Rajasekaran et al.

UJP 2013, 02 (05): Page 11-17

www.ujponline.com

Universal Journal of Pharmacy

Review Article
ISSN 2320-303X

Take Research to New Heights

LOCAL ANAESTHETICS SYSTEMIC TOXICITY

Rajasekaran SA1*, Kalaivani S2, Vasudevan K3, Regu P4
1

Professor and Head of Department, Oral and Maxillo facial Surgery Department, NA Facial Trauma Clinic, Raja Annamalai puram, Chennai, India
2
Professor, Department of Periodontics, Tamilnadu Government Dental College and Hospital, Chennai, India
3
Director, Department of Oral and Maxillo Facial Surgery, Thaaimoogambigai Dental College, Chennai, India
4
Assistant Professor, Department of Oral Medicine, Tamilnadu Government Dental College and Hospital, Chennai, India

Received 08-07-2013; Revised 10-08-2013; Accepted 14-09-2013

ABSTRACT
Local anaesthesia or regional anaesthesia is not a risk and complication free enterprise. The safety of regional
anaesthesia is a perennial topic of debate. The safe, effective performance of regional anaesthesia depends on
knowledge of the pharmacology and toxicity of the various local anaesthetic drugs and the technical proficiency in the
performance of the different regional anaethestic procedures. Local anaesthesia use is associated with potential
adverse reactions including central nervous system toxicity, selective cardiotoxicity, methemoglobinemia, tissue
toxicity and allergy. Accidental intravascular injection of local anaesthesia is a constant concern, as well as rapid
absorption of a large amount of drug injected into the tissues, but genuine hope has been brought by the use of
intravenous lipid treatment to treat patients who develop dangerous cardiac arrhythmia as a result. The newest and
perhaps the most promising, approach to the management of local anaesthetic induced circulatory collapse is neither
an inotrope, a vasopressor, nor any pharmacologic agent, per se, but the intravenous infusion of lipid.The physician or
dentist must give close attention to the prevention of adverse systemic responses to the local anaesthetic injected
during nerve blocks. Established toxicity may be very difficult to treat and no specific reversing therapy is available
yet. This review offers a brief overview of the current understanding of the circumstances that cause systemic toxicity
in the daily clinical practice and the management of clinical signs and symptoms.
Keywords: Local anaesthesia, central nervous system toxicity, Intravenous lipid treatment

INTRODUCTION
Local anaesthetic systemic toxicity (LAST) has been
recognized and reported since shortly after the
introduction of cocaine in the clinical practice in
1880s. From the beginning, systemic toxicity was
associated with seizures and respiratory failure1. Local
anaesthetic intoxication is a rare but catastrophic
occurrence. Despite the remarkable efficacy of local
anaesthetics, the risk of systemic toxicity associated
with these drugs has been a recurring problem since
their introduction to clinical medicine. Local
anaesthetic systemic toxicity continues to be a major
source of morbidity and mortality in regional
anaesthetic practice.
Peripheral nerve blocks have the potential to reduce
the incidence of persistent pain, nausea and
*Corresponding author:
S.A.RAJASEKARAN, M.D.S,*
Professor and Head of Department,
Oral and Maxillo facial Surgery Department,
NA Facial Trauma Clinic,16, Pattamal Street, 1st floor,
Raja Annamalai puram, Chennai 600 028. Tamilnadu,
India. Mobile no: 919444067605
E-mail Id: palayamkottaithothathiri@gmail.com

drowsiness, the three major barriers to early discharge

following general anaesthesia. Peripheral nerve blocks
should not be associated with significant changes in the
heart rate or blood pressure, thereby shortening the
patients time of recovery2.
Lignocaine is the most common local anaesthesia used
in dentistry and has been reported to cause systemic
toxicity. Articaine, even with its excellent safety
profile,
may
cause
systemic
intoxication
if
unintentional intravascular injection is performed
during a block; it has been reported that the rate of
intravenous injection for inferior alveolar block is as
high as 15.3% which can occur due to the high
vascularization of the oral mucosa3. Local anaesthetics
are xenobiotics substances foreign to the living cell
eliciting a response ranging in intensity from the faintly
annoying to the swiftly fatal.4 Modern local
anaesthetics are safer than their predecessors, but risk
persists, and even the experienced practitioner using
the correct dose may provoke fatal reactions5.
If local anaesthetic is introduced in the arterial
circulation of the brain, central nervous system toxicity
can be prompt and profound. The greatest risk for
direct cerebro vascular administration of local
anaesthetics is through the vertebral or carotid artery

Universal Journal of Pharmacy, 02(05), Sep-Oct 2013

11

Rajasekaran et al. UJP 2013, 02 (05): Page 11-17

during blocks. It has been demonstrated in baboons
that retrograde arterial flow can deliver local
anaesthetic to the brain arterial supply from forcible
injection in the lingual, brachial and femoral arteries.
Cardio pulmonary collapse after dental neural blockade
may be due to passage of anaesthetic through these
routes6.
Local anaesthetic toxicity can also occur where the
pharmacokinetics of the drug are altered by comorbidity such as cardiac, renal or hepatic failure,
alteration in plasma protein binding or interactions
with other drugs. Systemic toxicity from local
anaesthetic can be life threatening and very often
resistant to treatment7.
This article reviews the clinical features, management
and preventive measures of local anaesthetic systemic
toxicity (LAST) and emphasizes the importance of
preventing unintended intravascular injections of these
drugs.
Local anaesthetics systemic toxicity (LAST)
Toxicity is defined as the adverse reactions of an
organism to a given dose of an agent. Toxicity may be
either general or local. Systemic toxicity is the term
used to describe the clinical symptoms associated with
extreme plasma concentration of local anaesthetics.
General systemic toxicity refers to the effect of a drug
on the entire organism while local toxicity refers to the
effect on cellular structure and often termed as
cytotoxicty. Systemic reactions occur when organ
systems distant to the injection site respond adversely.
All of the clinical effects due to local anaesthetic
overdose are the result of the blockade of various ion
channels8. The incidence of local anaesthetic
intoxication is unknown9. It may pass unrecognized10.
The estimate of clinically important local anaesthetic
toxicity is from 7.5 to 20 occurrences per 10000
peripheral blocks7. The dose and blood level of local
anaesthetic that produces central nervous system
toxicity is lower than the dose that causes circulatory
collapse.
Therefore
central
nervous
system
manifestations tend to occur earlier. Although local
anaesthetic cardiovascular toxicity occurs less
frequently than central nervous system toxicity, it is
more serious and more difficult to treat.
Toxicity may be potentiated in patients with renal,
hepatic or cardiac failure, respiratory acidosis,
pregnancy, at the extreme of age or in hypoxic
patients. Several factors such as physico-chemical
properties, rate of absorption and route of
administration of the local anaesthetic also influence
the acute systemic toxicity. Highly vascular injection
sites such as sublingual region have a higher correlation
to an increased incidence of local anaesthetic toxicity
than less vascular areas7. Regarding site of injection,
rapid absorption occurs via infiltration of highly
vascular tissues such as oral mucosa3. Local
anaesthetics, being water and fat soluble compounds,

www.ujponline.com
do not remain confined to their injection site for long.
Local anaesthetics differ from most other drugs in that
they are deposited in close proximity to the target
neural structure11.
The drug is absorbed by capillaries from the site of
application, enters the blood stream, and so gains
access to every organ system and it is this very
presence that may cause untoward response in distant
organ. The local anaesthetic is taken up in each organ
according to its tissue plasma partition coefficient4.
In the setting of nerve blocks, toxic reactions may
result early from intravascular injection of the drug or
may be delayed until an extravascular bolus is
absorbed. Many of the major nerves are in the vicinity
of large vessels. Because failure to aspirate blood from
the block needle does not ensure that the injectate will
not enter a vessel, injection should proceed slowly and
incrementally to allow the identification of
intravascular injection before the full dose is
administered12.
Systemic clearance of amide linked local anaesthectics
depends primarily upon hepatic metabolism. Liver is
the main organ which clears the absorbed local
anaesthetics. Hepatic clearance is a function of the
hepatic extraction ratio and hepatic blood flow. The
hepatic extraction ratio, in turn, is dependent on the
ratio of free to protein bound drug. It is a known fact
that free or unbound fraction is bioactive. Lidocaine,
being moderately protein- bound, has a higher hepatic
extraction ratio. [70-75% per pass]. Hepatic blood flow
decides the clearance of the local anaesthetics. Factors
such as upper abdominal and laproscopic surgery,
volatile anaesthetic administration, hypocapnia,
congestive cardiac failure, and intra vascular volume
depletions which reduce the hepatic blood flow, reduce
the clearance of local anaesthesia. Certain drugs
example Histamine blockers and -blockers can reduce
the hepatic perfusion. Through its relationship to
hepatic blood flow, cardiac output may modify local
anaesthetic clearance. Heart failure, for example,
reduces hepatic blood flow, and so reduces lidocaine
clearance11.
Drug toxicity is less predictable in elderly patients
because of reduced blood flow and reduction in muscle
mass and total body water, together with an increase
in body fat, may result in a larger volume of
distribution of lipophilic anaesthetics with a prolonged
clearance time11.
In infants and children, the plasma concentration of
unbound amide local anaesthetic increases due to
immature hepatic metabolism and marked differences
in plasma protein binding. Susceptibility to toxicity is
more in because of the unbound fraction of local
anaesthetic is more in infancy11. Physiological
alterations associated with pregnancy may play a role
in the apparent increase in local anaesthetics
sensitivity during pregnancy13. When pregnancy

Universal Journal of Pharmacy, 02(05), Sep-Oct 2013

12

Rajasekaran et al. UJP 2013, 02 (05): Page 11-17

progress to the stage in which cardiac output is
increased blood perfusion to the site of local
anaesthetic injection will increase and the absorption
of local anaesthetic into the circulation is rapid14.
Relative potency for cardiovascular toxicity also
seems to follow the relative anaesthetic potency. More
potent agents such as bupivacaine, etidocaine, and
tetracaine have been shown to be more cardiotoxic
than less potent agent such as lidocaine, mepivacaine,
or prilocaine. Sadly the introduction of the potentially
safer local anaesthetics such as L-bupivacaine,
ropivacaine has not eliminated systemic toxicity.
The following factors determine the plasma
concentration of local anaesthesia:
-The dose of the drug administered
-The rate of absorption of the drug [site injected,
vasoactivity of the drug, use of vasoconstrictors]
-Biotransformation and elimination of the drug from
circulation.
Table 1. Clinical manifestations of lidocaine with
increasing dose:
Plasma
Effect
Concentration (g/ml)
1-5
Analgesic
Light headedness, tinnitus,
5-10
metallic taste in the tongue
10-15
Seizures, unconsciousness
15-25
Coma, respiratory arrest
More than 25
Cardiovascular depression
Data from Liu SS, Yi Lin, Local anaesthetics. In Barash
PG, Cullen BF, Stoelting RF, Cahalan MK, Stock MC
(Eds); Clinical Anaesthesia, Wolters Kluver | LippincottWilliams & Wilkins, Philadelphia, 6th edition, 2009,
p542.
Central Nervous System [CNS] Toxicity:
Local anaesthetic drugs accidentally injected into
arteries may reach the cerebral circulation following a
centripetal pathway and then produce central nervous
system toxic responses, because local anaesthetics can
readily cross the blood brain barrier6. CNS toxicity is
usually, the first sign of over dose in awake patient.
Signs of generalized CNS toxicity because of local
anaesthetics are dose dependent 15 (Table.1). Low dose
produce CNS depression and higher doses result in CNS
excitation and seizures. Symptoms such as dizziness,
ringing in the ear, numbness and tingling of lips or
tongue, metallic taste in the tongue, vague sensation
of light headedness, blurring or doubling of vision along
with difficulty in focusing and at times a flushed or
chilly sensation, slurred speech and fine skeletal
muscle twitching in face and digits are usually observed
as the initial indication of local anaesthetic toxicity16.
LAST is a dose dependant complication characterized
by neurological and cardio vascular symptoms. The
classic description of LAST is a step-wise progression of
symptoms with increasing local anaesthetic (LA) blood

www.ujponline.com
concentrations. LAs produce central nervous system
(CNS) excitation at low plasma concentration. At higher
concentration of LA, objective signs occur which are as
follows: agitation, garbled and slurred speech followed
by muscle twitching and eventually generalized tonicclonic seizures. With even higher blood concentrations
the earlier signs of CNS excitation are replaced with
signs of CNS depression, such as coma, and respiratory
arrest17.
Blockade of sodium channels can occur in any excitable
tissue, including brain, as well cardiac, skeletal, and
vascular smooth muscle and these widespread actions
are the basis for some important clinical application as
well as toxicities. The primary toxic manifestations are
due to blockade of sodium channels in the brain and
heart18.
Symptoms of CNS toxicity with higher plasma
concentration: 19
10.
Death
9.
Cardiac arrest
8.
Respiratory arrest
7.
Coma
6.
Seizures
5.
Muscular spasm
4.
Tinnitus and auditory hallucinations
3.
Tingling in the mouth and tongue
2.
Metallic taste
1.
Disorientation
Cardiovascular systemic toxicity: (CVS)
In 1979 Albrights editorial drew attention of the
anaesthetic community to the risks of intravascular
injection of local anesthesia. He highlighted the
unreliability of the aspiration test, the fact that
cardiovascular collapse could occur without preceding
hypoxia and resuscitation may be difficult.
Local
anaesthetics
differ
from
most
other
pharmacological agents since they are deposited in
close proximity to the target neural structure. Systemic
circulation absorbs a large portion of the injected drug
and distributes to distant organs. More than 90% of an
injected dose is taken up by the systemic circulation
within 30 minutes of injection20.
The local anaesthetics affect the cardiovascular system
has been known since cocaine first made its clinical
debut. These agents can affect directly not only
automaticity,
conductivity,
contractility,
and
arrhythmicity of the heart but also tone of the
muscular wall of blood vessels.
The distribution of local anaesthetics after absorption
is governed by organ perfusion, lipophilicity and
protein binding. Most importantly concentrations of
local anaesthetics may rapidly rise in the heart and
brain, potentially causing toxic effects21.
Higher level of plasma concentration or excessive
absorption of local anaesthetics by systemic circulation
leads to cardiotoxicity which follows a biphasic

Universal Journal of Pharmacy, 02(05), Sep-Oct 2013

13

Rajasekaran et al. UJP 2013, 02 (05): Page 11-17

pathway. At lower concentration, sympathetic nervous
system activation during the CNS excitatory phase can
lead to hypertension and tachycardia. This may conceal
the direct myocardial depressant effects occurring at
higher concentration, epitomized by ventricular
arrhythmias, myocardial conduction delays and
profound contractile dysfunction ultimately leading to
cardiovascular collapse22.
Vasoconstrictors are added to local anaesthetics to
reduce the absorption into the systemic circulation.
The value of doing so depends on vascularity of the
injection site and specific local anaesthetic agent,
which among other considerations vary in term of
intrinsic vasoactivity23.
Due to accidental intravascular injection (particularly
with injection into the carotid or vertebral arteries) of
local
anaesthetics,
systemic
toxicity
occurs,
premonitoring symptoms can be by passed and the
patient can rapidly develop seizure activity that may
progress
to
cardiac
excitation
(hypertension,
tachycardia, ventricular arrhythmia), with greatly
increased plasma concentration, cardiac excitation may
be followed by cardiac depression (bradycardia,
asystole, decreased contractility and hypotension) 1.
The cardiovascular system is more resistant to the toxic
effects of higher plasma concentrations of local
anaesthetics than the CNS. For example, lidocaine in
plasma concentration of < 5g/ml is devoid of adverse
cardiac effects, producing only a decrease in the rate
of spontaneous phase 4 depolarization (automaticity).
Nevertheless, plasma lidocaine concentration of 5 to 10
g/ml and equivalent plasma concentration of other
local anaesthetics may produce profound hypotension
due to relaxation of arteriolar vascular smooth muscle
and direct myocardial depression. As a result,
hypotension reflects both decreased systemic vascular
resistance and cardiac output24. Electrical disturbances
resulting from toxic systemic levels of local
anaesthetics
include
sino-arterial,
and
atrioventricular nodal depression, widening of the PR
interval and QRS complex, brady-arrhythmias with or
without AV block and reentrant arrhythmias including
ventricular tachycardia or fibrillation. All local
anaesthetics
can
severely depress myocardial
contractility, resulting in hypotension and electro
mechanical dissociation25. Initially, there is an increase
in blood pressure and heart rate, with higher levels of
local anaesthetics, hypotension (direct vasodilatory
effects on peripheral arterioles and negative inotropic
action) and arrhythmias ensure, resulting in cardiac
arrest26.
Prevention and treatment:
The physician or dentist must give close attention to
the prevention of adverse systemic responses to the
local anaesthetics injected during nerve blocks. The
single most important factor in the prevention of

www.ujponline.com
toxicity is the avoidance of accidental intravascular
injections.
In regional anesthesia, the aim of the anesthesiologist
is the prevention of complications (most of which can
be anticipated) and ensuring the highest quality patient
care. Proper patient selection through pre-operative
evaluation, meticulous attention to sterile technique,
and careful deliberate handling of the needle will be
helpful in preventing local anaesthetics toxicity. One
should know the importance of when to stop. Patient
comfort is the prime importance. The purpose of the
exercise of regional anesthesia is defeated, if, in the
process of performing these techniques, the patient is
injured22.
Failures to aspirate blood from the block needle do not
ensure that the injectate will not enter a vessel,
injection should proceed slowly and incrementally to
allow the identification of intravascular injection
before the full dose is administered.
Local anaesthetic dose can be limited by several
methods. Total dose [the product of concentration x
volume] should be tailored to the minimum mass of
local anaesthetic molecules necessary to achieve the
desired effect. Evidence suggests that most peripheral
nerve blocks are performed with significantly larger
doses than are necessary to achieve desired clinical
points1.
Maximum recommended doses for peripheral blocks
have been recommended by the manufactures, but this
scientific basis has been questioned14.
Of particular concern is the observation that blood
levels cannot be predicated on the milligrams per
kilogram basis and the body weight should not be used
as dosage guideline except in the paediatric
population. Local anaesthetic systemic toxicity has
occurred with lower doses and vigilance is essential27.
Dose reduction may be particularly important for those
patients of extreme of age (<4months or >70 years) or
those with cardiac conduction effect or a history of
ischemic heart diseases, renal or hepatic dysfunction.
For regional blocks involving sites of high vascularity,
the use of alternative long acting amide levo
enantiomers may be vindicated to further reduce the
risk to patients and this has already been suggested in
dentistry for inferior alveolar block3.
Immediate intervention at the earliest sign of local
anaesthetic toxicity is of paramount importance and
improves the chances of successful treatment28. In the
patient with suspected local anaesthetic toxicity, the
first step is to ensure adequate ventilation and
oxygenation, since hypoxemia and hypercarbia and
acidosis enhance the toxicity.
The importance of patient monitoring is often over
looked but impossible to over emphasize. While oxygen
therapy remains a prerequisite, all patients undergoing
a regional anaesthesia techniques should have

Universal Journal of Pharmacy, 02(05), Sep-Oct 2013

14

Rajasekaran et al. UJP 2013, 02 (05): Page 11-17

electrocardiography, blood pressure monitoring, and
pulse oximetry.
Recent case reports suggest that treatment with lipid
emulsion infusion can ameliorate altered mental status,
obtundation, agitation or seizures29. Hence measures
aimed at lowering the local anaesthetic blood level
such as using the lowest dose and the weakest
solutions,
plus
minimizing
absorption
with
vasoconstrictor, go far towards reducing the incidence
of systemic reactions in the patient population.
Although, initial recommendations suggested that lipid
rescue be applied only after standard resuscitation
measures have failed most recent recommendations
suggest that intralipid therapy should be considered at
the first sign of local anaesthetic induced
cardiotoxicity.
To date, intravenous lipid emulsion used to treat LAST
has a good track record of experimental and clinical
use without any major complication. Lipid emulsion has
become a crucial antidote to treating LAST17.
When other measures fail to reestablish the
independent circulation in the treatment of LAST, early
in the resuscitation sequence, it is well advised to
consider a cardio- pulmonary by pass. Cardiopulmonary by pass has served patients with, otherwise
fatal LAST29.
Although the toxicity of local anaesthetics is
indispensable and can be life threatening, it should be
emphasized that this drugs are very safe. The safe and
effective use of local anaesthetics depends primarily on
good clinical skills, proper dose, correct technique, and
precautions and readiness for emergencies.
All clinicians should be familiar prior to use of local
anaesthetics, with those protocols, and lipid emulsion
must be available in all areas where regional
anaesthesia is practiced.
In 2007 the Association of Anaesthetics of Great Britain
and Ireland published guidelines for the management of
severe local anaesthetic toxicity30.
In 2008 American Society of Anesthesiologists
committee on critical care Medicine 31 as well as the
Resuscitation council of the United Kingdom also
published protocols for the treatment of LAST32.
In 2010, the American Society of Regional Anesthesia
and Pain Medicine published its practice advisory on
LAST1.
These guidelines emphasize the importance of airway
management and early cardio pulmonary resuscitation.
They strongly advise use of lipid emulsions along with
resuscitative measures and have incorporated the use
of lipid emulsion therapy in their guidelines, in the
management of LAST.
Even though Advanced Cardiac Life Support (ACLS)
guidelines now support the use of vasopressin (40 in a
single intravenous dose) in addition to epinephrine
during cardio pulmonary resuscitation, Derek Dillane
etal do not recommend its use in local anaesthetic

www.ujponline.com
induced toxicity. The efficacy and safety of vasopressin
in cardiac arrest is controversial, while laboratory data
and human trials fail to provide conclusive evidence11.
Amiodarone, a primary drug in the ACLS arrhythmia
treatment algorithm, should be considered the
treatment of choice for serious ventricular arrhythmias
induced by potent local anaesthetic agents, and it
appears to be widely accepted as the first line
therapy33.
Local anaesthetic induced cardiac arrest requires rapid
restoration of coronary perfusion pressure to improve
myocardial contractility and theoretically to wash out
local anaesthetics from cardiac tissues through
improved tissue perfusion. Maintenance of cardiac
output and oxygen delivery to tissues is critical for
prevention and treatment of acidosis1.

CONCLUSION
It is clear from the above discussion that continued
investigation is needed to guide future methods for
preventing and treating LAST. Less toxic agents should
be developed. Considering (i) the extensive use of local
anaesthetics (ii) the frequent use of doses sufficient to
cause significant morbidity or mortality and (iii) the
imperfect nature of our ability to prevent, detect and
treat these complications, it remains the responsibility
of all clinicians using local anesthesia to understand
their potential for severe systemic toxicity and to be
prepared to respond immediately to these events when
they occur1.
The lack of standardized documentation for peripheral
blocks has several drawbacks, because it makes
retrospective analysis, whether for the purpose of
research, quality assurance, or medico-legal issues,
very difficult and sometimes impossible.
Prevention of LAST remains a milestone during the
performance of peripheral nerve blocks9.
International guidelines accept lipid therapy after
LAST. The first line treatment is still the standard
Advanced Cardiac Life Support. Educational programs
and advanced scenario training may facilitate
preventing, early detection, and management of LAST
in light of recently published guidelines34.
According to G. Weinberg, until non-toxic alternatives
to standard local anaesthetics are available LAST will
continue to occur even in the contest of optimal
clinical practice when standards of care are strictly
followed and outside direct intravascular injection.
Many specialties other than anesthesiology use local
anaesthetics.
Unfortunately, use implies risk and most nonanesthesiology specialties are woefully lacking in
knowledge of these risks and their proper management.
As an expert he suggests on the use of local
anaesthetics to inform and educate the colleagues
whenever possible about the current state-of-art in
understanding LAST35.

Universal Journal of Pharmacy, 02(05), Sep-Oct 2013

15

Rajasekaran et al. UJP 2013, 02 (05): Page 11-17

REFERENCES
1. Neal JM, Bernards CM, Butterworth JF, Di
Gregorio G, Drasner K, Hejtmanek MR. et al.
ASRA Practice Advisory on Local Anesthetic
Systemic Toxicity. Reg Anesth Pain Med, 2010;
35(2): 152-161.
2. Gilbert HC. Complications and controversies in
regional anesthesia. ASA Refresher Courses in
Anesthesiology, 2003; 31(1): 45-63.
3. Ciechanowicz S and Patil V. Lipid Emulsion for
Local
Anesthetic
Systemic
Toxicity.
Anesthesiology Research and Practice, 2012;
Article ID 131784: 11 pages.
4. de Jong RH. Local anesthetics. 1st edition.
St.Louis: Mosby, 1994. p.346-7.
5. Mclure HA, Rubin AP. Review of local
anesthetic agents. Minerva Anestesiol, 2005;
71(3): 59-74.
6. Aldrete JA, Romo-Salas F, Arora S, Wilson R,
Rutherford R. Reverse Arterial Blood Flow as a
Pathway for Central Nervous System Toxic
Responses Following Injection of Local
Anesthetics. Anesth Analg, 1978; 57(4):428-33.
7. NesekAdam V, Markic A, Sakic K, Grizelj
Stojcic E, Tonkovic D. Local anaesthetic
toxicity. Period biol, 2011; 113 (2): 141-146.
8. Dippenaar JM. Local anesthetic toxicity. SAJAA,
2007; 13 (3): 23-28.
9. Mulroy MF. Systemic Toxicity And Cardiotoxicity
From Local Anesthetics: Incidence and
Preventive Measures. Reg Anesth Pain Med,
2002; 27(6): 55661.
10. Schwartz D, VadeBoncouer T, Weinberg G. Was
Case Report a Case of Unrecognized Local
Anesthetic Toxicity? Anesth Analg, 2003;
96(6):1844-5.
11. Dillane D, Finucane BT. Local anesthetic
systemic toxicity. Can J Anesth / J Can Anesth,
2010; 57(4): 368-80.
12. Benumof JL, Saidman LJ. Anesthesia &
Perioperative Complications. 2nd edition. St.
Louis: Mosby, 1999. p.72.
13. Nimmo WS, Rowbatham DJ, Smith G.
Anaesthesia. 2nd edition. London: Oxford
Blackwell Scientific Publications, 2001.p. 1396.
14. Rosenberg
PH, Veering B Th, Urmey WF.
Maximum Recommended Doses of Local
Anesthetics: A Multifactorial Concept. Reg
Anesth Pain Med, 2004; 29(6): 564-75.
15. Barash PG, Cullen BF, Stoelting RK, Cahalan
MK, Stock MC. Clinical Anesthesia. 6th edition.
Philadelphia: Wolters Kluwer, Lippincott
Williams & Wilkins, 2009 .p. 542.
16. Covino BG. Systemic Toxicity of Local
Anesthetic Agents Editorial. Anesth Analg,
1978; 57(4):387-8.

www.ujponline.com
17. Morau D, Ahern S. Management of Local
Anesthetic
Toxicity.
International
Anaesthesiology Clinics, 2010; 48 (4): 117-40.
18. Guyuron B, Eriksson E, Persing JA, Chung KC,
Disa J J, Gosain AK, Kinney BM, Rubin JP.
Plastic Surgery: Indications and Practice. 1st
edition. Asia: Saunders, 2009. p.51.
19. Hadzic A, Vloka JD. Hadzic's Peripheral Nerve
Blocks and Anatomy for Ultrasound-Guided
Regional Anesthesia (New York School of
Regional Anesthesia). 1st edition. New Delhi,
McGraw-Hill, 2004.p.56.
20. Berde C.Local anesthetics in infants and
children: an update, Pediatric Anesthesia,
2004; 14 (5): 38793.
21. Lirk P, Hollmann MW. Local anesthetics
Substances,
Pharmacodynamics,
Pharmacokinetics. Reg Anesth Pain Med, 2012;
37 Suppl 7: E12-E13.
22. Finucane BT. Complications of regional
anesthesia. 2nd edition. New York: Springer,
2007 .p. ix (preface), 65.
23. Heavner JE. Local anesthetics, Cur Opin in
Anesthesiol, 2007; 20 (4): 33642.
24. Stoelting RK. Pharmacology and Physiology in
Anesthetic Practice. 3rd edition. Philadelphia:
Lippincott Raven; 1999.p.169.
25. Lobato EB, Gravenstein N, Kirby RR.
Complications in Anaesthesiology. 1st edition.
Philadelphia: Wolters Kluwer, Lippincott
Williams & Wilkins, 2008.p.868
26. Chelly JE. Peripheral Nerve Blocks. 3rd edition.
Philadelphia: Wolters Kluwer, Lippincott
Williams & Wilkins, 2009.p.15.
27. Mulroy MF, Hejtmanek MR. Prevention of Local
Anesthetic Systemic Toxicity. Reg Anesth Pain
Med, 2010; 35 (2): 177-80.
28. Feldman HS, Arthur GR, Pitkanen M, Hurley R,
Doucette AM, Covino B G. Treatment of Acute
Systemic Toxicity After the Rapid Intravenous
Injection of Ropivacaine and Bupivacaine in the
Conscious Dog. Anesth Analg, 1991; 73(4):37384.
29. Weinberg G L. Treatment of Local Anesthetics
Systemic Toxicity (LAST). Reg Anesth Pain Med,
2010; 35 (2): 188-93
30. AAGBI Safety Guidelines, Management of
Severe Local Anaesthetic Toxicity, 2007
31. Gabrielli A, Oconnor M F. Anesthesia Advanced
Circulatory Life Support. The American Society
of Critical Care Anesthesiologists and The
American
Society
of
Anesthesiologists,
Committee
on
Critical
care
Medicine
Anesthesiology/ perioperative ACLS, 2008.
32. Resuscitation Council (UK) Cardiac Arrest or
cardiovascular collapse caused by local
anesthetic. Available at

Universal Journal of Pharmacy, 02(05), Sep-Oct 2013

16

Rajasekaran et al. UJP 2013, 02 (05): Page 11-17

http://www.resus.org.uk/pages/caLocalA.htm.
[Cited 2008]
33. Corcoran W, Butterworth J, Weller RS, Beck JC,
Gerancher JC, Houle TT, Groban L. Local
Anesthetic-Induced Cardiac Toxicity: A Survey
of Contemporary Practice Strategies Among
Academic Anesthesiology Departments. Anesth
Analg, 2006; 103 (5): 1322-6.
34. Smith HM, Jacob AK, Segura LG, Dilger JA,
Torsher LC. Simulation Education in Anesthesia

www.ujponline.com
Training: A Case Report of Successful
Resuscitation of Bupivacaine-Induced Cardiac
Arrest Linked to Recent Simulation Training.
Anesth Analg, 2008; 106(5):1581-84.
35. Weinberg G, Refresher Course: Managing Local
Anesthetic Systemic Toxicity. Checklist and
other important practical issues, Reg Anesth
Pain Med, 2012; 37 Suppl 7: E1.

Source of support: Nil, Conflict of interest: None Declared

Universal Journal of Pharmacy, 02(05), Sep-Oct 2013

17