Anaesthesia 2021, 76 (Suppl. 1), 27–39 doi:10.1111/anae.

15282

Review Article

Updates in our understanding of local anaesthetic systemic

toxicity: a narrative review
A. J. R. Macfarlane,1,2 M. Gitman,3 K. J. Bornstein,4 K. El-Boghdadly5,6 and G. Weinberg7,8

1 Consultant, Department of Anaesthesia, Critical Care and Pain Medicine, Glasgow Royal Infirmary, Glasgow, UK
2 Honorary Clinical Associate Professor, University of Glasgow, Glasgow, UK
3 Associate Professor, 7 Professor, Department of Anaesthesia, University of Illinois College of Medicine, Chicago, IL,
USA
4 Medical Student, Department of Medical Education, University of Miami School of Medicine, Miami, FL, USA
5 Consultant, Department of Anaesthesia and Peri-operative Medicine, Guy’s and St Thomas’ NHS Foundation Trust,
London, UK
6 Honorary Senior Lecturer, King’s College London, London, UK
8 Staff Physician, Jesse Brown VA Medical Centre, Chicago, IL, USA

Summary
Despite advances in clinical practice, local anaesthetic systemic toxicity continues to occur with the therapeutic
use of local anaesthesia. Patterns of presentation have evolved over recent years due in part to the increasing
use of ultrasound which has been demonstrated to reduce risk. Onset of toxicity is increasingly delayed, a
greater proportion of clinical reports are secondary to fascial plane blocks, and cases are increasing where non-
anaesthetist providers are involved. The evolving clinical context presents a challenge for diagnosis and
requires education of all physicians, nurses and allied health professionals about these changing patterns and
risks. This review discusses: mechanisms; prevention; diagnosis; and treatment of local anaesthetic systemic
toxicity. The local anaesthetic and dose used, site of injection and block conduct and technique are all important
determinants of local anaesthetic systemic toxicity, as are various patient factors. Risk mitigation is discussed
including the care of at-risk groups, such as: those at the extremes of age; patients with cardiac, hepatic and
specific metabolic diseases; and those who are pregnant. Advances in the changing clinical landscape with
novel applications and settings for the use of local anaesthesia are also described. Finally, we signpost future
directions to potentially improve the management of local anaesthetic systemic toxicity. The utility of local
anaesthetics remains unquestionable in clinical practice, and thus maximising the safe and appropriate use of
these drugs should translate to improvements in patient care.

.................................................................................................................................................................
Correspondence to: G. Weinberg
Email: guyw@uic.edu
Accepted: 21 September 2020
Keywords: blocks; complications; critical incidents; local anaesthetic; regional anaesthesia
Twitter: @ajrmacfarlane; @bornsteinkasha; @elboghdadly; @lipidguy

Introduction missed. This review aims to illustrate the fundamentals of

Prompt diagnosis and management of local anaesthetic
systemic toxicity (LAST) are key to reducing risks associated
with regional anaesthesia. Local anaesthetic systemic
toxicity is, however, a relatively rare event and the diagnosis
and opportunity for effective treatment can be easily
LAST, including: mechanisms; prevention; diagnosis; and
treatment. We also consider advances in our understanding
with regard to changes that are emerging, including the
clinical context and presentation. Such focus on when,
where and how LAST occurs helps guide further strategies

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Anaesthesia 2021, 76 (Suppl. 1), 27–39
to diminish the risk, which ultimately may improve patient
care and safety. We also address risk mitigation, and
consider the future directions in the field of this iatrogenic
complication, including professional education that could
further reduce the likelihood of LAST.
Incidence
Recent analyses of two separate administrative databases,
each involving large numbers of cases, have agreed on an
overall rate of LAST of 1.8 per 1000 nerve blocks. There is,
however, wide variation in published incidences, ranging
from low rates at academic centres to higher rates in large,
multi-institutional registries. Based on the congruity of
Rubin et al. and Morwald et al., a LAST rate of 1–2 events per
thousand nerve blocks is reasonable [1, 2]. However, the
likelihood of under-reporting and misdiagnosis suggest
even this might underestimate the true incidence.
Clinical presentation
Although data from published case reports are
heterogeneous and often incomplete, in aggregate they
help identify evolving trends over time. Three previous
summaries of LAST case reports published between
October 1979 and November 2016 indicated trends to
increasing delay in the time to onset and an increased
prevalence of prodromal symptoms [3–5]. These changes
reflect the advent of ultrasound guidance and a reduction in
unidentified intravascular injections. There was also a shift in
the setting of LAST away from anaesthesia providers in an
operating suite to non-anaesthesia providers including
remote locations such as hospital wards and out-of-hospital
clinics. This is a concern if healthcare providers in these
areas are less familiar with the diagnosis and treatment of
LAST. Finally, there was a decrease in LAST secondary to
neuraxial procedures, and an increase in LAST associated
with nerve blocks, and more recently, field blocks.
Between December 2017 and May 2020, there were a
further 36 cases of LAST reported in 34 peer-reviewed
published articles [6–39]. These data indicated 30% of
patients were older than 65 y, and 6% were younger than
5 y. Sixty-one percent of cases occurred in the hospital; 17%
in outpatient surgery centres; and 14% in outpatient clinics
(e.g. dental, pain and urology). Of the reported in-hospital
cases of LAST, 68% occurred in the operating room and
32% occurred in off-site locations (ward, labour and delivery
suites, interventional radiology, intensive care unit and
echocardiography laboratory). Two cases involving
overdose occurred at home and one to a volunteer at an
awake tracheal intubation course [11, 26, 38]. Local
anaesthetic was identified as being delivered in 50% of the
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Macfarlane et al. | A review of local anaesthetic systemic toxicity
events by anaesthetists, 39% by surgeons or other
proceduralists, 5.5% by dentists and 5.5% were self-
administered.
Of these cases, 19% resulted from upper and lower
extremity blocks; 17% from naso-oropharyngeal and airway
infiltration or topicalisation; 14% during gynaecological/
urologic procedures (intraurethral or intravaginal local
anaesthetic administration or perineal nerve block); 14%
from neuraxial blocks (paravertebral, epidural); 11% from
subcutaneous infiltration; and 11% during intravenous
lidocaine administration for analgesia. The remaining 14%
included one retrobulbar block; two oral ingestions; one
superior hypogastric nerve block; and one transversus
abdominis plane (TAP) block. Out of these cases, 44%
involved lidocaine, and another 22% involved a
combination of lidocaine with another local anaesthetic.
Ropivacaine and bupivacaine individually each accounted
for only 11% of cases. There were 11 (31%) cases of obvious
overdosing of the drug, 10 (91%) of which were due to
lidocaine and one (9%) was due to bupivacaine. The three
cases of therapeutic intravenous lidocaine infusion involved
1
administration of a total dose of 1.5–2 mg.kg with the
highest reported serum lidocaine level of 16 µg.ml 1
[19,
30, 35]. One case of intravenous injection resulted from the
miscalculation of a dose intended for treatment of
laryngospasm in a paediatric patient [13].
Approximately half of events (53%) occurred either
during or within 10 min of completion of drug
administration. Nineteen percent happened between
11 min and 1 h, 8% between 1 and 12 h, and 8% after 12 h
and 11% did not report the timing of onset. Thirty-five
percent of patients exhibited both central nervous system
and cardiovascular effects. Thirty-two percent had an
isolated central nervous system, and 24% had isolated
cardiovascular findings. Twenty percent of patients had a
prodrome and 9% had isolated prodromal signs that did not
progress further.
Sixty-four percent of patients received some form of
infusion of lipid emulsion, however, the dosing varied
among cases. Two patients (0.6%) died from anoxic brain
injury [26, 29], neither of whom received lipid emulsion. A
33-year-old woman suffered cardiac arrest 2 h after
liposuction of the thighs during which she received a total of
5000 mg of subcutaneous lidocaine.
The clinical setting of LAST appears to be changing.
Lidocaine is the most commonly implicated local
anaesthetic agent, and was used most often in tissue
infiltration by surgeons and intravenous infusions for peri-
procedural analgesia. The evolving clinical context presents
a challenge for diagnosis and requires education of all
© 2021 Association of Anaesthetists
Macfarlane et al. | A review of local anaesthetic systemic toxicity
physicians, nurses and allied health professionals about
these changing patterns and risks.
Management
Checklists and guidelines, such as those produced by the
Association of Anaesthetists in the UK and the American
Society of Regional Anesthesia and Pain Medicine (ASRA),
should be used to guide the management of LAST [40, 41].
The key priorities are prompt airway and resuscitative
management and early infusion of lipid emulsion, aiming to
prevent the negative spiral of hypoxia, hypercarbia and
acidosis which all potentiate LAST, while also
simultaneously reversing the toxic tissue levels of local
anaesthesia. Interrupting this cycle at an early stage will
attenuate or altogether avoid pharmacotoxicity progression
and possible cardiovascular collapse [42, 43].
Immediate
Immediate management begins with stopping further local
anaesthetic injection and calling for help [40, 44].
Thereafter, airway management, ventilation and circulation
must be addressed and lipid emulsion infusion started. One
hundred percent oxygen should be administered, and the
airway secured if necessary. Hypercarbia increases cerebral
blood flow which in turn delivers greater amounts of local
anaesthetic to the brain. This should, therefore, be avoided,
but so too should hyperventilation which can reduce
cardiac output [45]. Some institutions have ‘lipid rescue’
boxes containing lipid emulsion, large syringes, needles
and cognitive aids stored in areas where local anaesthetic is
utilised [40].
Seizures
Seizures should preferably be controlled with
benzodiazepines, given the cardio-depressant effects of
thiopentone and propofol [44]. However, small, incremental
doses of these latter agents may be used with caution if
required. Ongoing muscle contraction secondary to refractory
tonic-clonic movements further worsens hypoxia and acidosis,
and in such cases neuromuscular blockers can be considered.
Cardiac
Conventional therapies should be used to treat
hypotension, bradycardia or arrhythmias, and standard
cardiopulmonary resuscitation should be commenced if
circulatory arrest occurs. The key physiological and
mechanistic differences, however, between ischaemic
arrest and cardiac pharmacotoxicity such as LAST demand
different approaches to pharmacological intervention. In
LAST, smaller-than-usual doses of intravenous adrenaline
© 2021 Association of Anaesthetists
Anaesthesia 2021, 76, 27–39
1
(e.g. < 1 µ.kg ) should be administered because the
standard 1 mg advanced life support dose is
arrhythmogenic, impairs pulmonary gas exchange,
increases afterload and plasma lactate and can interfere
directly with lipid-based resuscitation [46, 47]. Vasopressin
should not be used, as the intense systemic vasoconstriction
will reduce both cardiac output and tissue perfusion, as
reflected in the adverse outcomes seen in animal studies of
LAST [48].
Mechanisms of LAST and reversal with
lipid emulsion therapy
The general clinical presentation of LAST reflects the
relevant molecular and organ targets [49]. Local anaesthetic
pharmacotoxicity results from a combination of adverse
effects on ionotropic and metabotropic cell signalling as
well as energy transduction. However, the combination of
central nervous system and cardiac dysfunction as the major
signs of LAST points strongly to mitochondrial metabolism
as the most important clinical target of LAST. Heart and
brain are highly intolerant of anaerobic metabolism and
inhibition of oxidative phosphorylation, and the resulting
depletion of tissue adenosine triphosphate (ATP) could be
the most important underlying mechanism in severe LAST,
as it might explain why traditional haemodynamic
treatments (e.g. vasopressors and inotropes) are only
marginally effective. The best treatment is to address the
underlying toxicity directly by reducing tissue local
anaesthetic content.
Lipid emulsion reverses LAST in a multimodal fashion
with pharmacokinetic effects probably the most important.
It appears to function as a ‘shuttle’, partitioning positively
charged, lipophilic local anaesthetic from the tissue into the
negatively charged lipid particles before redistributing it
quickly from high blood-flow target organs such as the brain
and heart to organs of larger mass and high blood flow such
as skeletal muscle and liver [50]. The more lipid soluble local
anaesthetics like bupivacaine may be removed more
effectively than ropivacaine or mepivacaine [40]. However,
all clinically used local anaesthetics are sufficiently lipid
soluble to partition into the lipid droplets and several case
reports indicate that infusion of lipid emulsion can improve
even severe lidocaine overdose. Two other key benefits of
infusion of lipid emulsion include a direct inotropic effect
below a threshold concentration of myocyte local
anaesthetic, and also a reduction in ischaemia-reperfusion
injury (e.g. post-conditioning benefit) [51]. Lipid therapy
may also have a direct role in reversing mitochondrial
dysfunction, sodium channel blockade [20] and nitric oxide-
mediated vasodilatation [52–54].
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In cardiac arrest due to LAST, the goal is to rapidly
restore coronary perfusion and reduce tissue local
anaesthetic concentration, thereby increasing cardiac
contractility and attenuating arrhythmias. The shuttle effect
of lipid emulsion combined with inotropic support and/or
chest compressions improves coronary blood flow and
helps ‘wash out’ local anaesthetic from cardiac tissue,
essentially accelerating its redistribution. Arrhythmias in
LAST can be refractory to conventional treatment. Local
anaesthetics such as lidocaine should clearly be avoided, as
should drugs that depress contractility, such as calcium
channel blockers and beta blockers.
Much of the work surrounding our knowledge of LAST
derives from animal studies and case reports. Current
opinion suggests early lipid emulsion therapy can attenuate
progression of toxicity, and should be considered as soon
as the diagnosis of LAST is made. It is sensible to prepare to
give lipid emulsion while airway management and calling
for help are underway, since this will have the greatest
benefit as local anaesthetic plasma concentrations are rising
[40]. An initial bolus of 1.5 ml.kg 1
of 20% lipid over 2–
3 min (approximately 100 ml in a 70 kg adult patient) is
recommended, followed by an infusion of 0.25 ml.kg 1.min 1
until 10 min after stability is achieved (average total dose
approximately 2.8 ml.kg 1). All doses here and throughout
the article are based on ideal body weight. If stability is not
regained, a further bolus followed by increasing the infusion
rate (e.g. 0.5 ml.kg 1.min 1) can be considered. It is important
1
to observe the upper limit of dosing of 10–12 ml.kg during
initial treatment. Using repeat boluses, rather than an infusion,
to achieve this maximum limit may be superior [55].
Any potential adverse effects of lipid emulsion infusion
when used for LAST appear to be minor, yet all lipid
emulsions remain ‘off label’ for this indication. Long-chain
triglyceride-containing lipid emulsions might be superior to
lipid emulsions containing medium-chain triglycerides for
treating LAST; moreover, a medium-chain triglyceride-
containing emulsion has been shown in animal models to
increase systemic vascular resistance and reduce ventricular
contractility [56]. Propofol is not a substitute for lipid
emulsion due to its potent cardio-depressant effects and the
quantity that would be required to deliver the necessary
lipid mass [57].
Like all antidotes, lipid therapy is unfortunately not a
panacea and deaths from LAST continue to occur, even
when lipid infusion has been administered [52]. This can
occur if the tissue local anaesthetic load is simply too high; if
lipid emulsion is given too late; if coronary occlusion
prevents enough transport of lipid emulsion to the coronary
capillary bed where local anaesthetic ‘on-loading’ occurs; if
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Macfarlane et al. | A review of local anaesthetic systemic toxicity
underlying cardiac function is poor; or if other significant
comorbidities exist. Cardiopulmonary bypass or extra-
corporeal membrane oxygenation should be considered in
patients refractory to treatment.
Follow-up
In LAST events where cardiovascular compromise has
occurred, the patient should be observed for at least 6 h,
given that local anaesthetic can redistribute from tissue
depots. Two hours is recommended where there have been
neurological symptoms only. If the diagnosis is clear, and
LAST is limited in duration and does not involve
cardiovascular compromise, it may be acceptable to
proceed with planned surgery after treatment with lipid and
an additional 30–40 min of observation to assure that LAST
does not recur. Ideally, cases should be reported to national
registries where applicable and also to www.lipidrescue.
org, whether intravenous lipid emulsion has been used or
not.
Risk of LAST: contributing factors and
their mitigation
Clinical severity and risk of LAST depend the local
anaesthetic administered, the plasma concentration, and
the patient’s physiological status and comorbidities. Peak
plasma concentration is determined by: total dose; rate of
injection; location of injection; the technique of
administration: and patient factors which influence the
pharmacokinetics of local anaesthetic distribution,
metabolism and excretion. The pharmacodynamics of local
anaesthetics also varies among patients, with certain at-risk
groups predisposed to increased toxicity for any given
blood or tissue concentration of local anaesthetic. This
group includes patients with: pre-existing heart disease;
frailty; small muscle mass; extremes of age; poor hepatic
perfusion and function; reduced plasma ɑ-1 acid
glycoprotein levels; or acidosis that unfavourably shifts the
binding equilibrium and increases free plasma local
anaesthetic concentration (Fig. 1). These factors are
described below, alongside Table 1 which summarises
potential solutions to mitigate risk. No single measure is
likely to be enough.
Local anaesthetic
Lipid solubility of local anaesthetic tracks with its clinical
potency but also its potential for causing toxicity. Increasing
lipid solubility increases the risk of cardiotoxicity and
reduces the ratio of the dose needed to cause
cardiovascular toxicity compared with the dose necessary to
generate a convulsion, known as the CVS/CNS ratio. While
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Macfarlane et al. | A review of local anaesthetic systemic toxicity Anaesthesia 2021, 76, 27–39

Figure 1 Risk of local anaesthetic systemic toxicity depending on anaesthetic technique and patient factors. These estimates of
risk are arbitrary rather than evidence-based and are designed to highlight the variation in potential risk to different patient
demographics and regional anaesthetic techniques. (a) risks when ultrasound-guided regional anaesthesia is used with low
doses or less lipophilic local anaesthetic agents; and (b) risks when no ultrasound is used, or higher doses or more lipophilic
local anaesthetic agents are used. *Cardiac diseases of concern, in decreasing severity, are: low cardiac output states;
myocardial ischaemia; pre-existing conduction defects; and arrhythmias.

the absolute value varies between studies, the ratio is
consistently lowest for bupivacaine compared with less lipid
soluble local anaesthetics, such as lidocaine. While animal
studies suggest ropivacaine and levobupivacaine might be
marginally less cardiotoxic than bupivacaine, severe and
fatal LAST can occur with any of these drugs.
Dose
Each local anaesthetic has a maximum recommended dose
based on ideal body weight. However, it is more useful to
consider these limits as a general guide, taking into
consideration pharmacokinetic and pharmacodynamic
variables in each individual patient. Indeed, it has been
suggested that these long-held blanket
recommendations, which vary between countries, should
be abandoned [58]. Conversely, it is unreasonable to
perform a nerve block without any dosing or dose-limit
guidance. An ideal dose would maximise clinical success
(ED95, the dose required to achieve the desired effect in
95% of the population) and provide adequate duration of
anaesthesia or analgesia while respecting a safe dosing
limit. Different dose limits exist for topicalisation of the
airway, where much of the local anaesthetic is either
atomised or ingested and metabolised by first-pass
metabolism; this also applies to tumescent anaesthesia
1
where doses of up to 55 mg.kg lidocaine are used in
combination with adrenaline and other agents. While good
safety outcomes have been reported with these large doses
of tumescent anaesthesia, reports of deaths and serious
injury also exist, with studies suggesting the peak
effect of absorption may not be until 20 h after injection,
which is an important consideration in the ambulatory
setting [59–61].
dose
Site of injection
Both the area over which absorption occurs and local
vascularity correlate with peak local anaesthetic blood
levels and the potential for causing toxicity. Paravertebral,
intercostal and intrapleural blocks were classically reported
as having the highest risk of systemic absorption, with blood

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Anaesthesia 2021, 76 (Suppl. 1), 27–39 Macfarlane et al. | A review of local anaesthetic systemic toxicity

Table 1 Summary of the common risk-factors and mitigating measures to reduce the risk of local anaesthetic systemic toxicity.
Note that when combinations of patient comorbidities and/or other risk-factors make local anaesthetic systemic toxicity (LAST) a
sufficiently high risk for a given patient, it is reasonable to seek alternatives to peripheral nerve, fascial plane, field and other
blocks that require relatively high doses of local anaesthesia.
Risk-factors Mitigating factors
Local anaesthetic and method
Choose least cardiotoxic local anaesthetic (e.g. lidocaine) or method with lowest local anaesthetic dose
required (e.g. spinal) where possible
Block factors
Dosing Recognise maximum limits are only a guide and consider pharmacokinetic and pharmacodynamic variables in
individual patients
Use lowest dose possible to maximise success (ED95) while ensuring adequate duration of anaesthesia/analgesia
Extra care is needed with repeat dosing/catheters in at risk groups (children and low local anaesthetic
clearance in particular)
Site of injection Consider adrenaline to limit local anaesthetic bioavailability where risk of systemic absorption is high
Block conduct Ultrasound guidance significantly reduces risk
Incremental injection
Aspiration before injection
Consider using adrenaline as a marker of intravascular injection
Use NRFitâ technology
Blocks in awake patients theoretically allows earlier detection; avoid over-sedating the patient while placing a block
Patient factors
Age Reduce dose in infants
Reduce dose in elderly by 10–20%
Pregnancy Use minimum effective dose
Hepatic disease Reduce dose in continuous infusions
Renal disease Consider reducing dose in end stage renal failure or chronic renal insufficiency where uraemic and/or acidotic
Cardiac disease Recognise increased risk of LAST
Consider reduced dose in severe ventricular dysfunction or even consider avoiding nerve block altogether
Miscellaneous Recognise increased risk in malnourishment/hypoproteinemia; sarcopenia diabetes; mitochondrial
metabolic disease; and carnitine deficiency
Consider reduced dose
Non-technical factors
Knowledge and education of all staff where local anaesthetic is administered
At-risk patient groups
Signs and symptoms of LAST to facilitate prompt recognition
Treatment guidelines
Consider stocking a ‘local anaesthetic toxicity box’
Communication – be vigilant where other providers may also administer local anaesthetic in the peri-operative
period (e.g. surgeon; intravenous lidocaine) to avoid excessive total dose
Consider including local anaesthetic dosing in the surgical pause and sign-out
ED95, dose required to achieve the desired effect in 95% of the population.

concentrations reducing respectively in: caudal epidurals;
lumbar epidurals; brachial plexus blocks; and subcutaneous
injection. However, more contemporary data and the advent
of novel techniques, such as fascial plane blocks and
ultrasound-guided approaches, suggest that site-specific risks
have evolved. Recent analyses of LAST case reports found that
epidural, caudal and upper limb blocks constitute a smaller
proportion than documented in previous years, whereas local
anaesthetic infiltration and penile blocks accounted for 20%
each of the LAST events [4]. In another contemporary registry,
the frequency of LAST was greatest with paravertebral blocks,
lower with upper limb blocks and zero with lower limb blocks
[62]. Continuous catheter techniques, unsurprisingly, are
associated with a higher risk of LAST than single-shot
approaches due to the potential for accumulation of local
anaesthetic in tissue, particularly in patients with small muscle
mass [63]. In the context of post-surgical continuous catheter
infusions, higher levels of the acute phase protein alpha-1
glycoprotein might reduce elevations in free plasma local
anaesthetic concentration [64].

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Macfarlane et al. | A review of local anaesthetic systemic toxicity
Block conduct
The use of ultrasound for regional anaesthesia reduces risk
of LAST nearly four-fold [62]. Ultrasound guidance increases
precision, allowing lower doses of local anaesthetic to be
used, while direct visualisation of both vessels and local
anaesthetic spread helps reduce the risk of intravascular
injections. However, ultrasound alone must not be
considered a panacea. Incremental injection using 3–5 ml
aliquots, aspiration before injection and the introduction of
non-Luer NRFitâ technology to reduce wrong syringe and
drug errors may also help despite lack of strong evidence
demonstrating benefit [65]. The wait time of 15–30 s during
incremental injection should be increased in low cardiac
output states, although a longer wait risks needle
movement between injections. Aspirating before injection
to check for intravascular placement is recommended, but
there is a false negative rate of 2% [66, 67]. Adrenaline may
serve as an intravascular marker of injection, but users must
be aware of the limitations of this as a safety measure. There
is no robust evidence that performing blocks in awake
patients reduces the risk of LAST. However, it is not possible
to detect the central neurological signs of LAST in
anaesthetised patients using routine monitoring. It is
logical, therefore, that early presentations of LAST may be
detected sooner in awake patients, allowing both further
injection of local anaesthetic to be stopped as well as earlier
administration of lipid rescue therapy.
Age
While large contemporary registries of peripheral nerve
blocks [2] did not find a correlation between age and LAST,
case reports are still dominated by patients at the extremes
of age. Newborns, infants and the elderly have lower lean
muscle mass, a factor known to increase the risk of toxicity.
Skeletal muscle acts as a neutral local anaesthetic storage
reservoir and this may explain the observation that frailty
and sarcopenia can lower the threshold of LAST. Infants also
have reduced plasma concentrations of ɑ-1 acid
glycoprotein, depend on an increased cardiac output and
have an immature hepatic cytochrome P450 system that
metabolises amide local anaesthetics – all factors that
increase the risk of LAST [64]. The elimination half-life of a
single injection of bupivacaine can be up to 12 h in infants
compared with 3.5 h in adults, therefore increasing risk in
continuous infusions [68]. Elderly patients are more likely to
have relevant comorbidities, cardiac disease, sarcopenia
and diminished local anaesthetic clearance. These are
compounded by pharmacodynamic changes whereby
elderly patients are more sensitive to local anaesthetics
because tissues generally express fewer NaV channels [69].
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Cardiac disease
Patients with reduced cardiac contractility, conduction
abnormalities or pre-existing arrhythmias are at risk due to
both a reduced threshold for LAST but also potentially
increased severity. Ischaemia is also a recognised risk,
presumably resulting from the enhanced oxidative stress
where local anaesthetics impair mitochondrial metabolism
and ATP production. Poor cardiac output can also
dramatically increase the peak plasma concentration
passing through the coronary capillary bed after
intravascular absorption or injection.
Pregnancy
Alpha-1 acid glycoproteins are reduced in pregnancy while
cardiac output is increased. This leads to rapid absorption
and higher plasma concentrations of free local anaesthetic
[56]. Epidural vein engorgement and the space occupying
effect of the fetus combine to reduce the volume of the
epidural and subarachnoid space, meaning the dose of
local anaesthetic in neuraxial procedures should also be
reduced. However, even in the first trimester before the
advent of such physical changes, epidural block height is
higher, possibly due to progesterone increasing the
susceptibility of nerves to local anaesthetic conduction
blockade [70, 71]. Therefore, even in the first trimester, local
anaesthetic dosing should be reduced and it seems logical
to use the minimum effective dose.
Hepatic and renal disease
Decreased hepatic blood flow or impaired hepatic function
affect disposition of amide local anaesthetics which
undergo hepatic enzymatic degradation. However, ɑ-1 acid
glycoprotein is still synthesised in end-stage liver failure,
preventing a further rise in free plasma local anaesthetic. While
local anaesthetic clearance is reduced in renal impairment, ɑ-1
acid glycoprotein levels are increased so that free plasma
concentrations remain relatively unchanged. Patients with end-
stage renal failure may be uraemic and acidotic which can
increase free local anaesthetic concentrations.
Metabolic risks
Diabetes mellitus, mitochondrial disease and carnitine
deficiency are all recognised risk-factors, as is
malnourishment, which reduces plasma protein levels and
is associated with sarcopenia. Women appear to be at
higher risk than men based on evidence from case series.
Out-of-hospital use
Administration of local anaesthesia outside of hospitals and
ambulatory surgical centres most often occurs in: dental
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settings; pain medicine; urology; dermatology clinics; and
emergency departments. It is important that all clinicians
using local anaesthesia outside the hospital setting should
be trained to consider LAST in any patient presenting with
altered neurological or cardiovascular status, especially
with progressive hypotension and bradycardia or frank
cardiac arrest. This holds true even when LAST occurs after a
long delay, given plasma anaesthetic levels may peak
between 2 and 48 h following administration depending on
technique and procedure [63]. It is important that such
remote sites have a well-established plan for managing
LAST. Beyond immediate life support measures, including
airway management, cardiopulmonary resuscitation and
infusion of lipid emulsion, such plans should include methods
for contacting and transporting to the closest facility with a
capable emergency department, for example, those with an
anaesthesia service and cardiopulmonary bypass
extracorporeal membrane oxygenation facilities.
patients are treated optimally on arrival by a team including
anaesthetists, emergency physicians and the referring
physician who knows the patient. Special considerations for
LAST management in the prehospital setting without a LAST-
specific kit should focus on: airway management;
haemodynamic stabilisation with vasopressors; treating
seizures with benzodiazepines; and avoiding lidocaine, beta-
blockers, or calcium channel blockers.
Emergency departments represent a significant site for
potential LAST, given the frequency of local anaesthetic use
to facilitate procedural interventions. Many emergency
department-based case reports describe accidental
overdose or accidental intravascular infiltration of local
anaesthetic while performing incision and drainage of
abscesses, repairing lacerations, or nerve blocks for pre-
operative analgesia [72–75]. Use of therapeutic lidocaine
infusions as systemic analgesia has grown in the emergency
department in parallel to the increasing interest in its peri-
operative use. However, the use of lidocaine in the peri-
operative setting (operating room, post-anaesthetia care
unit) arguably differs from emergency department services
in terms of formularies, workflow, monitoring ability, and
clinician- and nurse-to-patient ratios. In a case series
evaluating efficacy of intravenous lidocaine for emergency
department pain management, Fitzpatrick et al. describe a
patient who accidentally received a massive overdose of
lidocaine [76]. The patient received a cumulative dose of
1
400 mg (3.7 mg.kg ) lidocaine, seized and developed
bradycardia progressing to cardiac arrest. The patient was
resuscitated successfully and a root cause analysis
determined that the ordering physician was unfamiliar with
lidocaine dosing for systemic analgesia.
34
Macfarlane et al. | A review of local anaesthetic systemic toxicity
Favourable patient outcomes in LAST depend on
quickly recognising the diagnosis. While use of local
anaesthetics is commonplace across medical specialties,
awareness of adverse outcomes may be inadequate among
non-anaesthetists. For instance, a 2015 assessment of
awareness of LAST among non-anaesthetic multi-specialty
postgraduate medical residents in India found that only
70% of responders believed that local anaesthetics were
toxic, 27% knew the toxic dose of lidocaine and only 7%
were aware of the toxic dose of bupivacaine. Only 2% of
residents knew that lipid emulsion is part of the treatment
for LAST [77].
In the absence of on-site antidote treatment capability,
it is important that prehospital and receiving facilities are
prepared to manage LAST. The American Association of
Poison Control Centres 2016 Annual Report detailed the
or case of a 55-year-old woman who experienced respiratory
Such depression, ventricular tachycardia and asystole following
accidental prehospital intra-osseous administration of
40 ml lidocaine 2% for procedural analgesia [78]. This
patient had a return of spontaneous circulation following
infusion of lipid emulsion and sodium bicarbonate
administration, but suffered an additional cardiac arrest and
died 1 h following the lidocaine overdose. Similarly, the
2018 Annual Report describes a case of prehospital
accidental intravenous administration of an unknown
volume of lidocaine 2% instead of dextrose for a patient with
hypoglycaemia [79]. Following an extensive resuscitative
effort with intravenous calcium, saline and noradrenaline,
the patient died. Lipid emulsion was not given in this case. It
is unknown if the paramedics involved in these cases were
familiar with the signs, symptoms and treatment of LAST, or
if the presentation of the toxidrome was masked by
hypoglycaemia-related altered sensorium. In either
circumstance, additional training to raise awareness of LAST
should be provided to prehospital providers, as lidocaine is
a standard drug stocked as prefilled syringes in ambulance
drug boxes.
Cao et al. reported 94 cases of lipid emulsion use in
emergency departments, and 47 of these involved LAST.
They recommended lipid emulsion be stocked in
emergency departments near procedure rooms and other
areas where local nerve blocks and laceration repairs are
performed [73,80]. Cognitive aids (ASRA Checklist or
Association of Anaesthetists Guidance) for treating LAST
should also be available in emergency departments [40]. As
anaesthetists are typically familiar with acute management
and post-event monitoring of LAST, they should be
available for consultation and participation if it occurs in the
emergency department.
© 2021 Association of Anaesthetists
Macfarlane et al. | A review of local anaesthetic systemic toxicity Anaesthesia 2021, 76, 27–39

Table 2 Suggested future directions to improve the management of local anaesthetic systemic toxicity.
Domain Implementation
Education Curriculum for all peri-operative healthcare professionals, including anaesthetists, surgeons and nursing staff
Training for healthcare professionals caring for patients after local anaesthetic administration (e.g. PACU and ward nurses)
Multidisciplinary simulation training
Systems Addition of local anaesthesia brief to the WHO checklist
Automated calculation of maximum safe dosing on electronic drug charts
Computer-generated dosing threshold reminders
Daily local anaesthetic systemic toxicity brief
Specific protocols in remote care areas (e.g. outpatients or clinics outside of hospital settings)
Research Dose-limiting techniques of local anaesthetic administration
Novel needle devices to detect intravascular injection
International standardisation of treatment algorithms
PACU, post-anaesthetic care unit; WHO, World Health Organization.

As use of intravenous lidocaine for systemic analgesia
grows, safety recommendations are required, including
maximal dosing (approximately 2 mg.kg 1.h 1
in adults),
continuous assessment of vital signs and ECG, and avoidance
in patients with absolute or relative contraindications [81].
Relative contraindications for systemic analgesic lidocaine
use include findings of: cardiac conduction block; prolonged
PR and/or QRS intervals; pregnancy; age < 6 months;
chronic alcoholism or substance misuse, due to the risk of
additive central nervous system effects; renal dysfunction;
hepatic dysfunction; drug interactions, including medications
that induce or inhibit CYP1A2 or CYP3A4; and concurrent
use of anti-arrhythmics [81, 82].
management if it does occur will enhance overall patient
safety and outcomes. Finally, novel techniques and designs
for local anaesthetic administration must be investigated.
This could include devices that increase safety during
injection of local anaesthetic, by making blood aspiration
more visible to mitigate intravascular injection. Critically,
international standardisation of treatment algorithms,
including the American Society of Regional Anaesthesia
and Pain Medicine, the European Society of Regional
Anaesthesia and Pain Therapy, Regional Anaesthesia UK
and the Association of Anaesthetists and other key
stakeholders will also lead to safer regional anaesthesia
(Fig. 2; [86]).

Future directions Conclusion

There remain opportunities for educators, researchers and
institutions to improve outcomes of patients who are at risk
of LAST (Table 2). Multidisciplinary simulation has a defined
role in the management of operating room crises, and
training all staff involved in the care of patients who have
received local anaesthesia is warranted, including surgeons,
nurses, paramedics and other healthcare professionals on
the wards and elsewhere [83]. This training must include
recognition of the protean manifestations of LAST, as this
aids early recognition and treatment [84]. The use of
checklists and electronic decision tools for the management
of LAST are beneficial in simulation settings, and having
ready access to these guidelines should be mandatory in all
settings in which local anaesthesia may be used [85].
Education of clinicians about risk stratification of patients
administered local anaesthetic agents must also be
prioritised. Institutional implementation of systems to
minimise the risks of LAST and to improve clinical
Local anaesthetic systemic toxicity may occur with any use of
local anaesthetics. The clinical picture today is the result of
an evolving paradigm and will likely continue to change in
the future. Event evolution includes the dramatic increase in
severe, lidocaine-related events. While large-volume nerve
blocks remain a concern, the large-volume infiltration or
topicalisation of highly vascular tissues that cannot be
guided by ultrasound are resulting in an unexpected spike
in LAST reports. Many events result more from enhanced
susceptibility than from drug overdose. While the
awareness and availability of lipid resuscitation has not
eliminated fatal outcomes from LAST, it is nevertheless
disappointing that only approximately half of reported
cases received infusion of lipid emulsion therapy.
Awareness of these changing patterns can improve system
design and patient care by reducing risk and providing
timely diagnosis and treatment. Despite advances in
ultrasound technique, education and treatment, LAST

© 2021 Association of Anaesthetists 35

Anaesthesia 2021, 76 (Suppl. 1), 27–39 Macfarlane et al. | A review of local anaesthetic systemic toxicity

Figure 2 Proposed management of local anaesthetic systemic toxicity. All doses are based on ideal body weight. Adapted
from [86] with permission. LAST, local anaesthetic systemic toxicity; CNS, central nervous system; CVS, cardiovascular system.

36 © 2021 Association of Anaesthetists

Macfarlane et al. | A review of local anaesthetic systemic toxicity
events persist and will continue to occur if local anaesthetics
are in clinical use. Regional anaesthesia using local
anaesthetics will always require awareness of LAST, since
the risk cannot be eliminated altogether, even with perfect
practice.
Acknowledgements
AM has received an honorarium from Heron Therapeutics.
KE or his institution have received travel, educational or
research funding from Fisher and Paykel, Ambu and GE
Healthcare. KE is an Editor of Anaesthesia. GW is an officer
and shareholder of ResQ Pharma, Inc. He manages the
educational site www.lipidrescue.org. No other competing
interests declared.
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