1
Title page:
Local Anaesthetics Systemic Toxicity
Authors:
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.
e-mail Id: palayamkottaithothathiri@gmail.com
Mobile no: 919444067605
S.KALAIVANI, M.D.S,
Professor,
Department of Periodontics,
Tamilnadu Government Dental College and Hospital,
Chennai,
India.
K. VASUDEVAN, M.D.S,
Director,
Department of Oral and Maxillo Facial Surgery,
Thaaimoogambigai Dental College,
Chennai,
India.
P.RAGU, M.D.S,
Assistant Professor,
Department of Oral Medicine,
Tamilnadu Government Dental College and Hospital,
Chennai,
India.
* Address for Correspondence
2
Local Anaesthetics Systemic Toxicity
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:
3
Local anaesthetic systemic toxicity (LAST) has been recognized and reported
since shortly after the introduction of cocaine in the clinical practice in 1880’s. From the
beginning, systemic toxicity was associated with seizures and respiratory failure. (1) 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 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, there by shortening the patient’s time of recovery.(2)
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 mucosa.(3)
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 reactions. (5)
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
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,
4
brachial and femoral arteries. Cardio pulmonary collapse after dental neural blockade may
be due to passage of anaesthetic through these routes. (6]
Local anaesthetic toxicity can also occur where the pharmacokinetics of the drug
are altered by co-morbidity such as cardiac, renal or hepatic failure, alteration in plasma
protein binding or interactions with other drugs. Systemic toxicity from local anaethetic
can be life threatening and very often resistant to treatment.(7)
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 channels.(8) The incidence of local anaesthetic
intoxication is unknown. (9) It may pass unrecognized. (10)
The estimate of clinically important local anaesthetic toxicity is from 7.5 to 20
occurrences per 10000 peripheral blocks. (7) 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 occur less frequently than central nervous system
toxicity , it is more serious and more difficult to treat.
5
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 areas.(7) Regarding site of
infection, rapid absorption occurs via infiltration of highly vascular tissues such as oral
mucosa.(3) Local anaesthetics, being water and fat soluble compounds, 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 structure.(11)
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 coefficient. (4)
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 administered. (12)
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
6
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 βblockers can reduce the hepatic perfusion. Through its relationship to hepatic blood flow,
cardiac out may modify local anaesthetic clearance. Heart failure, for example, reduces
hepatic blood flow, and so reduces lidocaine clearance.(11)
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 time. (11]
In infants and children, the plasma concentrafion 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 infancy. (11) Physiological alterations associated
with pregnancy may play a role in the apparent increase in local anaethetics sensitivity
during pregnancy. (13) When pregnancy progress to the stage in which cardiac output is
increased blood perfusion to the site of local anaethetic injection will increase and the
absorption of local anaesthetic into the circulation is rapid.(14)
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 Lbupivacaine, 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.
7
Systemic effect of Lidocaine: (15)
Plasma concentration (µg/ml)
Effect
1-5
Analgesic
5-10
Light headedness, tinnitus, metallic taste in
the tongue
10-15
Seziures, unconsciousness
15-25
Coma, respiratory arrest
More than 25
Cardiovascular depression
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 barrier.(6) CNS
toxicity is usually, the first sign of over dose in awake patient. Sign of local anaesthetic
CNS toxicity are dose dependent. 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
toxicity.(16)
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 concentrations. LA’s produce
8
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 tonic-clonic
seizures. With even higher blood concentrations the earlier signs of CNS excitation are
replaced with signs of CNS depression, such as coma, and respiratory arrest.(17)
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 heart. (18)
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 hallucitations
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.
9
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 injection.(20)
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 effects.(21)
Higher level of plasma concentration or excessive absorption of local anaesthetics by
systemic circulation leads to cardiotoxicity which follows a biphasic 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 contractitle dysfunction
ultimately leading to cardiovascular collapse.(22)
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
intrinisic vasoactivity.(23)
Due to accidental intravascular injection (particularly with injection into the carotid
or vertebral arteries) of local anaesthetics, systemic toxicity occurs, premonitoring
10
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 < 5µg/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 µg/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 output.(24) Electrical
disturbances resulting from toxic systemic levels of local anaesthetics include sinoarterial, and atrio- ventricular 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
dissociation.(25) 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
arrest.(26)
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 toxicity is the avoidance of accidental intravascular
injections.
11
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
injured.(22)
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 suggest that most peripheral
nerve blocks are performed with significantly larger doses than are necessary to achieve
desired clinical points.(1)
“Maximum recommended doses” for peripheral blocks have been recommended by
the manufactures, but this scientific basis has been questioned.(14)
Of particular concern is the observation that blood levels cannot be predictated 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 essential.(27)
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.
12
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 block. (3)
Immediate intervention at the earliest sign of local anaesthetic toxicity is of
paramount importance and improves the chances of successful treatment.(28) In the patient
with suspected local anaesthetic toxicity , the first step is to ensure adequate ventilation
and oxygenation, since hypoxemic and hypercarbina 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 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 seizures.(29) 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 LAST. (17)
13
When other measures fail to reestablish the indepentant circulation in the treatment of
LAST, early in the resuscitation sequence , it is well advised to consider a cardiopulmonary by pass. Cardio-pulmonary by pass has served patients with, otherwise fatal
LAST.(29)
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 toxicity. (30)
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 LAST.(32)
In 2010, the American Society of Regional Anesthesia and Pain Medicine published
its practice advisory on LAST.(1)
These guidelines emphasize the importance of airway management and early cardio
pulmonary resuscitation. They strongly advice 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.
14
Even though Advanced Cardiac Life Support (ACLS) guidelines now support the use
of vasopressin (40 µ in a single intravenous dose) in addition to epinephrine during cardio
pulmonary resuscitation, Derek Dillane etal do not recommend its use in local anaesthetic
induced toxicity. The efficacy and safety of vasopressin in cardiac arrest is controversial,
while laboratory data and human trials fail to provide conclusive evidence.(11)
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 therapy.(33)
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 tissuses through improved tissue perfusion. Maintenance of
cardiac output and oxygen delivery to tissues is critical for prevention and treatment of
acidosis. (1)
Emerging targets:
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 (1) the extensive use of local anaesthetics (2) the frequent use of doses
sufficient to cause significant morbidity or mortality and (3)the imperfect nature 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 occur.(1)
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.
15
Prevention of LAST remains a milestone during the performance of peripheral nerve
blocks. (9)
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 guidelines. (34)
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 non-anesthesiology 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 LAST. (35)
References:
1. Neal J M, Bernards C M, Butterworth J F, 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 H C. 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 R H. Local anesthetics. 1st edition. St.Louis: Mosby, 1994. p.346-7.
5. Mclure H A, Rubin A P. Review of local anesthetic agents. Minerva Anestesiol 2005;
71(3): 59-74.
16
6. Aldrete J A, 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. Nesek –Adam V, Markic A, Sakic K, Grizelj Stojcic E, Mrsic V, Tonkovic D. Local
anaesthetic toxicity. Period biol, 2011; 113 (2): 141-146.
8. Dippenaar J M. Local anesthetic toxicity. SAJAA 2007; 13 (3): 23-28.
9. Mulroy M F. Systemic Toxicity And Cardiotoxicity From Local Anesthetics:
Incidence and Preventive Measures. Reg Anesth Pain Med 2002; 27(6): 556–61.
10. Schwartz D, VadeBoncouer T, WeinbergG. Was Case Report a Case of Unrecognized
Local Anesthetic Toxicity? Anesth Analg 2003; 96(6):1844-5.
11. Dillane D, Finucane B T. Local anesthetic systemic toxicity. Can J Anesth / J Can
Anesth 2010; 57(4): 368-80.
12. Benumof J L, Saidman L J. Anesthesia & Perioperative Complications. 2nd edition.
St. Louis: Mosby, 1999. p.72.
13. Nimmo W S, Rowbatham D J, Smith G. Anaesthesia. 2nd edition. London: Oxford
Blackwell Scientific Publications, 2001.p. 1396.
14. Rosenberg P H, Veering B Th, Urmey W F. Maximum Recommended Doses of Local
Anesthetics: A Multifactorial Concept. Reg Anesth Pain Med 2004; 29(6): 564-75.
15. Barash P G, Cullen B F , Stoelting R K, Cahalan M K, Stock M C. Clinical
Anesthesia. 6th edition. Philadelphia: Wolters Kluwer, Lippincott Williams &
Wilkins, 2009 .p. 542.
16. Covino B G. Systemic Toxicity of Local Anesthetic Agents Editorial. Anesth Analg
1978; 57(4):387-8.
17. Morau D, Ahern S. Management of Local Anesthetic Toxicity. International
Anaesthesiology Clinics, 2010; 48 (4): 117-40.
18. Guyuron B, Eriksson E, Persing J A, Chung KC, Disa J J, Gosain A K, Kinney B M,
Rubin JP. Plastic Surgery: Indications and Practice. 1st edition. Asia: Saunders, 2009.
p.51.
17
19. Hadzic A, Vloka J D. Hadzic's Peripheral Nerve Blocks and Anatomy for UltrasoundGuided 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): 387–93.
21. Lirk P, Hollmann M W. 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): 336–42.
24. Stoelting R K. Pharmacology and Physiology in Anesthetic Practice. 3rd edition.
Philadelphia: Lippincott –Raven; 1999.p.169.
25. Lobato E B, Gravenstein N, Kirby R R. Complications in Anaesthesiology. 1st edition.
Philadelphia: Wolters Kluwer, Lippincott Williams & Wilkins, 2008.p.868
26. Chelly J E. Peripheral Nerve Blocks. 3rd edition. Philadelphia: Wolters Kluwer,
Lippincott Williams & Wilkins, 2009.p.15.
27. Mulroy M F, Hejtmanek M R.. Prevention of Local Anesthetic Systemic Toxicity. Reg
Anesth Pain Med 2010; 35 (2): 177-80.
28. Feldman H S, Arthur G R, 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, O’connor 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.
18
32. Resuscitation Council (UK) Cardiac Arrest or cardiovascular collapse caused by local
anesthetic. Available at http://www.resus.org.uk/pages/caLocalA.htm. [Cited 2008]
33. Corcoran W, Butterworth J, Weller R S, 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 H M, Jacob A K, Segura L G, Dilger J A, Torsher LC. Simulation Education in
Anesthesia Training: A Case Report of Successful Resuscitation of BupivacaineInduced 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.