Journal of Anesthesia

https://doi.org/10.1007/s00540-018-2542-4

GUIDELINE

Practical guide for the management of systemic toxicity caused

by local anesthetics
Safety Committee of Japanese Society of Anesthesiologists1

Received: 18 February 2018 / Accepted: 4 August 2018

© Japanese Society of Anesthesiologists 2018

Abstract
Systemic toxicity from local anesthetics can occur in any of the wide range of situations in which these agents are used.
This practical guide is created to generate a shared awareness of the prevention, diagnosis, and treatment of local anesthetic
systemic toxicity among all medical professionals who perform nerve blocks. Systemic toxicity of local anesthetic is induced
by an increase of its protein-unbound plasma concentration. Initial symptoms are characterized by central nervous system
signs such as excitation, convulsions, followed by loss of consciousness and respiratory arrest. These symptoms are often
accompanied with cardiovascular signs such as hypertension, tachycardia and premature ventricular contractions. Further
increase of plasma concentration of local anesthetic induces bradycardia, conduction disturbances, circulatory collapse and
asystole. The incidence of local anesthetic systemic toxicity is 1–11 cases per 10,000. Infants, patients with decreased liver
function and low cardiac output are vulnerable to systemic toxicity. When performing regional anesthesia, the guideline-
directed monitoring, securing a venous line, preparation of medication to treat convulsions and lipid emulsions are required.
For prevention of local anesthetic systemic toxicity, small-dose, divided administration, using agents with low toxicity
such as ropivacaine and levobupivacaine, performing an aspiration test are recommended. If systemic toxicity is suspected,
halt administration of local anesthetic, request assistance, secure venous line, airway, administration of 100% oxygen and
if necessary tracheal intubation and artificial respiration should be immediately performed. Benzodiazepines are recom-
mended to treat convulsions. Administration of 20% lipid emulsion according to the protocol is recommended to treat severe
hypotension and arrhythmia.

Keywords  Local anesthetic · Systemic toxicity · Central nervous system · Cardiovascular · Lipid emulsion

Introduction meant to controvert the validity of clinical decisions or med-

ical actions that deviate from it, and was not formulated to
This practical guide not only addresses anesthetic manage- inform decisions regarding legal liability.
ment performed by members of the Japanese Society of The content of this practical guide is based on the knowl-
Anesthesiologists (JSA), but can also be referenced dur- edge of and treatment methods for local anesthetic systemic
ing any procedure performed in Japan involving the use of toxicity at the time it was created (June 2017). Because these
local anesthetics when making clinical decisions to address will likely change over time, appropriate revisions should
systemic toxicity caused by these agents that could or has be made.
already occurred. However, this guide is not intended to The individuals involved in creating this practical guide
standardize how local anesthetic systemic toxicity is man- have no financial disclosures or conflicts of interest to
aged, nor does providing medical care based on its content declare.
guarantee a positive prognosis. Therefore, this guide is not
Process of formulating this practical guide
* Safety Committee of Japanese Society of Anesthesiologists
[email protected] The development of rapid-onset general anesthetics
has led to a heightened awareness of the importance of
1
Japanese Society of Anesthesiologists, Kobe KIMEC Center postoperative analgesia. Furthermore, an increase in the
Building 3F, 1‑5‑2 Minatojima‑Minamimachi, Chuo‑ku, number of patients with complicated heart diseases or
Kobe 650‑0047, Japan

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 Journal of Anesthesia

cerebrovascular lesions, and in patients taking antiplatelet and has reportedly saved the lives of numerous patients and,
agents or anticoagulants in the perioperative period to pre- therefore, merits consideration.
vent deep vein thrombosis, has created more opportunities
for selecting peripheral nerve block over epidural anesthe-
sia. Moreover, there have been many reports of surgery Purpose
being performed safely in patients with severe complica-
tions using only regional anesthesia to anesthetize a spe- This practical guide is not only intended for anesthesiolo-
cific and limited area. In ultrasound-guided nerve blocks, gists, but was created to generate a shared awareness of the
it is possible to visually confirm the precise anatomical prevention, diagnosis, and treatment of local anesthetic sys-
relationship between the needle tip and the nerve, which temic toxicity among all medical professionals who perform
has helped increase the success rate of nerve blocks and nerve blocks. The content of this practical guide has been
has made this method widely used not only among anes- scientifically scrutinized and the JSA has endorsed its con-
thesiologists, but particularly among orthopedic surgeons. tent. Sharing information with JSA members and other read-
Reported frequencies of systemic toxicity caused by ers will help raise the level of medical care. Accordingly,
local anesthetic(s) vary widely, from approximately 1/500 while this practical guide should be referenced to prevent,
to 1/10,000, due to the lack of a standard definition for quickly diagnose, and treat local anesthetic systemic toxicity
local anesthetic systemic toxicity, and because incidence when performing regional anesthesia using local anesthetics,
rates differ depending on the block technique and location. the decisions that need to be made in each clinical situa-
While precise figures are not available, there have been tion ultimately rest with the individual reader. The checklist
rare cases that progressed to circulatory collapse. Systemic included at the end of the guide is intended to help practi-
toxicity from local anesthetics can occur in any of the wide tioners provide treatment confidently and without hesitation
range of situations in which these agents are used. While in dangerous situations when systemic toxicity from local
it has been reported that ultrasound-guided nerve block anesthetic occurs. Thus, an easy-to-read, practical card that
reduces the frequency of local anesthetic toxicity, the cas- can be posted in an operating room was created.
ual use of large doses of local anesthetics in nerve blocks As new information regarding the mechanisms of local
without fully understanding the properties and toxicities anesthetic toxicity onset and/or treatment becomes available,
of these drugs is extremely dangerous. Thus, creating a this practical guide should be updated and revised accord-
standard protocol to prevent, diagnose, and appropriately ingly. To improve patient safety, the information in this prac-
treat systemic toxicity from local anesthetics carries great tical guide should be understood by all medical professionals
significance. who use local anesthetics.
To date, there have been no independent guidelines in
Japan for addressing and managing systemic toxicity caused Evidence level
by local anesthetics. In June 2010, the European Board of
Anaesthesiology and European Society of Anaesthesiology, Ideally, guidelines are based on a high level of evidence;
with the support of the World Health Organization, World however, the incidence of local anesthetic toxicity is exceed-
Federation of Societies of Anaesthesiologists, and European ingly low, and randomized clinical trials involving human
Patients Association, jointly proposed “The Helsinki Decla- subjects regarding therapies for serious cases of local anes-
ration on Patient Safety in Anaesthesiology” [1], which was thetic toxicity have not been performed. The literature that
signed by the Japanese Society of Anesthesiologists (JSA) forms the basis of this guide includes the results of animal
in June 2015. In this document, creating protocols for anes- experiments, case reports, reviews, and recommendations
thesia safety is listed as a principal requirement; accordingly, by specialists. Consequently, evidence or recommendation
the JSA created this “Practical guide for the management of levels are not listed in the references for this practical guide.
systemic toxicity caused by local anesthetics” as part of its
guidelines project.
Overseas, the American Society of Regional Anesthesia
and Pain Medicine [2] and the Association of Anaesthe- Preventing systemic toxicity from local
tists of Great Britain and Ireland [3] have formulated guide- anesthetics
lines on dealing with local anesthetic systemic toxicity; the
content of the present practical guide largely follows these Preventing systemic toxicity from local anesthetics should
overseas guidelines. The recommended treatments for local be a primary concern because toxicity may lead to serious
anesthetic systemic toxicity in these guidelines include lipid disability [5]. It is needed to consider patient background,
emulsion. While the effectiveness of this therapy is not sup- characteristics of local anesthetics, administration routes,
ported by a high level of evidence [4], it is a simple method and purposes for preventing systemic toxicity.

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Journal of Anesthesia

Background pathology of patients who receive local the racemic mixture bupivacaine because toxicity symptoms
anesthetics are more likely to appear with the latter [10].

The appearance of the effects of local anesthetics and sys-

Performing an aspiration test after puncture
temic toxicity thresholds can change depending on the
patient’s condition. In states of acidosis, there is an increase
It is preferable to perform an aspiration test from the punc-
in cationic forms of the anesthetic, which makes passage
ture needle or catheter when administering local anesthet-
through cell membranes more difficult, thereby delaying
ics to guard against intravascular administration. However,
onset of the effect. Moreover, a decreased protein binding
performing an aspiration test will not necessarily prevent
rate means an increase in unbound fraction, which leads to a
intravascular administration. Intravascular administration of
higher likelihood of systemic toxicity. Compared with older
local anesthetics has been reported even when blood back-
children and adults, infants have lower levels of metabolic
flow is not observed when an aspiration test was performed
enzyme activity in the liver. Moreover, metabolic enzyme
upon insertion of a continuous epidural catheter [11].
activity can decline in the presence of liver dysfunction;
therefore, increased caution is needed in such cases. In addi-
tion, when administering a large dose of an ester-type local Methods of detecting intravascular administration
anesthetic(s) to patients with liver dysfunction, reduced lev-
els of plasma cholinesterase causes the blood concentration Administering a small dose of local anesthetic as a test
of free-base local anesthetics to rise, also requiring increased dose before the intended dose may help prevent inadvert-
caution [6]. Patients with heart failure exhibit slower cir- ent intravascular or intrathecal administration. If heart
culation, which can cause the tissue concentration of local rate increases ≥ 10 beats/min, or systolic blood pressure
anesthetics to rise [2]. increases ≥ 15 mmHg after administration of 10–15 µg of
adrenalin (0.5 µg/kg for children) into a continuous epidural
Reducing the dose of local anesthetics catheter, there is a high likelihood that intravenous adminis-
tration has occurred [12]. However, if the patient is taking a
According to the United States Food and Drug Adminis- β-blocker, is elderly, or is sedated—all of which are associ-
tration, limiting the dose of local anesthetics is the most ated with lower heart rates—an increased heart rate may not
highly recommended method of preventing toxicity [7]. be an ideal indicator. Administering local anesthetics with
Large doses of high-concentration local anesthetics are not adrenaline is a useful method of preventing intravascular
recommended for use in subcutaneous infusion anesthesia, administration from puncture needles or catheters. However,
epidural, or peripheral nerve blocks. Moreover, while phar- there is no evidence demonstrating that test doses can pre-
maceutical companies provide maximum tolerated doses for vent systemic toxicity.
local anesthetics, this can change depending on patient fac-
tors; therefore, caution should be exercised [8]. Because it
Using ultrasound imaging to assess the location
can be difficult to estimate the blood concentration of local
of the needle or catheter
anesthetics, administration by simply referencing the maxi-
mum tolerated dose per unit of body weight is not recom-
Using ultrasound imaging to confirm the location of the
mended. Doses less than the maximum tolerated dose should
puncture needle or catheter in peripheral nerve blocks is a
be administered.
useful method of preventing intravascular administration.
However, even if ultrasound imaging is used, and even if the
Small‑dose, divided administration
needle puncture is performed with the parallel approach (the
needle is clearly detected when placing the ultrasound probe
Local anesthetics may be administered in small doses, in
and needle parallel to one another), it will not necessarily
separate volumes of 3–5  mL, and observing the patient
prevent intravascular administration [13].
between doses. Rapid administration or injecting a bolus
dose using intense pressure increases the risk for inadvertent
injection into a vessel and may also cause nerve damage [9].
Diagnosing local anesthetic systemic toxicity
Using local anesthetics associated with less risk
for causing systemic toxicity The diagnosis of local anesthetic toxicity is based on clini-
cal features that appear after administration. Thus, care-
When using local anesthetics at high doses, selecting the ful observation and monitoring of the patient is important
(S)-isomers ropivacaine or levobupivacaine is preferable to (Fig. 1).

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Fig. 1  Diagnosis of local anesthetic systemic toxicity

Monitoring 6. Ensure the facility is always stocked with lipid emul-

sions.
When performing regional anesthesia, monitoring should 7. Know the location of the nearest facility that can per-
be performed according to monitoring guidelines from the form extracorporeal circulation.
JSA. Moreover, anesthetic preparations should be made 8. When local anesthetic systemic toxicity occurs, treat-
so symptoms of local anesthetic systemic toxicity can be ment will need to be initiated quickly and assistance will
managed adequately and treated quickly [2, 14]. be required; therefore, when performing regional anes-
thesia, do so in an environment where multiple medical
1. Perform regional anesthesia under the condition that staff are present.
oxygen administration and airway management are
promptly available. Prepare the tools needed for anesthe- Signs, symptoms
sia and artificial ventilation, such as a bag-mask. Ensure
that the tools needed for endotracheal intubation, such as Central nervous system signs and symptoms [3, 6, 9, 15]
a laryngoscope and endotracheal tube, are readily avail- Initially, symptoms of excitation caused by blockade of
able for use at any time. the inhibitory neurons, such as tongue and lip numbness,
2. Attach an electrocardiograph monitor and pulse oxime- metallic taste in the mouth, talkativeness, difficult articula-
ter to the patient. tion, agitation, dizziness, sight and hearing impairments,
3. As a rule, measure blood pressure every 5 min. unsteadiness, and convulsions are manifested by local
4. Secure a venous line. anesthetics. After this, blockade of the excitatory route
5. Prepare medication to treat convulsions (i.e., midazolam, occurs, which is accompanied by inhibitory symptoms
diazepam, or barbital). such as delirium, loss of consciousness, and respiratory

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Journal of Anesthesia

arrest. In approximately 60% of cases, typical neurologi- Differential diagnosis

cal symptoms worsen gradually; however, convulsions or
cardiac arrest can occur more precipitously. Table 1 summarizes the symptoms and the corresponding
Cardiovascular signs and symptoms The initial neuro- conditions typically observed based on the type of regional
logical symptoms may be accompanied by hypertension, anesthesia performed, the amount of drug solution, and other
tachycardia, and premature ventricular contractions. This factors.
is followed by signs of inhibition, such as sinus brady-
cardia, conduction disturbances, circulatory collapse, and
asystole. However, in some cases, such as direct injection Treating local anesthetic systemic toxicity
of local anesthetic into a blood vessel, circulatory collapse
may occur without any neurological signs. Characteristic Facilities that use local anesthetics should maintain a stock
electrocardiographic signs are PR prolongation and QRS of 20% lipid emulsion in their pharmacies [2, 3]. Depart-
widening. ments that use local anesthetics frequently (surgery, obstet-
Atypical symptoms Only 16% of patients present with rics) should maintain a stock of lipid emulsion (stored at
precursor symptoms and, in 41%, signs and symptoms are room temperature) that can be used immediately (Fig. 2).
delayed or circulatory symptoms appear without neurolog-
ical symptoms [15]. Such atypical symptoms are associ- A. If local anesthetic toxicity is suspected, perform the fol-
ated with the preoperative presence of underlying diseases lowing:
involving the cardiovascular or nervous systems. In addi-
1 Halt administration of the local anesthetic.
tion, detection of symptoms may be delayed with general
2 Request assistance.
anesthesia or deep sedation; caution therefore, is needed.
3 Attach blood pressure monitor, electrocardiograph,
pulse oximeter.
4 Secure venous line.
Time until local anesthetic systemic toxicity appears
5 Secure an airway and administer 100% oxygen; if
necessary perform tracheal intubation and initiate
The time taken for systemic toxicity to appear varies [15].
artificial respiration.
Symptoms appear in one-half of cases within 50  s of
6 Treat convulsions (benzodiazepines are recom-
administration and in three-quarters of cases within 5 min.
mended; propofol cannot be used in patients with
There are immediate types caused by direct intravascu-
unstable blood pressure, heartbeat).
lar injection, and delayed types that occur after the drug
7 Collect blood to measure blood concentration of
migrates from tissue or active metabolites accumulate. In
local anesthetics (if time and resources permit).
immediate types, onset is caused by injection into a head
or neck vessel, such as the carotid or vertebral arteries. In
B. If severe hypotension or arrhythmia occurs:
delayed types, onset after an overdose occurs after a grad-
ual rise in blood levels. Onset may not occur for several 1 Administer 20% lipid emulsion according to the
days after starting continuous infusion. With single admin- method described below.
istration, onset sometimes does not occur until 15 min or 2 Initiate resuscitation according to standard proce-
more after administration; therefore, when large doses are dures.
used, patients should be observed for at least 30 min. 3 Prepare for extracorporeal circulation.

Table 1  Summary of typical Reaction Symptom/condition

reactions and symptoms
associated with systemic Reactions to vasoconstrictors Tachycardia, hypertension, headache, uneasiness
toxicity from local anesthetics
Vagal reflex Sudden bradycardia, hypotension, pallor, fainting
Allergy Anaphylaxis (hypotension, bronchospasm, edema)
High-level spinal anesthesia, high Gradual appearance of bradycardia, hypotension, respiratory arrest
epidural anesthesia
Complications Asthma, stroke, myocardial infarction, etc.
Use of sedatives Talkativeness, difficult articulation due to benzodiazepine-linked
disinhibition, drowsiness, loss of consciousness, respiratory arrest
due to overdose

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 Journal of Anesthesia

Fig. 2  What to do when local

anesthetic toxicity occurs

If severe hypotension or arrhythmia are not observed, 1 Administer 1.5  mL/kg (100  mL) over approxi-
provide symptomatic treatment while continuing to con- mately 1 min. Then, initiate continuous administra-
sider administering lipid emulsion based on careful obser- tion at 0.25 mL/kg/min (17 mL/min approximately
vation of the patient [3]. In either case, transfer the patient 1000 mL/h).
to a place where he/she can be treated immediately, and 2 If circulation has not improved after 5 min, admin-
continue observation. ister 1.5 mL/kg (100 mL) while doubling the con-
tinuous administration dose to 0.5  mL/kg/min
C. Outline of lipid emulsion administration method (70 kg (2000 mL/h). After an additional 5 min, administer
patient) (Fig. 3) 1.5 mL/kg (100 mL) (bolus administration is limited
to 3 attempts).

Fig. 3  Lipid emulsion admin-

istration method when local
anesthetic toxicity occurs

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Journal of Anesthesia

3 Continue to administer lipid emulsion for 10 min toxic drugs were taken orally; consequently, absorption
after circulation is restored and stabilizes. occurred in the gastrointestinal tract and persisted over a
4 Studies have reported a resuscitation effect at a total long period of time. Thus, these patients often required
dose of ≤ 10 mL/kg [16]; therefore, 12 mL/kg can be large doses of lipid emulsion given over long periods.
used as an approximate estimate for the maximum Regarding serious side effects, severe bradycardia and
dose [3]. cardiac arrest have been reported soon after lipid emulsion
administration for toxicity caused by high-dose circulatory
D. Areas of caution agonists [21]; however, it is unclear whether the cause in
these cases was lipid emulsion. Furthermore, pulmonary
1. Do not use lidocaine to treat tachycardia or arrhyth-
impairment (100 mL) [22] and pancreatitis (10.5 mL/kg)
mia.
[23] have been reported in young patients when lipid emul-
2. To treat convulsions, benzodiazepines, thiopental, or
sion was used to treat drug toxicity not caused by local
propofol can be used; however, all should be admin-
anesthetics. In the former case, adrenaline administered
istered at low doses [3]. Although propofol contains
during resuscitation may have had an effect. Hemofiltra-
lipid emulsion as a solvent, it should not be used as
tion has been attempted after lipid emulsion administra-
a substitute for lipid emulsion because it acts as a
tion; however, filter clogging has been reported [24]. After
direct cardiac suppressant and its lipid concentration
administering lipid emulsion, respiratory status and chest
is as low as 10% [2, 3, 6].
radiographs should be given close attention, and tests for
3. The adrenaline dose should be based on resuscita-
lipase and amylase should be performed.
tion guidelines such as those of the American Heart
Association. The American Society of Regional Acknowledgements  This practical guide was created by the Japanese
Anesthesia and Pain Medicine standard of < 1 µg/ Society of Anesthesiologists working group on local anesthetic toxicity
kg does not need to be strictly adhered to [2]. guidelines: Kiyonobu Nishikawa, Yutaka Oda, Katsushi Doi, Norihiro
4. Note that resuscitation from local anesthetic sys- Sakai, and Kazuya Sobue.
temic toxicity can sometimes take a long time.
5. Lipid emulsion has been reported to be effective at Compliance with ethical standards 
similar doses per unit of body weight for both chil-
Conflict of interest  All authors have no conflict of interest.
dren and adults [16].
6. After starting lipid emulsion administration, the
blood concentration of local anesthetics may rise
temporarily compared with before administration
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