Local Anesthetic Systemic Toxicity Journalspermissions.Nav DOI: 10.1177/1090820X14543102

AESXXX10.1177/1090820X14543102Aesthetic Surgery JournalDickerson and Apfelbaum research-article5431022014

Research

Aesthetic Surgery Journal Special Topic 2014, Vol. 34(7) 1111–1119 © 2014 The American Society for Aesthetic Plastic Surgery, Inc. Reprints and permission: Local Anesthetic Systemic Toxicity http://www.sagepub.com/ journalsPermissions.nav DOI: 10.1177/1090820X14543102 www.aestheticsurgeryjournal.com

David M. Dickerson, MD; and Jeffrey L. Apfelbaum, MD Downloaded from https://academic.oup.com/asj/article/34/7/1111/256461 by guest on 27 September 2021

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 safer local anesthetics, and greater understanding of the risk characterized by a pattern of discovery, application, obser- factors.11,12 As demonstrated by the case of an elastomeric vation, and innovation (Figure 1).1-5 Since the isolation of pump failure described in the July 2014 issue of Aesthetic cocaine (from coca leaves) in 1859 and its first clinical Surgery Journal,13 LAST occurs despite practice advisories application in 1884, local anesthesia (LA) has been used to and heightened awareness. This case emphasizes the need diminish the pain of medical procedures.1 The clinical ben- for vigilance and preparedness to prevent an unforeseen efits, however, were soon weighed against the adverse occurrence of toxicity.13 The safety of perioperative local effects: respiratory failure, seizures, palpitations, and irreg- anesthesia can be optimized by knowledge of its mechanism, ular cardiac function.2 Despite the advent of safer synthetic the clinical presentation of LAST, and techniques for prevent- local anesthetics, cases of toxicity persisted, culminating in ing and treating this condition. a 1979 report of the catastrophic consequences of LAST that noted a relationship between drug lipophilicity and Mechanism of Local Anesthetics the potential for cardiac toxicity.6 The unintended intravascular injection or uptake of potent amino amide anesthet- The analgesia produced by local anesthetics results from ics (eg, bupivacaine) appeared as a common theme. the binding of voltage-gated sodium (Na ) channels and v In early studies, the incidence of LAST ranged from 7.5 to blocking of the excitation threshold of nociceptive afferent 20 per 10 000 peripheral nerve blockades; more recently, the neurons. Binding prevents pain transmission by the periph- incidence was estimated to be low as 2.5 per 10 000 block- erally located primary afferent neuron.14-16 Additionally, ades.7-9 In one series, frequency was as high as 10 per 10 000 blockades, and in another, no events were recorded for over From the Department of Anesthesia and Critical Care, University of 12 000 blockades.10,11 The call for optimized management of Chicago, Chicago, Illinois. LAST has resulted in heightened awareness, the development of safety steps in local anesthetic administration, the discov- Corresponding Author: Dr David M. Dickerson, Department of Anesthesia and Critical ery of lipid emulsion therapy, and treatment and prevention Care, University of Chicago, 5841 S Maryland Ave, MC4028, O-416, guidelines with validated checklists. However, cases persist Chicago, IL 60637, USA. despite the application of ultrasonography, the availability of E-mail: [email protected] 1112 Aesthetic Surgery Journal 34(7) Downloaded from https://academic.oup.com/asj/article/34/7/1111/256461 by guest on 27 September 2021

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 inflam- site of administration, the dosage of the drug, its pharma- matory cascade and reduce hyperexcitability in the dorsal cokinetic profile, and whether a vasoconstrictor is added horn of the spinal cord.17,18 Local anesthetics have been (Table 2). synthesized with various potencies and duration of action. The characteristics of common local anesthetics are sum- Depo-Local Anesthetics in marized in Table 1. Analgesia Local Anesthetics in Analgesia Liposomal bupivacaine has been approved by the US Food and Drug Administration for single-dose wound infiltration As a cornerstone of multimodal analgesia, local anesthet- or administration as a depo-local anesthetic. Bupivacaine- ics provide myriad benefits. Local anesthetics bolster mul- impregnated collagen, a similar agent, is currently in a timodal analgesia by potentially improving quality of phase 3 study. Pharmacokinetically, the delayed yet recovery, decreasing opioid exposure, decreasing postop- sustained release of these agents results in continuous anal- erative nausea and vomiting, improving patient satisfac- gesic serum concentrations with attenuated peak concentration, decreasing length of hospital stay, and reducing the tions, suggesting a potential decrease in toxicity. However, risk of chronic postsurgical pain.17-20 With various routes the coadministration of nonliposomal anesthetics may cause and sites of administration and their utility as intermittent rapid release of bupivacaine molecules and potential for tox- or continuous therapy, local anesthetics are associated icity. Although these agents offer significant promise for with varying degrees and risks of toxicity. Toxicity is fur- sustained postoperative LA with decreased toxicity, addi- ther influenced by additional factors such as anatomic tional economic data and further study are needed to Dickerson and Apfelbaum 1113

Table 1. Characteristics of Local Anesthetics

Maximum Dose, mg/kg Local Anesthetic Class/Chemical Linkage pK (Onset Time) Protein Binding (Duration of Action) Lipophilicity (Potency) (Dose With Epinephrine) a

Lidocainea Amide 7.8 (fast) Moderate Moderate 4.5 (7)

Tumescent: 35-55

Bupivacainea Amide 8.1 (slow) Long Potent 2.5 (3)

Ropivacainea 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) Downloaded from https://academic.oup.com/asj/article/34/7/1111/256461 by guest on 27 September 2021

Articaine Ester 7.8 (fast) Short Moderate 4 (7)

2-Chloroprocainea 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

pKa denotes the negative logarithm of the ionization constant of an acid. aCommonly administered in plastic surgery. 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 man- has been suggested that the specific mechanism may vary agement of postoperative pain. with different anesthetics and their diverse binding of cardiac Na channels.16,21 v Mechanism of Local Anesthetic The ratio of cardiovascular to central nervous system (CNS) toxicity also varies among local anesthetics. With Systemic Toxicity lidocaine and mepivacaine, CNS symptoms typically appear 22 Two leading hypotheses prevail for the mechanism of before cardiovascular symptoms. CNS effects appear to LAST: LA-impaired electrophysiologic function of the heart be associated with disturbances in the transmission of and loss of cardiac energy at the mitochondrial level. Local γ-aminobutyric acid. Neuronal excitability is associated with anesthetics reduce sodium ion flux by binding Na , but this inhibition of the TASK potassium channel by anesthetics, v 23 binding is not exclusively in the peripheral nervous tissue. which contributes to the induction of seizures. However, Cardiac cells rely on Na -initiated depolarization during injury or death appears to be associated with cardiac v cardiac action potential cycles.15,16,21 Inhibition of cardiac toxicity. Na channels may result in conduction disturbances, ven- v tricular arrhythmias, and contractile dysfunction. This Characteristics of Local effect may be further exacerbated by inhibition of fatty Anesthetic Systemic Toxicity acid transport by local anesthetic at the inner mitochondrial membrane, resulting in a loss of cardiac energy from The classic presentation of LAST has possible variants. decreased oxidative phosphorylation. There is much Classically, toxicity appears on a continuum of adverse debate about whether systemic toxicity is the effect of elec- effects in the CNS that, with more toxic levels, progresses to trophysiologic dysfunction or contractile dysfunction. It 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. Downloaded from https://academic.oup.com/asj/article/34/7/1111/256461 by guest on 27 September 2021 cases published in the peer-reviewed literature during a Table 4. Comorbid Risk Factors for Local Anesthetic Systemic Toxicity 22 30-year period, Di Gregorio et al found that 60% were clas- Risk Factors sic (ie, rapid onset) with CNS symptoms and cardiovascular symptoms (Table 3). Conversely, some symptoms appeared Extremes of age (children and elderly) more than 5 minutes after injection or were isolated cardio- Hepatic dysfunction or altered hepatic perfusion (decreased plasma proteins, decreased vascular symptoms. Classic prodromal symptoms (eg, cir- hepatic clearance) cumoral numbness, metallic taste, auditory changes) Low cardiac output states (drug accumulation, reduced clearance) appeared in only 18% of their toxicity cases in this series. General anesthesia or heavy sedation is thought to influence High cardiac output states (increased gradient for vascular diffusion, increased absorption) the clinical pattern of toxicity in that CNS changes may go unnoticed and pharmacokinetics may be altered.22,24 Cardiac pathology (heart disease, conduction blocks, cardiac failure)

Certain patient characteristics may increase the risk of Reduced plasma proteins (increased free [active] fraction of local anesthetic) symptoms from an overdose of local anesthetics (Table 4). Risks include extremes of age (children and the elderly), Pregnancy (decreased plasma proteins, increased cardiac output) high cardiac output states due to increased vascular Concomitant use of β-blocker, digoxin, calcium antagonists, cytochrome P450 inhibitors absorption, and the presence of other comorbidities such 25 as cardiac disease, pregnancy, hepatic dysfunction, or met- Data from Ciechanowicz and Patil. abolic syndromes.25

Prevention of Toxicity: Safety Steps toxic threshold. Although specific serum concentration levels have been associated with toxicity, dosing guidelines Several safety steps have been advocated to identify or reduce that are weight based (mg/kg) fail to reliably predict these 26 the risk of toxicity. The following have been suggested for levels, resulting in potential toxicity at lower-than-anticipated safe administration of LA: limiting the cumulative dose, using doses.29,30 With topical LA and subcutaneously adminis- ultrasound or direct visualization for catheter placement, test tered solution via the tumescent technique, experience- dosing, incremental injections, negative catheter aspiration, derived, weight-based doses that are substantially higher and adherence to guidelines. Incorporation of multiple safety than recommended levels are often administered.31 Based steps may improve detection of intravascular injection or on pharmacokinetic data, it appears that these application impending toxicity. Although it appears that anesthetic infu- routes are associated with a lower risk of systemic toxicity, 27 sion pumps are safe in aesthetic and reconstructive surgery, yet toxicity still may occur. The American Society of Regional 28 a high rate of pump malfunction was observed in 1 series. Anesthesia and Pain Medicine (ASRA) advocates using Pump malfunction aside, applying safety steps such as those the lowest concentration and dose necessary for neuraxial used for peripheral nerve blockade may reduce risk in analgesia, and a similar philosophy should be applied to surgeon-initiated continuous anesthetic infusion. non-neuraxial applications.32 Postoperatively, analgesic concentrations (<0.25% bupivacaine or ropivacaine) are used Limiting the Cumulative Effect of for continuous infusion. Incisional injection is limited to Anesthetics recommended doses after consideration of the anesthetic being concurrently administered by the anesthesia team.29 Anesthetics are often additive. Concurrent administrations Liposomal bupivacaine should not be coadministered with of multiple local anesthetics contribute to a single systemic other local anesthetics due to the risk of toxicity. Dickerson and Apfelbaum 1115

Table 5. Suggested Test Doses for Detecting Unintentional Intravascular Injection

Test Agent Dose Positive Findings Limitations

Epinephrine36 • 15 µg • HR increase >10 beats/min • Beta blockade may impact sensitivity40 • SBP increase of 15 mm Hg • T-wave monitoring may require offline analysis of • T-wave increase of 25% amplitude ECG tracing41

Local anesthetic26,37 • Chloroprocaine or lidocaine 100 mg • Auditory disturbance • Premedication with benzodiazepines may affect • Bupivacaine 25 mg • Circumoral numbness sensitivity • Ropivacaine 60 mg • Metallic taste • Large doses neuraxially will result in total spinal anesthesia

Air38 • 2 mL • Audible response on precordial Doppler • Availability of Doppler monitoring monitoring • Potential paradoxical air embolism via patent

foramen ovale Downloaded from https://academic.oup.com/asj/article/34/7/1111/256461 by guest on 27 September 2021

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

ECG, electrocardiogram; HR, heart rate; SBP, systolic blood pressure.

Incremental Injections and Catheter Ultrasound-Guided Regional Aspiration Anesthesia Although lacking objective data, administering small incre- Systemic toxicity has been reversed with ultrasound-guided mental doses (3-5 mL) of local anesthetic has been recom- regional anesthesia, but reversal is not possible if periph- mended (assuming a negative test-dose result) so that the eral nerve blockade is performed without ultrasound.11,42,43 anesthesiologist or surgeon can readily monitor for inad- Although intravascular injection during peripheral nerve vertent intravascular injection.32 Data on the reliability of blockade is possible with ultrasound, the unexpected this technique are lacking because it can be impractical to absence of local anesthetic spread during injection, as well wait a full circulation period (30-45 seconds) between as the visualization of adequate coverage of neural struc- every 3-mL injection. Although recommended, catheter tures with less local anesthetic, serves to prevent intravas- aspiration for blood is unreliable for identifying catheters cular injection and delay the possibility of toxicity from placed intravascularly, with the possible exception of mul- tissue uptake.44,45 tiorifice catheters.33,34 The presence of negative aspiration via an infusion catheter should be verified before pump initiation. Treatment for Systemic Toxicity from Anesthetics Intravascular Test Dosing The treatment of LAST has been the subject of many Few studies have identified evidence-based techniques for reviews, including a practice advisory from the ASRA.32 catheter test dosing, yet test dosing with an intravascular The treatment of systemic toxicity is very different from marker is recommended when administration of poten- that of conventional cardiac arrest in that airway manage- tially toxic doses of LA is planned.32,35-37 Potential test-dose ment with optimal oxygenation and ventilation is of utmost agents include epinephrine, local anesthetic, air, opioid, importance (Figure 2).46 Prevention of hypoxia and acido- and isoproterenol. Although not without limitations, sis may eliminate or slow cardiovascular collapse and sei- epinephrine-containing test solutions are commonly given zures.47 If seizures ensue, benzodiazepines are administered during electrocardiography and while monitoring heart to prevent seizure-associated acidosis. Rarely, neuromus- rate and blood pressure.36 Several test-dose agents and cular blockade may be required if benzodiazepines fail to their associated effects and limitations are listed in Table stop the seizure. 5.35-41 Since other safety steps may not completely prevent Cardiac arrest is treated with chest compressions. intravascular injection by the aesthetic surgeon, catheter Epinephrine is recommended in low doses (<1 µg/kg); test dosing with an epinephrine-containing solution before persistent arrhythmia may occur with higher doses. pump initiation may have value. During application of an Negative inotropes such as β-blockers or calcium channel epinephrine-containing solution for a tumescent tech- blockers are not provided because they may cause myocar- nique, audible changes in heart rate may alert the surgeon dial depression. Amiodarone is administered for persistent to vascular uptake of both epinephrine and anesthetic. ventricular arrhythmia, but local anesthesia is avoided in 1116 Aesthetic Surgery Journal 34(7) Downloaded from https://academic.oup.com/asj/article/34/7/1111/256461 by guest on 27 September 2021

Figure 2. Quick guide to treating systemic toxicity due to local anesthesia. the treatment of arrhythmia. Vasopressin administration is paradoxical outcome led to the development of a novel not recommended. treatment. Lipid emulsion therapy reduced the median Rapid initiation of lipid emulsion therapy has been lethal dose (LD50) of bupivacaine and, more important, advocated, which may prevent a downward spiral of car- showed potential as a therapy for LAST.49 Several years diac dysfunction, progressing acidosis, and worsening car- after this discovery in rats and canines, intravenous lipid diac dysfunction.48 emulsion was applied to humans and added to resuscita- If LAST is suspected, the nearest available cardiac team tion guidelines internationally.50-52 should be notified and arrangements made for cardiopul- The mechanism of lipid emulsion therapy is not well monary bypass in the event the patient’s condition fails to defined, but several hypotheses exist. Lipid emulsion is improve. thought to provide a “lipid sink” to dissociate local anesthetic molecules from the cardiac Na .53,54 Binding of v Lipid Emulsion Therapy unbound free anesthetic results in its metabolism and clearance. The lipid emulsion may act as a direct energy When the effect of intravenous lipid emulsion on bupiva- source to the myocardium, providing fatty acid substrate, caine toxicity in carnitine-deficient rats was examined, a augmenting production of mitochondrial adenosine Dickerson and Apfelbaum 1117 triphosphate in the heart, and increasing cardiac output.55 continued heightened awareness; the guide also may serve Concomitantly, lipid emulsion elevates triglycerides, which as a helpful reference during treatment. Resuscitative equip- interact with myocardial calcium channels to increase car- ment, standard monitors, lipid emulsion, and practitioners diac function.56 It has been suggested that overdoses of skilled in the diagnosis and treatment of systemic toxicity other lipophilic drugs also may be treated by lipid emul- are essential for a successful outcome. sion therapy.57 Through clinical experience, the optimal administration Conclusions of lipid emulsion has been formalized. Current recommendations call for a bolus injection of 1.5 mL/kg followed by While patient comfort necessitates the administration of local an infusion at 0.25 mL/kg/min.48 The recurrence of cardio- anesthetics, a commitment to safe practice will optimize vascular collapse after cessation of liquid emulsion therapy patient outcomes. An understanding of the mechanism, treat- has been described in the literature.58 The immediate avail- ment, and prevention of LAST is requisite for plastic and Downloaded from https://academic.oup.com/asj/article/34/7/1111/256461 by guest on 27 September 2021 ability of sufficient lipid emulsion appears requisite. reconstructive surgeons who administer this medication. Marwick et al58 observed the return of cardiovascular col- Promoting awareness, vigilance, and preparedness may save lapse in a patient who received the only available quantity a life if this rare but devastating complication occurs. (500-mL bag) of lipid emulsion.58 The benefits of intralipid therapy appear to outweigh Disclosures the potential risks. Risks include allergic reaction (such as The authors declared no potential conflicts of interest with egg, soy, or peanut cross-reactivity), hyperthermia, pancre- respect to the research, authorship, and publication of this atitis, hypercoagulability, antineutrophil action, and ele- article. vated liver aminotransferases.57,59 Funding Preparation and Vigilance The authors received no financial support for the research, authorship, and publication of this article. The ability to identify patients at risk for systemic toxicity is critical to its prevention and treatment. A strong founda- References tion is needed for safe and effective LA dosing and admin- 1. Drasner K. Local anesthetic systemic toxicity. Reg Anesth istration. When pain pumps are in use, catheter test dosing Pain Med. 2010;35(2):162-166. should be performed before infusion is begun. Patients dis- 2. Mattison JB. Cocaine poisoning. Med Surg Rep. charged with continuous wound infusion or peripheral 1891;115:645-650. nerve catheters need established lines of communication 3. Bier AKG. Experiments in cocainization of the spinal and daily monitoring via telephone. Family members also cord, 1899. In: Faulconer A, Keys TE, trans. Foundations should be educated on pump care (including catheter of Anesthesiology. Springfield, IL: Charles C Thomas; removal, stopping the pump, and dressing maintenance) 1963:854. as well as adverse effects (eg, prodromal symptoms). In 4. Prentiss JE. Cardiac arrest following caudal anesthesia. our opinion, pumps should be connected and running Anesthesiology. 1979;50:51-53. 5. Adverse reactions with bupivacaine. FDA Drug Bull. under observation for at least 30 minutes before patient 1983;13:23. discharge to allow for assessment of infusion function. 6. Albright GA. Cardiac arrest following regional anes- Similarly, practitioners trained in resuscitation and the thesia with etidocaine or bupivacaine. Anesthesiology. treatment of LAST should be immediately available when 1979;51:285-287. pumps are initiated. Dedicating part of the recovery room 7. Auroy Y, Narchu P, Messiah A, et al. Serious complica- to patients who have received large local anesthetic doses tions related to regional anesthesia: results of a prospec- or infusions may allow prompt treatment if a patient tive survey in France. Anesthesiology. 1997;87:479-486. becomes unresponsive. 8. Auroy Y, Benhamou D, Laurent B, et al. Major compli- Use of the ASRA 2012 checklist for treatment of LAST cations of regional anesthesia in France. Anesthesiology. improved trainee performance during a simulation.60,61 2002;97(5):1274-1280. Because toxicity from local anesthetics is rare, simulation, 9. Brown DL, Ransom DM, Hall JA, et al. Regional anesthesia and local anesthetic-induced systemic toxicity: seizure checklists, and readily available reference algorithms may frequency and accompanying cardiovascular changes. lead to comprehensive rapid recall and implementation of Anesth Analg. 1995;81:321-328. therapy. Figure 2 provides a brief summary of the treatment 10. Barrington MJ, Watts SA, Gledhill SR, et al. Preliminary recommendations of the Association of Anaesthetists of results of the Australasian regional anaesthesia collabora- Great Britain and Ireland and the ASRA checklist, which tion. Reg Anesth Pain Med. 2009;34(6):534-541. may be included in a toxicity response kit.61,62 Prominent 11. Sites BD, Taenzer AH, Herrick MD, et al. Incidence display of this guide in clinical common areas may promote of local anesthetic systemic toxicity and postoperative 1118 Aesthetic Surgery Journal 34(7)

neurologic symptoms associated with 12,668 ultrasound- 29. Rosenberg PH, Veering BT, Urmey WF. Maximum recom- guided nerve blocks: an analysis from a prospective clini- mended doses of local anesthetics: a multifactorial con- cal registry. Reg Anesth Pain Med. 2012;37:478-412. cept. Reg Anesth Pain Med. 2004;29:564-575. 12. Zetlaoui PJ, Labbe JP, Benhamou D. Ultrasound guidance 30. Schoenmakers KP, Vree TB, Nigel TJ, et al. Pharma- for axillary plexus block does not prevent intravascular cokinetics of 450 mg ropivacaine with and without epi- injection. Anesthesiology. 2008;108:761-762. nephrine for combined femoral and sciatic nerve block in 13. Whiteman DM, Kushins SI. Case report: successful resus- lower extremity surgery: a pilot study. Br J Clin Pharmacol. citation with Intralipid after Marcaine overdose. Aesthetic 2012;75(5):1321-1327. Surg J. 2014;34:738-740. 31. Ostad A, Kageyama N, Moy RL. Tumescent anesthesia 14. Fukuda K, Nakajima T, Viswanathan PC, Balsar JR. with a lidocaine dose of 55 mg/kg is safe for liposuction. Compound-specific Na+ channel pore conforma- Dermatol Surg. 1996;22:921-927. tional changes induced by local anesthetics. J Physiol. 32. Neal JM, Bernards CM, Butterworth JF, et al. ASRA prac- 2005;564(pt 1):21-31. tice advisory on local anesthetic systemic toxicity. Reg Downloaded from https://academic.oup.com/asj/article/34/7/1111/256461 by guest on 27 September 2021 15. Ritchie JM, Ritchie B, Greengard P. The active structure of Anesth Pain Med. 2010;35:152-161. local anesthetics. Pharmacol Exp Ther. 1965;150(1):152-159. 33. Pan PH, Bogard TD, Owen MD. Incidence and character- 16. Butterworth J. Models and mechanisms of local anes- istics of failures in obstetric neuraxial analgesia and anesthetic cardiac toxicity: a review. Reg Anesth Pain Med. thesia. Int J Obstet Anesth. 2004;13:227-233. 2010;35:167-176. 34. Norris MC, Ferrenbach D, Dalman H, et al. Does epineph- 17. Pu LLQ. The use of a pain pump for optimal postoperative rine improve the diagnostic accuracy of aspiration during pain management. Plast Reconstr Surg. 2006;117:2066- labor epidural analgesia? Anesth Analg. 1999;88:1073-1076. 2069. 35. Guay J. The epidural test dose: a review. Anesth Analg. 18. Liu SS, Richman JM, Thirlby RC, Wu CL. Efficacy of con- 2006;102:921-929. tinuous wound catheters delivering local anesthetic for 36. Moore DC, Batra MS. The components of an effective test postoperative analgesia: a quantitative and qualitative dose prior to epidural block. Anesthesiology. 1981;55:693- review of randomized controlled trials. J Am Coll Surg. 696. 2006;203:914-932. 37. McCartney CJ, Murphy DB, Iagounova A, Chan VW. 19. Andreae MH, Andreae DA. Local anaesthetics and Intravenous ropivacaine bolus is a reliable marker of regional anaesthesia for preventing chronic pain after sur- intravascular injection in premedicated healthy volun- gery. Cochrane Database Syst Rev. 2012;10:CD007105. teers. Can J Anaesth. 2003;50:795-800. 20. Chester JF, Ravindranath K, White BD, Shanahan D, 38. Leighton BL, Gross JB. Air: an effective indicator of Taylor RS, Lloyd-Williams K. Wound perfusion with bupi- intravenously located epidural catheters. Anesthesiology. vacaine: objective evidence for efficacy in post-operative 1989;71:848-851. pain relief. Ann R Coll Surg Engl. 1989;71:394-396. 39. Tanaka M, Sato M, Kimura T, Nishikawa T. The efficacy 21. Wolfe JW, Butterworth JF. Local anesthetic systemic tox- of simulated intravascular test dose in sedated patients. icity: update on mechanisms and treatment. Curr Opin Anesth Analg. 2001;93:1612-1617. Anaesthesiol. 2011;24:561-566. 40. Pong RP, Bernards C, Hejtmanek MR, et al. Effect of chronic 22. Di Gregorio G, Neal JM, Rosenquist RW, et al. Clinical beta blockade on the utility of epinephrine-containing test presentation of local anesthetic systemic toxicity: a review dose to detect intravascular injection in nonsedated patients. of published cases. 1979 to 2009. Reg Anesth Pain Med. Reg Anesth Pain Med. 2013;38(5):403-408. 2010;35(2):181-187. 41. Takahashi S, Tanaka M, Toyooka H. The efficacy of 23. Du G, Chen X, Todorovic MS, et al. TASK channel dele- hemodynamic and T-wave criteria for detecting intra- tion reduces sensitivity to local anesthetic-induced sei- vascular injection of epinephrine test dose in propofol- zures. Anesthesiology. 2011;115(5):1003-1011. anesthetized adults. Anesth Analg. 2002;94:717-722. 24. Copeland SE, Ladd LA, Gu X, Mather LE. The effects of 42. Orebaugh SL, Kentor ML, Williams BA. Adverse outcomes general anesthesia on whole body regional pharmacoki- associate with nerve stimulator-guided and ultrasound- netics of local anesthetics at toxic doses. Anesth Analg. guided peripheral nerve blocks by supervised trainees: 2008;106(5):1440-1449. update of a single-site database. Reg Anesth Pain Med. 25. Ciechanowicz S, Patil V. Lipid emulsion for local 2012;37:577-582. anesthetic systemic toxicity. Anesthesiol Res Pract. 43. Barrington MJ, Kluger R. Ultrasound guidance reduces the 2012;2012:131784. risk of local anesthetic systemic toxicity following periph- 26. Mulroy MF, Norris MC, Liu SS. Safety steps for epidural eral nerve block. Reg Anesth Pain Med. 2013;38:289-297. injection of local anesthetics: review of the literature and 44. Abrahams MS, Axix ME, Fu RF, Horns JL. Ultrasound recommendations. Anesth Analg. 1997;85:1346-1356. guidance compared with electrical neurostimulation for 27. Chandran GJ, Lalonde DH. A review of pain pumps in peripheral nerve block: a systematic review and meta- plastic surgery. Can J Plast Surg. 2010;18(1):15-18. analysis of randomized controlled trials. Br J Anesth. 28. Rawlani V, Kryger ZB, Lu L, Fine NA. A local anesthetic 2009;102:408-417. pump reduces pain and narcotic and antiemetic use in 45. Neal JM. Local anesthetic systemic toxicity: improving breast reconstruction surgery: a randomized controlled patient safety one step at a time. Reg Anesth Pain Med. trial. Plast Reconstr Surg. 2008;122:39-52. 2013;38(4):259-261. Dickerson and Apfelbaum 1119

46. Moore DC, Crawford RD, Scurlock RD. Severe hypoxia 55. Silveira L, Hirabara SM, Alberici LC, et al. Effect of lipid and acidosis following local anesthetic-induced convul- infusion on metabolism and force of rat skeletal muscles sions. Anesthesiology. 1980;53(3):259-260. during intense contractions. Cell Phys Biochem. 2007;20(1- 47. Moore DC, Thompson GE, Crawford RD. Long-acting 4):213-226. local anesthetic drugs and convulsions with hypoxia and 56. Coat M, Pennec JP, Guillouet M, Arvieux CC, Gueret G. acidosis. Anesthesiology. 1982;56(3)230-232. Haemodynamic effects of Intralipid after local anaesthet- 48. Weinberg GL. Treatment of local anesthetic systemic tox- ics intoxication may be due to a direct effect of fatty acids icity (LAST). Reg Anesth Pain Med. 2010;35(2):188-193. on myocardial voltage-dependent calcium channels. Ann 49. Weinberg G, Vadeboncouer T, Ramaraju GA, Garcia-Amaro Fr Anesth Reanim. 2010;29(9):661. MF, Cwik MJ. Pretreatment or resuscitation with a lipid infu- 57. Cave G, Harvey M. Intravenous lipid emulsion as anti- sion shifts the dose-response to bupivacaine-induced asys- dote beyond local anesthetic toxicity: a systematic review. tole in rats. Anesthesiology. 1998;88:1071-1075. Acad Emerg Med. 2009;16(9):815-824. 50. Weinberg G, Ripper R, Feinstein DL, Hoffman W. Lipid 58. Marwick PC, Levin AI, Coetzee AR. Recurrence of car- Downloaded from https://academic.oup.com/asj/article/34/7/1111/256461 by guest on 27 September 2021 emulsion infusion rescues dogs from bupivacaine-induced diotoxicity after lipid rescue from bupivacaine-induced cardiac toxicity. Reg Anesth Pain Med. 2003;28:198-202. cardiac arrest. Anesth Analg. 2009;108(4):1344-1346. 51. Rosenblatt MA, Abel M, Fischer GW, Itzkovich CJ, 59. Driscoll DF. Lipid injectable emulsions: pharmacopeial Eisenkraft JB. Successful use of a 20% lipid emulsion to and safety issues. Pharm Res. 2006;23(9):1959-1969. resuscitate a patient after a presumed bupivacaine-related 60. Neal JM, Hsiung RL, Mulroy MG, et al. ASRA checklist cardiac arrest. Anesthesiology. 2006;105:217-218. improves trainee performance during a simulated episode 52. Gabriellis A, O’Connor M, Maccioli GA. Anesthesia of local anesthetic systemic toxicity. Reg Anesth Pain Advanced Circulatory Life Support. Schaumburg, IL: Med. 2012;37(1):8-15. Committee on Critical Care Medicine, Society of Critical Care 61. Neal JM, Mulroy MG, Weinberg GL. American Society of Anesthesiologists, and American Society of Anesthesiologists; Regional Anesthesia and Pain Medicine checklist for man- 2008. aging local anesthetic systemic toxicity: 2012 version. Reg 53. Kuo I, Akpa BS. Validity of the lipid sink as a mecha- Anesth Pain Med. 2012;37(1):16-18. nism for the reversal of local anesthetic systemic toxic- 62. Association of Anaesthetists of Great Britain and Ireland. ity: a physiologically based pharmacokinetic model study. Intralipid in the management of LA toxicity: guidance from Anesthesiology. 2013;118(6):1350-1361. the Association of Anaesthetists of Great Britain and Ireland 54. Shi K, Zia Y, Wang Q, et al. The effect of lipid emulsion on (AAGBI), 2007. http://www.aagbi.org/publications/guide- pharmacokinetics and tissue distribution of bupivacaine lines/docs/latoxicity07.pdf. Accessed April 10, 2014. in rats. Anesth Analg. 2013;116(4):804-809.