Journal Logo

Plastic Surgery Focus: Special Topics

Local Anesthetic Systemic Toxicity: A Narrative Literature Review and Clinical Update on Prevention, Diagnosis, and Management

Gitman, Marina M.D.; Fettiplace, Michael R. M.D., Ph.D.; Weinberg, Guy L. M.D.; Neal, Joseph M. M.D.; Barrington, Michael J. Ph.D., M.B.B.S., F.A.N.Z.C.A.

Author Information
Plastic and Reconstructive Surgery: September 2019 - Volume 144 - Issue 3 - p 783-795
doi: 10.1097/PRS.0000000000005989
  • Free
  • Patient Safety CME
  • Best Paper

Local anesthetics are ubiquitous in health care used by medical specialists in locations such as physician offices and ambulatory surgical centers.1–15 Local anesthetic systemic toxicity can result in serious patient harm, including seizure, cardiac compromise and, in the worst-case scenario, fatality. Despite advances in pharmacology and advances in local anesthetic systemic toxicity prevention and treatment, recent published cases show that local anesthetic systemic toxicity continues to occur.16–54 Accordingly, educating providers in all relevant specialties about the safe use of local anesthetics is paramount.55 The objective of this narrative review of local anesthetic systemic toxicity is to highlight key principles of local anesthetic pharmacology and to provide an update on the prevention, diagnosis, and management of local anesthetic systemic toxicity.

PATIENTS AND METHODS

The authors used a MEDLINE search strategy for this narrative review of combinations of the following terms to obtain an inclusive overview of local anesthetic toxicity that will be useful to clinicians: local anesthetic, regional anesthesia, nerve block, toxicity, cardiac arrest, resuscitation, myocardial depression, epinephrine, vasopressin, vasopressor, cardiopulmonary bypass, lipid, lipid rescue, emulsion, bupivacaine, levobupivacaine, mepivacaine, lidocaine, ropivacaine, and etidocaine. Searches were performed using human and animal studies and case reports from the previous 50 years.

PHARMACOLOGY OF LOCAL ANESTHETICS

Chemical Structure

The canonical molecular structure of local anesthetics contains a lipophilic aromatic ring system attached by an ester or amide intermediate chain to a hydrophilic tertiary amine. The potency and toxicity of the pipecoloxylidide molecules (mepivacaine, bupivacaine, ropivacaine) relate to the length of the alkyl substitutions and the resulting lipid solubility. At physiologic pH, local anesthetics exist as a mixture of a protonated acid and neutral base because of their tertiary amine. However, only the uncharged form can cross the membrane, and once intracellular, the ionized, cationic form binds to a site on the inner pore of the sodium channel.56 Lowering of the arterial pH may create intracellular ion trapping, thereby modifying cellular effects and potentially worsening toxicity.

Pharmacodynamics

Local anesthetics act on all parts of the nervous system and on all nerve types. The primary therapeutic effect of local anesthetics is to block the action potential being generated and propagated in peripheral nerves. Classically, this occurs by means of blockade of voltage-gated sodium channels in nerve membranes, which slows the rate of membrane depolarization (at low concentrations) and prevents cells from reaching the action potential threshold at high concentrations.57 Sodium channels are also responsible for initiating the cardiac action potential. Cardiac toxicity includes effects on both electrophysiology and contractility. Local anesthetics have a direct effect on cardiac tissue (e.g., sinus node, Purkinje fibers, ventricular muscle), decreasing the rate of depolarization and increasing the action potential duration. Different local anesthetic molecules have different mechanisms; therefore, cardiac effects are drug specific.58–60 Bupivacaine unbinds slowly from the sodium channel, resulting in a greater fraction of occupied channels. This is thought to be one mechanism explaining the increased potency (and toxicity) of bupivacaine compared with lidocaine.61 Local anesthetics also can potentially inhibit (at concentrations unrelated to that required for sodium channel blockade) mitochondrial metabolism and oxidative phosphorylation.62–70

Pharmacokinetics

Routes of administration include topical, subcutaneous, intermuscular, neuraxial, and perineural.71,72 Subsequent systemic absorption is delayed based on diffusion, the rate of which depends on the site of injection; the area over which absorption occurs; drug lipophilicity (e.g., bupivacaine is greater than lidocaine); plasma protein binding; molecular weight; and patient factors such as age, size, and comorbidities. Coadministration of epinephrine can delay absorption of local anesthetic into the circulation and reduce peak serum concentration.73,74 Increasing the rate of administration or total dose increases the concentration gradient between tissue depot and blood, thereby increasing the rate of rise in plasma concentration and thus the risk of toxicity.75 Ester local anesthetics are metabolized in the circulation by plasma esterases, whereas amide local anesthetics (i.e., lidocaine, mepivacaine, bupivacaine, ropivacaine) are processed in the liver by cytochrome P450–linked enzymes,76 dependent on liver blood flow. Metabolism of amide local anesthetics is reduced by any pathophysiologic state that decreases cardiac output or hepatic blood flow or impairs hepatic enzyme function.77 Reduced cardiac output will delay both the rate of absorption of local anesthetic from the site of injection into the circulation and subsequent transit of amide local anesthetic to its site of metabolism. Patients with liver disease or congestive cardiac failure have elevated blood local anesthetic levels, placing them at increased risk of local anesthetic systemic toxicity. The metabolites of amide type local anesthetics are excreted by means of the kidney into the urine. The hepatic metabolites are largely inactive, although some metabolites retain some local anesthetic activity.

Adverse clinical effects caused by local anesthetic accumulating in the heart and brain can be compensated for by redistribution to muscle.78 However, other factors can influence distribution of local anesthetic; for example, elevated arterial carbon dioxide increases cerebral blood flow, increasing delivery of local anesthetic to the brain.79 Hypercapnia and acidosis decrease plasma protein binding of local anesthetic, increasing its free fraction and thereby potentially worsening toxicity.

Key Messages on Pharmacology

  • Local anesthetics impair nerve conduction by binding and inhibiting voltage-gated sodium channels.
  • Local anesthetics impair a broad range of biological processes, blocking signaling at sites independent of sodium channels, many of which may moderate toxicity.
  • Local anesthetic type, dosage, and volume; site of injection; binding to plasma proteins; and patient comorbidities influence the rate of absorption from the site of injection, subsequent tissue distribution, and biodegradation of local anesthetics.
  • Lipophilic local anesthetics are more potent and longer acting, and have a greater potential for clinical toxicity.
  • At toxic blood levels, bupivacaine is more likely to cause arrhythmias than lidocaine, whereas the latter may depress cardiac contractility without arrhythmias.

EPIDEMIOLOGY

The incidence of local anesthetic systemic toxicity can be estimated from registries,54,80–82 population studies,83 and administration databases,84,85 but it is likely that many episodes of local anesthetic systemic toxicity are unreported. A recent American Society of Regional Anesthesia and Pain Medicine practice advisory54 reports that, between March of 2014 and November of 2016, 47 separate cases of local anesthetic systemic toxicity were described. Local anesthetic systemic toxicity events occurred as a result of penile blocks (23 percent), local infiltration (17 percent), upper/lower extremity (17 percent), torso (8.5 percent), and neuraxial blockade (13 percent). Twenty-two patients (47 percent) were treated with intravenous lipid emulsion and two patients (4.3 percent) died.54 Case reports remind us that even if local anesthetic systemic toxicity occurs infrequently, these events do occur and can result in catastrophic outcomes.16–18,20–25,28,29,31,33,39–42,47,48,50,55,86

DIAGNOSIS

If a potentially toxic dose of local anesthetic is planned, minimum recommended monitoring includes noninvasive blood pressure, electrocardiography, and pulse oximetry. Seizure (53 and 61 percent from case reports and registries, respectively) was the most common presenting feature reported in the above-mentioned American Society of Regional Anesthesia and Pain Medicine review.54 Other common presenting central nervous system features of local anesthetic systemic toxicity are prodromal symptoms such as lightheadedness, dizziness, auditory and visual disturbance (blurred vision), tinnitus, and perioral numbness. The sympathetic stimulus associated with central nervous system toxicity may cause tachycardia and hypertension and influence the cardiac effect of the local anesthetic. Loss of consciousness, seizures, dysrhythmias, myocardial depression, ventricular tachycardia, ventricular fibrillation, pulseless electrical activity, and cardiac arrest may occur (Table 1).86,87 All local anesthetics exert a dose-dependent depression of cardiac contractility and cardiac conduction.86 Hypoxia, hypercarbia, and acidosis worsen the negative inotropy of local anesthetic systemic toxicity. Acidosis increases the charged form of local anesthetic, which is then trapped inside the cell.

Table 1. - Symptoms and Signs of Local Anesthetic Systemic Toxicity
Prodrome
 Perioral numbness
 Tinnitus
 Confusion
 Dysarthria
 Dysphoria
 Dizziness
 Drowsiness
 Dysgeusia
Neurologic
 Agitation
 Loss of consciousness
 Seizure
Cardiovascular
 Arrhythmias (bradycardia, tachycardia, ventricular ectopy/tachycardia/fibrillation)
 Hypotension or hypertension
 Conduction disturbances (e.g., widened QRS complex)
 Cardiac arrest (asystole, pulseless electrical activity)

Although local anesthetic systemic toxicity usually manifests as central nervous system and/or cardiovascular disturbances, it is important to recognize atypical manifestations.86,87 The classic teaching that prodromal symptoms precede seizures, which then progress to cardiovascular collapse, is not always true. Cardiovascular toxicity can occur without prodromal symptoms or seizures.86 Bupivacaine may cause severe arrhythmias coincident with or before the onset of central nervous system toxicity. Local anesthetic systemic toxicity can result from either inadvertent intravascular injection or delayed absorption into the circulation from the site of injection or application. Accordingly, the timing of onset is variable, ranging from immediate (more common with direct intravascular injection) to hours after administration (either from local tissue absorption, slowly increasing levels from continuous infusions, decreased clearance, or intravascular migration of indwelling catheters). There appears to be a trend toward delayed-onset local anesthetic systemic toxicity outside of the operating room,88 and this may present with more subtle manifestations—instead of cardiovascular collapse, refractory relative hypotension may be the only sign.86,87 Local anesthetic systemic toxicity has presented in patients after discharge from the postanesthesia care unit or the hospital. One patient experienced central nervous system toxicity 14 hours after lidocaine infiltration for liposuction surgery,89 highlighting the importance of continued vigilance and patient monitoring. The safe period of observation following local anesthetic administration depends on the dosage and mode of delivery. For example, following performance of a major plexus block for anesthesia, we recommend a minimum period of observation of 30 minutes; however, following tumescent infiltration, anesthesia blood levels may not reach their maximum levels for several hours following injection, and therefore a substantially longer period of observation may be required. The ability to distinguish local anesthetic systemic toxicity from disease processes and patient comorbidities in the setting of confounding factors such as sedation and general anesthesia is important.33,90

Key Messages on Diagnosis

  • The presenting features and timing of onset of local anesthetic systemic toxicity vary. The spectrum of neurologic and cardiovascular symptoms and signs are broad; atypical and some central nervous system features can be subtle.86–88,91
  • The safe period of observation following local anesthetic administration depends on the dosage and mode of delivery.
  • Diagnosis of local anesthetic systemic toxicity may be obscured by perioperative processes, sedation, and general anesthesia or be wrongly attributed to patient comorbidities.

RISK FACTORS

Patient-Dependent Risk Factors: Body Mass, Protein Binding, and Systemic Disease

Most patients, particularly young and healthy ones, tolerate weight-based doses of local anesthetics; however, patients at extremes of age and those with coexisting systemic disease may be at increased risk. Newborns, infants and the very old have a low lean muscle mass, which makes them prone to toxicity when total body weight is used for dosing. Infants have lower levels of plasma binding proteins and lower muscle mass than a healthy adult patient, so slight variation in calculations can result in excessive or even toxic doses.86,92 Adults at-risk tend to have several coinciding problems (age; disease; cachexia; hypoalbuminemia; impaired cardiac, hepatic, and renal function) that increase the risk of local anesthetic systemic toxicity.33,40,93–96 Case reports of local anesthetic systemic toxicity in patients with low albumin levels is concordant with the free fraction of local anesthetic being increased.40,94,97,98 Patients’ with metabolic and/or mitochondrial disease are at increased risk (independent of sodium channel) of local anesthetic systemic toxicity.40,99–101 The pharmacokinetics section contains more detail on the metabolism of local anesthetics.

Patient-Independent Risk Factors: Local Anesthetic Type, Dosage and Volume, Absorption, and Site of Injection

Local anesthetics have differing effects on cardiac conduction, myocardial contractility, chronotropy, and peripheral vascular tone. Local anesthetic potency and toxicity are linked, and local anesthetics inhibit cardiac conduction proportional to their potency to induce nerve blockade. For example, bupivacaine and etidocaine contribute to an increased risk of cardiotoxicity relative to the risk of lidocaine and mepivacaine.102 Bupivacaine and etidocaine tend to cause conduction disturbances, arrhythmias, and impaired contractility, whereas lidocaine is less likely to cause arrhythmias.103 Ropivacaine is a pure S(-) enantiomer and was developed as a safer alternative to racemic bupivacaine and introduced into clinical practice in the early 1990s. The R(+) isomer of bupivacaine binds cardiac sodium channels more avidly than the S(-) isomers (ropivacaine, levobupivacaine); however, the mechanism underlying cardiac toxicity may not necessarily be the result of local anesthetic binding to one specific site.58 In experimental models, ropivacaine has been shown to be less cardiotoxic than bupivacaine.59,104 However, the relative safety of ropivacaine compared with bupivacaine is complicated by the in vitro potency of ropivacaine being approximately 25 percent less than that of bupivacaine. Patients typically receive higher doses of ropivacaine than bupivacaine, with ropivacaine available in 0.75% and in some countries 1.0% concentrations (compared to bupivacaine available up to 0.5%). Because potency and toxicity are closely linked, it is possible that in equipotent doses and tissue concentrations, there may be slight differences only in the potential for ropivacaine and bupivacaine to cause toxicity.

Liposomal bupivacaine (Exparel; Pacira Biosciences, Inc., Parsippany, N.J.) has a delivery platform that results in slow dissociation of local anesthetic and delayed absorption from the site of injection into the circulation. Currently, there are no reports in the peer-reviewed literature of local anesthetic systemic toxicity following liposomal bupivacaine administration. However, the Adverse Event Reporting System database of the U.S. Food and Drug Administration has identified a pharmacovigilance signal indicating an association between local anesthetic systemic toxicity and liposomal bupivacaine.105,106 We recommend that liposomal bupivacaine be afforded the same degree of vigilance regarding local anesthetic systemic toxicity.

A large mass (calculated by the product of concentration and volume) of local anesthetic increases the risk of toxicity,80 but even a large volume of dilute local anesthetic may increase the area of drug absorption and lead to local anesthetic systemic toxicity. For example, there have been case reports of local anesthetic systemic toxicity after transversus abdominis plane block.35,107,108 Local infiltration analgesia for orthopedic surgery27 and local tissue infiltration24,25,109 frequently involve the use of large volumes and dosages of local anesthetics. Albeit dilute, large volumes of local anesthetics are also used for cosmetic procedures, including tumescent liposuction. Klein and Jeske have been leaders in the study of safe tumescent anesthesia and have recently performed studies in 14 volunteers suggesting that, when followed by liposuction, infiltration of lidocaine doses up to 45 ml/kg is safe.109 However, the reader should be aware that individual patient sensitivities, comorbidities, and physician or practice deficiencies may predispose to catastrophic outcomes. Furthermore, there are no universal mandated or regulatory reporting requirements that would reliably capture all catastrophic local anesthetic systemic toxicity events. Reporting of fatalities attributable to lidocaine toxicity in otherwise healthy patients following tumescent liposuction have occurred.110 Cardiac arrest and death caused by local anesthetic systemic toxicity have occurred at outpatient plastic surgery centers, possibly related to the large volumes or improper administration.28–30 However, these cases provide no context to the scope of the problem. A procedure identified relatively frequently in recent case reports associated with local anesthetic systemic toxicity is dorsal penile block for circumcision; the toxicity with this procedure is related at least in part to dosage and technique-related issues.16,18,20–22 The mechanism of local anesthetic systemic toxicity in circumcision is likely inadvertent intravascular injection. Relative overdosage and lack of understanding of relevant pharmacokinetics may be relevant to local anesthetic systemic toxicity persisting as a clinical issue following topical anesthesia of the airway for awake tracheal intubation and/or bronchoscopy.111,112 The less invasive nature of topical formulations (i.e., gels, liquids, sprays, ointments, and creams) of local anesthetics and the availability in nonhospital settings may give a false sense of safety that may result in overdosing.17,23,113 Equal doses of the same local anesthetic when injected at different sites result in different blood levels, also impacting the risk of local anesthetic systemic toxicity.80,114 Mixing local anesthetics can confound calculation of a safe total dosage and does not confer safety because local anesthetic toxicity is additive.

Key Messages on Risk Factors

  • Dose, dose/weight, and volume of local anesthetic; extremes of age; low body mass; and cardiovascular, hepatic, renal, and metabolic dysfunction increase the risk of local anesthetic systemic toxicity.
  • Cardiac toxicity is influenced by local anesthetic type; however, local anesthetic systemic toxicity events have been reported following all local anesthetic types.

PREVENTION

Established “safety steps” include use of incremental injections with intermittent aspiration and the use of a test dose with intravascular markers.115,116 Incremental injection and intermittent aspiration can detect accidental intravascular needle-tip migration. Injecting the total local anesthetic dose over a longer period reduces its peak serum concentration and risk of local anesthetic systemic toxicity.75 When combined, these two steps may help prevent or decrease the amount of local anesthetic injected in the event of an intravascular puncture, because it will be recognized during the next aspiration. A commonly used direct intravascular marker is low-dose epinephrine (2.5 to 5 μg/ml). In the case of an intravascular injection, epinephrine causes the heart rate to increase by more than 10 beats/minute and/or the systolic blood pressure to increase by more than 15 mm Hg.115 Safe administration techniques and vigilant monitoring are the first-line measures of prevention. Suggested maximum safe doses of local anesthetics are summarized in Table 2.

Table 2. - Recommended Local Anesthetic Dosages
Local Anesthetic Maximum Recommended Dose (mg/kg) Maximum Recommended Dose in Adults (mg) Indications Comments
2-Chloroprocaine 12 800 (1000 with adrenaline*) Infiltration, epidural, intrathecal, nerve block
Lignocaine (lidocaine) 4.5 (7 with adrenaline) 200 (500 with adrenaline) Infiltration, nerve block, ophthalmic, epidural, intrathecal, IVRA, topical use (i.e., gels, ointment, liquid, cream, spray, patch) Safe dosage of tumescent lidocaine anesthesia has been estimated up to 45 ml/kg with liposuction from volunteer studies (14 subjects)
Cocaine 1.5 Fiberoptic endotracheal intubation, topical anesthesia for surgery on the ear, nose, and throat Contraindications: IVRA, administration by injection, use with sympathomimetics and monoamine oxidase inhibitors
Prilocaine 6 (8 with adrenaline) 400 (600 with adrenaline) Infiltration, IVRA, topical (used in eutectic mixture with lignocaine) Recommended for IVRA (outside North America) because less toxic than other amide LAs; avoid with concurrent use of drugs that cause methemoglobinemia
Mepivacaine 4.5 (7 with adrenaline) 400 (550 with adrenaline) Infiltration, epidural, intrathecal, nerve block
Ropivacaine 3 225 Infiltration, nerve block, epidural, intrathecal, wound infusion Contraindicated for IVRA; suitable for epidural or wound infusion; maximum daily dosage is 800 mg; pure S enantiomer
Bupivacaine 2 (2 with adrenaline) 150 Infiltration, nerve block, ophthalmic, epidural, intrathecal Contraindicated for IVRA; maximum daily dose in adults is 400 mg; suitable for epidural infusion
Levobupivacaine 2 150 Infiltration, nerve block, ophthalmic, epidural, intrathecal Contraindicated for IVRA; S-isomer of bupivacaine
IVRA, intravenous regional anesthesia; LAs, local anesthetics.
*Adrenaline (epinephrine) is commonly used in 5 μg/ml (1:200,000) or 2.5 μg/ml (1:400,000). IVRA is known eponymously as Bier block. Adrenaline is contraindicated for penile block, infiltration near terminal arteries, and IVRA. Dosages are guidelines only; in specific circumstances, specialists performing major regional anesthesia procedures may exceed these recommended doses. For intrathecal and epidural administration during pregnancy, LA dosage should be reduced because of increased sensitivity and anatomical/physiologic changes in the neuraxis.
Source of recommended dosages: Australian Medicines Handbook Pty Ltd. Available at: https://amhonline.amh.net.au.acs.hcn.com.au/?acc=36265, and remainder from Butterworth JF IV, Mackey DC, Wasnick JD. Local anesthetics. In: Butterworth JF IV, Mackey DC, Wasnick JD, eds. Morgan & Mikhail’s Clinical Anesthesiology. 5th ed. New York: McGraw-Hill Medical; 2013: 263–276; Rosenberg PH, Veering BT, Urmey WF. Maximum recommended doses of local anesthetics: A multifactorial concept. Reg Anesth Pain Med. 2004;29:564–575; and Klein JA, Jeske DR: Estimated maximal safe dosages of tumescent lidocaine. Anesth Analg. 2016;122:1350–1359.

Key Messages for Prevention

  • Simple preventive steps include adopting an incremental injection technique with frequent aspiration.
  • Consider use of a pharmacological marker such as epinephrine 2.5 to 5 μg/ml.
  • Individualized local anesthetic dosing based on body mass, site of injection, and patients’ unique factors are a safer alternative to total maximum doses; identify at-risk patients.
  • Consider discussing appropriate local anesthetic dosages as a component of the surgical time-out.

MANAGEMENT

The management of serious local anesthetic systemic toxicity is different from that of other cardiac arrest scenarios. Standard resuscitation guidelines for cardiopulmonary arrest emphasize immediate commencement of cardiopulmonary resuscitation, including effective chest compression and, if indicated, early defibrillation. For local anesthetic systemic toxicity, airway maintenance and oxygenation (Fig. 1) are the priority in treatment, because both hypoxia and acidosis exacerbate clinical local anesthetic systemic toxicity.102 Drug administration in response to cardiac arrest caused by local anesthetic systemic toxicity is also different because the standard adult dose of epinephrine (1 mg) can impair resuscitation from local anesthetic systemic toxicity. Therefore, in a local anesthetic systemic toxicity cardiac arrest scenario, the individual doses of epinephrine should be reduced to less than 1 μg/kg. The pharmacologic management of local anesthetic systemic toxicity should avoid use of vasopressin, calcium channel blockers, beta adrenergic blockers, or other local anesthetics. A practitioner who suspects local anesthetic systemic toxicity should call for assistance and use cognitive aids such as checklists, crisis resource algorithms, and/or an electronic decision support tool to guide treatment. The American Society of Regional Anesthesia and Pain Medicine has developed a checklist and electronic decision support tool, the ASRA LAST smartphone app, available from https://www.asra.com/page/150/asra-apps or the Apple App Store or Google Play.88,91 Refer to the section below, Key Messages on Treatment, for further detail.

Fig. 1.
Fig. 1.:
Summary of critical steps required in the management of local anesthetic systemic toxicity. IV, intravenous; ACLS, advanced cardiac life support.

Supportive Treatment

Treatment of patients exhibiting isolated central nervous system symptoms of local anesthetic systemic toxicity should focus on avoiding hypoxia and suppressing seizures. Immediate airway management is essential for preventing hypoxia and acidosis.102,117 Benzodiazepines are the treatment of choice for seizure control. Patients with cardiac arrest should receive immediate advanced cardiac life support, with the above-mentioned differences being noted.91,118 Successful initiation of cardiopulmonary bypass for cardiac arrest caused by local anesthetic systemic toxicity that is refractory to advanced cardiac life support has also been described.119

Lipid Emulsion Therapy

Until one decade ago, the treatment of local anesthetic systemic toxicity was limited to the modalities described above. However, it was shown by Weinberg et al. in 1998 that giving lipid emulsion in the form of a standard total parenteral nutrition solution could improve outcomes in a rat model of bupivacaine-induced cardiac arrest.120 Since then, there have been numerous case reports of intravenous lipid emulsion use for the treatment of local anesthetic systemic toxicity in adult and pediatric patients.19,21–25,27,33,35,42,93,100,121–155 Since 2010, the American Society of Regional Anesthesia and Pain Medicine and other society guidelines for the management of severe local anesthetic systemic toxicity recommend early use of intravenous lipid emulsion in the form of a bolus (1.5 ml/kg) followed by a continuous infusion (0.25 ml/kg/minute) up to 10 ml/kg in the first 30 minutes.102,156 The American Society of Regional Anesthesia and Pain Medicine guidelines were revised in 2017 and recommend that, in adults weighing more than 70 kg, the initial 20% lipid emulsion bolus should be 100 ml over 2 to 3 minutes followed by 200 to 250 ml over 15 to 20 minutes.91 The weight-based dosage should be used for the smaller adult (<70 kg) or child with local anesthetic systemic toxicity. The upper limit of total dosage is now recommended to be 12 ml/kg or up to 1 liter in the larger adult. Cognitive aids and intralipid should be available wherever potentially toxic doses of local anesthetics are used.

Significant progress toward our understanding of the mechanism of intravenous lipid emulsion therapy has been made recently.157 The reversal of local anesthetic systemic toxicity is moderated by a multimodal effect of the lipid. First, the lipid provides a dynamic, intravascular compartment for partitioning of local anesthetics. This lipid compartment accelerates the redistribution of drug, moving it away from heart and brain and toward skeletal muscle for storage and liver for metabolic processing.78,158 The redistribution effect is rapid, and elevated levels of drug are seen only transiently in blood. Following removal of drug from cardiac tissue, intravenous lipid emulsion provides a direct cardiac effect that improves cardiac output and further accelerates redistribution of the drug.78,159 Finally, lipid emulsion adds postinsult cardiac protection, reducing ischemia-reperfusion injury to a recovering heart.65,160 Intravenous lipid emulsion infusion may reduce acute lung injury if given before epinephrine.161,162

Uncommon risks of acute intravenous lipid emulsion infusion include allergic reactions, nausea, vomiting, thrombocytopenia, hypercoagulability, pancreatitis, fat deposition in extracorporeal membrane oxygenation circuits, and renal replacement therapy filter collapse.163,164 Temporary interference with laboratory values is expected and can be mitigated by centrifuging samples.

Key Messages on Treatment

  • Management of local anesthetic systemic toxicity should include the use of cognitive aids such as checklists or an electronic decision support tool.91
  • Oxygenation, ventilation, and advanced cardiac life support are the priorities in treatment of local anesthetic systemic toxicity.
  • Lipid emulsion therapy should be given at the first sign of serious local anesthetic systemic toxicity, with an initial bolus dose of 100 ml (for adults weighing >70 kg) and 1.5 ml/kg in adults weighing less than 70 kg and in children.
  • Pharmacology: use epinephrine less than 1 μg/kg, and avoid vasopressin, calcium channel blockers, beta adrenergic blockers, or other local anesthetics.
  • Avoid large doses of propofol; treat hypotension and bradycardia; commence cardiopulmonary resuscitation if pulseless.

EDUCATION

Medical professionals must be educated about local anesthetic systemic toxicity, its diagnosis, and its treatment.55 Given that local anesthetic systemic toxicity is a rare occurrence, medical simulation is an effective educational tool for improving recognition and management of this problem.165

CONCLUSIONS

Local anesthetic systemic toxicity is a life-threatening complication of local anesthetic administration with potentially devastating results. The variable presenting features and onset of local anesthetic systemic toxicity coupled with general lack of experience, practice, and knowledge can leave providers ill-prepared to handle local anesthetic systemic toxicity, especially as the situation escalates to a crisis. Local anesthetic systemic toxicity occurs in a wide range of practice locations following local anesthetic administration by a wide range of practitioners. It is paramount that all physicians who administer local anesthetics are educated regarding the unpredictable and insidious nature of local anesthetic systemic toxicity and contemporary management algorithms that include intravenous lipid emulsion therapy. Education, mandatory safety requirements, and systems improvements can help minimize the occurrence and impact of local anesthetic systemic toxicity on patients and physicians.

REFERENCES

1. Haines L, Dickman E, Ayvazyan S, et al. Ultrasound-guided fascia iliaca compartment block for hip fractures in the emergency department. J Emerg Med. 2012;43:692–697.
2. Beaudoin FL, Nagdev A, Merchant RC, Becker BM. Ultrasound-guided femoral nerve blocks in elderly patients with hip fractures. Am J Emerg Med. 2010;28:76–81.
3. Sambrook PJ, Goss AN. Severe adverse reactions to dental local anaesthetics: Prolonged mandibular and lingual nerve anaesthesia. Aust Dent J. 2011;56:154–159.
4. Singh P. An emphasis on the wide usage and important role of local anesthesia in dentistry: A strategic review. Dent Res J (Isfahan) 2012;9:127–132.
5. Brydone AS, Souvatzoglou R, Abbas M, Watson DG, McDonald DA, Gill AM. Ropivacaine plasma levels following high-dose local infiltration analgesia for total knee arthroplasty. Anaesthesia 2015;70:784–790.
6. Puffer RC, Tou K, Winkel RE, Bydon M, Currier B, Freedman BA. Liposomal bupivacaine incisional injection in single-level lumbar spine surgery. Spine J. 2016;16:1305–1308.
7. Cummings DR, Yamashita DD, McAndrews JP. Complications of local anesthesia used in oral and maxillofacial surgery. Oral Maxillofac Surg Clin North Am. 2011;23:369–377.
8. Scherrer V, Compere V, Loisel C, Dureuil B. Cardiac arrest from local anesthetic toxicity after a field block and transversus abdominis plane block: A consequence of miscommunication between the anesthesiologist and surgeon. A A Case Rep. 2013;1:75–76.
9. Isley MM, Jensen JT, Nichols MD, Lehman A, Bednarek P, Edelman A. Intrauterine lidocaine infusion for pain management during outpatient transcervical tubal sterilization: A randomized controlled trial. Contraception 2012;85:275–281.
10. Ovalle A, López PJ, Guelfand M, Zubieta R. Neonatal circumcision with local anesthesia: Results of a standardized protocol (in Spanish). Rev Chil Pediatr. 2016;87:175–179.
11. Wang J, Wang L, Du Y, et al. Addition of intrarectal local analgesia to periprostatic nerve block improves pain control for transrectal ultrasonography-guided prostate biopsy: A systematic review and meta-analysis. Int J Urol. 2015;22:62–68.
12. Zaiac M, Shah VV, Mlacker S, Bray FN, Alsaidan M. Local anesthesia injection technique for aesthetic removal of dermal nevi. J Cosmet Dermatol. 2016;15:559–560.
13. Kohn T, Zari S. Local anesthesia techniques in hair restoration surgery. J Cutan Med Surg. 2016;20:610–612.
14. Cohen JL. Pain management with a topical lidocaine and tetracaine 7%/7% cream with laser dermatologic procedures. J Drugs Dermatol. 2013;12:986–989.
15. Alster T, Garden J, Fitzpatrick R, Rendon M, Sarkany M, Adelglass J. Lidocaine/tetracaine peel in topical anesthesia prior to laser-assisted hair removal: Phase-II and phase-III study results. J Dermatolog Treat. 2014;25:174–177.
16. French LK, Cedar A, Hendrickson RG. Case report: Bupivacaine toxicity with dorsal penile block for circumcision. Am Fam Physician 2012;86:222.
17. Larson A, Stidham T, Banerji S, Kaufman J. Seizures and methemoglobinemia in an infant after excessive EMLA application. Pediatr Emerg Care 2013;29:377–379.
18. Kumar KJ, Manjunath VG. Seizures following lignocaine administration. Indian Pediatr. 2013;50:521–522.
19. Shenoy U, Paul J, Antony D. Lipid resuscitation in pediatric patients: Need for caution? Paediatr Anaesth. 2014;24:332–334.
20. Özer AB, Erhan ÖL. Systemic toxicity to local anesthesia in an infant undergoing circumcision. Agri 2014;26:43–46.
21. Doye E, Desgranges FP, Stamm D, de Queiroz M, Valla FV, Javouhey E. Severe local anesthetic intoxication in an infant undergoing circumcision (in French). Arch Pediatr. 2015;22:303–305.
22. Buck D, Kreeger R, Spaeth J. Case discussion and root cause analysis: Bupivacaine overdose in an infant leading to ventricular tachycardia. Anesth Analg. 2014;119:137–140.
23. Kargl S, Hornath F, Rossegg U, et al. Status epilepticus, cardiac resuscitation, and posterior reversible encephalopathy syndrome after ingestion of viscous lidocaine: A plea for more childproof packaging of pharmaceuticals. Pediatr Emerg Care 2014;30:185–187.
24. Kamel I, Trehan G, Barnette R. Intralipid therapy for inadvertent peripheral nervous system blockade resulting from local anesthetic overdose. Case Rep Anesthesiol. 2015;2015:486543.
25. Musielak M, McCall J. Lipid rescue in a pediatric burn patient. J Burn Care Res. 2016;37:e380–e382.
26. Hernandez MA, Boretsky K. Chloroprocaine: Local anesthetic systemic toxicity in a 9-month infant with paravertebral catheter. Paediatr Anaesth. 2016;26:665–666.
27. Fenten MG, Rohrbach A, Wymenga AB, Stienstra R. Systemic local anesthetic toxicity after local infiltration analgesia following a polyethylene tibial insert exchange: A case report. Reg Anesth Pain Med. 2014;39:264–265.
28. Patty A. Cardiac arrest during cosmetic surgery: Overdose of local anaesthetic likely. The Sydney Morning Herald. July 28, 2015. Available at: https://www.smh.com.au/national/nsw/cardiac-arrest-during-cosmetic-surgery-overdose-of-local-anaesthetic-likely-20150723-gijcn8.html. Accessed September 20, 2016.
29. Scott S. Patients at cosmetic surgery clinics being drugged into unconsciousness without their consent. PM, with Mark Colvin. Available at: http://www.abc.net.au/pm/content/2015/s4274438.htm. Accessed September 20, 2016.
30. Peschel GL. Medical negligence wrongful death claim against Sono Bello and Dr. Marco Sobrino settled for $1.9 million. Available at: http://www.glpattorneys.com/1876636-79-settlement-medical-negligence-wrongful-death-claim-sono-bello-dr-marco-sobrino/. Accessed September 20, 2016.
31. Yarwood S. Retired surgeon’s botched injection of Sri Lankan anaesthetic killed successful Welsh businessman. Wales Online. November 5, 2014. Available at: https://www.walesonline.co.uk/news/wales-news/retired-surgeons-botched-injection-sri-8058067. Accessed September 20, 2016.
32. Gurnaney H, Kraemer FW, Maxwell L, Muhly WT, Schleelein L, Ganesh A. Ambulatory continuous peripheral nerve blocks in children and adolescents: A longitudinal 8-year single center study. Anesth Analg. 2014;118:621–627.
33. Vadi MG, Patel N, Stiegler MP. Local anesthetic systemic toxicity after combined psoas compartment-sciatic nerve block: Analysis of decision factors and diagnostic delay. Anesthesiology 2014;120:987–996.
34. Widfeldt N, Kolmodin L. CNS symptoms of ropivacaine in bloodless field disappeared with Intralipid (in Swedish). Lakartidningen 2014;111:742–743.
35. Weiss E, Jolly C, Dumoulin JL, et al. Convulsions in 2 patients after bilateral ultrasound-guided transversus abdominis plane blocks for cesarean analgesia. Reg Anesth Pain Med. 2014;39:248–251.
36. Akimoto K, Yamauchi C, Fujimoto K, Kurahashi K. A case of delayed arousal after anesthesia due to aberrant epidural catheter placement in a blood vessel (in Japanese). Masui 2014;63:814–816.
37. Díaz-Crespo J, Moreno-Martín A, Jover-Rodrigálvarez R, Pérez-Sánchez T. A case of systemic toxicity due to local anaesthetics. Is Intralipid the only emulsion available? (in Spanish). Rev Esp Anestesiol Reanim. 2014;61:584–585.
38. Güngör İ, Akbaş B, Kaya K, Çelebi H, Tamer U. Sudden developing convulsion during interscalene block: Does propofol anesthesia diminish plasma bupivacaine level? Agri 2015;27:54–57.
39. Prakash R, Gautam S, Kumar S, Singh R. Local anaesthetic systemic toxicity in a patient under general anaesthesia (GA): A diagnostic challenge. J Clin Diagn Res. 2015;9:UD03–UD04.
40. Grigg E, Anderson C, Pankovich M, Martin L, Flack S. Systemic ropivacaine toxicity from a peripheral nerve infusion in a medically complex patient. J Clin Anesth. 2015;27:338–340.
41. Pinheiro LC, Carmona BM, de Nazareth Chaves Fascio M, de Souza IS, de Azevedo RAA, Barbosa FT. Cardiac arrest after epidural anesthesia for a esthetic plastic surgery: A case report (in Portuguese). Rev Bras Anestesiol. 2017;67:544–547.
42. Tierney KJ, Murano T, Natal B. Lidocaine-induced cardiac arrest in the emergency department: Effectiveness of lipid therapy. J Emerg Med. 2016;50:47–50.
43. Haldar R, Dubey M, Rastogi A, Singh PK. Intravenous lignocaine to blunt extubation responses: A double-edged sword. Am J Ther. 2016;23:e646–e648.
44. Jayanthi R, Nasser K, Monica K. Local anesthetics systemic toxicity. J Assoc Physicians India 2016;64:92–93.
45. Nicholas E, Thornton MD. Lidocaine toxicity during attempted epistaxis cautery. J Emerg Med. 2016;51:303–304.
46. Shapiro P, Schroeck H. Seizure after abdominal surgery in an infant receiving a standard-dose postoperative epidural bupivacaine infusion. A A Case Rep. 2016;6:238–240.
47. Gaïes E, Jebabli N, Lakhal M, Klouz A, Salouage I, Trabelsi S. Delayed convulsion after lidocaine instillation for bronchoscopy (in French). Rev Mal Respir. 2016;33:388–390.
48. Tsang TM, Okullo AT, Field J, Mamo P. Lipid rescue for treatment of delayed systemic ropivacaine toxicity from a continuous thoracic paravertebral block. BMJ Case Rep. 2017;2017:bcr2016215071corr1.
49. Yu RN, Houck CS, Casta A, Blum RH. Institutional policy changes to prevent cardiac toxicity associated with bupivacaine penile blockade in infants. A A Case Rep. 2016;7:71–75.
50. Najafi N, Veyckemans F, Du Maine C, et al. Systemic toxicity following the use of 1% ropivacaine for pediatric penile nerve block. Reg Anesth Pain Med. 2016;41:549–550.
51. Eizaga Rebollar R, García Palacios MV, Morales Guerrero J, Torres Morera LM. Lipid rescue in children: The prompt decision. J Clin Anesth. 2016;32:248–252.
52. Ho AM, Karmakar MK, Ng SK, et al. Local anaesthetic toxicity after bilateral thoracic paravertebral block in patients undergoing coronary artery bypass surgery. Anaesth Intensive Care 2016;44:615–619.
53. Moellentin DL, Stewart D, Barbour J. Case study of fatal stroke following intranasal lidocaine. Hosp Pharm. 2016;51:662–664.
54. Gitman M, Barrington MJ. Local anesthetic systemic toxicity: A review of recent case reports and registries. Reg Anesth Pain Med. 2018;43:124–130.
55. Barrington MJ, Weinberg GL, Neal JM. A call to all readers: Educating all surgeons on preventing and treatment of local anaesthetic systemic toxicity. ANZ J Surg. 2016;86:636–637.
56. Butterworth JF IV, Strichartz GR. Molecular mechanisms of local anesthesia: A review. Anesthesiology 1990;72:711–734.
57. Hille B. Local anesthetics: Hydrophilic and hydrophobic pathways for the drug-receptor reaction. J Gen Physiol. 1977;69:497–515.
58. Butterworth JF IV.. Models and mechanisms of local anesthetic cardiac toxicity: A review. Reg Anesth Pain Med. 2010;35:167–176.
59. Royse CF, Royse AG. The myocardial and vascular effects of bupivacaine, levobupivacaine, and ropivacaine using pressure volume loops. Anesth Analg. 2005;101:679–687, table of contents.
60. Onyüksel H, Sethi V, Weinberg GL, Dudeja PK, Rubinstein I. Bupivacaine, but not lidocaine, disrupts cardiolipin-containing small biomimetic unilamellar liposomes. Chem Biol Interact. 2007;169:154–159.
61. Clarkson CW, Hondeghem LM. Mechanism for bupivacaine depression of cardiac conduction: Fast block of sodium channels during the action potential with slow recovery from block during diastole. Anesthesiology 1985;62:396–405.
62. Coyle DE, Sperelakis N. Bupivacaine and lidocaine blockade of calcium-mediated slow action potentials in guinea pig ventricular muscle. J Pharmacol Exp Ther. 1987;242:1001–1005.
63. Groban L, Dolinski S. Differences in cardiac toxicity among ropivacaine, levobupivacaine, bupivacaine, and lidocaine. Tech Reg Anesth Pain Manage. 2001;5:48–55.
64. Piegeler T, Votta-Velis EG, Bakhshi FR, et al. Endothelial barrier protection by local anesthetics: Ropivacaine and lidocaine block tumor necrosis factor-α-induced endothelial cell Src activation. Anesthesiology 2014;120:1414–1428.
65. Fettiplace MR, Kowal K, Ripper R, et al. Insulin signaling in bupivacaine-induced cardiac toxicity: Sensitization during recovery and potentiation by lipid emulsion. Anesthesiology 2016;124:428–442.
66. Nouette-Gaulain K, Forestier F, Malgat M, Marthan R, Mazat JP, Sztark F. Effects of bupivacaine on mitochondrial energy metabolism in heart of rats following exposure to chronic hypoxia. Anesthesiology 2002;97:1507–1511.
67. Weinberg GL, Palmer JW, VadeBoncouer TR, Zuechner MB, Edelman G, Hoppel CL. Bupivacaine inhibits acylcarnitine exchange in cardiac mitochondria. Anesthesiology 2000;92:523–528.
68. Fettiplace MR, Pichurko A, Ripper R, et al. Cardiac depression induced by cocaine or cocaethylene is alleviated by lipid emulsion more effectively than by sulfobutylether-β-cyclodextrin. Acad Emerg Med. 2015;22:508–517.
69. Karniel M, Beitner R. Local anesthetics induce a decrease in the levels of glucose 1,6-bisphosphate, fructose 1,6-bisphosphate, and ATP, and in the viability of melanoma cells. Mol Genet Metab. 2000;69:40–45.
70. Dabadie P, Bendriss P, Erny P, Mazat JP. Uncoupling effects of local anesthetics on rat liver mitochondria. FEBS Lett. 1987;226:77–82.
71. Mazoit JX, Dalens BJ. Pharmacokinetics of local anaesthetics in infants and children. Clin Pharmacokinet. 2004;43:17–32.
72. Tucker GT. Pharmacokinetics of local anaesthetics. Br J Anaesth. 1986;58:717–731.
73. Tucker GT, Moore DC, Bridenbaugh PO, Bridenbaugh LD, Thompson GE. Systemic absorption of mepivacaine in commonly used regional block procedures. Anesthesiology 1972;37:277–287.
74. Karmakar MK, Ho AM, Law BK, Wong AS, Shafer SL, Gin T. Arterial and venous pharmacokinetics of ropivacaine with and without epinephrine after thoracic paravertebral block. Anesthesiology 2005;103:704–711.
75. Mather LE, Copeland SE, Ladd LA. Acute toxicity of local anesthetics: Underlying pharmacokinetic and pharmacodynamic concepts. Reg Anesth Pain Med. 2005;30:553–566.
76. Gantenbein M, Attolini L, Bruguerolle B, et al. Oxidative metabolism of bupivacaine into pipecolylxylidine in humans is mainly catalyzed by CYP3A. Drug Metab Dispos. 2000;28:383–385.
77. Stenson RE, Constantino RT, Harrison DC. Interrelationships of hepatic blood flow, cardiac output, and blood levels of lidocaine in man. Circulation 1971;43:205–211.
78. Fettiplace MR, Lis K, Ripper R, et al. Multi-modal contributions to detoxification of acute pharmacotoxicity by a triglyceride micro-emulsion. J Control Release 2015;198:62–70.
79. Kety SS, Schmidt CF. The effects of altered arterial tensions of carbon dioxide and oxygen on cerebral blood flow and cerebral oxygen consumption of normal young men. J Clin Invest. 1948;27:484–492.
80. Barrington MJ, Kluger R. Ultrasound guidance reduces the risk of local anesthetic systemic toxicity following peripheral nerve blockade. Reg Anesth Pain Med. 2013;38:289–299.
81. Polaner DM, Taenzer AH, Walker BJ, et al. Pediatric Regional Anesthesia Network (PRAN): A multi-institutional study of the use and incidence of complications of pediatric regional anesthesia. Anesth Analg. 2012;115:1353–1364.
82. Bomberg H, Huth A, Wagenpfeil S, et al. Psoas versus femoral blocks: A registry analysis of risks and benefits. Reg Anesth Pain Med. 2017;42:719–724.
83. Heinonen JA, Litonius E, Pitkänen M, Rosenberg PH. Incidence of severe local anaesthetic toxicity and adoption of lipid rescue in Finnish anaesthesia departments in 2011-2013. Acta Anaesthesiol Scand. 2015;59:1032–1037.
84. Mörwald EE, Zubizarreta N, Cozowicz C, Poeran J, Memtsoudis SG. Incidence of local anesthetic systemic toxicity in orthopedic patients receiving peripheral verve blocks. Reg Anesth Pain Med. 2017;42:442–445.
85. Rubin DS, Matsumoto MM, Weinberg G, Roth S. Local anesthetic systemic toxicity in total joint arthroplasty: Incidence and risk factors in the United States from the National Inpatient Sample 1998-2013. Reg Anesth Pain Med. 2018;43:131–137.
86. Vasques F, Behr AU, Weinberg G, Ori C, Di Gregorio G. A review of local anesthetic systemic toxicity cases since publication of the American Society of Regional Anesthesia recommendations: To whom it may concern. Reg Anesth Pain Med. 2015;40:698–705.
87. Di Gregorio G, Neal JM, Rosenquist RW, Weinberg GL. Clinical presentation of local anesthetic systemic toxicity: A review of published cases, 1979 to 2009. Reg Anesth Pain Med. 2010;35:181–187.
88. Neal JM, Barrington MJ, Fettiplace MR, et al. The third American Society of Regional Anesthesia and Pain Medicine practice advisory on local anesthetic systemic toxicity: Executive summary 2017. Reg Anesth Pain Med. 2018;43:113–123.
89. Nordström H, Stånge K. Plasma lidocaine levels and risks after liposuction with tumescent anaesthesia. Acta Anaesthesiol Scand. 2005;49:1487–1490.
90. Barrington MJ, Weinberg GL. Did preoperative fixation on choice of anesthetic confound assessment of alternative techniques? Anesthesiology 2014;121:1131.
91. Neal JM, Woodward CM, Harrison TK. The American Society of Regional Anesthesia and Pain Medicine checklist for managing local anesthetic systemic toxicity: 2017 version. Reg Anesth Pain Med. 2018;43:150–153.
92. Lönnqvist PA. Toxicity of local anesthetic drugs: A pediatric perspective. Paediatr Anaesth. 2012;22:39–43.
93. Hartley RA, Foster PN, Moore JA. Local anaesthetic toxicity with continuous local anaesthetic infusion following hepatic resection. Eur J Anaesthesiol. 2012;29:455–456.
94. Fagenholz PJ, Bowler GM, Carnochan FM, Walker WS. Systemic local anaesthetic toxicity from continuous thoracic paravertebral block. Br J Anaesth. 2012;109:260–262.
95. Petrar S, Montemurro T. Total local anesthetic administered is integral to the syndrome of local anesthetic systemic toxicity. Anesthesiology 2014;121:1130–1131.
96. Bazerbachi F, Rank K, Chan A. Intravenous lipid rescue and ropivacaine systemic toxicity. J Anesth. 2014;28:139.
97. Monti M, Monti A, Borgognoni F, Vincentelli GM, Paoletti F. Treatment with lipid therapy to resuscitate a patient suffering from toxicity due to local anesthetics. Emerg Care J. 2014;10:41–44.
98. Calenda E, Baste JM, Hajjej R, Danielou E, Peillon C. Toxic plasma concentration of ropivacaine after a paravertebral block in a patient suffering from severe hypoalbuminemia. J Clin Anesth. 2014;26:149–151.
99. Weinberg GL, Laurito CE, Geldner P, Pygon BH, Burton BK. Malignant ventricular dysrhythmias in a patient with isovaleric acidemia receiving general and local anesthesia for suction lipectomy. J Clin Anesth. 1997;9:668–670.
100. Wong GK, Joo DT, McDonnell C. Lipid resuscitation in a carnitine deficient child following intravascular migration of an epidural catheter. Anaesthesia 2010;65:192–195.
101. Wong GK, Crawford MW. Carnitine deficiency increases susceptibility to bupivacaine-induced cardiotoxicity in rats. Anesthesiology 2011;114:1417–1424.
102. Neal JM, Bernards CM, Butterworth JF IV, et al. ASRA practice advisory on local anesthetic systemic toxicity. Reg Anesth Pain Med. 2010;35:152–161.
103. Kotelko DM, Shnider SM, Dailey PA, et al. Bupivacaine-induced cardiac arrhythmias in sheep. Anesthesiology 1984;60:10–18.
104. Feldman HS, Arthur GR, Covino BG. Comparative systemic toxicity of convulsant and supraconvulsant doses of intravenous ropivacaine, bupivacaine, and lidocaine in the conscious dog. Anesth Analg. 1989;69:794–801.
105. Aggarwal N. Local anesthetics systemic toxicity association with Exparel (bupivacaine liposome): A pharmacovigilance evaluation. Expert Opin Drug Saf. 2018;17:581–587.
106. Dagenais S, Scranton R, Joyce AR, Vick CC. A comparison of approaches to identify possible cases of local anesthetic systemic toxicity in the FDA Adverse Event Reporting System (FAERS) database. Expert Opin Drug Saf. 2018;17:545–552.
107. Sakai T, Manabe W, Kamitani T, Takeyama E, Nakano S. Ropivacaine-induced late-onset systemic toxicity after transversus abdominis plane block under general anesthesia: Successful reversal with 20% lipid emulsion (in Japanese). Masui 2010;59:1502–1505.
108. Griffiths JD, Le NV, Grant S, Bjorksten A, Hebbard P, Royse C. Symptomatic local anaesthetic toxicity and plasma ropivacaine concentrations after transversus abdominis plane block for caesarean section. Br J Anaesth. 2013;110:996–1000.
109. Klein JA, Jeske DR. Estimated maximal safe dosages of tumescent lidocaine. Anesth Analg. 2016;122:1350–1359.
110. Rao RB, Ely SF, Hoffman RS. Deaths related to liposuction. N Engl J Med. 1999;340:1471–1475.
111. Giordano D, Panini A, Pernice C, Raso MG, Barbieri V. Neurologic toxicity of lidocaine during awake intubation in a patient with tongue base abscess: Case report. Am J Otolaryngol. 2014;35:62–65.
112. Woodall NM, Harwood RJ, Barker GL. Lidocaine toxicity in volunteer subjects undergoing awake fiberoptic intubation. Anesth Analg. 2005;101:607; author reply 607.
113. Institute for Safe Medication Practices. Tragic deaths related to pharmacy compounded high-strength lidocaine/tetracaine creams. ISMP Medication Safety Alert! Acute Care.February 10, 2005. Available at: http://www.ismp.org/newsletters/acutecare/articles/20050210-1.asp. Accessed September 20, 2016.
114. Tucker GT, Mather LE. Clinical pharmacokinetics of local anaesthetics. Clin Pharmacokinet. 1979;4:241–278.
115. Mulroy MF, Hejtmanek MR. Prevention of local anesthetic systemic toxicity. Reg Anesth Pain Med. 2010;35:177–180.
116. Yaddanapudi S. Prevention of local anesthetic systemic toxicity. J Anaesthesiol Clin Pharmacol. 2011;27:438–439.
117. Weinberg GL. Treatment of local anesthetic systemic toxicity (LAST). Reg Anesth Pain Med. 2010;35:188–193.
118. Link MS, Berkow LC, Kudenchuk PJ, et al. Part 7: Adult advanced cardiovascular life support: 2015 American Heart Association guidelines update for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation 2015;132(Suppl 2):S444–S464.
119. Soltesz EG, van Pelt F, Byrne JG. Emergent cardiopulmonary bypass for bupivacaine cardiotoxicity. J Cardiothorac Vasc Anesth. 2003;17:357–358.
120. Weinberg GL, VadeBoncouer T, Ramaraju GA, GarciaAmaro MF, Cwik MJ. Pretreatment or resuscitation with a lipid infusion shifts the doseresponse to bupivacaineinduced asystole in rats. Anesthesiology 1998;88:1071–1075.
121. Arora NP, Berk WA, Aaron CK, Williams KA. Usefulness of intravenous lipid emulsion for cardiac toxicity from cocaine overdose. Am J Cardiol. 2013;111:445–447.
122. Bilotta F, Titi L, Rosa G. Local anesthetic-induced complete atrioventricular block during awake craniotomy. J Neurosurg Anesthesiol. 2012;24:238.
123. Charbonneau H, Marcou TA, Mazoit JX, Zetlaoui PJ, Benhamou D. Early use of lipid emulsion to treat incipient mepivacaine intoxication. Reg Anesth Pain Med. 2009;34:277–278.
124. Diaz J, Bernasinski M, Malinovsky JM. Reversal of neurologic symptoms related to lidocaine toxicity with a lipid emulsion administration (in French). Ann Fr Anesth Reanim. 2012;31:647.
125. Espinet AJ, Emmerton MT. The successful use of intralipid for treatment of local anesthetic-induced central nervous system toxicity: Some considerations for administration of intralipid in an emergency. Clin J Pain 2009;25:808–809.
126. Foxall G, McCahon R, Lamb J, Hardman JG, Bedforth NM. Levobupivacaine-induced seizures and cardiovascular collapse treated with Intralipid. Anaesthesia 2007;62:516–518.
127. Gallagher C, Tan JM, Foster CG. Lipid rescue for bupivacaine toxicity during cardiovascular procedures. Heart Int. 2010;5:e5.
128. Gnaho A, Eyrieux S, Gentili M. Cardiac arrest during an ultrasound-guided sciatic nerve block combined with nerve stimulation. Reg Anesth Pain Med. 2009;34:278.
129. Lamblin A, Jean FX, Turc J, de Laroullière C, Puidupin M. Fiberoptic bronchoscopies under local anesthesia using lidocaine: Be careful of systemic toxicity (in French). Ann Fr Anesth Reanim. 2012;31:979–980.
130. Landy C, Schaeffer E, Raynaud L, Favier JC, Plancade D. Convulsions after normal dose of lidocaine: A probable drug interaction. Br J Anaesth. 2012;108:701.
131. Lange DB, Schwartz D, DaRoza G, Gair R. Use of intravenous lipid emulsion to reverse central nervous system toxicity of an iatrogenic local anesthetic overdose in a patient on peritoneal dialysis. Ann Pharmacother. 2012;46:e37.
132. Litz RJ, Popp M, Stehr SN, Koch T. Successful resuscitation of a patient with ropivacaine-induced asystole after axillary plexus block using lipid infusion. Anaesthesia 2006;61:800–801.
133. Litz RJ, Roessel T, Heller AR, Stehr SN. Reversal of central nervous system and cardiac toxicity after local anesthetic intoxication by lipid emulsion injection. Anesth Analg. 2008;106:1575–1577, table of contents.
134. Marwick PC, Levin AI, Coetzee AR. Recurrence of cardiotoxicity after lipid rescue from bupivacaine-induced cardiac arrest. Anesth Analg. 2009;108:1344–1346.
135. Mazoit JX. Cardiac arrest and local anaesthetics (in French). Presse Med. 2013;42:280–286.
136. McCutchen T, Gerancher JC. Early intralipid therapy may have prevented bupivacaine-associated cardiac arrest. Reg Anesth Pain Med. 2008;33:178–180.
137. Mizutani K, Oda Y, Sato H. Successful treatment of ropivacaine-induced central nervous system toxicity by use of lipid emulsion: Effect on total and unbound plasma fractions. J Anesth. 2011;25:442–445.
138. Nguyen VH, White JL. Further support for the early administration of lipid emulsion in the treatment of ropivacaine-induced central nervous system toxicity. J Anesth. 2012;26:479–480.
139. Shih YH, Chen CH, Wang YM, Liu K. Successful reversal of bupivacaine and lidocaine-induced severe junctional bradycardia by lipid emulsion following infraclavicular brachial plexus block in a uremic patient. Acta Anaesthesiol Taiwan 2011;49:72–74.
140. Smith HM, Jacob AK, Segura LG, Dilger JA, Torsher LC. Simulation education in anesthesia training: A case report of successful resuscitation of bupivacaine-induced cardiac arrest linked to recent simulation training. Anesth Analg. 2008;106:1581–1584, table of contents.
141. Sonsino DH, Fischler M. Immediate intravenous lipid infusion in the successful resuscitation of ropivacaine-induced cardiac arrest after infraclavicular brachial plexus block. Reg Anesth Pain Med. 2009;34:276–277.
142. Spence AG. Lipid reversal of central nervous system symptoms of bupivacaine toxicity. Anesthesiology 2007;107:516–517.
143. Varela H, Bums SM. Use of lipid emulsions for treatment of local anesthetic toxicity: A case report. AANA J 2010;78:359–364.
144. Warren JA, Thoma RB, Georgescu A, Shah SJ. Intravenous lipid infusion in the successful resuscitation of local anesthetic-induced cardiovascular collapse after supraclavicular brachial plexus block. Anesth Analg. 2008;106:1578–1580, table of contents.
145. Zhurda T, Muzha D, Caushi GJ, Bajaktari M, Kerci M. Usefulness of lipidic solution for the treatment of systemic toxicity related to bupivacaine injected in a sub-coracoid brachial plexus block (in French). Ann Fr Anesth Reanim. 2010;29:592–593.
146. Admani B, Essajee F. Successful resuscitation of a three month old child with intralipid infusion, presumed to have bupivacaine induced seizures and cardiovascular complications: Case report. East Afr Med J. 2010;87:354–356.
147. Al-Alami AA. Successful treatment of early ropivacaine toxicity with intralipid in a patient with attention deficit hyperactivity disorder. Middle East J Anaesthesiol. 2011;21:427–429.
148. Cordell CL, Schubkegel T, Light TR, Ahmad F. Lipid infusion rescue for bupivacaine-induced cardiac arrest after axillary block. J Hand Surg Am. 2010;35:144–146.
149. Fuzaylov G, Ying B, Tang Y, Sethna NF. Successful resuscitation after inadvertent intravenous injection of bupivacaine in an adolescent. Paediatr Anaesth. 2010;20:958–959.
150. Ludot H, Tharin JY, Belouadah M, Mazoit JX, Malinovsky JM. Successful resuscitation after ropivacaine and lidocaine-induced ventricular arrhythmia following posterior lumbar plexus block in a child. Anesth Analg. 2008;106:1572–1574, table of contents.
151. Markowitz S, Neal JM. Immediate lipid emulsion therapy in the successful treatment of bupivacaine systemic toxicity. Reg Anesth Pain Med. 2009;34:276.
152. Lin EP, Aronson LA. Successful resuscitation of bupivacaine-induced cardiotoxicity in a neonate. Paediatr Anaesth. 2010;20:955–957.
153. Presley JD, Chyka PA. Intravenous lipid emulsion to reverse acute drug toxicity in pediatric patients. Ann Pharmacother. 2013;47:735–743.
154. Shah S, Gopalakrishnan S, Apuya J, Shah S, Martin T. Use of Intralipid in an infant with impending cardiovascular collapse due to local anesthetic toxicity. J Anesth. 2009;23:439–441.
155. 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.
156. Association of Anaesthetists of Great Britain and Ireland. Management of severe local anaesthetic toxicity 2 (A4 sheet and accompanying notes). Available at: https://www.wfsahq.org/components/com_virtual_library/media/bf1f1de5f1ad459d42924f3614d2c0ab-Management-of-Local-Anaesthetic-Toxicity--Update-25-2-2009-.pdf. Accessed September 20, 2016.
157. Fettiplace MR, Weinberg G. The mechanisms underlying lipid resuscitation therapy. Reg Anesth Pain Med. 2018;43:138–149.
158. Shi K, Xia Y, Wang Q, et al. The effect of lipid emulsion on pharmacokinetics and tissue distribution of bupivacaine in rats. Anesth Analg. 2013;116:804–809.
159. Fettiplace MR, Akpa BS, Ripper R, et al. Resuscitation with lipid emulsion: Dose-dependent recovery from cardiac pharmacotoxicity requires a cardiotonic effect. Anesthesiology 2014;120:915–925.
160. Li J, Iorga A, Sharma S, et al. Intralipid, a clinically safe compound, protects the heart against ischemia-reperfusion injury more efficiently than cyclosporine-A. Anesthesiology 2012;117:836–846.
161. Hiller DB, Di Gregorio G, Kelly K, et al. Safety of high volume lipid emulsion infusion: A first approximation of LD50 in rats. Reg Anesth Pain Med. 2010;35:140–144.
162. Luo M, Yun X, Chen C, et al. Giving priority to lipid administration can reduce lung injury caused by epinephrine in bupivacaine-induced cardiac depression. Reg Anesth Pain Med. 2016;41:469–476.
163. Mirtallo JM, Dasta JF, Kleinschmidt KC, Varon J. State of the art review: Intravenous fat emulsions. Current applications, safety profile, and clinical implications. Ann Pharmacother. 2010;44:688–700.
164. Fettiplace MR, Akpa BS, Rubinstein I, Weinberg G. Confusion about infusion: Rational volume limits for intravenous lipid emulsion during treatment of oral overdoses. Ann Emerg Med. 2015;66:185–188.
165. Cropsey CL, McEvoy MD. Local anesthetic systemic toxicity in a nonoperative location. Simul Healthc. 2015;10:326–328.
Copyright © 2019 by the American Society of Plastic Surgeons