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543102 AESXXX10.1177/1090820X14543102Aesthetic Surgery JournalDickerson and Apfelbaum research-article2014 Research
543102 AESXXX10.1177/1090820X14543102Aesthetic Surgery JournalDickerson and Apfelbaum
research-article2014
Research

special topic

Local Anesthetic Systemic Toxicity

David M. Dickerson, MD; and Jeffrey L. Apfelbaum, MD

David M. Dickerson, MD; and Jeffrey L. Apfelbaum, MD Aesthetic Surgery Journal 2014, Vol. 34(7) 1111–1119

Aesthetic Surgery Journal 2014, Vol. 34(7) 1111–1119 © 2014 The American Society for Aesthetic Plastic Surgery, Inc. Reprints and permission:

DOI:10.1177/1090820X14543102

www.aestheticsurgeryjournal.com

DOI:10.1177/1090820X14543102 www.aestheticsurgeryjournal.com abstract Local anesthetic systemic toxicity (LAST) is a

abstract Local anesthetic systemic toxicity (LAST) is a rare yet devastating complication from the administration of local anesthesia. The ability to recognize and treat LAST is critical for clinicians who administer these drugs. The authors reviewed the literature on the mechanism, treatment, and prevention of LAST, with the goal of proposing a practical method for its management.

Keywords local anesthetic toxicity, lipid emulsion, bupivacaine toxicity, acute pain, ambulatory surgery

Accepted for publication April 18, 2014.

The history of local anesthetic systemic toxicity (LAST) is characterized by a pattern of discovery, application, obser- vation, and innovation (Figure 1). 1-5 Since the isolation of cocaine (from coca leaves) in 1859 and its first clinical application in 1884, local anesthesia (LA) has been used to diminish the pain of medical procedures. 1 The clinical ben-

efits, however, were soon weighed against the adverse effects: respiratory failure, seizures, palpitations, and irreg- ular cardiac function. 2 Despite the advent of safer synthetic local anesthetics, cases of toxicity persisted, culminating in

a 1979 report of the catastrophic consequences of LAST

that noted a relationship between drug lipophilicity and the potential for cardiac toxicity. 6 The unintended intravas-

cular injection or uptake of potent amino amide anesthet- ics (eg, bupivacaine) appeared as a common theme. In early studies, the incidence of LAST ranged from 7.5 to 20 per 10 000 peripheral nerve blockades; more recently, the incidence was estimated to be low as 2.5 per 10 000 block-

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 12 000 blockades. 10,11 The call for optimized management of LAST has resulted in heightened awareness, the development

of safety steps in local anesthetic administration, the discov-

ery of lipid emulsion therapy, and treatment and prevention guidelines with validated checklists. However, cases persist despite the application of ultrasonography, the availability of

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safer local anesthetics, and greater understanding of the risk factors. 11,12 As demonstrated by the case of an elastomeric pump failure described in the July 2014 issue of Aesthetic Surgery Journal, 13 LAST occurs despite practice advisories and heightened awareness. This case emphasizes the need for vigilance and preparedness to prevent an unforeseen occurrence of toxicity. 13 The safety of perioperative local anesthesia can be optimized by knowledge of its mechanism, the clinical presentation of LAST, and techniques for prevent- ing and treating this condition.

MechanisM of LocaL anesthetics

The analgesia produced by local anesthetics results from the binding of voltage-gated sodium (Na v ) channels and blocking of the excitation threshold of nociceptive afferent neurons. Binding prevents pain transmission by the periph- erally located primary afferent neuron. 14-16 Additionally,

From the Department of Anesthesia and Critical Care, University of Chicago, Chicago, Illinois.

Corresponding Author:

Dr David M. Dickerson, Department of Anesthesia and Critical Care, University of Chicago, 5841 S Maryland Ave, MC4028, O-416, Chicago, IL 60637, USA. E-mail: ddickerson@dacc.uchicago.edu

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Aesthetic Surgery Journal 34(7)

1112 Aesthetic Surgery Journal 34(7) Figure 1. History of local anesthetic toxicity. AMA, American Medical Association;

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- matory cascade and reduce hyperexcitability in the dorsal horn of the spinal cord. 17,18 Local anesthetics have been synthesized with various potencies and duration of action. The characteristics of common local anesthetics are sum- marized in Table 1.

LocaL anesthetics in anaLgesia

As a cornerstone of multimodal analgesia, local anesthet- ics provide myriad benefits. Local anesthetics bolster mul- timodal analgesia by potentially improving quality of recovery, decreasing opioid exposure, decreasing postop- erative nausea and vomiting, improving patient satisfac- tion, decreasing length of hospital stay, and reducing the risk of chronic postsurgical pain. 17-20 With various routes and sites of administration and their utility as intermittent or continuous therapy, local anesthetics are associated with varying degrees and risks of toxicity. Toxicity is fur- ther influenced by additional factors such as anatomic

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site of administration, the dosage of the drug, its pharma- cokinetic profile, and whether a vasoconstrictor is added (Table 2).

Depo-LocaL anesthetics in anaLgesia

Liposomal bupivacaine has been approved by the US Food and Drug Administration for single-dose wound infiltration or administration as a depo-local anesthetic. Bupivacaine- impregnated collagen, a similar agent, is currently in a phase 3 study. Pharmacokinetically, the delayed yet sustained release of these agents results in continuous anal- gesic serum concentrations with attenuated peak concentra- tions, suggesting a potential decrease in toxicity. However, the coadministration of nonliposomal anesthetics may cause rapid release of bupivacaine molecules and potential for tox- icity. Although these agents offer significant promise for sustained postoperative LA with decreased toxicity, addi- tional economic data and further study are needed to

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Table 1. Characteristics of Local Anesthetics

Local Anesthetic

Class/Chemical Linkage

pK a (Onset Time)

Protein Binding (Duration of Action)

Lipophilicity (Potency)

Maximum Dose, mg/kg (Dose With Epinephrine)

Lidocaine a

Amide

7.8

(fast)

 

Moderate

Moderate

4.5

(7)

   

Tumescent: 35-55

Bupivacaine a

Amide

8.1

(slow)

 

Long

Potent

2.5

(3)

Ropivacaine a

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)

Articaine

Ester

7.8

(fast)

 

Short

Moderate

4

(7)

2-Chloroprocaine a

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

pK a denotes the negative logarithm of the ionization constant of an acid. a Commonly 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- agement of postoperative pain.

MechanisM of LocaL anesthetic systeMic toxicity

Two leading hypotheses prevail for the mechanism of LAST: LA-impaired electrophysiologic function of the heart and loss of cardiac energy at the mitochondrial level. Local anesthetics reduce sodium ion flux by binding Na v , but this binding is not exclusively in the peripheral nervous tissue. Cardiac cells rely on Na -initiated depolarization during cardiac action potential cycles. 15,16,21 Inhibition of cardiac Na v channels may result in conduction disturbances, ven- tricular arrhythmias, and contractile dysfunction. This effect may be further exacerbated by inhibition of fatty acid transport by local anesthetic at the inner mitochon- drial membrane, resulting in a loss of cardiac energy from decreased oxidative phosphorylation. There is much debate about whether systemic toxicity is the effect of elec- trophysiologic dysfunction or contractile dysfunction. It

v

has been suggested that the specific mechanism may vary with different anesthetics and their diverse binding of car- diac Na v channels. 16,21 The ratio of cardiovascular to central nervous system (CNS) toxicity also varies among local anesthetics. With lidocaine and mepivacaine, CNS symptoms typically appear before cardiovascular symptoms. 22 CNS effects appear to be associated with disturbances in the transmission of γ-aminobutyric acid. Neuronal excitability is associated with inhibition of the TASK potassium channel by anesthetics, which contributes to the induction of seizures. 23 However, injury or death appears to be associated with cardiac

toxicity.

chaRacteRistics of LocaL anesthetic systeMic toxicity

The classic presentation of LAST has possible variants. Classically, toxicity appears on a continuum of adverse effects in the CNS that, with more toxic levels, progresses to cardiovascular symptoms. In a review of systemic toxicity

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Table 3. Classic Presentation of Local Anesthetic Systemic Toxicity

Presentation

Characteristics

Rapid onset

<5 min

Prodromal symptoms (18%)

Dizziness, drowsiness, tinnitus, confusion, dysphoria, dysarthria, auditory disturbances, circumoral numbness, metallic taste in mouth

CNS symptoms (more likely to occur with lidocaine than bupivacaine)

Prodrome symptoms, seizures, loss of consciousness, agitation

CVS symptoms

Bradycardia/asystole, tachycardia, hypotension, wide complex, ST-segment changes, pain, dyspnea, hypertension, ventricular ectopy, ventricular tachycardia, ventricular fibrillation

Data from Di Gregorio et al. 22 CNS, central nervous system; CVS, cardiovascular system.

cases published in the peer-reviewed literature during a 30-year period, Di Gregorio et al 22 found that 60% were clas- sic (ie, rapid onset) with CNS symptoms and cardiovascular symptoms (Table 3). Conversely, some symptoms appeared more than 5 minutes after injection or were isolated cardio- vascular symptoms. Classic prodromal symptoms (eg, cir- cumoral numbness, metallic taste, auditory changes) appeared in only 18% of their toxicity cases in this series. General anesthesia or heavy sedation is thought to influence the clinical pattern of toxicity in that CNS changes may go unnoticed and pharmacokinetics may be altered. 22,24 Certain patient characteristics may increase the risk of symptoms from an overdose of local anesthetics (Table 4). Risks include extremes of age (children and the elderly), high cardiac output states due to increased vascular absorption, and the presence of other comorbidities such as cardiac disease, pregnancy, hepatic dysfunction, or met- abolic syndromes. 25

pRevention of toxicity: safety steps

Several safety steps have been advocated to identify or reduce the risk of toxicity. 26 The following have been suggested for safe administration of LA: limiting the cumulative dose, using ultrasound or direct visualization for catheter placement, test dosing, incremental injections, negative catheter aspiration, and adherence to guidelines. Incorporation of multiple safety steps may improve detection of intravascular injection or impending toxicity. Although it appears that anesthetic infu- sion pumps are safe in aesthetic and reconstructive surgery, 27 a high rate of pump malfunction was observed in 1 series. 28 Pump malfunction aside, applying safety steps such as those used for peripheral nerve blockade may reduce risk in surgeon-initiated continuous anesthetic infusion.

Limiting the Cumulative Effect of Anesthetics

Anesthetics are often additive. Concurrent administrations of multiple local anesthetics contribute to a single systemic

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Table 4. Comorbid Risk Factors for Local Anesthetic Systemic Toxicity

Risk Factors

Extremes of age (children and elderly)

Hepatic dysfunction or altered hepatic perfusion (decreased plasma proteins, decreased hepatic clearance)

Low cardiac output states (drug accumulation, reduced clearance)

High cardiac output states (increased gradient for vascular diffusion, increased absorption)

Cardiac pathology (heart disease, conduction blocks, cardiac failure)

Reduced plasma proteins (increased free [active] fraction of local anesthetic)

Pregnancy (decreased plasma proteins, increased cardiac output)

Concomitant use of β-blocker, digoxin, calcium antagonists, cytochrome P450 inhibitors

Data from Ciechanowicz and Patil. 25

toxic threshold. Although specific serum concentration lev- els have been associated with toxicity, dosing guidelines that are weight based (mg/kg) fail to reliably predict these levels, resulting in potential toxicity at lower-than-anticipated doses. 29,30 With topical LA and subcutaneously adminis- tered solution via the tumescent technique, experience- derived, weight-based doses that are substantially higher than recommended levels are often administered. 31 Based on pharmacokinetic data, it appears that these application routes are associated with a lower risk of systemic toxicity, yet toxicity still may occur. The American Society of Regional Anesthesia and Pain Medicine (ASRA) advocates using the lowest concentration and dose necessary for neuraxial analgesia, and a similar philosophy should be applied to non-neuraxial applications. 32 Postoperatively, analgesic con- centrations (<0.25% bupivacaine or ropivacaine) are used for continuous infusion. Incisional injection is limited to recommended doses after consideration of the anesthetic being concurrently administered by the anesthesia team. 29 Liposomal bupivacaine should not be coadministered with other local anesthetics due to the risk of toxicity.

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Table 5. Suggested Test Doses for Detecting Unintentional Intravascular Injection

Test Agent

Dose

Positive Findings

Limitations

Epinephrine 36

•  15 µg

•  HR increase >10 beats/min •  SBP increase of 15 mm Hg •  T-wave increase of 25% amplitude

•  Beta blockade may impact sensitivity 40 •   T-wave monitoring may require offline analysis of  ECG tracing 41

Local anesthetic 26,37

•  Chloroprocaine or lidocaine 100 mg •  Bupivacaine 25 mg •  Ropivacaine 60 mg

•  Auditory disturbance

•   Premedication with benzodiazepines may affect  sensitivity •   Large doses neuraxially will result in total spinal  anesthesia

•  Circumoral numbness

•  Metallic taste

Air 38

•  2 mL

•   Audible response on precordial Doppler  monitoring

•  Availability of Doppler monitoring •   Potential paradoxical air embolism via patent  foramen ovale

Opioid

•  Fentanyl 100 µg

•  Drowsiness or sedation

•  Respiratory depression •  Requires awake, participating patient

Isoproterenol 39

•  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 Aspiration

Although lacking objective data, administering small incre- mental doses (3-5 mL) of local anesthetic has been recom- mended (assuming a negative test-dose result) so that the anesthesiologist or surgeon can readily monitor for inad- vertent intravascular injection. 32 Data on the reliability of this technique are lacking because it can be impractical to wait a full circulation period (30-45 seconds) between every 3-mL injection. Although recommended, catheter aspiration for blood is unreliable for identifying catheters placed intravascularly, with the possible exception of mul- tiorifice catheters. 33,34 The presence of negative aspiration via an infusion catheter should be verified before pump initiation.

Intravascular Test Dosing

Few studies have identified evidence-based techniques for catheter test dosing, yet test dosing with an intravascular marker is recommended when administration of poten- tially toxic doses of LA is planned. 32,35-37 Potential test-dose agents include epinephrine, local anesthetic, air, opioid, and isoproterenol. Although not without limitations, epinephrine-containing test solutions are commonly given during electrocardiography and while monitoring heart rate and blood pressure. 36 Several test-dose agents and their associated effects and limitations are listed in Table 5. 35-41 Since other safety steps may not completely prevent intravascular injection by the aesthetic surgeon, catheter test dosing with an epinephrine-containing solution before pump initiation may have value. During application of an epinephrine-containing solution for a tumescent tech- nique, audible changes in heart rate may alert the surgeon to vascular uptake of both epinephrine and anesthetic.

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Ultrasound-Guided Regional Anesthesia

Systemic toxicity has been reversed with ultrasound-guided regional anesthesia, but reversal is not possible if periph- eral nerve blockade is performed without ultrasound. 11,42,43 Although intravascular injection during peripheral nerve blockade is possible with ultrasound, the unexpected absence of local anesthetic spread during injection, as well as the visualization of adequate coverage of neural struc- tures with less local anesthetic, serves to prevent intravas- cular injection and delay the possibility of toxicity from tissue uptake. 44,45

tReatMent foR systeMic toxicity fRoM anesthetics

The treatment of LAST has been the subject of many reviews, including a practice advisory from the ASRA. 32 The treatment of systemic toxicity is very different from that of conventional cardiac arrest in that airway manage- ment with optimal oxygenation and ventilation is of utmost importance (Figure 2). 46 Prevention of hypoxia and acido- sis may eliminate or slow cardiovascular collapse and sei- zures. 47 If seizures ensue, benzodiazepines are administered to prevent seizure-associated acidosis. Rarely, neuromus- cular blockade may be required if benzodiazepines fail to stop the seizure. Cardiac arrest is treated with chest compressions. Epinephrine is recommended in low doses (<1 µg/kg); persistent arrhythmia may occur with higher doses. Negative inotropes such as β-blockers or calcium channel blockers are not provided because they may cause myocar- dial depression. Amiodarone is administered for persistent ventricular arrhythmia, but local anesthesia is avoided in

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Aesthetic Surgery Journal 34(7)

1116 Aesthetic Surgery Journal 34(7) Figure 2. Quick guide to treating systemic toxicity due to local

Figure 2. Quick guide to treating systemic toxicity due to local anesthesia.

the treatment of arrhythmia. Vasopressin administration is not recommended. Rapid initiation of lipid emulsion therapy has been advocated, which may prevent a downward spiral of car- diac dysfunction, progressing acidosis, and worsening car- diac dysfunction. 48 If LAST is suspected, the nearest available cardiac team should be notified and arrangements made for cardiopul- monary bypass in the event the patient’s condition fails to improve.

Lipid Emulsion Therapy

When the effect of intravenous lipid emulsion on bupiva- caine toxicity in carnitine-deficient rats was examined, a

paradoxical outcome led to the development of a novel treatment. Lipid emulsion therapy reduced the median lethal dose (LD50) of bupivacaine and, more important, showed potential as a therapy for LAST. 49 Several years after this discovery in rats and canines, intravenous lipid emulsion was applied to humans and added to resuscita- tion guidelines internationally. 50-52 The mechanism of lipid emulsion therapy is not well defined, but several hypotheses exist. Lipid emulsion is thought to provide a “lipid sink” to dissociate local anes- thetic molecules from the cardiac Na v . 53,54 Binding of unbound free anesthetic results in its metabolism and clearance. The lipid emulsion may act as a direct energy source to the myocardium, providing fatty acid substrate, augmenting production of mitochondrial adenosine

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Dickerson and Apfelbaum

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triphosphate in the heart, and increasing cardiac output. 55 Concomitantly, lipid emulsion elevates triglycerides, which interact with myocardial calcium channels to increase car- diac function. 56 It has been suggested that overdoses of other lipophilic drugs also may be treated by lipid emul- sion therapy. 57 Through clinical experience, the optimal administration of lipid emulsion has been formalized. Current recommen- dations call for a bolus injection of 1.5 mL/kg followed by an infusion at 0.25 mL/kg/min. 48 The recurrence of cardio- vascular collapse after cessation of liquid emulsion therapy has been described in the literature. 58 The immediate avail- ability of sufficient lipid emulsion appears requisite. Marwick et al 58 observed the return of cardiovascular col- lapse in a patient who received the only available quantity (500-mL bag) of lipid emulsion. 58 The benefits of intralipid therapy appear to outweigh the potential risks. Risks include allergic reaction (such as egg, soy, or peanut cross-reactivity), hyperthermia, pancre- atitis, hypercoagulability, antineutrophil action, and ele- vated liver aminotransferases. 57,59

pRepaRation anD vigiLance

The ability to identify patients at risk for systemic toxicity is critical to its prevention and treatment. A strong founda- tion is needed for safe and effective LA dosing and admin- istration. When pain pumps are in use, catheter test dosing should be performed before infusion is begun. Patients dis- charged with continuous wound infusion or peripheral nerve catheters need established lines of communication and daily monitoring via telephone. Family members also should be educated on pump care (including catheter removal, stopping the pump, and dressing maintenance) as well as adverse effects (eg, prodromal symptoms). In our opinion, pumps should be connected and running under observation for at least 30 minutes before patient discharge to allow for assessment of infusion function. Similarly, practitioners trained in resuscitation and the treatment of LAST should be immediately available when pumps are initiated. Dedicating part of the recovery room to patients who have received large local anesthetic doses or infusions may allow prompt treatment if a patient becomes unresponsive. Use of the ASRA 2012 checklist for treatment of LAST improved trainee performance during a simulation. 60,61 Because toxicity from local anesthetics is rare, simulation, checklists, and readily available reference algorithms may lead to comprehensive rapid recall and implementation of therapy. Figure 2 provides a brief summary of the treatment recommendations of the Association of Anaesthetists of Great Britain and Ireland and the ASRA checklist, which may be included in a toxicity response kit. 61,62 Prominent display of this guide in clinical common areas may promote

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continued heightened awareness; the guide also may serve as a helpful reference during treatment. Resuscitative equip- ment, standard monitors, lipid emulsion, and practitioners skilled in the diagnosis and treatment of systemic toxicity are essential for a successful outcome.

concLusions

While patient comfort necessitates the administration of local anesthetics, a commitment to safe practice will optimize patient outcomes. An understanding of the mechanism, treat- ment, and prevention of LAST is requisite for plastic and reconstructive surgeons who administer this medication. Promoting awareness, vigilance, and preparedness may save a life if this rare but devastating complication occurs.

Disclosures

The authors declared no potential conflicts of interest with respect to the research, authorship, and publication of this article.

funding

The authors received no financial support for the research, authorship, and publication of this article.

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