatory arrest. Conventional therapies
caine in that order.21 may be used to treat hypotension, bradycardia or tachyar-
Guidelines for the Management of Severe Local Anesthetic rhythmia in patients without circulatory arrest.
Toxicity based on the 2010 update by the Association of Treatment with lipid emulsion should be started simulta-
Anaesthetists of Great Britain and Ireland1 are as follows- neously with an intravenous bolus injection of 20% lipid
emulsion 1.5 ml/kg over 1 min followed by an infusion at
For the immediate management 15 ml/kg/h. A maximum of three repeat boluses (in not less
than 5 min interval) can also be given 5 min later if the
Recognize symptoms of severe toxicity and stop the LA cardiovascular stability has not been restored or has deterio-
injection immediately. Maintain airway (if required with rated further. The infusion dose may also be doubled after
a tracheal tube) and administer 100% oxygen. Confirm 5 min if required, and the infusion should be continued till the
intravenous access and control seizures with either stabilization of circulation or maximum lipid emulsion dose

Fig. 1 e Guidelines for the management of Local Anesthetic Systemic Toxicity (LAST).
374 m e d i c a l j o u r n a l a r m e d f o r c e s i n d i a 6 8 ( 2 0 1 2 ) 3 7 1 e3 7 5

given (12 ml/kg cumulative dose). It should be noted that references

prolonged resuscitation may be required in these cases and
CPR should be continued along with lipid emulsion.
It is most important to emphasize the need for awareness 1. The Association of Anaesthetists of Great Britain & Ireland.
of the antidote so that its immediate availability could be Guidelines for the Management of Severe Local Anaesthetic
made. All the members of the medical and paramedical staff Toxicity. Available from: http://aagbi.org/sites/default/files/
must be aware of clinical presentation of LAST and the exact la_toxicity_2010_0.pdf Last Accessed 30.01.12.
2. Neal JN, Bernards CM, Butterworth JF, et al. ASRA practice
place where lipid emulsion (commonly 20% Intralipid) is
advisory on local anesthetic systemic toxicity. Regional Anesth
available in their set up. A copy of the institutional guideline to Pain Med. 2010;35(2):152e161.
treat LAST should be displayed in common treating areas of 3. Mattison JB. Cocaine poisoning. Med Surg Rep. 1891;115:645e650.
the hospital. Fig. 1 shows a prototype of guidelines which may 4. Mayer E. The toxic effects following the use of local
be used for the armed forces medical units. anesthetics. JAMA. 1924;82:876e885.
Once signs of local anesthetic toxicity are manifest, the 5. Di Gregorio G, Neal JM, Rosenquist RW, Weinberg GL. Clinical
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unsuccessful cardiopulmonary resuscitation. The therapeutic Amaro MF, Cwik MJ. Pretreatment or resuscitation with a lipid
potential of lipids has also been highlighted by the National emulsion shifts the dose-response to bupivacaine-induced
Patient Safety Agency of UK.22 asystole in rats. Anesthesiology. 1998;88:1071e1075.
7. Rosenblatt MA, Abel M, Fischer GW, Itzkovich CJ,
Eisenkraft JB. Successful use of a 20% lipid emulsion to
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The exact mechanism of how lipid emulsion works is yet not bupivacaine and lidocaine-induced severe junctional
clearly established despite several animal trials and bradycardia by lipid emulsion following infraclavicular
convincing reports of its clinical success.23,24 Among the brachial plexus block in a uremic patient. Acta Anaesthesiol
various theories proposed, the ‘lipid sink’ theory25 is widely Taiwan. 2011;49(2):72e74.
9. Dix SK, Rosner GF, Nayar M, et al. Intractable cardiac arrest
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plasma. The lipid thus acts as a ‘sink’ by binding and 10. Man D, Podichetty VK. Lipid rescue in resuscitation of local
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being more lipophilic than others in the group, explains this 11. Smith HM, Jacob AK, Segura LG, Dilger JA, Torsher LC.
Simulation education in anesthesia training: a case report of
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successful resuscitation of bupivacaine-induced cardiac
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arrest linked to recent simulation training. Anesth Analg.
on inotropy of the heart.26 It improves cardiac contractility and 2008;106(5):1581e1584.
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cant role in treating myocardial depression due to LA. lipid infusion in the successful resuscitation of local
Last but not the least is the theory by Weinberg et al sug- anesthetic-induced cardiovascular collapse after
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2008;106(5):1578e1580.
metabolism in cardiac myocyte. Bupivacaine inhibits acyl-
13. Catterall WA, Mackie K. Local anesthetics. In: Brunton L,
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inhibits mitochondrial function by affecting the fatty acid Therepeutics. 11th ed. The McGraw-Hill Companies; 2006.
transport at its inner membrane. Lipid emulsion improves 14. Dillane D, Finukane BT. Local anesthetic toxicity. Can J Anesth.
mitochondrial fatty acid uptake by providing a high plasma 2010;57:368e380.
triglyceride concentration or more specifically by acting on the 15. Yaddanapuddi S. Prevention of Local anesthetic systemic
flux of acylcarnitine.27 toxicity. J Anaesth Clin Pharmacol. 2011;27:438e439.
16. Rosenberg PH, Veering BT, Urmey WF. Maximum
Lipid emulsion should be immediately available in all areas
recommended doses of local anesthetics: a multifactorial
where potentially cardiotoxic doses of LA are given, along concept. Reg Anesth Pain Med. 2004;29:564e575.
with guidelines for its use. However, future laboratory and 17. Spencer SL, Lin Y. Local anesthetics. In: Barash PG, Cullen BF,
clinical experiences are likely to bring refinement to the Stoelting RK, et al., eds. Clinical Anesthesia. 6th ed. New Delhi:
method. Wolters Kluwer/Lippincott Williams & Wilkins; 2009:540.
LAST does happen and we should be prepared to detect it 18. Pitkanen M, Feldman HS, Arthur GR, Covino BG. Chronotropic
and inotropic effects of ropivacaine, bupivacaine, and
in time and take all necessary measures to prevent any
lidocaine in the spontaneously beating and electrically
morbidity or mortality.
paced isolated, perfused rabbit heart. Reg Anesth.
1992;17:183e192.
19. Moller R, Covino BG. Cardiac electrophysiologic properties of
Conflicts of interest bupivacaine and lidocaine compared with those of
ropivacaine, a new amide local anesthetic. Anesthesiology.
All authors have none to declare. 1990;72:322e329.
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20. Lerman J, Nolan J, Eyres R, et al. Efficacy, safety, and 24. Foxall G, McCahon R, Lamb J, Hardman JG, Bedforth NM.
pharmacokinetics of levobupivacaine with and without Levobupivacaine-induced seizures and cardiovascular
fentanyl after continuous epidural infusion in children: collapse treated with Intralipid. Anaesthesia. 2007;62:516e518.
a multicenter trial. Anesthesiology. 2003;99:1166e1174. 25. Weinberg GL, Ripper R, Murphy P, et al. Lipid infusion
21. Groban L, Deal DD, Vernon JC, et al. cardiac resuscitation after accelerates removal of bupivacaine and recovery from
incremental overdosage with lidocaine, bupivacaine, bupivacaine toxicity in the isolated rat heart. Reg Anesth Pain
levobupivacaine, and ropivacaine in anesthetized dogs. Med. 2006;31:296e303.
Anesth Analg. 2001;92:37. 26. Sther SN, Ziegeler JC, Pexa A, et al. The effects of lipid infusion on
22. Patient Safety Alert 21 (28 March 2007) e Safer practice with myocardial function and bioenergetics in L-Bupivacaine toxicity
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Book review
P. Ganjei-Azar, M. Jorda, A. Krishna, Effusion Cytology e A discussed. Illustrated examples and the basic cytodiagnostic
Practical Guide to Cancer Diagnosis 2011, Demos Medical criteria of malignant cells and their markers as well as
Publishing LLC, 11W, 42nd Street, 15th Floor, New York, pointing out the pitfalls in the use of ICC have been covered
NY10036, USA (2011). pp. 192, Paperback, Price-85$, ISBN: lucidly. Tables listing the differential expression of specific
13 9781933864655 markers for the diagnosis of various types of tumors are
shown. Last chapter briefly discusses flow cytometry as
a diagnostic tool for detection of malignant cells in body cavity
The presence of malignant cells in body cavity fluids fluids. Examples of flow cytometric data used to identify
commonly indicates an advanced cancer stage associated malignant cells on the basis of their DNA aneuploidy and
with poor prognosis. The detection in effusions is extremely tumor cell associated markers’ expression are discussed.
important and presents a challenging task. There is an urgent This book will serve as a practical text for the budding and
need to reduce the high false negative rates of conventional practicing pathologists, who face daily diagnostic dilemmas
cytology by using a simple systematic approach to the diag- in effusions cytology, requiring the use of ICC. Cross-
nosis of malignancy, the potential subclassification of the references are extensive and are intended to help the reader
neoplastic process and by determining the site of origin without having to read preceding chapters. A short list of
whenever possible. The authors have used a practical and suggested readings complement each chapter for further
simple approach for the diagnosis of malignancy in effusions information.
including a primer on the most effective use of immunocy-
tochemistry (ICC) with small panels of antibodies for select Contributed by:
cases. Lt Col Ajay Malik*
This book emphasizes on easily accessible diagnostic Associate Professor, Department of Pathology, AFMC,
clues. Initial chapters offer an introduction and discussion on Pune 40, India
cellular content of pleural, peritoneal, and pericardial effu-
sions. General diagnostic criteria used to differentiate benign Brig Vibha Datta, SM
from malignant cells are discussed along with detailed list of Prof & HOD, Department of Pathology, AFMC, Pune 40, India
the types of malignancies found in effusions. Major differen- *Corresponding author.
tial diagnoses such as adenocarcinoma versus reactive
mesothelium and malignant mesothelioma are covered. Next Available online 22 August 2012
few chapters explain the detection of primary tumor site
based on morphology, site of sample and patients’ gender. 0377-1237/$ e see front matter
Chapter 6 is dedicated to cerebrospinal fluid cytology. Sample http://dx.doi.org/10.1016/j.mjafi.2012.07.005
collection, fixation, and preparation of slides for ICC are