PHARMACOLOGY FACTS
Local Anesthetic Systemic Toxicity:
Reviewing Updates From the American
Society of Regional Anesthesia and Pain
Medicine Practice Advisory
Rachel C. Wolfe, PharmD, Alexander Spillars
THE AMERICAN SOCIETY OF REGIONAL
ANESTHESIA (ASRA) and Pain Medicine recently
published updated guidance on the management
of local anesthetic systemic toxicity (LAST).1,2
Organ systems that are primarily disrupted by
toxic doses of local anesthetics include the
cardiovascular system and central nervous system
(CNS). Mild prodromal symptoms may progress to
major complications such as seizures, cardiac
arrest, or death. Treatment is multifactorial and
involves the use of 20% lipid emulsion therapy as
the antidote.3 The updated practice advisory shares
information about contemporary knowledge on the
mechanism of lipid emulsion reversal along with re-
structured guidance as it relates to prevention,
detection, and treatment of LAST.
The use of local anesthetics is widespread among
health care facilities. With initiatives to reduce
opioid consumption and incorporate multimodal
therapy into pain management pathways, local an-
esthetics are becoming a prominent tool in the
analgesia toolbox.4 Potential benefits of local an-
esthetics include reduced exposure to opioids,
decreased postoperative nausea and vomiting,
reduced incidence of persistent postoperative
pain, decreased hospital length of stay, and an
overall improvement in patient satisfaction and
quality of surgical recovery.5,6 Although local
anesthetics have potential to provide countless
benefits, their use is not without risk. Toxicity
associated with these agents may occur, and may
Rachel C. Wolfe, PharmD, BCCCP, Pharmacy Department,
Barnes-Jewish Hospital, St. Louis, MO; and Alexander Spillars,
St. Louis College of Pharmacy, St. Louis, MO.
Conflict of interest: None to report.
Address correspondence to Rachel C. Wolfe, One Barnes-
Jewish Hospital Plaza, Mailstop 90-52-411, St. Louis, MO
63110; e-mail address: rachel.wolfe@bjc.org.
Ó 2018 by American Society of PeriAnesthesia Nurses
1089-9472/$36.00
https://doi.org/10.1016/j.jopan.2018.09.005
1000
be potentially life-threatening. Published case re-
ports from 2010 to 2014 evaluating the outcomes
of LAST indicated nearly a 10% mortality rate.
Only one of the six patients that died received
lipid emulsion therapy.7 Innovative regional tech-
niques, advances in local anesthetic formulations,
and local anesthetic-based therapy plans have re-
sulted in increased use of local anesthetics in
and out of perioperative and procedural areas.
Despite enhanced knowledge related to preven-
tion, detection, and treatment, LAST remains to
be a serious adverse event that warrants educa-
tion of all perioperative health care clinicians.
This review aims to impart knowledge on the
risk factors, signs, symptoms, and pharmacologic
interventions associated with local anesthetic
toxicity.
The overall reported incidence of local anesthetic
toxicity is derived from registry studies, administra-
tive databases, case reports, and case series. In
2017, M€ orwald et al8 used an administrative data-
base, surrogate markers, and International Classifi-
cation of Disease Codes from over 400 hospitals for
nearly 238,500 patients who received a peripheral
nerve block for total joint arthroplasty between
2006 and 2014. The overall incidence of LAST, as
defined by occurrence of cardiac arrest, seizure,
or administration of lipid emulsion on the day of
surgery was 1.8 per 1,000 peripheral nerve blocks.
During the 9-year study period, the overall inci-
dence of LAST trended down. Advances in localiza-
tion techniques, such as ultrasound-guided blocks,
and implementation of safety steps that reduce
intravascular injection of local anesthetics are
thought to contribute to this decline. In compari-
son to this administrative database study, Gitman
and Barrington9 conducted a review of published
cases and online registries between 2010 and
2016. The incidence of LAST reported was 0.3
per 1,000 peripheral nerve blocks. Although the
Journal of PeriAnesthesia Nursing, Vol 33, No 6 (December), 2018: pp 1000-1005
PHARMACOLOGY FACTS
frequency of LAST appears to be low, every institu-
tion or clinic using local anesthetics should be pre-
pared to manage such an event, should it occur.
Pharmacology and Pharmacokinetics
Pharmacologically, local anesthetics exert their ef-
fect by blocking voltage-gated sodium channels at
the alpha-subunit, preventing sodium influx, depo-
larization, and action potential generation. Block-
ing this conduction prevents pain transmission
from neuronal cells to the cerebral cortex, ulti-
mately producing local anesthesia.10 Cardiac
toxicity is hypothesized to occur when local
anesthetics inhibit sodium channels in the myocar-
dium leading to conduction disturbances, ventric-
ular arrhythmias, contractile dysfunction, and
ultimately cardiac arrest.11,12 Neurotoxicity is
thought to occur when local anesthetics bind to
thalamocortical neurons in the brain. This leads
to altered mental status, paresthesia, visual
changes, muscle twitching, and seizures.13
All local anesthetics can produce systemic toxicity,
although the ratio of cardiovascular to CNS
toxicity varies among them. Potential causes of
toxicity include accidental intravascular injection,
absorption from a tissue depot, repeated adminis-
tration of local anesthetics (commonly by different
health care clinicians) without balanced elimina-
tion, and inadvertent enteral or mucosal absorp-
tion. The pKa, lipophilicity, and protein binding
all contribute to individual pharmacokinetic differ-
ences and toxicity profiles. A lower pKa indicates
that a greater proportion exists in the uncharged
state. Uncharged molecules readily cross the lipo-
philic cellular membrane to the effector site,
yielding a faster onset. Lipophilicity correlates to
potency. More potent local anesthetics induce car-
diac toxicity because the higher lipophilicity al-
Table 1. Characteristics of Common Local Anesthetics5,14-16
Local Onset Protein Duration
Anesthetic Class pKa Time Binding of Action Lipophilicity
Lidocaine Amide 7.8 Fast 11 Moderate
Bupivacaine Amide 8.1 Slow 1111 Long
Ropivacaine Amide 8.1 Slow 111 Long
Mepivacaine Amide 7.7 Fast 11 Moderate
Chloroprocaine Ester 8 Fast 1 Short
1001
lows for better penetration across the lipid
bilayer to the target receptor. Finally, a higher affin-
ity for protein binding decreases the circulating
levels of free local anesthetic. This translates to
an increased duration of action (Table 1).14-16
Clinical Presentation
Classical presentation of local anesthetic toxicity
emerges on a continuum, beginning with mild, sub-
jective prodromal symptoms such as perioral numb-
ness, metallic taste, muscle twitching, and anxiety
that progressively worsens to more severe complica-
tions such as seizures and cardiac arrest as local anes-
thetic concentrations in the blood increase
(Figure 1). The clinical spectrum of LASTwas charac-
terized in a retrospective study encompassing a 30-
year period from 1979 to 2009. In this study, 60%
of cases followed the classic presentation.17 Gitman
and Barrington categorized presenting symptoms
and discovered that CNS features, particularly sei-
zures, were the most common. Frequency of pre-
senting features, in order of prevalence, includes
isolated neurologic symptoms (43%), combined car-
diovascular and neurologic symptoms (33%), and
isolated cardiovascular symptoms (24%).9 Because
of substantial variation in the classical presentation,
health care practitioners must be vigilant for atypical
presentations of LAST.
The timing of LAST presentation is also variable. Fea-
tures presenting within 1 minute suggest direct intra-
vascular injection of local anesthetics. It is speculated
that these events are less frequent because of the use
of ultrasound guidance during the placement of
blocks. Noted in the literature, however, is a shift to-
ward delayed presentation. Mildly delayed presenta-
tion may indicate intermittent intravascular
injection, lower extremity injection, delayed tissue
absorption, or absorption from a combination of
Max Dose Max Dose
(Plain) w/Epi
Potency (mg/kg) (mg/kg)
11 Moderate 4.5 7
1111 Potent 2.5 3
111 Potent 3 3.5
11 Moderate 4.5 7
11 Moderate 11 14
1002 WOLFE AND SPILLARS

Anxiety

Visual
Hypotension
changes

Auditory Hypertension
Drowsiness Braydcardia
changes

CNS Metallic CNS Cardiac Cardiac Conducon

Seizures Coma Tachycardia
Excitement taste Depression Excitement Depression block

Perioral Respiratory Ventricular Decreased

paresthesia arrest arrhythmias contraclity

Muscle
Asystole
twitching

Agitaon

Figure 1. Classical description of local anesthetic systemic toxicity. This figure is available in color online at www.
jopan.org.

routes or locations. Presentations characterized by
delays of several minutes to hours may be because
of the use of multiple local tissue infiltration sites or
use of continuous local anesthetic infusions (neurax-
ial, perineural, or intravenous). Overall, the timing of
LAST presentation is highly variable and should be
suspected whenever physiological changes occur af-
ter, or simultaneous with, administration of a local
anesthetic.
A thorough review of nearly four decades of re-
ported cases of LAST has confirmed the expected
clinical presentation of toxicity while also
providing insight into the unexpected. Reported
cases support that toxicity events are skewed to
the extremes of age (infants and the elderly), rein-
forcing the recent finding that large amounts of
local anesthetics are stored in skeletal muscle,
making patients with low muscle mass at risk
for LAST. In addition, all local anesthetics are
capable of causing toxicity and it is probably
that when viewed on an equipotent basis, ropiva-
caine is likely similar in toxicity to bupivacaine.
Nonetheless, vigilance with regard to dosing
and safety steps is needed for all local anesthetics,
even those purportedly to be less toxic. As a
result of the review, pattern changes in LAST pre-
sentation were revealed. Approximately 15% of
recent toxicity events involved a continuous local
anesthetic infusion with toxicity presenting 1 to
4 days after initiation of therapy. It was also noted
that an increasing number of events (20%) are
occurring outside the traditional hospital setting,
half of which involved a nonanesthesiologist.1,18

Table 2. American Society of Regional Anesthesia Guidance on Local Anesthetic Systemic

Toxicity (LAST)2
Be Sensible
 Use the lowest effective dose of local anesthetic
 Identify patients at risk for LAST
 Consider using a pharmacologic marker (eg, epineph-
rine) to assist in identifying intravascular injection
 Aspirate the syringe before each injection while
observing for blood in the syringe or tubing
 Inject incrementally, while observing for signs and
inquiring for symptoms of toxicity between each in-
jection
 Be aware of additive nature of local anesthetics and
adjust accordingly
 Consider discussing local anesthetic dose as part of the
preprocedural or presurgical time out
 Use ultrasound guidance when possible to reduce the
risk of LAST
Be Vigilant
 Monitor the patient during and after completing in-
jection. Observe for at least 30-45 min after the block
 Communicate frequently with the patient to query for
symptoms of toxicity
 Consider LAST in any patient with changes in neuro-
logic or cardiovascular status after regional anesthesia
or local anesthesia with
1. Small doses in susceptible patients
2. Atypically administered doses (eg, subcutaneous,
mucosal, and topical)
3. Doses administered by surgeon or nonanesthesia
clinician
4. Recent tourniquet deflation
PHARMACOLOGY FACTS 1003

Table 3. Key Differences in the 2010 and 2018 Local Anesthetic Systemic Toxicity Checklists2,21,22
Timing of lipid emulsion therapy
Timeframe for postevent monitoring
20% Lipid emulsion dosing
Upper limit of lipid emulsion
therapy
Resuscitation is different than
standard advanced cardiac life
support
Alert the cardiopulmonary
bypass team
LAST rescue kit
ASRA, American Society of Regional Anesthesia; CNS, central nervous system; IV, intravenous; LAST, local anesthetic
systemic toxicity.
2010
Consider on the basis of clinical
severity and rate of progression of
LAST
Significant LAST should be observed
for .12 h
 1.5 mL/kg bolus followed by
0.25 mL/kg/min infusion,
continued for at least 10 min after
circulatory stability is attained
 If circulatory stability is not at-
tained, consider rebolus and
increasing infusion to 0.5 mL/kg/
min
Approximately 10 mL/kg
Differentiation not made in 2010
although incorporated in the 2012
revised checklist
Not incorporated into the 2010
checklist
Incorporated in the 2012 revised
checklist under ‘‘Initial Focus’’
Not mentioned
2018
Consider administering at the first
sign of a serious LAST event
Monitor at least 4-6 h after a significant
cardiovascular event
Monitor at least 2 h after a CNS event
that resolves quickly
 Patients weighing $70 kg: 100 mL
IV bolus followed by an IV infusion
of 200-250 mL over 15-20 min
 Patients weighing , 70 kg: 1.5 mL/
kg IV bolus followed by 0.25 mL/
kg/min IV infusion dosed on ideal
body weight
 If patient remains unstable, rebolus
once or twice at the same dose and
double the infusion rate
Do not exceed 12 mL/kg, particularly
important in the small adult or child
Displayed at the top of the checklist
and includes simplified drug-
specific dose modifications (reduce
epinephrine bolus to , 1 mcg/kg;
avoid vasopressin, beta-blockers,
calcium channel blockers, and
other local anesthetics)
Moved higher on the checklist,
coincident with calling for help
Suggest contents of a LAST rescue kit
 1 L (total) lipid emulsion 20%
 Several large syringes and needles
for administration
 Standard IV tubing
 ASRA LAST Checklist

Although no single measure can prevent LAST in
clinical practice, ASRA recommends to be sensible
and vigilant (Table 2). Patients at risk for LAST
include infants, elderly, patients with low body
mass index, heart failure, ischemic heart disease,
conduction abnormalities, rhythm disorders, meta-
bolic disease, liver disease, low plasma protein
concentration, and acidosis.1,2 Use of lidocaine
4% topical is common in the perioperative and
procedural areas and commonly administered in
the at risk population. Although it is often
perceived to be without risk, overdosing or
swallowing the medication may result in toxicity.
As a result, use of lidocaine 4% necessitates
extreme vigilance including clarity around
dosing, clear administration instructions, and
confirmed patient understanding to prevent
toxicity events from occurring.
Treatment
The ASRA practice advisory guidelines unequivo-
cally recommend lipid emulsion therapy
following airway protection in the management
1004
of any LAST event judged to be potentially
serious. This differs from the 2010 guidelines sec-
ondary to evidence that lipid emulsion therapy is
most effective early in the toxic event.3 The pre-
cise mechanism of lipid emulsion therapy acting
as lipid resuscitation in LAST is not fully under-
stood. The most current research believes that
lipid emulsion works as a carrier to move local
anesthetic away from high blood flow organs
that are sensitive to local anesthetics such as
the heart and the brain. This is known as the
‘‘shuttling effect’’ as positively charged fat-
soluble local anesthetic molecules bind to nega-
tively charged lipid particles. This complex is
then redistributed to the muscle for storage and
to the liver for detoxification.3,19,20
Lipid emulsion therapy in the updated guidelines
is simplified. It includes a fixed 100 mL bolus fol-
lowed by the infusion of 200 to 250 mL over 15
to 20 minutes for all patients weighing more than
70 kg. Weight-based dosing is reserved for patients
weighing less than 70 kg. Although the precise vol-
ume and flow rate are not critical, the guidelines
recommend not to exceed 12 mL/kg. Airway man-
agement is also highlighted as a treatment recom-
mendation because hypoxia, hypercapnia, and
acidosis can potentiate LAST. For the management
of seizures, benzodiazepines are preferred.
Small doses of propofol may be used as an alterna-
tive if benzodiazepines are not readily available. In
the event cardiac arrest occurs, the guidelines
make it clear that the pharmacologic treatment
of LAST is different from other cardiac arrest sce-
narios. Specifically, epinephrine bolus doses
should be reduced to 1 mcg/kg or less and medica-
tions such as vasopressin, beta-blockers, calcium
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WOLFE AND SPILLARS
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table (Table 3).2,21
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