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AESXXX10.1177/1090820X14543102Aesthetic Surgery JournalDickerson and Apfelbaum
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Special Topic
Local Anesthetic Systemic Toxicity
Aesthetic Surgery Journal
2014, Vol. 34(7) 1111­–1119
© 2014 The American Society for
Aesthetic Plastic Surgery, Inc.
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DOI: 10.1177/1090820X14543102
www.aestheticsurgeryjournal.com
David M. Dickerson, MD; and Jeffrey L. Apfelbaum, MD
Abstract
Local anesthetic systemic toxicity (LAST) is a rare yet devastating complication from the administration of local anesthesia. The ability to recognize and treat
LAST is critical for clinicians who administer these drugs. The authors reviewed the literature on the mechanism, treatment, and prevention of LAST, with
the goal of proposing a practical method for its management.
Keywords
local anesthetic toxicity, lipid emulsion, bupivacaine toxicity, acute pain, ambulatory surgery
Accepted for publication April 18, 2014.
The history of local anesthetic systemic toxicity (LAST) is
characterized by a pattern of discovery, application, observation, and innovation (Figure 1).1-5 Since the isolation of
cocaine (from coca leaves) in 1859 and its first clinical
application in 1884, local anesthesia (LA) has been used to
diminish the pain of medical procedures.1 The clinical benefits, however, were soon weighed against the adverse
effects: respiratory failure, seizures, palpitations, and irregular cardiac function.2 Despite the advent of safer synthetic
local anesthetics, cases of toxicity persisted, culminating in
a 1979 report of the catastrophic consequences of LAST
that noted a relationship between drug lipophilicity and
the potential for cardiac toxicity.6 The unintended intravascular injection or uptake of potent amino amide anesthetics (eg, bupivacaine) appeared as a common theme.
In early studies, the incidence of LAST ranged from 7.5 to
20 per 10 000 peripheral nerve blockades; more recently, the
incidence was estimated to be low as 2.5 per 10 000 blockades.7-9 In one series, frequency was as high as 10 per 10 000
blockades, and in another, no events were recorded for over
12 000 blockades.10,11 The call for optimized management of
LAST has resulted in heightened awareness, the development
of safety steps in local anesthetic administration, the discovery of lipid emulsion therapy, and treatment and prevention
guidelines with validated checklists. However, cases persist
despite the application of ultrasonography, the availability of
safer local anesthetics, and greater understanding of the risk
factors.11,12 As demonstrated by the case of an elastomeric
pump failure described in the July 2014 issue of Aesthetic
Surgery Journal,13 LAST occurs despite practice advisories
and heightened awareness. This case emphasizes the need
for vigilance and preparedness to prevent an unforeseen
occurrence of toxicity.13 The safety of perioperative local
anesthesia can be optimized by knowledge of its mechanism,
the clinical presentation of LAST, and techniques for preventing and treating this condition.
Mechanism of Local Anesthetics
The analgesia produced by local anesthetics results from
the binding of voltage-gated sodium (Nav) channels and
blocking of the excitation threshold of nociceptive afferent
neurons. Binding prevents pain transmission by the peripherally located primary afferent neuron.14-16 Additionally,
From the Department of Anesthesia and Critical Care, University of
Chicago, Chicago, Illinois.
Corresponding Author:
Dr David M. Dickerson, Department of Anesthesia and Critical
Care, University of Chicago, 5841 S Maryland Ave, MC4028, O-416,
Chicago, IL 60637, USA.
E-mail: [email protected]
1112
Aesthetic Surgery Journal 34(7)
Figure 1. History of local anesthetic toxicity. AMA, American Medical Association; ASA, American Society of
Anesthesiologists; ASCCA, American Society of Critical Care Anesthesiologists; ASRA, American Society of Regional Anesthesia
and Pain Medicine; CV, cardiovascular; FDA, US Food and Drug Administration; LA, local anesthesia; LD50, lethal dose for
50% of subjects; LAST, local anesthetic systemic toxicity; LET, lipid emulsion therapy.
LA may inhibit the free-end nociceptor-sensitizing inflammatory cascade and reduce hyperexcitability in the dorsal
horn of the spinal cord.17,18 Local anesthetics have been
synthesized with various potencies and duration of action.
The characteristics of common local anesthetics are summarized in Table 1.
Local Anesthetics in Analgesia
As a cornerstone of multimodal analgesia, local anesthetics provide myriad benefits. Local anesthetics bolster multimodal analgesia by potentially improving quality of
recovery, decreasing opioid exposure, decreasing postoperative nausea and vomiting, improving patient satisfaction, decreasing length of hospital stay, and reducing the
risk of chronic postsurgical pain.17-20 With various routes
and sites of administration and their utility as intermittent
or continuous therapy, local anesthetics are associated
with varying degrees and risks of toxicity. Toxicity is further influenced by additional factors such as anatomic
site of administration, the dosage of the drug, its pharmacokinetic profile, and whether a vasoconstrictor is added
(Table 2).
Depo-Local Anesthetics in
Analgesia
Liposomal bupivacaine has been approved by the US Food
and Drug Administration for single-dose wound infiltration
or administration as a depo-local anesthetic. Bupivacaineimpregnated collagen, a similar agent, is currently in a
phase 3 study. Pharmacokinetically, the delayed yet
sustained release of these agents results in continuous analgesic serum concentrations with attenuated peak concentrations, suggesting a potential decrease in toxicity. However,
the coadministration of nonliposomal anesthetics may cause
rapid release of bupivacaine molecules and potential for toxicity. Although these agents offer significant promise for
sustained postoperative LA with decreased toxicity, additional economic data and further study are needed to
Dickerson and Apfelbaum1113
Table 1. Characteristics of Local Anesthetics
Local Anesthetic
Lidocainea
Class/Chemical Linkage
pKa (Onset Time)
Amide
7.8 (fast)
Protein Binding (Duration of Action)
Moderate
Lipophilicity (Potency)
Moderate
Maximum Dose, mg/kg
(Dose With Epinephrine)
4.5 (7)
Tumescent: 35-55
Bupivacainea
Amide
8.1 (slow)
Long
Potent
2.5 (3)
a
Ropivacaine
Amide
8.1 (slow)
Long
Potent
3 (3.5)
Prilocaine
Amide
8.0 (fast)
Moderate
Weak
5-7 (7-8.5)
Mepivacaine
Amide
7.7 (fast)
Moderate
Moderate
4.5 (7)
Ester
7.8 (fast)
Short
Moderate
4 (7)
2-Chloroprocaine
Ester
8.0 (very fast)
Short
Moderate
11 (14)
Cocaine
Ester
8.7 (slow)
Moderate
Moderate
12
Procaine
Ester
8.9 (slow)
Short
Weak
3
Articaine
a
pKa denotes the negative logarithm of the ionization constant of an acid.
Commonly administered in plastic surgery.
a
Table 2. Local Anesthetic Routes of Administration and Magnitude of Absorption
Route
Type
Intravenous/systemic
Continuous or intermittent
Intercostal
Continuous or intermittent
Perineural/regional/compartment (caudal > epidural > brachial plexus)
Continuous or intermittent
Subcutaneous/incisional (infiltrative/tumescent)
Continuous or intermittent
Transdermal/topical
Intermittent
Routes are listed by magnitude of absorption, from greatest (intravenous/systemic) to least (transdermal/topical).
establish a cost-effective role for them in the routine management of postoperative pain.
Mechanism of Local Anesthetic
Systemic Toxicity
Two leading hypotheses prevail for the mechanism of
LAST: LA-impaired electrophysiologic function of the heart
and loss of cardiac energy at the mitochondrial level. Local
anesthetics reduce sodium ion flux by binding Nav, but this
binding is not exclusively in the peripheral nervous tissue.
Cardiac cells rely on Nav-initiated depolarization during
cardiac action potential cycles.15,16,21 Inhibition of cardiac
Nav channels may result in conduction disturbances, ventricular arrhythmias, and contractile dysfunction. This
effect may be further exacerbated by inhibition of fatty
acid transport by local anesthetic at the inner mitochondrial membrane, resulting in a loss of cardiac energy from
decreased oxidative phosphorylation. There is much
debate about whether systemic toxicity is the effect of electrophysiologic dysfunction or contractile dysfunction. It
has been suggested that the specific mechanism may vary
with different anesthetics and their diverse binding of cardiac Nav channels.16,21
The ratio of cardiovascular to central nervous system
(CNS) toxicity also varies among local anesthetics. With
lidocaine and mepivacaine, CNS symptoms typically appear
before cardiovascular symptoms.22 CNS effects appear to
be associated with disturbances in the transmission of
γ-aminobutyric acid. Neuronal excitability is associated with
inhibition of the TASK potassium channel by anesthetics,
which contributes to the induction of seizures.23 However,
injury or death appears to be associated with cardiac
toxicity.
Characteristics of Local
Anesthetic Systemic Toxicity
The classic presentation of LAST has possible variants.
Classically, toxicity appears on a continuum of adverse
effects in the CNS that, with more toxic levels, progresses to
cardiovascular symptoms. In a review of systemic toxicity
1114
Aesthetic Surgery Journal 34(7)
Table 3. Classic Presentation of Local Anesthetic Systemic Toxicity
Presentation
Characteristics
Rapid onset
<5 min
Prodromal symptoms (18%)
Dizziness, drowsiness, tinnitus, confusion, dysphoria, dysarthria, auditory disturbances, circumoral numbness,
metallic taste in mouth
CNS symptoms (more likely to occur with lidocaine than bupivacaine)
Prodrome symptoms, seizures, loss of consciousness, agitation
CVS symptoms
Bradycardia/asystole, tachycardia, hypotension, wide complex, ST-segment changes, pain, dyspnea,
hypertension, ventricular ectopy, ventricular tachycardia, ventricular fibrillation
Data from Di Gregorio et al.22 CNS, central nervous system; CVS, cardiovascular system.
cases published in the peer-reviewed literature during a
30-year period, Di Gregorio et al22 found that 60% were classic (ie, rapid onset) with CNS symptoms and cardiovascular
symptoms (Table 3). Conversely, some symptoms appeared
more than 5 minutes after injection or were isolated cardiovascular symptoms. Classic prodromal symptoms (eg, circumoral numbness, metallic taste, auditory changes)
appeared in only 18% of their toxicity cases in this series.
General anesthesia or heavy sedation is thought to influence
the clinical pattern of toxicity in that CNS changes may go
unnoticed and pharmacokinetics may be altered.22,24
Certain patient characteristics may increase the risk of
symptoms from an overdose of local anesthetics (Table 4).
Risks include extremes of age (children and the elderly),
high cardiac output states due to increased vascular
absorption, and the presence of other comorbidities such
as cardiac disease, pregnancy, hepatic dysfunction, or metabolic syndromes.25
Prevention of Toxicity: Safety Steps
Several safety steps have been advocated to identify or reduce
the risk of toxicity.26 The following have been suggested for
safe administration of LA: limiting the cumulative dose, using
ultrasound or direct visualization for catheter placement, test
dosing, incremental injections, negative catheter aspiration,
and adherence to guidelines. Incorporation of multiple safety
steps may improve detection of intravascular injection or
impending toxicity. Although it appears that anesthetic infusion pumps are safe in aesthetic and reconstructive surgery,27
a high rate of pump malfunction was observed in 1 series.28
Pump malfunction aside, applying safety steps such as those
used for peripheral nerve blockade may reduce risk in
surgeon-initiated continuous anesthetic infusion.
Limiting the Cumulative Effect of
Anesthetics
Anesthetics are often additive. Concurrent administrations
of multiple local anesthetics contribute to a single systemic
Table 4. Comorbid Risk Factors for Local Anesthetic Systemic Toxicity
Risk Factors
Extremes of age (children and elderly)
Hepatic dysfunction or altered hepatic perfusion (decreased plasma proteins, decreased
hepatic clearance)
Low cardiac output states (drug accumulation, reduced clearance)
High cardiac output states (increased gradient for vascular diffusion, increased
absorption)
Cardiac pathology (heart disease, conduction blocks, cardiac failure)
Reduced plasma proteins (increased free [active] fraction of local anesthetic)
Pregnancy (decreased plasma proteins, increased cardiac output)
Concomitant use of β-blocker, digoxin, calcium antagonists, cytochrome P450 inhibitors
Data from Ciechanowicz and Patil.25
toxic threshold. Although specific serum concentration levels have been associated with toxicity, dosing guidelines
that are weight based (mg/kg) fail to reliably predict these
levels, resulting in potential toxicity at lower-than-anticipated
doses.29,30 With topical LA and subcutaneously administered solution via the tumescent technique, experiencederived, weight-based doses that are substantially higher
than recommended levels are often administered.31 Based
on pharmacokinetic data, it appears that these application
routes are associated with a lower risk of systemic toxicity,
yet toxicity still may occur. The American Society of Regional
Anesthesia and Pain Medicine (ASRA) advocates using
the lowest concentration and dose necessary for neuraxial
analgesia, and a similar philosophy should be applied to
non-neuraxial applications.32 Postoperatively, analgesic concentrations (<0.25% bupivacaine or ropivacaine) are used
for continuous infusion. Incisional injection is limited to
recommended doses after consideration of the anesthetic
being concurrently administered by the anesthesia team.29
Liposomal bupivacaine should not be coadministered with
other local anesthetics due to the risk of toxicity.
Dickerson and Apfelbaum1115
Table 5. Suggested Test Doses for Detecting Unintentional Intravascular Injection
Test Agent
Dose
Positive Findings
Limitations
• 15 µg
• HR increase >10 beats/min
• SBP increase of 15 mm Hg
• T-wave increase of 25% amplitude
• Beta blockade may impact sensitivity40
• T-wave monitoring may require offline analysis of
ECG tracing41
Local anesthetic26,37
• Chloroprocaine or lidocaine 100 mg
• Bupivacaine 25 mg
• Ropivacaine 60 mg
• Auditory disturbance
• Circumoral numbness
• Metallic taste
• P remedication with benzodiazepines may affect
sensitivity
• Large doses neuraxially will result in total spinal
anesthesia
Air38
• 2 mL
• A udible response on precordial Doppler
monitoring
• Availability of Doppler monitoring
• Potential paradoxical air embolism via patent
foramen ovale
Opioid
• Fentanyl 100 µg
• Drowsiness or sedation
• Respiratory depression
• Requires awake, participating patient
Isoproterenol39
• 3 µg
• HR increase >20 beats/min
• Neurotoxicity unknown
• Transient systolic hypotension
Epinephrine
36
ECG, electrocardiogram; HR, heart rate; SBP, systolic blood pressure.
Incremental Injections and Catheter
Aspiration
Ultrasound-Guided Regional
Anesthesia
Although lacking objective data, administering small incremental doses (3-5 mL) of local anesthetic has been recommended (assuming a negative test-dose result) so that the
anesthesiologist or surgeon can readily monitor for inadvertent intravascular injection.32 Data on the reliability of
this technique are lacking because it can be impractical to
wait a full circulation period (30-45 seconds) between
every 3-mL injection. Although recommended, catheter
aspiration for blood is unreliable for identifying catheters
placed intravascularly, with the possible exception of multiorifice catheters.33,34 The presence of negative aspiration
via an infusion catheter should be verified before pump
initiation.
Systemic toxicity has been reversed with ultrasound-guided
regional anesthesia, but reversal is not possible if peripheral nerve blockade is performed without ultrasound.11,42,43
Although intravascular injection during peripheral nerve
blockade is possible with ultrasound, the unexpected
absence of local anesthetic spread during injection, as well
as the visualization of adequate coverage of neural structures with less local anesthetic, serves to prevent intravascular injection and delay the possibility of toxicity from
tissue uptake.44,45
Intravascular Test Dosing
Few studies have identified evidence-based techniques for
catheter test dosing, yet test dosing with an intravascular
marker is recommended when administration of potentially toxic doses of LA is planned.32,35-37 Potential test-dose
agents include epinephrine, local anesthetic, air, opioid,
and isoproterenol. Although not without limitations,
epinephrine-containing test solutions are commonly given
during electrocardiography and while monitoring heart
rate and blood pressure.36 Several test-dose agents and
their associated effects and limitations are listed in Table
5.35-41 Since other safety steps may not completely prevent
intravascular injection by the aesthetic surgeon, catheter
test dosing with an epinephrine-containing solution before
pump initiation may have value. During application of an
epinephrine-containing solution for a tumescent technique, audible changes in heart rate may alert the surgeon
to vascular uptake of both epinephrine and anesthetic.
Treatment for Systemic Toxicity
from Anesthetics
The treatment of LAST has been the subject of many
reviews, including a practice advisory from the ASRA.32
The treatment of systemic toxicity is very different from
that of conventional cardiac arrest in that airway management with optimal oxygenation and ventilation is of utmost
importance (Figure 2).46 Prevention of hypoxia and acidosis may eliminate or slow cardiovascular collapse and seizures.47 If seizures ensue, benzodiazepines are administered
to prevent seizure-associated acidosis. Rarely, neuromuscular blockade may be required if benzodiazepines fail to
stop the seizure.
Cardiac arrest is treated with chest compressions.
Epinephrine is recommended in low doses (<1 µg/kg);
persistent arrhythmia may occur with higher doses.
Negative inotropes such as β-blockers or calcium channel
blockers are not provided because they may cause myocardial depression. Amiodarone is administered for persistent
ventricular arrhythmia, but local anesthesia is avoided in
1116
Aesthetic Surgery Journal 34(7)
Figure 2. Quick guide to treating systemic toxicity due to local anesthesia.
the treatment of arrhythmia. Vasopressin administration is
not recommended.
Rapid initiation of lipid emulsion therapy has been
advocated, which may prevent a downward spiral of cardiac dysfunction, progressing acidosis, and worsening cardiac dysfunction.48
If LAST is suspected, the nearest available cardiac team
should be notified and arrangements made for cardiopulmonary bypass in the event the patient’s condition fails to
improve.
Lipid Emulsion Therapy
When the effect of intravenous lipid emulsion on bupivacaine toxicity in carnitine-deficient rats was examined, a
paradoxical outcome led to the development of a novel
treatment. Lipid emulsion therapy reduced the median
lethal dose (LD50) of bupivacaine and, more important,
showed potential as a therapy for LAST.49 Several years
after this discovery in rats and canines, intravenous lipid
emulsion was applied to humans and added to resuscitation guidelines internationally.50-52
The mechanism of lipid emulsion therapy is not well
defined, but several hypotheses exist. Lipid emulsion is
thought to provide a “lipid sink” to dissociate local anesthetic molecules from the cardiac Nav.53,54 Binding of
unbound free anesthetic results in its metabolism and
clearance. The lipid emulsion may act as a direct energy
source to the myocardium, providing fatty acid substrate,
augmenting production of mitochondrial adenosine
Dickerson and Apfelbaum1117
triphosphate in the heart, and increasing cardiac output.55
Concomitantly, lipid emulsion elevates triglycerides, which
interact with myocardial calcium channels to increase cardiac function.56 It has been suggested that overdoses of
other lipophilic drugs also may be treated by lipid emulsion therapy.57
Through clinical experience, the optimal administration
of lipid emulsion has been formalized. Current recommendations call for a bolus injection of 1.5 mL/kg followed by
an infusion at 0.25 mL/kg/min.48 The recurrence of cardiovascular collapse after cessation of liquid emulsion therapy
has been described in the literature.58 The immediate availability of sufficient lipid emulsion appears requisite.
Marwick et al58 observed the return of cardiovascular collapse in a patient who received the only available quantity
(500-mL bag) of lipid emulsion.58
The benefits of intralipid therapy appear to outweigh
the potential risks. Risks include allergic reaction (such as
egg, soy, or peanut cross-reactivity), hyperthermia, pancreatitis, hypercoagulability, antineutrophil action, and elevated liver aminotransferases.57,59
continued heightened awareness; the guide also may serve
as a helpful reference during treatment. Resuscitative equipment, standard monitors, lipid emulsion, and practitioners
skilled in the diagnosis and treatment of systemic toxicity
are essential for a successful outcome.
Conclusions
While patient comfort necessitates the administration of local
anesthetics, a commitment to safe practice will optimize
patient outcomes. An understanding of the mechanism, treatment, and prevention of LAST is requisite for plastic and
reconstructive surgeons who administer this medication.
Promoting awareness, vigilance, and preparedness may save
a life if this rare but devastating complication occurs.
Disclosures
The authors declared no potential conflicts of interest with
respect to the research, authorship, and publication of this
article.
Funding
Preparation and Vigilance
The ability to identify patients at risk for systemic toxicity
is critical to its prevention and treatment. A strong foundation is needed for safe and effective LA dosing and administration. When pain pumps are in use, catheter test dosing
should be performed before infusion is begun. Patients discharged with continuous wound infusion or peripheral
nerve catheters need established lines of communication
and daily monitoring via telephone. Family members also
should be educated on pump care (including catheter
removal, stopping the pump, and dressing maintenance)
as well as adverse effects (eg, prodromal symptoms). In
our opinion, pumps should be connected and running
under observation for at least 30 minutes before patient
discharge to allow for assessment of infusion function.
Similarly, practitioners trained in resuscitation and the
treatment of LAST should be immediately available when
pumps are initiated. Dedicating part of the recovery room
to patients who have received large local anesthetic doses
or infusions may allow prompt treatment if a patient
becomes unresponsive.
Use of the ASRA 2012 checklist for treatment of LAST
improved trainee performance during a simulation.60,61
Because toxicity from local anesthetics is rare, simulation,
checklists, and readily available reference algorithms may
lead to comprehensive rapid recall and implementation of
therapy. Figure 2 provides a brief summary of the treatment
recommendations of the Association of Anaesthetists of
Great Britain and Ireland and the ASRA checklist, which
may be included in a toxicity response kit.61,62 Prominent
display of this guide in clinical common areas may promote
The authors received no financial support for the research,
authorship, and publication of this article.
References
1. Drasner K. Local anesthetic systemic toxicity. Reg Anesth
Pain Med. 2010;35(2):162-166.
2.
Mattison JB. Cocaine poisoning. Med Surg Rep.
1891;115:645-650.
3.Bier AKG. Experiments in cocainization of the spinal
cord, 1899. In: Faulconer A, Keys TE, trans. Foundations
of Anesthesiology. Springfield, IL: Charles C Thomas;
1963:854.
4.Prentiss JE. Cardiac arrest following caudal anesthesia.
Anesthesiology. 1979;50:51-53.
5.Adverse reactions with bupivacaine. FDA Drug Bull.
1983;13:23.
6.Albright GA. Cardiac arrest following regional anesthesia with etidocaine or bupivacaine. Anesthesiology.
1979;51:285-287.
7.Auroy Y, Narchu P, Messiah A, et al. Serious complications related to regional anesthesia: results of a prospective survey in France. Anesthesiology. 1997;87:479-486.
8.Auroy Y, Benhamou D, Laurent B, et al. Major complications of regional anesthesia in France. Anesthesiology.
2002;97(5):1274-1280.
9. Brown DL, Ransom DM, Hall JA, et al. Regional anesthesia and local anesthetic-induced systemic toxicity: seizure
frequency and accompanying cardiovascular changes.
Anesth Analg. 1995;81:321-328.
10.Barrington MJ, Watts SA, Gledhill SR, et al. Preliminary
results of the Australasian regional anaesthesia collaboration. Reg Anesth Pain Med. 2009;34(6):534-541.
11.Sites BD, Taenzer AH, Herrick MD, et al. Incidence
of local anesthetic systemic toxicity and postoperative
1118
neurologic symptoms associated with 12,668 ultrasoundguided nerve blocks: an analysis from a prospective clinical registry. Reg Anesth Pain Med. 2012;37:478-412.
12. Zetlaoui PJ, Labbe JP, Benhamou D. Ultrasound guidance
for axillary plexus block does not prevent intravascular
injection. Anesthesiology. 2008;108:761-762.
13. Whiteman DM, Kushins SI. Case report: successful resuscitation with Intralipid after Marcaine overdose. Aesthetic
Surg J. 2014;34:738-740.
14.Fukuda K, Nakajima T, Viswanathan PC, Balsar JR.
Compound-specific Na+ channel pore conformational changes induced by local anesthetics. J Physiol.
2005;564(pt 1):21-31.
15. Ritchie JM, Ritchie B, Greengard P. The active structure of
local anesthetics. Pharmacol Exp Ther. 1965;150(1):152-159.
16.Butterworth J. Models and mechanisms of local anes
thetic cardiac toxicity: a review. Reg Anesth Pain Med.
2010;35:167-176.
17. Pu LLQ. The use of a pain pump for optimal postoperative
pain management. Plast Reconstr Surg. 2006;117:20662069.
18. Liu SS, Richman JM, Thirlby RC, Wu CL. Efficacy of continuous wound catheters delivering local anesthetic for
postoperative analgesia: a quantitative and qualitative
review of randomized controlled trials. J Am Coll Surg.
2006;203:914-932.
19.Andreae MH, Andreae DA. Local anaesthetics and
regional anaesthesia for preventing chronic pain after surgery. Cochrane Database Syst Rev. 2012;10:CD007105.
20.Chester JF, Ravindranath K, White BD, Shanahan D,
Taylor RS, Lloyd-Williams K. Wound perfusion with bupivacaine: objective evidence for efficacy in post-operative
pain relief. Ann R Coll Surg Engl. 1989;71:394-396.
21. Wolfe JW, Butterworth JF. Local anesthetic systemic toxicity: update on mechanisms and treatment. Curr Opin
Anaesthesiol. 2011;24:561-566.
22.Di Gregorio G, Neal JM, Rosenquist RW, et al. Clinical
presentation of local anesthetic systemic toxicity: a review
of published cases. 1979 to 2009. Reg Anesth Pain Med.
2010;35(2):181-187.
23.Du G, Chen X, Todorovic MS, et al. TASK channel deletion reduces sensitivity to local anesthetic-induced seizures. Anesthesiology. 2011;115(5):1003-1011.
24.Copeland SE, Ladd LA, Gu X, Mather LE. The effects of
general anesthesia on whole body regional pharmacokinetics of local anesthetics at toxic doses. Anesth Analg.
2008;106(5):1440-1449.
25.Ciechanowicz S, Patil V. Lipid emulsion for local
anesthetic systemic toxicity. Anesthesiol Res Pract.
2012;2012:131784.
26.Mulroy MF, Norris MC, Liu SS. Safety steps for epidural
injection of local anesthetics: review of the literature and
recommendations. Anesth Analg. 1997;85:1346-1356.
27.Chandran GJ, Lalonde DH. A review of pain pumps in
plastic surgery. Can J Plast Surg. 2010;18(1):15-18.
28. Rawlani V, Kryger ZB, Lu L, Fine NA. A local anesthetic
pump reduces pain and narcotic and antiemetic use in
breast reconstruction surgery: a randomized controlled
trial. Plast Reconstr Surg. 2008;122:39-52.
Aesthetic Surgery Journal 34(7)
29. Rosenberg PH, Veering BT, Urmey WF. Maximum recommended doses of local anesthetics: a multifactorial concept. Reg Anesth Pain Med. 2004;29:564-575.
30.Schoenmakers KP, Vree TB, Nigel TJ, et al. Pharma
cokinetics of 450 mg ropivacaine with and without epinephrine for combined femoral and sciatic nerve block in
lower extremity surgery: a pilot study. Br J Clin Pharmacol.
2012;75(5):1321-1327.
31.Ostad A, Kageyama N, Moy RL. Tumescent anesthesia
with a lidocaine dose of 55 mg/kg is safe for liposuction.
Dermatol Surg. 1996;22:921-927.
32. Neal JM, Bernards CM, Butterworth JF, et al. ASRA practice advisory on local anesthetic systemic toxicity. Reg
Anesth Pain Med. 2010;35:152-161.
33. Pan PH, Bogard TD, Owen MD. Incidence and characteristics of failures in obstetric neuraxial analgesia and anesthesia. Int J Obstet Anesth. 2004;13:227-233.
34. Norris MC, Ferrenbach D, Dalman H, et al. Does epinephrine improve the diagnostic accuracy of aspiration during
labor epidural analgesia? Anesth Analg. 1999;88:1073-1076.
35.Guay J. The epidural test dose: a review. Anesth Analg.
2006;102:921-929.
36. Moore DC, Batra MS. The components of an effective test
dose prior to epidural block. Anesthesiology. 1981;55:693696.
37.McCartney CJ, Murphy DB, Iagounova A, Chan VW.
Intravenous ropivacaine bolus is a reliable marker of
intravascular injection in premedicated healthy volunteers. Can J Anaesth. 2003;50:795-800.
38.Leighton BL, Gross JB. Air: an effective indicator of
intravenously located epidural catheters. Anesthesiology.
1989;71:848-851.
39. Tanaka M, Sato M, Kimura T, Nishikawa T. The efficacy
of simulated intravascular test dose in sedated patients.
Anesth Analg. 2001;93:1612-1617.
40. Pong RP, Bernards C, Hejtmanek MR, et al. Effect of chronic
beta blockade on the utility of epinephrine-containing test
dose to detect intravascular injection in nonsedated patients.
Reg Anesth Pain Med. 2013;38(5):403-408.
41.Takahashi S, Tanaka M, Toyooka H. The efficacy of
hemodynamic and T-wave criteria for detecting intravascular injection of epinephrine test dose in propofolanesthetized adults. Anesth Analg. 2002;94:717-722.
42. Orebaugh SL, Kentor ML, Williams BA. Adverse outcomes
associate with nerve stimulator-guided and ultrasoundguided peripheral nerve blocks by supervised trainees:
update of a single-site database. Reg Anesth Pain Med.
2012;37:577-582.
43. Barrington MJ, Kluger R. Ultrasound guidance reduces the
risk of local anesthetic systemic toxicity following peripheral nerve block. Reg Anesth Pain Med. 2013;38:289-297.
44.Abrahams MS, Axix ME, Fu RF, Horns JL. Ultrasound
guidance compared with electrical neurostimulation for
peripheral nerve block: a systematic review and metaanalysis of randomized controlled trials. Br J Anesth.
2009;102:408-417.
45.Neal JM. Local anesthetic systemic toxicity: improving
patient safety one step at a time. Reg Anesth Pain Med.
2013;38(4):259-261.
Dickerson and Apfelbaum1119
46.Moore DC, Crawford RD, Scurlock RD. Severe hypoxia
and acidosis following local anesthetic-induced convulsions. Anesthesiology. 1980;53(3):259-260.
47.Moore DC, Thompson GE, Crawford RD. Long-acting
local anesthetic drugs and convulsions with hypoxia and
acidosis. Anesthesiology. 1982;56(3)230-232.
48. Weinberg GL. Treatment of local anesthetic systemic toxicity (LAST). Reg Anesth Pain Med. 2010;35(2):188-193.
49. Weinberg G, Vadeboncouer T, Ramaraju GA, Garcia-Amaro
MF, Cwik MJ. Pretreatment or resuscitation with a lipid infusion shifts the dose-response to bupivacaine-induced asystole in rats. Anesthesiology. 1998;88:1071-1075.
50.Weinberg G, Ripper R, Feinstein DL, Hoffman W. Lipid
emulsion infusion rescues dogs from bupivacaine-induced
cardiac toxicity. Reg Anesth Pain Med. 2003;28:198-202.
51.Rosenblatt MA, Abel M, Fischer GW, Itzkovich CJ,
Eisenkraft JB. Successful use of a 20% lipid emulsion to
resuscitate a patient after a presumed bupivacaine-related
cardiac arrest. Anesthesiology. 2006;105:217-218.
52.Gabriellis A, O’Connor M, Maccioli GA. Anesthesia
Advanced Circulatory Life Support. Schaumburg, IL:
Committee on Critical Care Medicine, Society of Critical Care
Anesthesiologists, and American Society of Anesthesiologists;
2008.
53.Kuo I, Akpa BS. Validity of the lipid sink as a mechanism for the reversal of local anesthetic systemic toxicity: a physiologically based pharmacokinetic model study.
Anesthesiology. 2013;118(6):1350-1361.
54. Shi K, Zia Y, Wang Q, et al. The effect of lipid emulsion on
pharmacokinetics and tissue distribution of bupivacaine
in rats. Anesth Analg. 2013;116(4):804-809.
55.Silveira L, Hirabara SM, Alberici LC, et al. Effect of lipid
infusion on metabolism and force of rat skeletal muscles
during intense contractions. Cell Phys Biochem. 2007;20(14):213-226.
56.Coat M, Pennec JP, Guillouet M, Arvieux CC, Gueret G.
Haemodynamic effects of Intralipid after local anaesthetics intoxication may be due to a direct effect of fatty acids
on myocardial voltage-dependent calcium channels. Ann
Fr Anesth Reanim. 2010;29(9):661.
57.Cave G, Harvey M. Intravenous lipid emulsion as antidote beyond local anesthetic toxicity: a systematic review.
Acad Emerg Med. 2009;16(9):815-824.
58.Marwick PC, Levin AI, Coetzee AR. Recurrence of cardiotoxicity after lipid rescue from bupivacaine-induced
cardiac arrest. Anesth Analg. 2009;108(4):1344-1346.
59.Driscoll DF. Lipid injectable emulsions: pharmacopeial
and safety issues. Pharm Res. 2006;23(9):1959-1969.
60.Neal JM, Hsiung RL, Mulroy MG, et al. ASRA checklist
improves trainee performance during a simulated episode
of local anesthetic systemic toxicity. Reg Anesth Pain
Med. 2012;37(1):8-15.
61. Neal JM, Mulroy MG, Weinberg GL. American Society of
Regional Anesthesia and Pain Medicine checklist for managing local anesthetic systemic toxicity: 2012 version. Reg
Anesth Pain Med. 2012;37(1):16-18.
62.Association of Anaesthetists of Great Britain and Ireland.
Intralipid in the management of LA toxicity: guidance from
the Association of Anaesthetists of Great Britain and Ireland
(AAGBI), 2007. http://www.aagbi.org/publications/guidelines/docs/latoxicity07.pdf. Accessed April 10, 2014.