Drugs & Aging

https://doi.org/10.1007/s40266-019-00718-0

CURRENT OPINION

Local Anesthetic Toxicity in the Geriatric Population

Rachel Waldinger1 · Guy Weinberg1,2 · Marina Gitman1 

© Springer Nature Switzerland AG 2019

Abstract
This article provides a concise overview of local anesthetic systemic toxicity, its history, mechanisms, risk factors, prevention,
clinical presentation, and treatment, with a special emphasis on issues specific to the geriatric population. The authors used
MEDLINE, Scopus, and Google Scholar to search for original research articles (human and animal studies), registries data,
case reports, review articles, and pertinent online publications using the combinations of the following search terms: local
anesthetics, local anesthetic systemic toxicity, intralipid, lipid emulsion, Exparel, ultrasound-guidance, regional anesthesia,
lidocaine, bupivacaine, ropivacaine, cocaine, procaine, tetracaine, levobupivacaine, liposomal bupivacaine, lignocaine. Local
anesthetic systemic toxicity continues to occur despite the use of putatively less cardiotoxic formulations of local anesthetics
and more common use of ultrasound guidance. The elderly appear to be at a disproportionately increased risk for toxicity
owing to the presence of relevant comorbidities and decreased muscle mass. Examination of recent case reports involving
patients over the age of 65 years demonstrates that inadvertent overdosing is responsible for some cases of local anesthetic
systemic toxicity. Elderly patients are at increased risk of local anesthetic systemic toxicity. When considering use of local
anesthetics in older patients, special attention should be paid to the presence of systemic disease and muscle wasting. The
safety of regional anesthesia and multi-modal analgesia among these at-risk patients will be improved by educating physi-
cians and staff to recognize and manage local anesthetic systemic toxicity.

Key Points  1 Introduction

Despite advances in the diagnosis, treatment, and pre-
vention of local anesthetic systemic toxicity, it continues
to occur.
Elderly patients are at an increased risk for toxicity
as a result of comorbidities and a higher likelihood of
exposure.
Physicians should employ added caution when adminis-
tering local anesthetics to these patients.
* Marina Gitman
gitman@uic.edu; marina_gitman@yahoo.com
1
Department of Anesthesiology, University of Illinois
Hospital, 1740 W. Taylor St, Suite 3200W, Chicago,
IL 606012, USA
2
Research and Development Service, Jesse Brown Veterans
Affairs Medical Center, Chicago, IL 606012, USA
Local anesthetics (LAs) have been integral to the practice
of medicine since cocaine was first used for ophthalmologic
and dental anesthesia in the 1880s [1]. The incidence of
acute toxicity and risk for dependence prompted the devel-
opment of the amino-ester local anesthetic Novocain (pro-
caine) in 1905, but toxicity remained a problem [2]. A 1924
report sponsored by the American Medical Association doc-
umented 43 fatalities linked to the administration of LAs [3].
The introduction of the amino-amide bupivacaine into clini-
cal practice in the 1960s [4] was accompanied by a parallel
increase in reports of severe cardiovascular (CV) and cen-
tral nervous system (CNS) toxicity [5]. Many early reports
described fetal death and maternal cardiac arrest associated
with paracervical blocks and epidural anesthesia using bupi-
vacaine. Bupivacaine toxicity was noted for its rapid onset
of CV collapse and for being refractory to electrical defi-
brillation. The levo-rotatory enantiomers ropivacaine and
levobupivacaine are shown in certain non-clinical models
to be less cardiotoxic than bupivacaine, but like virtually
all LAs, their use can also result in severe local anesthetic

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systemic toxicity (LAST) [5]. Notably, many published cases
of LAST involve elderly patients.
People aged older than 65 years comprise 16% of the US
population and will exceed 56 million by 2020 [6]. Elderly
patients (aged older than 65 years) account for more than
one third of all surgeries in the USA. The rate of periopera-
tive complications increases with age, and patients over the
age of 80 years are especially vulnerable [7]. Local anesthet-
ics play a major role in the anesthetic care of the elderly.
Peripheral nerve blocks and neuraxial anesthesia are fre-
quently used for orthopedic procedures such as joint replace-
ments. Intravenous infusion of lidocaine (lignocaine) is now
a common component of a multi-modal analgesia regimen.
As more elderly patients undergo surgery, and the use of
local anesthetics increases, practice in this specific patient
population warrants a re-evaluation.
2 Pharmacology of Local Anesthetics
and Mechanism of Local Anesthetic
Systemic Toxicity
Local anesthetics reduce the sodium ion flux across plasma
membranes by binding to voltage-gated sodium channels
throughout the body, and inhibiting action potential propaga-
tion in neuronal axons and action potential cycles in cardiac
myocytes and the cardiac conduction system. These effects
contribute to the numbing and antiarrhythmic properties that
make local anesthetics clinically useful [5]. However, LAs
also inhibit a wide array of other ion channels, enzymes,
signaling systems, and drug receptors leading to pleiotropic
and potentially harmful effects at high blood and tissue
concentrations [5]. For instance, bupivacaine reduces the
production of secondary messengers such as cyclic adeno-
sine monophosphate and drives the rapid dephosphoryla-
tion of protein kinase B and the activation of 5′-adenosine
monophosphate kinase, an indication of depleted cellular
energy stores. The latter is expected because bupivacaine at
high tissue concentrations potently inhibits mitochondrial
oxidative phosphorylation and adenosine triphosphate pro-
duction by several mechanisms: blocking fatty-acid transport
into the mitochondria, degrading the proton motive force,
and directly inhibiting elements of the hydrogen-electron
transport system, including adenosine triphosphate synthase
[8]. This array of effects accounts for the predominant CNS
and CV signs of LAST as these organs are uniquely sensi-
tive to anaerobic metabolism. The resulting tissue adenosine
triphosphate depletion contributes to the potential clinical
severity of LAST and, presumably, the difficulty treating it.
High plasma concentrations of LAs also decrease systemic
vascular resistance, worsening cardiogenic shock and con-
tributing to CV collapse [8].
R. Waldinger et al.
3 Risk Factors
The frequency of patient-specific risk factors for LAST,
especially cardiac, liver, and kidney disease among older
patients contributes to the increased risk of LAST observed
in this population. Reduced muscle mass is another impor-
tant risk factor seen among the elderly [9, 10]. Several
recently published case reports of LAST involved patients
over the age of 65 years with either cardiac disease and/or
liver and kidney dysfunction [11–15]. A poorly functioning
ventricle is more susceptible to contractile depression by
LA toxicity and contributes to decreased drug distribution.
Moreover, low circulation times can increase the likelihood
of ‘stacking’ injections that increase plasma and tissue drug
concentrations if the time interval between incremental
injections is shorter than the time needed for an intravascular
(IV) injection to cause recognizable hemodynamic change.
Liver and kidney disease decrease drug metabolism and
clearance. Advanced liver disease complicated by hypoalbu-
minemia and plasma cholinesterase deficiency increases the
unbound (active) fraction of LA and decreases its metabo-
lism [16]. Mitochondrial and metabolic disorders, such as
carnitine deficiency also increase the risk of LAST [10].
Analysis of a national sample (patients aged older than
57 years) from 1998 to 2013 looking at LAST in total joint
arthroplasty procedures showed that 59% (n = 737) of
patients with LAST had some type of metabolic disorder,
followed by cardiac (22.3%) and pulmonary (17.9%) dis-
ease. Shoulder arthroplasty carried the highest risk of LAST
when compared with hip and knee arthroplasty [17]. Finally,
hypoxemia and acidosis lower the threshold for LAST and
make resuscitation more difficult.
Drug-specific risk factors include the volume, dose,
and delivery mode. When bupivacaine was introduced in
the 1960s, its frequent use for paracervical blocks for labor
analgesia was associated with a high incidence of fetal brad-
ycardia and death [18]. While the CNS is generally more
sensitive to the toxic effects of LA, the more lipid-soluble
LAs such as bupivacaine are particularly potent in terms
of cardiac toxicity, and their relative ratio of toxic CV to
CNS doses is closer to one than seen among the less lipid-
soluble LAs. One hypothesis to explain the association of
enhanced cardiac toxicity with lipid solubility is that this
physical property enhances the interaction of (positively
charged) LAs with (negatively charged) cardiolipin, a key
phospholipid in the mitochondrial inner membrane [19, 20].
Bupivacaine is typically avoided for intravenous regional
anesthesia (Bier block) and is used with a vasoconstrictor
such as epinephrine near highly vascular tissues. For con-
tinuous epidural infusions, very low concentrations of bupiv-
acaine are used. Case reports from March 2010 to November
2016 indicate slightly conflicting relative frequencies of LAs
Local Anesthetic Toxicity in the Geriatric Population
associated with LAST [9, 21]. Earlier reports show that the
majority of LAST events involved either lidocaine (33%) or
ropivacaine (33%) followed by bupivacaine (23%), while
more recent reports show bupivacaine (36%) was most com-
monly involved followed by lidocaine (26%) and ropivacaine
(21%) [9, 21]. A better interpretation of this information is
that commonly used LAs, lidocaine, ropivacaine, and bupi-
vacaine, are likely to be the top three common causes of
LAST.
Administering large amounts (e.g., high concentrations,
volumes or both) of LAs or the rapid perivascular injec-
tion without epinephrine will increase the risk for toxicity
[22]. Continuous peripheral nerve catheters and intrave-
nous lidocaine infusions are also associated with LAST.
A recent review included seven cases of LAST caused by
continuous infusions. Five patients presented between 24 h
and 4 days after initiation [21]. Intravenous lidocaine infu-
sions are becoming ubiquitous among hospitals’ periopera-
tive multimodal analgesia regimens and enhanced recovery
after surgery protocols—these will undoubtedly increase the
occurrence of perioperative LAST. A systematic review of
intravenous lidocaine infusions for postoperative analgesia
found ten cases of LAST among 2802 patients (four CV
and six CNS) with infusion rates ranging from 1 to 5 mg/
kg/h [23]. While no details about the ages of patients who
developed LAST were provided, it can be assumed that a
continuous infusion of higher LA doses in elderly patients
carries an increased risk of LAST.
Liposomal formulations of bupivacaine (e.g., Exparel;
Pacira Pharmaceuticals, Parsippany, NJ, USA) present a
special concern for LAST. One ampule of Exparel contains
266 mg of bupivacaine that has two peak plasma concentra-
tions (immediate and 36 h) and can last as long as 96 h [24].
Administration of other LAs within 20 min of Exparel can
release more bupivacaine and result in toxicity as the effects
of the two LAs are additive [25, 26]. A dis-proportionality
analysis of retrospective data from the US Food and Drug
Administration Adverse Event Reporting System showed
a statistically significant association between Exparel and
LAST. This association holds for both CNS and CV toxicity.
Among 1940 LAST events reported between Q1-2012 and
Q2-2016, 130 cases were related to Exparel compared with
346 cases with non-liposomal bupivacaine [27]. Among
these 130 events, 11 (8.5%) were fatal. Exparel is commonly
used for intra- and peri-articular injections after total knee
arthroplasty [28], suggesting the risk of LAST secondary
to liposomal bupivacaine could disproportionately affect
elderly patients.
Table 1 describes the recommended maximum doses of
commonly used LAs; however, as previously mentioned,
patient-specific risk factors and both the site and route of
injection should be considered when calculating individual
dosing. Furthermore, drug formulations may vary among
pharmaceutical companies; therefore, each drug’s manu-
facturer’s insert should be reviewed for detailed safety
information.
4 Prevention
Data regarding the incidence of LAST are conflicting. Stud-
ies from different cohorts show substantial differences: Liu
et al. found a rate of LAST to be 0.4/10,000 (n = 80,661)
at the Hospital for Special Surgery while Barrington and
Kluger found a rate of 8.7/10,000 (n = 25,336) across several
academic hospitals in Australia [29, 30]. Studies by Mor-
wald et al. (n = 238,473) and Rubin et al. (n = 710,327) used
different criteria to measure the occurrence of LAST in very
large but distinct administrative databases and found rates of
18/10,000 and 10/10,000, respectively [17, 31]. Moreover,
confounding by misdiagnosis or under-reporting suggests
the actual incidence of LAST could be considerably higher.
The American Society of Regional Anesthesia and Pain
Medicine (ASRA) recommends adopting measures in a
three-pronged approach to prevent LAST: active avoidance
and early detection of an IV injection of LA, decreasing
systemic uptake of LA from soft tissues, and identifying
patients at increased risk for toxicity [10]. Standard tech-
niques to avoid accidental IV administration include fre-
quent serial aspiration between small divided (3–5 mL)
doses of LAs. Using an IV marker such as epinephrine
5 μg/mL allows earlier detection of IV injection (e.g., an
increase in the heart rate of 10 bpm and/or increase in the
systolic blood pressure of 15 mmHg) [32]. Recent studies
demonstrated that ultrasound guidance of peripheral nerve
blocks can significantly decrease the incidence of LAST pre-
sumably by reducing the occurrence of IV injection and by
allowing the use of smaller volumes of the drug [30, 33, 34].
In addition to these safety steps, anesthesia providers
should account for each patient’s potential susceptibility
to LAST and maintain vigilance of the total number of
doses administered by all providers. Standard monitoring
is required for at least 30 min after any regional anesthetic
procedure. Higher risk patients should be identified preop-
eratively, and the drug, technique, and/or dosage should be
adjusted accordingly. Because there is no entirely “safe” LA
or dose, the administration of all LAs warrants a basic level
of caution. Understanding this risk is important because any
LA can result in LAST, and any dose can become toxic if
injected in the wrong location or a given to a particularly
susceptible patient.
 R. Waldinger et al.

Table 1  Recommended dosages of common local anesthetics (LAs)

Local anesthetic Route(s) of administration Recommended dose (mg/ Single maximum dose (mg) Comments
kg)

Benzocaine Topicala 200 (1) Can cause methemo-

globinemia
(2) 1-second spray of 20%
solution delivers 150–
200 mga
Chloroprocaine Infiltration, PNB, epidural, 12 800
intrathecal 1000 (with epinephrine)
Cocaine Topical 1.5 150 Contraindicated with other
sympathomimetics and
MAOIs
Lidocaine (lignocaine) Topical, infiltration, PNB, 4.5 300 (1) For intravenous infusion,
epidural, intrathecal, 7 (with epinephrine) 400 (with epinephrine) 1–3 mg/kg bolus followed
IVRA, intravenous by 1–3 mg/kg/h infusion
(2) 35–55 mg/kg for
tumescent solution (0.5%
or 0.1% with epinephrine
1:1,000,000)
Bupivacaine Infiltration, PNB, epidural, 2 150
intrathecal
Levobupivacaine Infiltration, PNB, epidural, 2 150
intrathecal
Liposomal bupivacaine Infiltration 266 (1) Single-dose administra-
tion only
(2) Administration of
non-bupivacaine LAs
within 20 min may cause
an immediate release of
bupivacaine
Mepivacaine Infiltration, PNB, epidural, 4.5 400
intrathecal 7 (with epinephrine) 500 (with epinephrine)
Ropivacaine Infiltration, PNB, epidural, 3 225
intrathecal

The information in this table was compiled from the following sources: Kane et al. [45], Bailey et al. [46], Weibel et al. [47], Gitman et al. [48],
FDA [49], Australian Medicines Handbook Pty Ltd. [50], Butterworth et al. [51], Liu and Lin [52], Rosenberg [53], Klein and Jeske [54]
IVRA intravenous regional anesthesia, MAOIs monoamine oxidase inhibitors, PNB peripheral nerve block
a
 A strong case can be made to avoid topical benzocaine given that the associated occurrence of methemoglobinemia is neither clearly dose
dependent nor predictable. This life-threatening complication can occur after even one spray (Weinberg [55])

5 Diagnosis of Local Anesthetic Systemic
Toxicity
Timely diagnosis of LAST depends on the context-specific
recognition of clinical features. A wide array of clinical
presentations was described in several reviews of cases and
summarized in professional societies’ practice guidelines [9,
10, 21, 35, 36]. Early manifestations typically include CNS
excitation (e.g., agitation, acute psychosis, or seizure) fol-
lowed by CNS depression (e.g., loss of consciousness or res-
piratory arrest). Hypertension and tachycardia are early CV
signs of toxicity that, as toxicity worsens, progress to brady-
cardia, hypotension, or cardiac arrest [10, 36]. The classical
sequence of a mild prodrome (e.g., perioral paresthesia and
tinnitus) followed by seizures and hemodynamic instability
was not identified in the majority of patients described in a
review of cases published between April 2014 and Novem-
ber 2016 [21]. Interestingly, CNS and CV toxicity can occur
simultaneously without any prodrome, and cardiac arrest can
occur suddenly without any CNS features at all [10, 16, 36].
A recent shift in the timing of LAST was observed from
sudden onset as often seen in the past to a delayed onset
occurring many minutes or hours after administration of LA.
This presumably results from the increased use of ultrasound
guidance and a parallel reduction in the incidence of direct
IV injection. As more cases result from delayed IV absorp-
tion from the site of injection, delayed onset of LAST will
become more common. Moreover, increased use of continu-
ous catheter or intravenous infusions also leads to instances
where LAST is delayed. This shift in timing warrants
Local Anesthetic Toxicity in the Geriatric Population
prolonged monitoring of patients for signs of delayed toxic-
ity and improved education of staff because the longer the
interval from treatment to the onset of toxicity, the more
challenging it becomes to link symptoms to their root cause,
thereby increasing barriers to making the correct diagnosis
and providing proper timely treatment [10, 21].
6 Treatment
The Association of Anaesthetists of Great Britain and Ire-
land and ASRA provide stepwise algorithms for the treat-
ment of LAST. Immediate supportive treatment includes: (1)
airway management to maintain oxygenation and ventilation
to prevent hypercapnia and acidosis; (2) management of sei-
zures with benzodiazepines; (3) standard therapy for CV
instability, including cardiopulmonary resuscitation when
indicated; and (4) lipid emulsion infusion, which should be
delivered for any signs or symptoms of LAST. Treatment of
cardiac arrest caused by LAST is fundamentally different
from other, more common causes (e.g., ischemia) because
the underlying pharmacotoxicity can be reversed by lipid
resuscitation. It is prudent to use lower doses of epinephrine
(e.g., ≤ 1 μg/kg) because higher standard doses (e.g., 1 mg)
are shown in animal models of LAST to interfere with lipid
resuscitation. Beta-blockers, calcium channel blockers, or
lidocaine for the treatment of arrhythmias should be avoided
[10, 36]. Vasopressin is deleterious in animal models of
LAST and should be avoided for treatment of LAST-related
hypotension. This is rational in LAST because increasing
systemic vascular resistance is not helpful in the setting of
very low cardiac contractility as occurs in severe LAST.
Infusing lipid emulsion creates a bulk lipid phase in
plasma that reduces toxicity by scavenging/shuttling LA
from affected organs (heart, brain) to large reservoir organs
such as the liver and skeletal muscle. Lipid emulsion also
directly exerts both cardiotonic and vasoconstricting effects
and attenuates cardiac ischemia-reperfusion injury [8]. The
Association of Anaesthetists of Great Britain and Ireland
and ASRA guidelines recommend an initial bolus of 1.5 mL/
kg of a 20% lipid emulsion delivered over 2–3 min, followed
by a 0.25-mL/kg/min infusion until hemodynamic stabil-
ity is achieved without exceeding a total dose of 12 mL/kg
[10, 36]. The total dose for treating LAST including lipid
delivered by bolus and infusion is usually 3–5 mL/kg. For
patients 70 kg or larger, a recent ASRA working group rec-
ommended giving an initial bolus of a 100-mL 20% lipid
emulsion, followed by an infusion of 200–250 mL over
15–20 min. This simpler regimen reflects experience sug-
gesting that the precise dose delivered is less important than
rapidly establishing modest lipemia.
7 Local Anesthetic Systemic Toxicity
in Elderly Patients
Older patients are at greater risk for LAST owing to both
the increasing rates of surgery with anesthesia/analgesia
using LAs and the relevant co-morbidities associated with
aging. Among patients having joint arthroplasty, Rubin
et al. showed that 60% were aged older than 65 years [17].
Table 2 summarizes peer-reviewed cases of LAST published
between January 2014 and June 2019 involving patients aged
older than 65 years [11–15, 37–42]. Table 3 summarizes
cases of LAST that were submitted to an online registry (lip-
idrescue.org) during the same timeframe [43]. Three pub-
lished cases provide examples of toxicity from inadvertent
IV injections of LA and are not unique to the elderly but may
be more difficult to treat in this population. Remaining cases
show two dominant patterns: obvious overdose of LA or an
apparently appropriate dose in a patient with multi-system
organ disease. Several of the “overdoses” are minimal, sug-
gesting that the combination of the dose with age-related
comorbidities likely contributed to toxicity. A similar pattern
appears among cases submitted to lipidrescue.org. Surpris-
ingly, five of the 11 published cases did not report adminis-
tration of lipid emulsion despite the fact that four of the five
exhibited significant neurological derangements.
A more comprehensive appreciation of the problem
comes from combining information from large datasets with
that provided by the more granular detail derived from case
reports. For instance, Litz et al. describes combined CNS
and CV toxicity in a 91-year-old (57 kg) man shortly after a
supplemental ulnar nerve block with 100 mg of prilocaine
15 min following an infraclavicular brachial plexus block
with 300 mg of mepivacaine [44]. While weight-based dos-
ing does not accurately predict plasma drug concentrations,
this aggregate LA dose seems high for a small patient with
coronary artery disease. This case highlights the value in
awareness of the increased risks of LAST in elderly patients
generally and particularly among cachectic patients with car-
diac disease.
Similarly, Vadi et al. described fatal LAST in an 88-year-
old woman (45  kg) with hypertension, coronary artery
disease, peripheral vascular disease, cerebrovascular dis-
ease, renal artery stenosis, aortic stenosis, and a history of
a subdural hematoma [15]. Twenty minutes after a com-
bined psoas compartment and sciatic nerve block using a
total of 25 mg of bupivacaine with 1:200,000 epinephrine
and 450 mg of plain mepivacaine, she had a grand mal sei-
zure, followed by severe bradycardia, which progressed to
pulseless electrical activity that was refractory to resusci-
tation. The diagnosis of LAST was considered and lipids
were administered after 30 min of resuscitation that was ulti-
mately unsuccessful. This case illustrates that ‘anchoring’


Table 2  Peer-reviewed local anesthetic systemic toxicity (LAST) cases from January 2014 to June 2019 for patients aged older than 65 years
Author, journal, year Patient age/sex Patient comorbidities Mode of administration, type and dose LAST description
of LA

Vadi et al., Anesthesiology, ­2014a
Fenten et al., Reg Anesth Pain Med, ­2014a 67 F
Monti et al., Emerg Care, ­2014a
Akimoto et al., Masui, 2014
Gungor et al., Agri, 2015
Gaies et al., Rev Mal Respir, 2016
Tsang et al., BMJ Case Rep, ­2016a
Nelson et al., J Emerg Med, 2018
Hickey et al., J Anaesth Clin Pharmacol,
­2018a
Tunney et al., J Clin Pharm Ther, 2018
Bacon et al, J Cardiothorac Vasc Anesth,
­2019a
88 F HTN, CAD, PVD, CKD, CVD Combined psoas compartment/sciatic
nerve block with 25 mg of bupivacaine
with 1:200,000 epinephrine and 450 mg
of mepivacaine
Not reported Local infiltration analgesia of the lower
extremity with 400 mg of ropivacaine
(200 mg with epinephrine)
73 M HTN, NAFLD, neuropathic pain Local tissue infiltration (lower leg wound)
with 30 mg of bupivacaine
71 M Not reported Epidural bolus of 56.25 mg of ropiv-
acaine over 1 h later discovered to be
intravascular
67 F HTN, DM Interscalene block with 93.75 mg of
bupivacaine
74 F Bronchiolitis obliterans Endotracheal 2% lidocaine, dose not
reported
66 M GERD, hyperlipidemia Paravertebral block with initial bolus
of 50 mg of bupivacaine followed by
a continuous infusion of 20 mg/h of
ropivacaine
66 M CAD, DM, hypothyroidism, OSA, lung Interscalene nerve block with 150 mg of
cancer bupivacaine and 200 mg of lidocaine
73 M CAD, HTN, DM, CKD Subcutaneous infiltration with 60 mg of
lidocaine and 30 mg of bupivacaine
plus 3375 mg of lidocaine in tumescent
solution
71 M CAD, ICM (post LVAD and ICD implan- Intravenous bolus of 210 mg of lidocaine
tation), pAF, VT followed by a 2-mg/min continuous
infusion for treatment of refractory VT
76 F HFpEF, moderate MR, OSA, obesity, Topical lidocaine (airway topicalization)
hypothyroidism, new-onset AF with 4800 mg of lidocaine
15 minutes after completion of block, LOC
followed by grand mal seizure, bradycar-
dia, heart block, PEA, and death
80 minutes after local infiltration analgesia,
LOC with atrial fibrillation with RVR,
clonic seizure
30 seconds after infiltration, LOC, tonic-
clonic seizure, cardiac arrest
Tachycardia, mild HTN, delayed arousal
after general anesthesia
Immediate tonic-clonic seizure
3½ h after tonic-clonic seizure, which
recurred 7 h later
37 hours after initiation of block, agita-
tion and paresthesias, followed by focal
seizures, HTN, and tachycardia
Minutes after completion of the block,
bradycardia, hypotension, ECG changes,
dyspnea, hypotension, LOC
Unclear timeline of when LA was adminis-
tered, but 10 min after arrival in recovery,
incoherent speech, tachycardia, HTN,
muscle rigidity of all four limbs, LOC
22 hours after initiation of lidocaine infu-
sion, altered mental status, tremors
45 minutes after topicalization, altered
mental status, bradycardia, hypoxia,
LOC, seizure, cardiac arrest

AF atrial fibrillation, CAD coronary artery disease, CKD chronic kidney disease, CVD cerebrovascular disease, DM diabetes mellitus, F female, GERD gastroesophageal reflux disease, HFpEF
heart failure with preserved ejection fraction, HTN hypertension, ICD implantable cardioverter-defibrillator, ICM ischemic cardiomyopathy, IV intravenous, LA local anesthetic, LOC loss of
consciousness, LVAD left ventricular assist device, M male, MR mitral regurgitation, NAFLD non-alcoholic fatty liver disease, OSA obstructive sleep apnea, pAF paroxysmal atrial fibrillation,
PVD peripheral vascular disease, VT ventricular tachycardia
a
 Lipid emulsion was administered
R. Waldinger et al.
Local Anesthetic Toxicity in the Geriatric Population

Table 3  Cases of local anesthetic systemic toxicity (LAST) involving patients aged older than 65 years submitted to lipidrescue.org from Janu-
ary 2014 to June 2019
Date submitted Patient age/sex Patient comorbidities Mode of administration, type and LAST description
dose of LA

6 February, ­2014a 66 F HTN, DM, seizure disorder Periarticular block (hip) with Immediate severe bradycardia fol-
200 mg of ropivacaine lowed by multifocal ectopy and
Takotsubo cardiomyopathy
22 December, ­2014a 70 M HTN Supraclavicular block with 2 hours after initial block and
400 mg of lidocaine and 55 min after tourniquet inflation,
56 mg of levobupivacaine plus immediately after tourniquet
peripheral radial, median, and deflation, bradycardia, hypoten-
ulnar nerve blocks with a total sion, and headache
of 60 mg of lidocaine, 1 h
later 50 mg of lidocaine with
epinephrine
17 June, ­2015a 66 F GERD Peribulbar block with 80 mg of 1 minute after injection, tachy-
ropivacaine cardia and hypertension, LOC,
grand-mal seizure
6 May, ­2016a 66 M Not reported Adductor canal block with 2 minutes after block, LOC, sei-
unknown dose of 0.5% bupiv- zure, cardiac arrest
acaine with epinephrine
29 March, ­2017a 96 F HTN, chronic AF, CVD, anemia Psoas compartment block with 5 minutes after block, convulsions,
150 mg of lidocaine and 75 mg altered mental status, hemody-
of ropivacaine plus sciatic nerve namic instability
block with 100 mg of lidocaine
and 50 mg of ropivacaine
9 January, 2­ 018a 72 M Not reported Suprascapular nerve block with Immediate tonic-clonic seizure,
75 mg of bupivacaine with LOC
1:200,000 epinephrine
6 March, ­2018a 75 F No coexisting disease 40 mg of lignocaine with Timeline unclear, altered mental
1:200,000 epinephrine for a status, altered taste sensation,
dental procedure vomiting, shivering, palpita-
tions (atrial flutter), tachycardia,
hypertension
22 May, ­2019a 69 M HTN iPACK and adductor canal block 2 minutes following block,
with a total of 150 mg of bupi- bradycardia, hypotension, focal
vacaine seizures, LOC

AF atrial fibrillation, CVD cerebrovascular disease, DM diabetes mellitus, F female, GERD gastroesophageal reflux disease, HTN hypertension,
iPACK infiltration between popliteal artery and capsule of knee, LA local anesthetic, LOC loss of consciousness, M male
a
 Lipid emulsion was administered

to a presumptive diagnosis (here, ischemic arrest) can delay
correctly identifying LAST. Relevant co-morbidities in this
patient that are known to increase the risks of LAST includ-
ing age, small size, and coronary artery disease. This case
emphasizes that LAST must be considered in any patient
experiencing neurologic or hemodynamic alterations after
receiving LAs.
Gaies et al. described LAST after the use of endotracheal
lidocaine for a bronchoscopy [40]. Although no dose was
reported, it is important to recognize that LAST is not lim-
ited to peripheral nerve blocks and can occur with virtu-
ally any exposure to LAs, including topicalization of the
airway, oral ingestion, mucosal application, and subcuta-
neous or submucosal injection. Tsang et al. and Tunney
et al. described delayed-onset LAST during continuous LA
infusions (paravertebral and intravenous) [11, 41]. As con-
tinuous catheter and intravenous infusions (e.g., intravenous
lidocaine for perioperative multimodal analgesia) become
more common, associated LAST events will increase. This
makes it imperative for departments to educate responsible
ward personnel on best practices for preventing, recognizing,
and treating LAST.
8 Conclusions
Elderly patients are at increased risk of toxicity related to
the use of LAs. Demographic and surgical trends assure that
LAST will continue to disproportionately affect this popu-
lation. Improved awareness of LAST, progress in adopting

standard preventive measures (e.g., monitors and test dos-
ing), along with refined practice (e.g., ultrasound guidance)
and treatment algorithms have dramatically improved our
management of LAST over the past several decades. Unfor-
tunately, systems and physician errors as well as patient
co-morbidities guarantee that LAST will continue to occur.
An aging population that increasingly experiences surgical
interventions and the increased use of LAs for their perio-
perative anesthesia and analgesia further assure that LAST
will remain a particularly important, iatrogenic complica-
tion among the elderly. Educating all physicians and non-
physicians who administer LAs or care for these patients is
essential to improving patient safety. The educational and
practical focus should be on the diagnosis, prevention, and
treatment of LAST and on identifying patients at a higher
risk for toxicity. The frail elderly with relevant coexisting
disease exemplify this cohort. Individually tailored dosing
and more vigilant monitoring will improve the safety of
using LAs in general and this population specifically.
Compliance with Ethical Standards  15. Vadi MG, Patel N, Stiegler MP. Local anesthetic systemic tox-
Funding  No sources of funding were received for the preparation of
this article.
Conflict of interest Rachel Waldinger and Marina Gitman have no
conflicts of interest that are directly relevant to the content of this ar-
ticle. Guy Weinberg is a shareholder and officer of ResQ Pharma, Inc.
References
1. Redman M. Cocaine: what is the crack? A brief history of the use
of cocaine as an anesthetic. Anesth Pain Med. 2011;1(2):95–7.
https​://doi.org/10.5812/kowsa​r.22287​523.1890.
2. Calatayud J, Gonzalez A. History of the development and evo-
lution of local anesthesia since the coca leaf. Anesthesiology.
2003;98(6):1503–8. https​://doi.org/10.1097/00000​542-20030​
6000-00031​.
3. Drasner K. Local anesthetic systemic toxicity: a historical per-
spective. Reg Anesth Pain Med. 2010;35(2):162–6. https​://doi.
org/10.1097/AAP.0b013​e3181​d2306​c.
4. Ruetsch YA, Boni T, Borgeat A. From cocaine to ropivacaine:
the history of local anesthetic drugs. Curr Top Med Chem.
2001;1(3):175–82.
5. Wolfe JW, Butterworth JF. Local anesthetic systemic toxicity:
update on mechanisms and treatment. Curr Opin Anaesthesiol.
2011;24(5):561–6. https​://doi.org/10.1097/ACO.0b013​e3283​
4a939​4.
6. Bureau UC. Older Americans, Table 2; 2018. https​://www.censu​
s.gov/newsr​oom/stori​es/2018/older​-ameri​cans.html. Accessed 29
July 2019.
7. Gajdos C, Kile D, Hawn MT, Finlayson E, Henderson WG, Rob-
inson TN. Advancing age and 30-day adverse outcomes after non-
emergent general surgeries. J Am Geriatr Soc. 2013;61(9):1608–
14. https​://doi.org/10.1111/jgs.12401​.
8. Fettiplace MR, Weinberg G. The mechanisms underlying lipid
resuscitation therapy. Reg Anesth Pain Med. 2018;43(2):138–49.
https​://doi.org/10.1097/AAP.00000​00000​00071​9.
R. Waldinger et al.
9. Vasques F, Behr AU, Weinberg G, Ori C, Di Gregorio G. A review
of local anesthetic systemic toxicity cases since publication of the
American Society of Regional Anesthesia recommendations: to
whom it may concern. Reg Anesth Pain Med. 2015;40(6):698–
705. https​://doi.org/10.1097/AAP.00000​00000​00032​0.
10. Neal JM, Barrington MJ, Fettiplace MR, Gitman M, Memt-
soudis SG, Morwald EE, et al. The Third American Society of
Regional Anesthesia and Pain Medicine practice advisory on
local anesthetic systemic toxicity: executive summary 2017. Reg
Anesth Pain Med. 2018;43(2):113–23. https​://doi.org/10.1097/
AAP.00000​00000​00072​0.
11. Tunney RK Jr, Whyte K, DeAntonio HJ. Lidocaine toxicity in the
setting of HeartMate II left ventricular assist device. J Clin Pharm
Ther. 2018;43(5):733–6. https​://doi.org/10.1111/jcpt.12717​.
12. Hickey TR, Casimir M, Holt NF. Local anesthetic systemic toxic-
ity after endovenous laser therapy. J Anaesthesiol Clin Pharmacol.
2018;34(3):401–2. https:​ //doi.org/10.4103/joacp.​ JOACP_​ 113_17.
13. Nelson M, Reens A, Reda L, Lee D. Profound prolonged brady-
cardia and hypotension after iterscalene brachial plexus block
with bupivacaine. J Emerg Med. 2018;54(3):e41–3. https​://doi.
org/10.1016/j.jemer​med.2017.12.004.
14. Monti M, Monti A, Borgognoni F, Vincentelli GM, Paoletti
F. Treatment with lipid therapy to resuscitate a patient suf-
fering from toxicity due to local anesthetics. Emerg Care J.
1820;2014(10):41–4.
icity after combined psoas compartment-sciatic nerve block:
analysis of decision factors and diagnostic delay. Anesthesiology.
2014;120(4):987–96. https​://doi.org/10.1097/ALN.00000​00000​
00015​4.
16. Safety Committee of Japanese Society of Anesthesiologists.
Practical guide for the management of systemic toxicity caused
by local anesthetics. J Anesth. 2019;33(1):1–8. https​: //doi.
org/10.1007/s0054​0-018-2542-4.
17. Rubin DS, Matsumoto MM, Weinberg G, Roth S. Local anesthetic
systemic toxicity in total joint arthroplasty: incidence and risk
factors in the United States from the national inpatient sample
1998–2013. Reg Anesth Pain Med. 2018;43(2):131–7. https:​ //doi.
org/10.1097/AAP.00000​00000​00068​4.
18. Beck L, Martin K. Hazards of paracervical block in obstetrics: a
survey of 107 hospitals for women with a total of 32, 652 cases.
Geburtshilfe Frauenheilkd. 1969;29(11):961–7.
19. Tsuchiya H, Mizogami M. R(+)-, Rac-, and S(−-bupivacaine
stereostructure-specifically interact with membrane lipids
at cardiotoxically relevant concentrations. Anesth Analg.
2012;114(2):310–2. https​://doi.org/10.1213/ANE.0b013​e3182​
3ed41​0.
20. Onyuksel H, Sethi V, Weinberg GL, Dudeja PK, Rubinstein I.
Bupivacaine, but not lidocaine, disrupts cardiolipin-containing
small biomimetic unilamellar liposomes. Chem Biol Interact.
2007;169(3):154–9. https​://doi.org/10.1016/j.cbi.2007.06.002.
21. Gitman M, Barrington MJ. Local anesthetic systemic toxicity:
a review of recent case reports and registries. Reg Anesth Pain
Med. 2018;43(2):124–30. https​://doi.org/10.1097/AAP.00000​
00000​00072​1.
22. Choi JW, Kim DK, Cho CK, Park SJ, Son YH. Trends in medi-
cal disputes involving anesthesia during July 2009–June 2018:
an analysis of the Korean Society of Anesthesiologists data-
base. Korean J Anesthesiol. 2019;72(2):156–63. https​://doi.
org/10.4097/kja.d.18.00198​.
23. Weibel S, Jokinen J, Pace NL, Schnabel A, Hollmann MW,
Hahnenkamp K, et al. Efficacy and safety of intravenous lido-
caine for postoperative analgesia and recovery after surgery: a
systematic review with trial sequential analysis. Br J Anaesth.
2016;116(6):770–83. https​://doi.org/10.1093/bja/aew10​1.
Local Anesthetic Toxicity in the Geriatric Population
24. Balocco AL, Van Zundert PGE, Gan SS, Gan TJ, Hadzic A.
Extended release bupivacaine formulations for postoperative anal-
gesia: an update. Curr Opin Anaesthesiol. 2018;31(5):636–42.
https​://doi.org/10.1097/ACO.00000​00000​00064​8.
25. Burbridge M, Jaffe RA. ­Exparel®: a new local anesthetic with
special safety concerns. Anesth Analg. 2015;121(4):1113–4. https​
://doi.org/10.1213/ANE.00000​00000​00082​2.
26. US Food and Drug Administration. Label for Exparel; 2014.
http://www.access​ data.​ fda.gov/drugsa​ tfda_​ docs/label/​ 2014/02249​
6s005​lbl.pdf. Accessed 10 July 2019.
27. Aggarwal N. Local anesthetics systemic toxicity association with
Exparel (bupivacaine liposome): a pharmacovigilance evalu-
ation. Expert Opin Drug Saf. 2018;17(6):581–7. https​://doi.
org/10.1080/14740​338.2017.13353​04.
28. Smith EB, Kazarian GS, Maltenfort MG, Lonner JH, Sharkey
PF, Good RP. Periarticular liposomal bupivacaine injection versus
intra-articular bupivacaine infusion catheter for analgesia after
total knee arthroplasty: a double-blinded, randomized controlled
trial. J Bone Joint Surg Am. 2017;99(16):1337–44. https​://doi.
org/10.2106/JBJS.16.00571​.
29. Liu SS, Ortolan S, Sandoval MV, Curren J, Fields KG, Memt-
soudis SG, et al. Cardiac arrest and seizures caused by local anes-
thetic systemic toxicity after peripheral nerve blocks: should we
still fear the reaper? Reg Anesth Pain Med. 2016;41(1):5–21. https​
://doi.org/10.1097/AAP.00000​00000​00032​9.
30. Barrington MJ, Kluger R. Ultrasound guidance reduces the risk
of local anesthetic systemic toxicity following peripheral nerve
blockade. Reg Anesth Pain Med. 2013;38(4):289–99. https​://doi.
org/10.1097/AAP.0b013​e3182​92669​b.
31. Morwald EE, Zubizarreta N, Cozowicz C, Poeran J, Memtsoudis
SG. Incidence of local anesthetic systemic toxicity in orthopedic
patients receiving peripheral nerve blocks. Reg Anesth Pain Med.
2017;42(4):442–5. https​://doi.org/10.1097/AAP.00000​00000​
00054​4.
32. Tucker GT, Mather LE. Clinical pharmacokinetics of local
anaesthetics. Clin Pharmacokinet. 1979;4(4):241–78. https​://doi.
org/10.2165/00003​088-19790​4040-00001​.
33. Neal JM. Ultrasound-guided regional anesthesia and patient
safety: update of an evidence-based analysis. Reg Anesth Pain
Med. 2016;41(2):195–204. https​://doi.org/10.1097/AAP.00000​
00000​00029​5.
34. Barrington MJ, Uda Y. Did ultrasound fulfill the promise of safety
in regional anesthesia? Curr Opin Anaesthesiol. 2018;31(5):649–
55. https​://doi.org/10.1097/ACO.00000​00000​00063​8.
35. Di Gregorio G, Neal JM, Rosenquist RW, Weinberg GL. Clini-
cal presentation of local anesthetic systemic toxicity: a review
of published cases, 1979 to 2009. Reg Anesth Pain Med.
2010;35(2):181–7.
36. Association of Anaesthetists of Great Britain and Ireland. Man-
agement of severe local anaesthetic toxicity 2 (A4 sheet and
accompanying notes); 2010. https​://www.aagbi​.org/publi​catio​ns/
publi​catio​ns-guide​lines​/M/R. Accessed 23 July 2016.
37. Fenten MG, Rohrbach A, Wymenga AB, Stienstra R. Systemic
local anesthetic toxicity after local infiltration analgesia following
a polyethylene tibial insert exchange: a case report. Reg Anesth
Pain Med. 2014;39(3):264–5. https:​ //doi.org/10.1097/AAP.00000​
00000​00007​7.
38. Akimoto K, Yamauchi C, Fujimoto K, Kurahashi K. A case of
delayed arousal after anesthesia due to aberrant epidural catheter
placement in a blood vessel. Masui. 2014;63(7):814–6.
39. Gungor I, Akbas B, Kaya K, Celebi H, Tamer U. Sudden develop-
ing convulsion during interscalene block: does propofol anesthesia
diminish plasma bupivacaine level? Agri. 2015;27(1):54–7. https​
://doi.org/10.5505/agri.2015.82160​.
40. Gaies E, Jebabli N, Lakhal M, Klouz A, Salouage I, Trabelsi S.
Delayed convulsion after lidocaine instillation for bronchoscopy.
Rev Mal Respir. 2016;33(5):388–90. https​://doi.org/10.1016/j.
rmr.2015.09.010.
41. Corrections: Lipid rescue for treatment of delayed systemic ropi-
vacaine toxicity from a continuous thoracic paravertebral block.
BMJ Case Rep. 2017;2017. https​://doi.org/10.1136/bcr-2016-
21507​1corr​1.
42. Bacon B, Silverton N, Katz M, Heath E, Bull DA, Harig J, et al.
Local anesthetic systemic toxicity induced cardiac arrest after
topicalization for transesophageal echocardiography and subse-
quent treatment with extracorporeal cardiopulmonary resuscita-
tion. J Cardiothorac Vasc Anesth. 2019;33(1):162–5. https​://doi.
org/10.1053/j.jvca.2018.01.044.
43. LipidRescue™ Resuscitation. 20% Lipid emulsion for rescue from
drug toxicity; 2019. http://lipidr​ escue​ .org. Accessed 13 June 2019.
44. Litz RJ, Roessel T, Heller AR, Stehr SN. Reversal of central nerv-
ous system and cardiac toxicity after local anesthetic intoxication
by lipid emulsion injection. Anesth Analg. 2008;106(5):1575–
7. https​: //doi.org/10.1213/ane.0b013​e 3181​6 83dd​7 (table of
contents).
45. Kane G, Hoehn S, Behrenbeck T, et  al. Benzocaine-induced
methemoglobinema based on the Mayo Clinic experience from
28478 transesophageal echocardiograms. Arch Intern Med.
2007;167(18):1977–82.
46. Bailey M, Corcoran T, Schug S, et al. Perioperative lidocaine
infusions for the prevention of chronic postsurgical pain: a sys-
tematic review and meta-analysis of efficacy and safety. Pain.
2018;159(9):1696–704.
47. Weibel S, Jokinen J, Pace NL, et al. Efficacy and safety of intra-
venous lidocaine for postoperative analgesia and recovery after
surgery: a systematic review with trial sequential analysis. BJA.
2016;116(6):770–83.
48. Gitman M, Fettiplace M, Weinberg G, et al. Local anesthetic sys-
temic toxicity: a narrative literature review and clinical update
on prevention, diagnosis, and management. Plast Reconstr Surg.
2019;144(3):783–95.
49. FDA: label for Exparel. http://www.access​ data.​ fda.gov/drugsa​ tfda​
_docs/label​/2014/02249​6s005​lbl/pdf.
50. Australian Medicines Handbook Pty Ltd. https​://amhon​line.amh.
net.au.acs.hcn.com.au/?acc=36265​.
51. Butterworth JF, Mackey DC, Wasnick JD. Local anesthetics. In:
Butterworth JF, Mackey DC, Wasnick JD, editors. Morgan and
Mikhail’s clinical anesthesiology. 5th ed. New York: McGraw-Hill
Medical; 2013. p. 263–76.
52. Liu S, Lin Y. Local anesthetics. In: Barash PG, Cullen BF, Stoelt-
ing RK, et al., editors. Clinical anesthesia. 6th ed. Philadelphia:
Lippincott Williams and Wilkins; 2009. p. 531–48.
53. Rosenberg PH, Veering BT, Urmey WF. Maximum recommended
doses of local anesthetics: a multifactorial concept. Reg Anesth
Pain Med. 2004;29:564–75.
54. Klein JA, Jeske DR. Estimated maximal safe dosages of tumescent
lidocaine. Anesth Analg. 2016;122:1350–9.
55. Weinberg GL. Banning benzocaine: of bananas, bureaucrats, and
blue men. Anesth Analg. 2009;108(3):699–701.