Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ictx20 Download by: [UPSTATE Medical University Health Sciences Library] Date: 03 August 2016, At: 08:21 Clinical Toxicology ISSN: 1556-3650 (Print) 1556-9519 (Online) Journal homepage: http://www.tandfonline.com/loi/ictx20 Systematic review of the effect of intravenous lipid emulsion therapy for local anesthetic toxicity Lotte C. G. Hoegberg, Theodore C. Bania, Valéry Lavergne, Benoit Bailey, Alexis F. Turgeon, Simon H. L. Thomas, Martin Morris, Andrea Miller-Nesbitt, Bruno Mégarbane, Sheldon Magder, Sophie Gosselin & Lipid Emulsion Workgroup To cite this article: Lotte C. G. Hoegberg, Theodore C. Bania, Valéry Lavergne, Benoit Bailey, Alexis F. Turgeon, Simon H. L. Thomas, Martin Morris, Andrea Miller-Nesbitt, Bruno Mégarbane, Sheldon Magder, Sophie Gosselin & Lipid Emulsion Workgroup (2016) Systematic review of the effect of intravenous lipid emulsion therapy for local anesthetic toxicity, Clinical Toxicology, 54:3, 167-193, DOI: 10.3109/15563650.2015.1121270 To link to this article: http://dx.doi.org/10.3109/15563650.2015.1121270 Published online: 06 Feb 2016. Submit your article to this journal Article views: 714 View related articles View Crossmark data Citing articles: 3 View citing articles
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Full Terms & Conditions of access and use can be found athttp://www.tandfonline.com/action/journalInformation?journalCode=ictx20
Download by: [UPSTATE Medical University Health Sciences Library] Date: 03 August 2016, At: 08:21
Systematic review of the effect of intravenous lipidemulsion therapy for local anesthetic toxicity
Lotte C. G. Hoegberg, Theodore C. Bania, Valéry Lavergne, Benoit Bailey,Alexis F. Turgeon, Simon H. L. Thomas, Martin Morris, Andrea Miller-Nesbitt,Bruno Mégarbane, Sheldon Magder, Sophie Gosselin & Lipid EmulsionWorkgroup
To cite this article: Lotte C. G. Hoegberg, Theodore C. Bania, Valéry Lavergne, Benoit Bailey,Alexis F. Turgeon, Simon H. L. Thomas, Martin Morris, Andrea Miller-Nesbitt, Bruno Mégarbane,Sheldon Magder, Sophie Gosselin & Lipid Emulsion Workgroup (2016) Systematic review ofthe effect of intravenous lipid emulsion therapy for local anesthetic toxicity, Clinical Toxicology,54:3, 167-193, DOI: 10.3109/15563650.2015.1121270
To link to this article: http://dx.doi.org/10.3109/15563650.2015.1121270
Published online: 06 Feb 2016. Submit your article to this journal
Article views: 714 View related articles
View Crossmark data Citing articles: 3 View citing articles
Systematic review of the effect of intravenous lipid emulsion therapy for localanesthetic toxicity
Lotte C. G. Hoegberga, Theodore C. Baniab, Valery Lavergnec, Benoit Baileyd,e, Alexis F. Turgeonf, Simon H.L. Thomasg, Martin Morrish, Andrea Miller-Nesbitth, Bruno Megarbanei, Sheldon Magderj and Sophie Gosseline,k;Lipid Emulsion Workgroup*
aDepartment of Anesthesiology, Danish Poisons Information Centre, Copenhagen University Hospital Bispebjerg, Copenhagen, Denmark;bDepartment of Emergency Medicine, Mt Sinai Roosevelt, Mt Sinai St. Luke’s, Icahn School of Medicine, New York, NY, USA; cDepartment ofMedical Biology, Sacre-Coeur Hospital, University Of Montreal, Montreal, Canada; dDivision of Emergency Medicine, Department of Pediatrics,CHU Sainte-Justine, Montreal, Canada; eCentre Antipoison du Quebec, Quebec, Canada; fDivision of Critical Care Medicine, Department ofAnesthesiology and Critical Care Medicine, CHU de Quebec – Universite Laval Research Center, Population Health and Optimal Health PracticesUnit, Universite Laval, Quebec City, Canada; gNational Poisons Information Service (Newcastle) and Medical Toxicology Centre, Institute ofCellular Medicine, Newcastle University, Newcastle, United Kingdom; hSchulich Library of Science and Engineering, McGill University, Montreal,Canada; iDepartment of Medical and Toxicological Intensive Care, Lariboisiere Hospital, Paris-Diderot University, Paris, France; jDepartment ofCritical Care, McGill University Health Centre, Montreal, Canada; kDepartment of Emergency Medicine, McGill University Health Centre, Montreal,Canada
ABSTRACT
Background: Following national and regional recommendations, intravenous lipid emulsion (ILE) hasbecome established in clinical practice as a treatment for acute local anesthetic (LA) toxicity, althoughevidence of efficacy is limited to animal studies and human case reports. A collaborative lipid emulsionworkgroup was therefore established by the American Academy of Clinical Toxicology to review theevidence on the effect of ILE for LA toxicity.Methods: We performed a systematic review of the literaturepublished through 15 December 2014. Relevant articles were determined based on pre-defined inclusionand exclusion criteria. Pre-treatment experiments, pharmacokinetic studies not involving toxicity andstudies that did not address antidotal use of ILE were excluded. Results: We included 113 studies andreports. Of these, 76 were human and 38 animal studies. One publication included both a human casereport and an animal study. Human studies included one randomized controlled crossover trial involving16 healthy volunteers. The subclinical LA toxicity design did not show a difference in the effects of ILEversus saline. There was one case series and 73 case reports of ILE use in the context of toxicity (83patients) including CNS depression or agitation (n¼ 45, 54%), seizures (n¼ 49, 59%), hypotension,hypertension, EKG changes, arrhythmias (n¼ 39, 47%), cardiac arrest (n¼ 18, 22%), cardiopulmonaryresuscitation, and/or requirement for endotracheal intubation and/or mechanical ventilation (n¼ 35,42%). There were 81 (98%) survivors including 63 (76%) with no reported sequelae from the LApoisoning or ILE, although the presence or absence of sequelae was not reported in 15 (18%) cases.Animal studies included 29 randomized controlled studies, three observational studies, five case series,and one case report; bupivacaine was used in 29 of these reports (76%). Of 14 controlled experiments inanimals, eight showed improved survival or time to return of spontaneous circulation and five no benefitof ILE versus saline or non-ILE treatments. Combining ILE with epinephrine improved survival in five ofthe six controlled animal experiments that studied this intervention. The studies were heterogeneous inthe formulations and doses of ILE used as well as the doses of LA. The body of the literature identified bythis systematic review yielded only a very low quality of evidence. Conclusion: ILE appears to beeffective for reversal of cardiovascular or neurological features in some cases of LA toxicity, but there iscurrently no convincing evidence showing that ILE is more effective than vasopressors or to indicatewhich treatment should be instituted as first line therapy in severe LA toxicity.
ARTICLE HISTORY
Received 3 June 2015Revised 21 October 2015Accepted 11 November 2015Published online 4 February2016
There has been increasing interest in the use of intravenous
lipid emulsion (ILE) for the treatment of acute local anesthetic
(LA) poisoning following the publication of a case report in
2006.[1] Since then, national and regional anesthesiology
societies have published recommendations for use of ILE in
the treatment of LA toxicity after iatrogenic overdose.[2–4]
However, evidence supporting the use of ILE in the context of
toxicity involving local anesthetics or other toxins reported by
previous reviews consists primarily of human case reports and
CONTACT Lotte C. G. Hoegberg [email protected] Danish Poisons Information Centre, Department of Anaesthesiology, Copenhagen UniversityHospital Bispebjerg, Copenhagen, Denmark*The other members of the Lipid Emulsion Workgroup are: Ashish Bhalla, Diane Calello, Ryan Chuang, Brian Gilfix, Andis Graudins, Ami Grunbaum, Bryan D. Hayes,Robert S. Hoffman, Michael Levine, Jose Morais, Carol Rollins, Samuel Stellpflug, Christine Stork.
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controlled animal experiments that cannot necessarily be
extrapolated to human clinical settings.[5–8]
The American Academy of Clinical Toxicology (AACT)
initiated a collaboration between the European Association
of Poison Centres and Clinical Toxicologists (EAPCCT), the Asia
Pacific Association of Medical Toxicology (APAMT), the
Canadian Association of Poison Control Centres (CAPCC), the
American College of Medical Toxicology (ACMT) and the
American Association of Poison Control Centers (AAPCC) to
create the Lipid Emulsion Therapy in Clinical Toxicology
Workgroup, which included clinical experts in clinical toxicol-
ogy, anesthesiology, emergency medicine, critical care, and
pharmacy with assistance of medical librarians and epidemi-
ologists. This workgroup was tasked to review all appropriate
evidence pertaining to the use of lipid emulsion in toxicology,
with the ultimate goal of providing a comprehensive evalu-
ation of the published evidence and consensus-based recom-
mendations.[9] Here, we present the results of our systematic
review of human and animal studies regarding the effect of ILE
in the treatment of LA toxicity. Use for treating toxicity from
other substances and adverse effects of ILE will be presented in
other systematic reviews.
Methods
A working subgroup (the authors) of the lipid emulsion therapy
workgroup [9] was formed to gather and review the evidence
on the effect of ILE in the treatment of LA toxicity. This
subgroup was formed based on the best possible match to
represent the clinical experts and various stakeholders and
involved in the workgroup. It also included two medical
librarians who assisted in conducting the systematic searches
and the retrieval of potentially eligible publications, as well as
an epidemiologist with specific methodological expertise in
conducting systematic reviews. Subgroup members divulged
all potential conflicts of interests prior to inclusion in the
workgroup. All communication was performed by email
exchanges and by telephone conferences.
Two medical librarians created a systematic search strategy
for Medline (Ovid), which is provided in the Appendix. The
strategy comprised a combination of Medical Subject
Headings, title/abstract key words, truncations, and Boolean
operators, and included the concepts of ILE and toxicology
(including but not limited to local anesthetics). It was subse-
quently translated for Embase (via Ovid), CINAHL (via EBSCO),
BIOSIS Previews (via Ovid), Web of Science, Scopus, and the
Cochrane Library/DARE. All databases were searched from
inception to 15 December 2014. Subsequently, articles were
triaged into local anesthetics and non-local anesthetics for
review by each designated groups.
In addition, conference abstracts from the European
Association for Poison Centers and Clinical Toxicologists, and
the North American Congress of Clinical Toxicology (both from
2000 to 2014) and previous reviews were hand-searched by
various group members. Abstracts from the Asia Pacific
Association of Medical Toxicology were searched in the same
way from 2007 to 2014. Group members also performed cross-
referencing of full-text articles. No limits were applied for
language, and candidate studies in languages not known to
any of the authors were translated.
In summary, the criteria for publication inclusion in the
evaluation of the effect of ILE include studies in humans and
animals to whom ILE was given for the purpose of treating
poisoning, and exclusion criteria are non-original data, animal
studies with methods and results that cannot be extrapolated
or are uninterpretable to humans, pre-treatment models, and
experimental in vitro or ex vivo models. A complete method-
ology of the larger project of which this systematic review is
one part was previously published, and describes in detail all
relevant methodological aspects such as clinical questions,
search strategies, eligibility of publications, data extraction and
summary, and assessment of the risk of bias.[9]
The log D, which is based on the partition coefficient, and is
a measure of lipophilicity, is reported for each local anesthetic.
The degree of lipophilicity directly corresponds with the log D;
as the log D increases, so does the lipophilicity of a substance.
Results
Our combined search for the effect of ILE retrieved 838 full text
articles that were subsequently analyzed for their pertinence to
LA. Of these, 113 publications were included in our systematic
review. Among the included publications, 76 were conducted
in a human setting and 38 in an animal setting. One article
included both a case report and an animal experiment. One
human study was published as two publications. The flow
diagram of study selection is presented in Figure 1.
Human studies
Randomized controlled trials
One phase-II randomized controlled trial (unpublished, avail-
able as conference abstract at the time of writing) evaluated
the efficacy of ILE on the pharmacokinetic properties of LA in
16 healthy volunteers (8 female and 8 male) aged 18–40 years
(Table 1).[10,11] This was a double-blind crossover study
consisting of a first phase of habituation to LA with an infusion
of lidocaine, followed by a second phase of either a continuous
infusion of ropivacaine or levobupivacaine at 8mg/min treated
with either a bolus of 120 mL of 20% ILE or of 0.9% saline,
administered 2 min after the start of the LA infusion. The
primary outcome of interest was the duration of drug infusion
(expressed as total dose) required to induce early clinical signs
of neurotoxicity such as paresthesiae and a sensation of
inebriation, as evaluated by an examiner blinded to the
treatment. Secondary outcome measures were detection of
sub-clinical seizure activity based on electroencephalogram
(EEG), duration of PR, QRS intervals based on electrocardio-
gram (EKG), and pharmacokinetics of local anesthetics [max-
imum concentration (Cmax) and area under the plasma
concentration versus time curve (AUC)].
No significant difference in the total LA dose given to
reach early signs of clinical toxicity was observed between
ILE and control groups: Ropivacaine/ILE (75.7mg± 29.1mg) or
saline (81.7mg± 22.3mg) and Levobupivacaine/ILE (69.4mg±
26.2mg) or saline (80.8mg± 31.7mg; p¼ 0.61). The LA dose
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was provided at 8mg/min, and maximum allowed dose was
120mg. Four of the 16 volunteers received the maximum dose
of LA allowed in the protocol. No EEG abnormalities were seen.
QRS prolongation was present at the end of the LA infusion as
compared to baseline (p50.001), but no significant difference
was observed between the ILE and control groups (p¼ 0.68).[11]
Small pharmacokinetic differences between groups, including a
25–30% reduction in Cmax and a 20% increase in volume of
distribution of the LA at a comparable mean dose, were not
statistically significant and disappeared after 45 min [10]. The
authors concluded that their study confirmed the lipid sink
hypothesis in humans, but that no clinical efficacy of ILE could
be observed in this systemic toxicity model, where a 3.8ms
prolongation in QRS was induced by the LA perfusion. No
obvious risk of bias was identified from the research protocol
&rank¼1), but concerns remain regarding indirectness (use of
surrogate markers and uncertain generalizability to a poisoning
context) and imprecision of the reported results due to the
small sample size (potentially underpowered study).
No published peer-reviewed clinical controlled or observa-
tional studies were retrieved by our search.
(n=19,447)
(n=11,353)
(n=10,515)
(n=11,353)
a a
b
Figure 1. Selection of articles flow diagram. Search date 15 December 2014.aOne citation included both one animal study and one human case report.b2 citations for abstracts of a single experiment with 2 parts thus counted as one experiment.RCS: randomized controlled study; RCT: randomized controlled trial.
CLINICAL TOXICOLOGY 169
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Table
1.Summaryofthe16volunteersfrom
acrossoverrandomized
controlledtrial,and83patients
from
73case
reportsandonecase
series
included
inthesystem
aticreview
.
References
Studytype
Age/sex,weight
Localanesthetic
anddose
LogD
[129]
Route
of
administration
Symptoms
ILEused
ILEdose
aILEonly
used
Other
treatm
ents
received,dose
included
ifreported
ILEeffect
Outcome
RCT
Dureau
etal.(2014)
R010+R011
[10,11]b
RCT,cross-
over
Age18–40years/
8F+8M
Ropivacaineor
Levobupivacaine;
Continued
infusion
doses8mg/m
in,
maximum
120mgor
untilearlysignsof
toxicity
such
aspar-
esthesiasorinebri-
ationsensation
reached.
4.21
2.68
Infusion
Neurologicimpregna-
tion(paresthesia,
inebriation)
QRSbroadeningat
LAcessation
20%,
Intralipid
120mLbolus
Yes
Saline(120ml)on
twostudydays
(Controlgroup)
Studyconfirm
sthe
Lipid
Sinkhypothesis
inhumans,but
unable
todem
on-
strate
anyclinical
benefitofILE
4outof16volunteers
reached
maximum
dose.
Meandose
toreachmild
toxicity
threshold
was
not
differentin
ILEversus
controlgroups(75.7¼/
�29.1mgversus81.7¼/-
22.3
mgforropivacaine
and69.4¼/-26.2
mg
versus80.8¼/-31.7
mg
forlevobupivacaine
Case
reports/series
Admani&Essajee
(2010)[12]
Casereport
3months/
M,5.9
kgBupivacaine25mg,
Lidocaine100mg
2.68
1.26
Subcutaneous
Seizure.bradycardia
withblock
then
Ventricularfibrillation
andVentricular
tachycardia
20%,
Intralipid
9mL(0.31g/kg)
bolusthen
0.25mL/
kg/m
in(0.51g/kg/h)
No
Dexam
ethasone
2mg,hydrocortisone
20mg,thiopental
5mg
Mechanical
ventilation
Probablynoeffect
required
benzodi-
azepineafterseizures
restartedin
ICU
Survival,
nosequelae
Al-Alami(2011)[13]
Casereport
16years/M,
58kg
Ropivacaine300mg
4.21
Nerve
block
Confusion,visual
hal-
lucinationsslurred
speech
trem
or
Sinustachycardiaand
hypertension
20%,
Intralipid
0.0015g/kgbolus
then
0.015g/kg/h
in3h
No
Midazolam
0.5
mg
ILEwas
safe
andsuc-
cessfulin
reversing
LA-inducedearlyCNS
andcardiac
abnorm
alities
Survival,
nosequelae
Avelineet
al.(2010)
[14]
Casereport
52years/F,
57kg
Lidocaine400mg,
Ropivacaine112.5mg
1.26
4.21
Nerve
block
GCS7,agitated,con-
fused,jerkingarms/
head
20%,
Intralipid
100mL(0.35g/
kg)�
2bolus
No
Midazolam
3mg,
thiopental300mg
andsuxamethonium
80mg
Intubation
ILEnoteffective
Survival,
nosequelae
Bazerbachiet
al.
(2014)[15]
Casereport
57years/M,
weightNR
Ropivacaine1540mg
4.21
Nerve
block
Lethargic,hallucin-
ations
Bradycardia,wide
QRS,prolonged
QT,
ejectionfraction20%
Cardiacarrest
Tinnitus,dysgeusia
20%,
Intralipid
Totaldose
2480mL
No
Plasm
apheresis
Suggestthefailure
ofILErescue
Diedfrom
cardiacarrest
Bilottaet
al.(2012)
[16]
Casereport
53years/M,
weightNR
Lidocaine500mg,
Ropivacaine3000mg
1.26
4.21
Nerve
block
AVblock,HR28/m
in,
MAP40mmHg
20%,
Intralipid
100mLbolus(55
min)then
100mLin
20min
No
Atropine0.5
mg,
phenylephrine10mg
Rapid
beneficial
effect
Survival,
nosequelae
Buckenmaier
etal.(2012)[17]
Casereport
29years/M,
weightNR
Ropivacaine,
Mepivacaine.
Bolusandcontinued
infusiondosesof
both,totaldose
NR
4.21
1.40
Nerve
block
Unresponsive,cardiac
arrest
Intralipid
1mL/kg
�3bolus
No
Epinephrine,atro-
pine,am
iodarone,
calcium,sodium
bicarbonate,magne-
sium,thrombolytic
therapy
CPR
NR
Diedfrom
blast
injuries
complicated
byLA
toxicity
resultingin
afatalcardiac
arrhythmia
Calenda&Dinescu
(2009)[18]
Casereport
72years/M,
60kg
Mepivacaine300mg,
Ropivacaine112.5mg
1.40
4.21
Nerve
block
Numbmouth/tongue
Seizures
Tachycardia
(130/
min)
20%,
Intralipid
250mL(0.83g/kg)
bolus
No
Midazolam
5mg,
propofol150mg(first
seizure);Thiopental
125mg(second
seizure)
Mechanical
ventilation
ILEnoteffectivein
stoppingsecond
seizure
Survival,
nosequelae
Caveet
al.(2014)
(Lipid
Registry)
[19]
Caseseries,
No1
AgeNR/M
,weightNR
Lidocaine560mg
1.26
Nerve
block
Hypertension
Drowsy
NR
NR
NR
NR
NR
Survival,
sequelae
NR
(continued)
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Table
1.Continued
References
Studytype
Age/sex,weight
Localanesthetic
anddose
LogD
[129]
Route
of
administration
Symptoms
ILEused
ILEdose
aILEonly
used
Other
treatm
ents
received,dose
included
ifreported
ILEeffect
Outcome
Caveet
al.(2014)
(Lipid
Registry)
[19]
Caseseries,
No2
67years/F,
49kg
Lidocaine200mg,
Bupivacaine75mg
1.26
2.68
Nerve
block
Seizure
20%,
Intralipid
1.5
mL/kg
(0.30g/kg)
bolusthen
400mL
(4.9
g/kg/h)in
20
min.Totaldose
500
mL(2.04g/kg)
No
Midazolam
ILEwas
thoughtto
havepreventeddeath
Survival,
sequelae
NR
Caveet
al.(2014)
(Lipid
Registry)
[19]
Caseseries,
No3
NR
Mepivacaine900mg,
Bupivacaine100mg
1.40
2.68
Nerve
block
Decreased
levelof
consciousness
NR
NR
NR
NR
NR
Survival,
sequelae
NR
Caveet
al.(2014)
(Lipid
Registry)
[19]
Caseseries,
No4
68years/M,
75kg
Ropivacaine200mg
4.21
Nerve
block
Seizure
Cardiacarrest
20%,
Intralipid
100mL(0.27g/
kg)�
3bolus.
Totaldose
300mL
(0.80g/kg)
No
Midazolam,epineph-
rine,sodium
bicar-
bonate,magnesium,
andhydrocortisone
NR
Survival,
sequelae
NR
Caveet
al.(2014)
(Lipid
Registry)
[19]
Caseseries,
No5
69years/F,
80kg
Bupivacaine150mg
2.68
Nerve
block
Seizure
Cardiovascular
collapse
20%,
Intralipid
1.5
mL/kg
(0.30g/kg)
bolusthen
400mL/h
(1.0g/kg/h)
Totaldose
500mL
(1.25g/kg)
NR
NR
ILEwas
thoughtto
havepreventeddeath
Survival,
sequelae
NR
Caveet
al.(2014)
(Lipid
Registry)
[19]
Caseseries,
No6
NR
Bupivacaine50mg
2.68
Nerve
block
Seizure
NR
NR
NR
NR
NR
Survival,
sequelae
NR
Caveet
al.(2014)
(Lipid
Registry)
[19]
Caseseries,
No7
NR
Bupivacaine100mg
2.68
Nerve
block
Seizure
NR
NR
NR
NR
NR
Survival,
sequelae
NR
Caveet
al.(2014)
(Lipid
Registry)
[19]
Caseseries,
No8
30years/M,
81kg
Bupivacaine100mg
2.68
Nerve
block
Seizure
20%,
Lipofundin
1.5
mL/kg
(0.30g/kg)
bolusthen
15mL/
min
(2.22g/kg/h)
Totaldose
640mL
1.58g/kg)
NR
NR
ILEwas
thoughtto
havepreventeddeath
Survival,
sequelae
NR
Caveet
al.(2014)
(Lipid
Registry)
[19]
Caseseries,
No9
47years/F,
60kg
Bupivacaine187.5mg
2.68
Subcutaneous
Decreased
levelof
consciousness
20%,
Intralipid
1.5
mL/kg
(0.30g/kg)
bolusthen
13mL/
min
(2.58g/kg/h)
Totaldose
900mL
(3.0
g/kg)
NR
NR
NR
Survival,
sequelae
NR
Caveet
al.(2014)
(Lipid
Registry)
[19]
Caseseries,
No10
75years/F,
57kg
Bupivacaine1595mg
2.68
Nerve
block
Seizure
20%,
Intralipid
1.5
mL/kg
(0.30g/kg)
bolusthen
870mL/h
(3.05g/kg/h)
Totaldose
587mL
1.95g/kg)
NR
NR
NR
Survival,
sequelae
NR
Charbonneauet
al.
(2009)[20]
Casereport
19years/sexNR,
67kg
Mepivacaine1000mg
1.40
Nerve
block
Dysarthria,myoclo-
nia,confusion
20%,
Medialipid
100mL(0.30g/kg)
bolus
No
Midazolam
1mg,
clonazepam
1mg
Efficacy
was
immedi-
ateandcomplete
Survival,
nosequelae
Contargyriset
al.
(2012)[21]
Casereport
26years/F,34
weeks
pregnant,
51/58kg
Bupivacaine7mg,
Ropivacaine90mg
2.68
4.21
Nerve
block
Headache,metallic
taste,hallucinations
20%,
Intralipid
200mL(0.78g/kg
mother)bolus
Yes
NR
Resolutionof
symptoms
Survival,
sequelae
NR
Cordellet
al.(2010)
[22]
Casereport
17years/F,
weightNR
Bupivacaine75mg
2.68
Nerve
block
Seizure
Tachycardia
(180/
min)
20%,
brandNR
100mL�3bolus,
then
infusion.Total
dose
NR
No
Midazolam
2mg,
propofol100mg
andepinephrine
1mg
CPR,intubation
Resolutionofcardiac
andneurologic
symptoms
Survival,
nosequelae
Dacosta(2009)[23]b
Casereport
44years/F,
104kg
Lidocaine150mg
Bupivacaine200mg
1.26
2.68
Nerve
block
Metallic
taste
Sinusbradycardia
(34/m
in),hypoten-
sion(80/45mmHg)
NR
100mlin
10min
No
Atropine2mg,
ephedrine5mg,
saline500mL
Resolutionofcardiac
symptomsin
15min
Survival,
nosequelae
Diazet
al.(2012)
[24]
Casereport
Adult/F,
75kg
Levobupivacaine
34.25mg,
Lidocaine340mg
2.68
1.26
Nerve
block
Somnolent,devel-
oped
trem
or,nystag-
musandbecam
ecomatose
Decreasein
blood
pressure
Nausea
20%,
Medialipid
(MCT/LCT)
100mL(0.27g/kg)
bolusthen
400mL
(0.53g/kg/h)in
2h
No
Phenylephrine,
ondansetron4mg,
sufentanil20.5
mcg,
clonidine138mcg
Resolutionofcardiac
andneurologic
symptoms
Survival,
nosequelae
(continued)
CLINICAL TOXICOLOGY 171
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rary
] at
08:2
1 0
3 A
ugust
2016
Table
1.Continued
References
Studytype
Age/sex,weight
Localanesthetic
anddose
LogD
[129]
Route
of
administration
Symptoms
ILEused
ILEdose
aILEonly
used
Other
treatm
ents
received,dose
included
ifreported
ILEeffect
Outcome
Dixet
al.(2011)[25]Casereport
57years/M,
weightNR
Lidocaine120mg+2
mg/m
ininfusion,
totaldose
NR
1.26
Intravenous
Somnolent,confused,
unresponsive
QRSwidening,
Suffered
from
cardio-
vasculardisease
already.
Pulseless,electro-
mechanical
dissoci-
ation
Trem
or,difficulty
perform
ingcerebellar
testing
20%,
Intralipid
1mL/kg
bolusthen
0.25mL/kg/m
inin
30min
No
Epinephrine,am
io-
darone,magnesium
sulfate,calcium
glu-
conate,andsodium
bicarbonate,dopa-
mine7mcg/kg/m
inCPR
Resolutionofcardiac
symptoms
Survival,
nosequelae
Egan
(2013)[26]b
Casereport
38years/F,
62kg
Ropivacaine100mg,
Lidocaine200mg
4.21
2.26
Nerve
block
Grandmal
seizures1
min
post-injection
Coma
20%,
Intralipid
100mL(0.32g/kg)
bolusthen
0.25mg/
kg/h
infusion,dur-
ationNR
No
Midazolam42mg
Intubation
Resolutionofseizure
uncleartiming
Resolutionofcoma
30minuteslater
Survival,
nosequelae
Espinet
&Em
merton
(2009)[27]
Casereport
36years/M,
80kg
Bupivacaine100mg,
Lidocaine100mg
2.68
1.26
Nerve
block
Perioraltingling,
headache,dizziness,
lightheadedness,
diplopia
Tachycardia
(153/
min),BP180/110
mmHg,ST
depression
20%,
Intralipid
100mL(0.25g/kg)�
2bolusthen
100mL
(0.25g/kg/h)in
1h
No
Crystalloid
(Hartm
ann’ssolution)
1L
Oxygen
Resolutionofcardiac
andneurologic
symptoms
Survival,
nosequelae
Etesse
etal.(2011)
[28]
Casereport
23years/F,38
weeks
pregnant,
weightNR
Ropivacaine46mg
4.21
Nerve
block
Visual
hallucination,
nausea
7hourpriorto
developmentof
statusepilepticus
Hypertension
NR
100mL
No
Midazolam
2mg,
magnesium
sulfate
1gin
20min
and
then
1g/h
Oxygen
Resolutionofneuro-
logicsymptoms
Survival,
nosequelae
Fentenet
al.(2014)
[29]
Casereport
67years/F,
weightNR
Ropivacaine400mg
4.21
Intra-articular/
Subcutaneous
Chestpain
Coma
Seizure
20%,
brandNR
Infusion
Unknownduration
No
Nitroglycerin(spray),
metoprolol5mg,
midazolam
1mg
boluses
Oxygen
Resolutionofinitial
seizure
butrecur-
rence
ofseizuresand
twitchingfor5.5
hafter
Survival,
nosequelae
Foxallet
al.(2007)
[30]
Casereport
75years/F,
85kg
Levobupivacaine
100mg
2.68
Nerve
block
Unresponsiveness
Seizures
QRSwidening;
Suffered
from
cardio-
vasculardisease
already
Groaned
20%,
Intralipid
100mL(0.24g/kg)
bolusin
5min
No
Metaram
inol0.5
mg,
propofol80mg,
suxamethonium
100mg
Oxygen,intubation
Resolutionofcardiac
symptoms
Survival,
nosequelae
French
etal.(2012)
[31]b
Casereport
11months/M,
9.9
kgLidocaine100mg
1.26
Intraosseous
Statusepilepticus
20%,
Intralipid
12mL(0.24g/kg)
bolus
No
Lorazepam
0.1mg/kg
NR
Survival,
nosequelae
Fuzaylovet
al.
(2010)[32]
Casereport
13years/F,
50kg
Bupivacaine25mg
2.68
Intravenous
Decreased
BP(from
90to
60mmHg)and
broad
complexven-
triculartachycardia
20%,
Intralipid
100mL(0.4
g/kg)
bolus
No
Saline500mL.
Epinephrine10
mcg
�2bolus+0.1
mcg/kg/m
ininfusion,
dopam
ine10mcg/
kg/m
ininfusion
CPR
Possible
effect
inresolutionof
symptoms
Survival,
pulmonaryedem
a,resolved
day
4 (continued)
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cien
ces
Lib
rary
] at
08:2
1 0
3 A
ugust
2016
Table
1.Continued
References
Studytype
Age/sex,weight
Localanesthetic
anddose
LogD
[129]
Route
of
administration
Symptoms
ILEused
ILEdose
aILEonly
used
Other
treatm
ents
received,dose
included
ifreported
ILEeffect
Outcome
Gallagher
etal.
(2010)[33]
Casereport
28years/M
55.8
kgLidocaine2%,
Bupivacaine0.5%,
50mLmixture
LAratioNR
1.26
2.68
Subcutaneous
Dizzinessthen
coma
Apnea
Generalized
seizure
activity
withsevere
tonic-clonicactivity
Sudden
cardiacarrest
20%,
brandNR
2units(m
Lnot
reported)
No
Sodium
bicarbonate
200mEq,salinebolus
Epinephrine4mg,
vasopressin
40U,
atropine4mg,mid-
azolam
1mg,loraze-
pam
2mg
CPR
Resolutionofcardiac
symptoms
Survival,
nosequelae
Gnahoet
al.(2009)
[34]
Casereport
82years/F,
45kg
Ropivacaine100mg
4.21
Nerve
block
Lost
consciousness
Generalized
tonic-
clonicseizure
Ventricularfibrilla-
tion,nopulse
Difficultiesin
speaking
20%,
Intralipid
70mL(0.31g/kg)
bolus
No
Thiopental325mg,
suxamethonium
100
mg,propofol30mg,
epinephrine0.3
mg
Oxygen,intubation,
CPR
Rapid
beneficial
effect
oncardiac
resuscitation
Survival,
nosequelae
Goyalet
al.(2011)
[35]
Casereport
26years/M,
75kg
Bupivacaine25mg
2.68
Nerve
block
Tachycardia
(244–
250/m
in)andBP50–
56/30–36mmHg
10%,
Intralipid
150mL(0.20g/kg)
in15min
Yes
NA
Resolutionofcardiac
symptoms
Survival,
nosequelae
Grencet
al.(2011)
[36]b
Casereport
84years/F,
weightNR
Lidocaine20mg,
Triamcinolone80mg
1.26
0.92
Nerve
block
Generalized
tonic-
clonicseizures
Cardiacarrest
20%,
Intralipid
100mL�2bolus
No
Epinephrine2mg,
atropine3mg
Intubation,CPR
Resolutionofcardiac
symptoms;bolusILE
repeateddueto
per-
sistenthypotension
Survival,
nosequelae
Hartley
etal.(2012)
[37]
Casereport
46years/F,
46kg
Bupivacaine37.5
mg+18.75mg/h,
totaldose
NR
2.68
Nerve
block
Coma
Seizures
20%,
Intralipid
NR
Yes
Intubation
Unclearifeffect
isrelatedto
ILE
Survival,
sequelae
NR
Harveyet
al.(2011)
[38]
Casereport
69years/F,
80kg
Lidocaine50mg,
Bupivacaine150mg
1.26
Nerve
block
Unresponsiveness,
GCS3
Seizure
HR50/m
in,AVblock,
BP51/29mmHg
20%,
Intralipid
100mL(0.25g/kg)
bolusthen
400mL
1.33g/kg/h)in
45min
No
Midazolam
5mg,
atropine,600mcg,
epinephrine100mcg,
metaram
inol4mg
Intubation,mechan-
ical
ventilation
Resolutionofcardiac
symptoms
Survival,
nosequelae
Heavner
&Heavner
(2012)[39]b
Casereport
60years/F,
weightNR
Lidocaine1500mg
1.26
Intrapleural
Seizure
Cardiacarrest
20%,
brandNR
500mLbolusthen
50
mL/h
No
Unspecifiedconven-
tional
therapy
Resolutionofcardiac
symptoms
Survival,
nosequelae
Hurley
&Hanlon
(2009)[40]b
Casereport
54years/M,
weightNR
Bupivacaine,dose
NR
2.68
NR
Cardiacarrest
Asystole
NR
NR
NR
NR
Resolutionoftoxicity
within
afew
minutes
Survival,
nosequelae
Jensen&Borglum
(2011)[41]b
Casereport
41years/M,
weightNR
Ropivacaine600mg
4.21
Nerve
block
Loss
ofconsciousness
Seizure
20%,
Intralipid
100mLbolus
No
Diazepam
2.5
mg
Resolutionofneuro-
logicsymptoms
Survival,
nosequelae
Landyet
al.(2012)
[42,p.463]
Casereport
59years/sexNR,
weightNR
Ropivacaine2250mg
4.21
Nerve
block
Seizures
20%,
Intralipid
200mLbolus
Yes
NR
Resolutionofneuro-
logicsymptoms
Survival,
nosequelae
Landyet
al.(2012)
[43,p.701]
Casereport
74years/F,
60kg
Lidocaine380mg
1.26
Nerve
block
Tonic-clonic
movements
20%,
Intralipid
200mL(3
mL/kg
(0.60g/kg))bolus
No
Flecainide
Resolutionof
symptoms
Survival,
nosequelae
(continued)
CLINICAL TOXICOLOGY 173
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rary
] at
08:2
1 0
3 A
ugust
2016
Table
1.Continued
References
Studytype
Age/sex,weight
Localanesthetic
anddose
LogD
[129]
Route
of
administration
Symptoms
ILEused
ILEdose
aILEonly
used
Other
treatm
ents
received,dose
included
ifreported
ILEeffect
Outcome
Langeet
al.(2012)
[44]
Casereport
31years/M,
61kg
Lidocaine1600mg
1.26
Subcutaneous/
Intraperitoneal
Visual
hallucinations,
dysarthria,lower
level
ofconsciousnessand
becam
enon-verbal
20%,
Intralipid
100mL(0.33g/kg)in
10min
Yes
NR
Resolutionofneuro-
logicsymptoms
Survival,
nosequelae
Larsonet
al.(2013)
[45]
Casereport
4months/F,
6.54kg
Lidocaine1500mg,
Prilocaine1500mg
1.26
1.33
Topical
Single
seizure
Tachycardia
(147/
min)
Methem
oglobin
level
was
22.8%
20%,
brandNR
1g/kgbolus
No
Lorazepam
0.2mg/kg
i.m.and0.2
mg/kg
i.o.,fosphenytoin
20
mgPE/kg.Methylene
blue10mg(1.5
mg/
kg)
Topical
decontamin-
ation
Intubation,mechan-
ical
ventilation
Unclearifeffect
isrelatedto
ILE
Survival,
nosequelae
Levineet
al.(2014)
[46]
Casereport
20years/F,
weightNR
Bupivacaine,dose
NR
2.68
Nerve
block
Seizure
20%,
brandNR
20mL/kg
bolusthen
0.25mL/kg/m
infor
3h
Yes
NR
NR
Survival,
increasedlipase185IU/L
suggestingpancreatitis,
resolved
after14days
Li&Wardhan
(2013)
[47]b
Casereport
57years/F,
weightNR
Ropivacaine75mg,
Lidocaine400mg
4.21
1.26
Nerve
block
Severe
pain,somno-
lent,pinpointpupils
Intralipid,
conc.NR
75mLbolusthen
infusion,dose
and
durationNR
No
Naloxone80mcg,
midazolam
1mg,
propofol30mg
Resolutionofsymp-
toms,butconfused
andagitated
Survival,
nosequelae
Lin&Aronson
(2010)[48]
Casereport
2days/M,
3.2
kgBupivacaine8mg
2.68
Nerve
block
ST-segmenteleva-
tion,QRSwidening
Bradycardia
20%,
Intralipid
1mL/kg
(0.2
g/kg)
bolus
Yes
Nopharmaceuticals
Intubation,CPR
Resolutionofcardiac
symptoms
Survival,
nosequelae
Litz
etal.(2006)[49]Casereport
84years/F,
50kg
Ropivacaine400mg
4.21
Nerve
block
Dizziness,drowsiness
Seizures
Asystole
20%,
Intralipid
100mL(2
mL/kg
(0.40g/kg))bolus,
then
10mL/min
(2.4
g/kg/h)
Totaldose
200mL
(0.8
g/kg)
No
Thiopental150mg,
epinephrine3�1mg
Intubation,CPR
Resolutionofcardiac
symptoms
Survival,
nosequelae
Litz
etal.(2008)[50]Casereport
91years/M,
57kg
Mepivacaine300mg,
Prilocaine100mg
1.40
1.33
Nerve
block
Dizziness,agitation
anddeveloped
unre-
sponsiveness
Bigem
inyandPVCs
20%,
Intralipid
100mL(0.35g/kg)
bolusthen
0.25mL/
kg/m
in(3
g/kg/h)
Totaldose
200mL
(0.70g/kg)
No
Dolastrone12.5
mg
Resolutionofcardiac
andneurologic
symptoms
Survival,
nosequelae
Liuet
al.(2012)[51]b
Casereport
NR
Bupivacaine200mg
2.68
Intravenous
Unclearsymptoms
Intralipid,
conc.NR
110mL(1.5
mL/kg)
bolusthen
‘low
dose’
infusionin
2h
Yes
NR
Unclearifanysymp-
tomsdeveloped
or
werereversed
Survival,
sequelae
NR
Ludotet
al.(2008)
[52]
Casereport
13years/F,
55kg
Lidocaine200mg,
Ropivacaine150mg
1.26
4.42
Nerve
block
Ventriculartachycar-
dia
withwideQRS
20%,
Medialipid
150mL(3
mL/kg
(0.60g/kg))bolus
Yes
Nopharmaceuticals
Manual
ventilation
Resolutionofcardiac
symptoms
Survival,
nosequelae
Markowitz&Neal
(2009)[53]
Casereport
17years/M,
61kg
Bupivacaine100mg
2.68
Nerve
block
Coma
Statusepilepticus
Ventricularfibrillation
20%,
Intralipid
500mL(8
ml/kg
(1.6
g/kg)),dose
regimen
NR
No
Midazolam
3mg
Intubation
Unclearifeffect
isrelatedto
ILE
Survival,
nosequelae
Marraffa&Stork
(2013)[54]b
Casereport
66years/F,
weightNR
Bupivacaine420mg
2.68
Subcutaneous
CNSdepression,
decliningmental
status
Generalizetonic-
clonicseizure
activity
Systolic
hypotension
to60mmHg
20%,
brandNR
500mL�2bolus
No
Hydromorphone60
mgwiththeLA.
Bicarbonateem
piric-
allygiven,dopam
ine.
Naloxone0.4
mg�2,
icepacks
wereapplied
every2hat
the
injectionsite,loraze-
pam
0.2
mg
Intubation
Resolutionofcardiac
symptoms
Survival,
nosequelae
(continued)
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ersi
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h S
cien
ces
Lib
rary
] at
08:2
1 0
3 A
ugust
2016
Table
1.Continued
References
Studytype
Age/sex,weight
Localanesthetic
anddose
LogD
[129]
Route
of
administration
Symptoms
ILEused
ILEdose
aILEonly
used
Other
treatm
ents
received,dose
included
ifreported
ILEeffect
Outcome
Marwicket
al.(2009)
[55]
Casereport
33years/M,
72kg
Bupivacaine112.5mg
2.68
Nerve
block
Seizure
WideQRS
Cardiacarrest
Dry
mouth,apnea
20%,
Intralipid
150mL(0.43g/kg)
bolusthen
350mL
(1.94g/kg/h)in
30
min
No
Epinephrine1
mg+0.06mcg/kg/
min
infusion,total
timeNR.Thiopental
250mg,sodium
bicarbonate,insulin,
potassium,am
iodar-
one300mgin30min
Oxygen,intubation,
CPR
Resolutionofcardiac
symptoms
Survival,
amylase608IU/L
Mazoit(2013)[56]
Casereport
44years/M,
weightNR
Ropivacaine260mg
4.21
Nerve
block
Metallic
taste,myo-
clonicmovement
Seizure
Cardiacarrest
with
asystole
20%,
Intralipid
100mLbolus
No
Epinephrine100mcg
Manualventilation,
CPR
Resolutionofcardiac
symptoms
Survival,
nosequelae
McCutchen
&Gerancher
(2008)
[57]
Casereport
82years/F,
weightNR
Bupivacaine150mg
2.68
Nerve
block
Seizures�2
VTat
200/m
in20%,
Intralipid
100mLbolusthen
400mLover15min
No
Midazolam
3mg,
amiodarone150mg,
unspecifiedACLS
drugs
Oxygen,defibrillation
Unclearifeffect
isrelatedto
ILE
Survival,
nosequelae
Mizutaniet
al.
(2011)[58]
Casereport
24years/M,
66kg
Ropivacaine200mg
4.21
Nerve
block
Disappearance
of
motorresponse
tostimulation
20%,
brandNR
100mL(0.30g/kg)
bolus
No
Propofol(titrated),
fentanyl100mg
Mechanical
ventila-
tionduringgeneral
anesthesia
Resolutionofneuro-
logicsymptoms,but
unclearifeffect
isrelatedto
ILE
Survival,
nosequelae
Nguyen&White
(2012)[59]
Casereport
19years/M,
72kg
Ropivacaine75mg
4.21
Nerve
block
Visual
hallucinations
Sinustachycardiaand
hypertension
Myoclonicmove-
ments
ofthehead
andneck
20%,
Intralipid
100mL(0.28g/kg)
bolus
No
Midazolam
2mg�2
Oxygen
Resolutionofneuro-
logicsymptoms
Survival,
nosequelae
Oguguaet
al.(2009)
[60]b
Casereport
47years/F,
weightNR
Bupivacaine165mg
2.68
Nerve
block
Seizure
Asystole
20%,
brandNR
160mLbolusthen
200mLinfusion,dur-
ationNR
No
Midazolam
2mg,
epinephrine9mg,
ACLS
protocolto
ROSC
Intubation
Apparentimprove-
mentin
cardiac
output
Survival,
nosequelae
Reddy&Lahm
(2010)[61]b
Casereport
59years/M,
weightNR
Mepivacaine,
Ropivacaine
50mL50/50mixture,
conc.NR
1.40
4.21
Nerve
block
Agitation
Seizures
Tachycardia
(160–
170/m
in)
Slurred
speech
20%,
Intralipid
1.5
mL/kg
bolusthen
0.25mL/kg/m
inin
60
min
Yes
Nopharmaceuticals
Oxygen
Resolutionofcardiac
andneurologic
symptoms
Survival,
nosequelae
Rosenblattet
al.
(2006)[1]
Casereport
58years/M,
82kg
Bupivacaine100mg,
Mepivacaine300mg
2.68
1.40
Nerve
block
Incoherent
Repeatedseizures
Apneic
Asystole
20%,
Intralipid
100mL(0.24g/kg)
bolusthen
0.5mL/kg/
min(6.0g/kg/h)in60
min
No
Epinephrine3mg,
atropine2mg,argin-
inevasopressin
40U,
amiodarone300mg,
propofol150mg
Mechanical
ventila-
tion,CPR,
defibrillation
Resolutionofcardiac
symptoms
Survival,
nosequelae
Sakaiet
al.(2010)
[62]
Casereport
40years/F,
40kg
Ropivacaine150mg
4.21
Nerve
block
Lowered
responsive-
ness,paleness,per-
ipheral
coldness,
restlessness,hypo-
tension,shallow
irregularbreathing,
clonicconvulsionsin
thelim
bs
20%,
Intralipos
5�10ml(0.25g/kg)
bolus,then
100ml
(0.5
g/kg)in
50min,
then
20ml/h(0.1
g/
kg/h).Totaldose
230ml
No
Etilefrine(dose
NR),
diazepam
5mg
Resolutionof
symptoms
Survival,
nosequelae
(continued)
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Table
1.Continued
References
Studytype
Age/sex,weight
Localanesthetic
anddose
LogD
[129]
Route
of
administration
Symptoms
ILEused
ILEdose
aILEonly
used
Other
treatm
ents
received,dose
included
ifreported
ILEeffect
Outcome
Schaeffer
etal.
(2010)[63]
Casereport
74years/F,
60kg
Lidocaine400mg
1.26
Nerve
block
Confused,disori-
ented,had
loss
of
consciousnessand
myoclonusoftheface
20%,
Intralipid
200mL(0.67g/kg)
bolus
Yes
NR
Apparentimprove-
mentofsymptoms,
butunclearifeffect
isrelatedto
ILE
Survival,
nosequelae
Schellham
mer
&Milde(2011)[64]
Casereport
54years/F,
weightNR
Mepivacaine1000mg
1.40
Nerve
block
Dysphagia,dyspnea,
PVCwithbigem
iny,
ventriculartachycar-
dia145bpm,perioral
automatisms,dys-
arthria,hallucinations,
progressiveloss
of
consciousnessand
finallyseizure
20%,
Lipofundin
Infusion,specificdose
anddurationNR
No
Amiodarone5mg/kg,
midazolam,propofol
Oxygen
Transientimprove-
mentin
levelof
consciousness
Survival,
nosequelae
Scherreret
al.(2013)
[65]b
Casereport
25years/F,
weightNR
Ropivacine450mg
4.21
Intraperitoneal/
nerve
block
Seizure,ventricular
arrhythmia
20%,
brandNR
Infusion,specificdose
anddurationNR
Yes
NR
Ventriculararrhyth-
mia
converted
tosinusrhythm
Survival,
sequelae
NR
Schwarzkopfet
al.
(2011)[66]b
Casereport
NR
Prilocaine300mg,
Bupivacaine50mg
1.33
2.68
Nerve
block
Seizures
Hypertension
20%,
brandNR
1.5
mL/kg
bolusthen
0.1
mL/kg
in30min
No
Midazolam
10mg
Manualventilation
Unclearifeffect
isrelatedto
ILE
Survival,
sequelae
NR
Shah
etal.(2009)
[67]
Casereport
40days/M,
4.96kg
Bupivacaine10mg
2.68
Nerve
block
BP31/19mmHg;
tachycardia
(170/
min);TheST
segment
was
notedto
beele-
vated2–3mm
and
theT-wavewas
inverted
20%,
Intralipid
10mL(2
mL/kg
(0.4
g/kg))bolus
No
Epinephrine2mcg/
kg�2,albumin
5%
20mL.Mechanical
ventilationduring
general
anesthesia
Resolutionofcardiac
symptoms
Survival,
nosequelae
Shenoyet
al.(2014)
[68]
Casereport
3years/sexNR,
11kg
Bupivacaine25mg
2.68
Nerve
block
Pulselessventricular
tachycardia
20%,
brandNR
15mL(0.27g/kg)
bolusthen
150mL/h
(2.73g/kg/h)in
15
min,then
5mL(0.091
g/kg)bolus.Total
dose
170mL
(3.1
g/kg)
No
Epinephrine0.03mg
Oxygen,CPR
Beneficialeffect
with
resolutionofcardiac
symptomstogether
withother
treatm
ents.
Survival,
nosequelae
Shih
etal.(2011)
[69]
Casereport
69years/F,
48.5
kgLidocaine225mg,
Bupivacaine37.5
mg
1.26
2.68
Nerve
block
Bradycardia,reduced
bloodpressure
Obtunded,unable
tofully
arouse
20%,
Lipovenoes
50mL(0.21g/kg)
bolus
No
Atropine0.5
mg�3,
ephedrine10mg
Resolutionofcardiac
andneurologic
symptoms
Survival,
nosequelae
Smithet
al.(2008)
[70]
Casereport
83years/M,
75kg
Bupivacaine130mg
2.68
Nerve
block
Loss
ofconsciousness
Seizure
Pulselesswidecom-
plextachycardia
and
asystole
20%,
brandNR
250mL(3
mL/kg
(0.60g/kg))bolus
then
0.2
mL/kg/m
in(2.4
g/kg/h)
No
Epinephrine1mg,
atropine1mg(dosed
afterlipid
emulsion),
midazolam
2mg.
Oxygen,manual
ven-
tilation,CPR;then
intubation,mechan-
ical
ventilation
Resolutionofcardiac
symptoms,but
unclearofeffect
isrelatedto
ILE
Survival,
nosequelae
Sonsino&Fischler
(2009)[71]
Casereport
92years/F,
weightNR
Ropivacaine150mg
4.21
Nerve
block
Generalized
tonic-
clonicseizure�1
Asystole
Kabiven
2000,
conc.NR
50mLbolus
No
Propofol30mg,epi-
nephrine0.3
mg
(ACLS).
Intubation,mechan-
ical
ventilation
Resolutionofcardiac
symptoms
Survival,
nosequelae
(diedfrom
bronchopneumonia
10
daysafter)
Sorrentiet
al.(2014)
[72]b
Casereport
46years/M,
weightNR
Mepivacaine360mg
1.40
Nerve
block
Dysarthria,confusion,
loss
ofverbalcontact,
agitation,tachycardia,
hypertension
20%,
Intralipid
150mLbolusthen
0.25mL/kg/m
in.Total
dose
250mL
No
Midazolam
2.5
mg
Resolutionofneuro-
logical
andcardiac
symptoms
Survival,
nosequelae
Spence
(2007)[73]
Casereport
18years/F,38
weeks
pregnant,
86kg
Lidocaine80mg,
Bupivacaine65mg
1.26
2.68
Nerve
block
Restless,agitated,did
notobey
commands,
unresponsive.Fetal
heartrate
decelerating
20%,
Intralipid
50mL(0.12g/kg)�
2bolus
No
General
anesthesia
fordelivery
Neonatal
intubation
Resolutionofneuro-
logicsymptoms
Survival,
nosequelae
(continued)
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Table
1.Continued
References
Studytype
Age/sex,weight
Localanesthetic
anddose
LogD
[129]
Route
of
administration
Symptoms
ILEused
ILEdose
aILEonly
used
Other
treatm
ents
received,dose
included
ifreported
ILEeffect
Outcome
Sturiniet
al.(2010)
[74]b
Casereport
NR
Mepivacaine750mg
1.40
Intravenous
Numbness,light
headednessdizziness
slurred
speech
20%,
Intralipid
100mLbolus
Yes
NR
Possibly
prevented
cardiacsymptoms
from
LAtoxicity
Survival,
nosequelae
Suzeret
al.(2011)
[75]
Casereport
71years/M,
78kg
Bupivacaine50mg,
Lidocaine200mg
2.68
1.26
Nerve
block
Loss
ofconscious-
ness,dyspnea,hypo-
tension65/40mmHg,
ventricularextrasys-
toles,tachycardia140
bpm,seizures
20%,
Intralipid
0.5
mL/kg/m
in(6.0
g/kg/h)infusion.
Totaldose
500mL
(1.3
g/kg)
No
Midazolam
5mg,
epinephrine10mg,
amiodarone150mg
Intubation
Resolutionofcardiac
symptomswithin
3min,resolutionof
neurological
symp-
tomswithin
total
dose
administered
Survival,
nosequelae
TerHorstet
al.
(2010)[76]
Casereport
27years/F,
weightNR
Ropivacaine300mg
4.21
Nerve
block
Decreased
levelof
consciousness
Seizure
20%,
Intralipid
100mL(1.5
mL/kg)
bolusthen
400mL
in1.5
h
No
Midazolam
5mg�2.
Mechanical
ventila-
tionuntilresolution
ofrespiratory
symptoms
Rapid
beneficial
effect
onneurologic
symptoms
Survival,
nosequelae
Varela&Bums
(2010)[77]
Casereport
83years/F,
70kg
Bupivacaine150mg,
Ropivacaine300mg
2.68
4.21
Nerve
block
Repeatedseizures
Bradycardia,hypo-
tension,firstdegree
heartblock,multi-
focalPVC,VT
20%,
Liposyn
250mL(1.43g/kg/h)
�2infusion,each
in30min
No
Atropine1mg,mid-
azolam
4mg.ACLS
protocol).Intubation,
oxygen,manual
ventilation
Resolutionofcardiac
symptoms
Survival,
nosequelae
Warrenet
al.(2008)
[78]
Casereport
60years/M,
83kg
Mepivacaine450mg,
Bupivacaine50mg
1.40
2.68
Nerve
block
Unresponsiveness
Cardiacarrest
Laboredrespiration
20%,
LiposynIII
250mL(1.2
g/kg/h)
infusionin
30min
No
Sodium
bicarbonate
8.4%
100mL,atro-
pine1mg,epineph-
rine1mg�3,
vasopressin
40U,
magnesium
sulfate
6g
CPR,
defibrillation�11
Longer
intervalsof
sustained
cardiac
rhythm
during
defibrillation
Survival,
nosequelae
Whitem
an&Kushins
(2014)[79]
Casereport
32years/F,
62kg
Bupivacaine870mg
2.68
Nerve
block
Confusion,agitation,
combativethen
seiz-
ures,cardiac
arrhythmia
20%,
Intralipid
1.5
mL/kg
(0.3
g/kg)
bolusthen
0.25mL/
kg/m
in(3.0
g/kg/h)
for60min
No
Unspecifiedmedical
therapy,cardiac
defibrillation�2,sur-
gerywithevacuation
of60mLfluid
from
therightrectus
sheath
CPR
ROSC
andnorm
ocar-
dia
after45min
Resolutionofcardiac
arrhythmia
thefol-
lowingday
Survival,
nosequelae
Whiteside(2008)
[80]
Casereport
Elderly/F,
74kg
Levobupivacaine
21.65mg
2.68
Nerve
block
Seizure
20%,
Intralipid
100mL(1.5
mL/kg
(0.30g/kg))bolus
Yes
Nopharmaceuticals
Oxygen,manual
ventilation
Unclearofeffect
isrelatedto
ILE
Survival,
nosequelae
Widfeldt&Kolmodin
(2014)[81]
Casereport
62years/F,
weightNR
Ropivacaine150mg
4.21
Nerve
block
Unconsciousness,
nystagmus,muscle
twitching
20%,
Intralipid
100mL(1.5
mL/
kg)�
2bolus–10
min
interval,then
50mL/hfor10h
No
Diazepam
,few
doses
(specificdose
NR)
Resolutionofneuro-
logicsymptoms
Survival,
nosequelae
Wonget
al.(2010)
[82]
Casereport
6years/M,
24kg
Bupivacaine,dose
NR
2.68
Nerve
block
Sinusbradycardia
(60/m
in)that
rapidly
proceeded
toawide
complexventricular
arrhythmia
at40/m
inandhypotensionto
BP65/35mmHgand
tachycardia
120/m
in
20%,
Intralipid
20mL(0.17g/kg)
bolus
No
Crystalloid
fluid
boluses20mL/kg,
atropine0.4
mg,epi-
nephrine0.2mgthen
continued
0.1
mg
bolusesto
maintain
asystolic
pressure4
60
mmHgthen
0.2
mg/
kg/m
ininfusion.
Packedredcells
(300mL)+5%
albu-
min
(250mL)
CPR
Resolutionofcardiac
symptoms
Survival,
nosequelae
for3days.
After
8days,brain
stem
death
from
cerebral
ischem
ianotrelatedto
ILEtreatm
ent (continued)
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Human case reports
There were 73 case reports and one case series, including 10
cases not individually reported elsewhere, that described the
effect of ILE for treating LA toxicity.[1,12–84] These articles
involved 83 patients, aged from 2 days to 91 years, of whom
two died and 81 (98%) survived (Table 1). The local anesthetics
involved, often in combination, are shown in Tables 1 and 2.
The most common lipid concentration administered in
these publications was 20% (71 cases; 86%), while a 10%
concentration was used in one case,[35] and the lipid
concentration used was not reported in the remaining 11
cases (Table 1).[17,19,23,28,40,47,51,71] Lipid emulsion was
administered as a bolus in 30 (36%) cases, as a bolus followed
by infusion in 34 (41%) cases, and as an infusion without bolus
in eight cases (10%). The dose regimen used was not specified
or not reported in 11 (13%) cases. The median bolus dose was
0.30 g/kg (range: 0.0015–0.83 g/kg) and the median infusion
dose was 1.9 g/kg/h (range: 0.015–6.0 g/kg/h). Overall, the
total volume of lipid emulsion administered ranged from 9 to
2480 mL (Table 1). The bolus dose in infants up to the age of 1
year was 1–2mL/kg (Table 1).
In 52 cases (63%), the lipid emulsion used was Intralipid�;
other formulations used were Medialipid� (n¼ 3, 4%),
lidocaine (n¼ 1, 3%), mepivacaine (n¼ 1, 3%), and ropivacaine
(n¼ 4, 11%). Two studies combined two local anesthetics,
bupivacaine/mepivacaine and levobupivacaine/ropivacaine
(Table 3).
Lipid concentrations used were 20% (n¼ 22, 58%), 30%
(n¼ 8, 21%), or not described (n¼ 2, 5%). A bolus dose was
used in 29 (76%) studies and was followed by an infusion in 22
studies (58%). In three (8%) studies, an infusion was used
without an initial bolus. The median bolus dose was 0.80 g/kg
or 4mL/kg of 20% ILE (range: 0.20–3.0 g/kg) and median
infusion dose was 6.0 g/kg/h (range: 0.60–54 g/kg/h). In 22
studies (58%), the lipid emulsion used was Intralipid� while
two studies used the medium chain/long chain triglyceride
preparations Lipovenos� MCT (n¼ 2, 5%) or Medialipid�
(n¼ 1, 3%). Other products used in one study each (3%) were
Lipovenos�, Ivelip�, SMOFLipid�, ClinOleic�, and Liposyn
II�; an un-named Soybean oil emulsion was used in one study
and the ILE formulation used was not reported in five studies
(Table 3).
Animal randomized controlled studies
In 12 of the 29 randomized controlled studies, ILE was
compared to the vasopressors epinephrine and/or vasopressin,
either alone or in combination, or with vasopressors combined
with ILE (Table 3).[88,89,91,92,97,102–105,107,110,111]
The ILE versus epinephrine studies [88,89,91,102–
104,107,110,111] showed therapeutic benefit on survival or
return to spontaneous circulation for ILE compared to
epinephrine in four studies (14% of the animal RCS) [102–
104,107] and for epinephrine + vasopressin in one study (3% of
the animal RCS).[105] There were comparable efficacy of ILE
and epinephrine in five studies (17% of the animal RCS).
[88,89,91,110,111]
Combining epinephrine + ILE gave a better survival outcome
compared to ILE alone in six studies (21% of the animal
RCS),[88,89,97,102,104,111] and of these, two studies con-
cluded comparable efficacy of epinephrine and
epinephrine + ILE.[102,104]
In two studies (7% of the animal RCS), the combination
vasopressin + ILE did not improve survival over ILE alone and
was not as effective as epinephrine or epinephrine + ILE
treatment.[102,104] ILE was superior in one study (4% of the
animal RCS) comparing ILE with vasopressin alone or
epinephrine + vasopressin.[92]
Lipid infusion was compared to crystalloids, either saline
[17,85–87,90,91,94,96,97,106–111] or Ringer’s acetate [101] in
15 of the 29 randomized controlled studies (Table 3). Nine (31%
of the animal RCS) studies showed therapeutic benefit
[85,87,90,91,94,97,106,109,110] and six (21%) no benefit if
ILE.[17,86,96,101,107,111] In one study comparing ILE and
saline, the control groups were different (electrically initiated
ventricular fibrillation versus LA induced venticular fibrillation);
this study was therefore considered not useful for evaluating
the efficacy of ILE.[108]
Various LA doses were evaluated in the included studies,
and these doses were provided in varying units. These doses
depended on the type of LA and the secondary outcome
symptom severity. For bupivacaine, used in 22 (76%) out of the
29 studies,[86,87,90–97,100–106,108–112] the dose ranged
from 1mg/kg/min to 10mg/kg/min given over 10 s or 4–
30mg/kg (Table 3). Levobupivacaine was used in four studies
(14%),[88,89,98,99] with a dose of 500mg/h,[88] 10mg/kg,[99]
or 3–8.3mg/kg/min.[89,98] Mepivacaine was used in one study
(3%) at an infusion rate of 6mg/kg/min.[101] Ropivacaine was
used in three studies (10%),[17,85,107] at 1.5mg/kg/min as
lowest infusion dose up to a maximum of 14.9 ± 2.8mg/kg
given as a bolus (Table 3).
Table 2. Reported local anesthetics in the 16 volunteers from the randomizedcontrolled study and the 83 patients from case reports and case series includedin the systematic review.