Download Nick Wytiaz September 11, 2011 University of Pittsburgh npw6@pitt

Nick Wytiaz
University of Pittsburgh
Acute Care APPE – UPMC McKeesport
September 11, 2011
[email protected]
Local Anesthetic Systemic Toxicity: Bupivacaine and Lipid Emulsion Therapy
Local anesthetics produce their epidural effect by binding to voltage-gated sodium channels and
preventing conduction of sodium (Na) ions during the depolarization in heart and nerve tissue. In
addition to their therapeutic effect, these agents also have the potential to cause local anesthetic
systemic toxicity (LAST), an adverse reaction affecting the central nervous system (CNS) and/or
cardiovascular system.1 CNS symptoms are wide-ranging and nonspecific and may include excitation
(agitation, confusion, seizures), depression (drowsiness, apnea, coma), diplopia, and/or tinnitus.
Cardiovascular signs most often include hypotension and/or bradycardia, presenting an hour or more
after injection. If left untreated, progressive hypotension and bradycardia could lead to asystole,
ventricular fibrillation, and CV collapse.2 Although the mechanism of local anesthetic cardiac toxicity is
not fully understood, it is most likely due to the blockade of cardiac Na channels. Bupivacaine, when
compared to lidocaine, binds to Na channels more avidly and detaches more slowly. This variability in
binding affinity and longer duration of action is suspected to be responsible for the greater presentation
of conduction disturbances and ventricular arrhythmia of LAST seen in more potent agents, such as
bupivacaine.3 The theory is supported by multiple animal studies suggesting that lidocaine and
mepivacaine are less likely than bupivacaine to produce cardiac toxicity.
Though little clinical evidence supporting treatment regimens for LAST has been established, standard
guidelines have been published to guide practitioners in the management of LAST. Generally, minor CNS
manifestations (dizziness, tinnitus, etc.) do not merit drug therapy since these symptoms will most likely
dissipate if the offending anesthetic agent is discontinued. When more severe signs and symptoms of
LAST occur, the following step-wise treatment recommendations have been established by the
American Society of Regional Anesthesia and Pain Medicine4:
1. Discontinuation of local anesthetic agent
2. Prompt airway management to prevent hypoxia and acidosis
3. Lipid emulsion therapy at first signs of LAST and after airway management
a. 1.5 mL/kg 20% lipid emulsion bolus, infusion of 0.25 mL/kg/min continued for at least 10
minutes after circulatory stability attained
b. Consider additional bolus and 0.5 mL/kg/min infusion if circulatory stability unattained
c. Propofol can NOT be used as substitute for lipid emulsion
4. If seizures, benzodiazepines (BZD) or small doses of propofol if BZD not readily available
a. Small doses of neuromuscular blocker (succinylcholine) if seizure persists despite BZD
5. If cardiac arrest, standard advanced cardiac life support (ACLS) with the following changes:
a. Small initial doses of epinephrine (1ug/kg bolus)
b. Limit additional epinephrine and vasopressin to “second-line” treatment
c. Avoid calcium channel blockers, beta-adrenergic receptor blockers
6. If failure to respond to lipid emulsion and vasopressor therapy, cardiopulmonary bypass
Lipid emulsion therapy seems to be the most effective addition to standard treatments for LAST, with
most evidence coming from animal models and case reports.5 While the exact mechanism by which lipid
emulsion stabilizes LAST remains unclear, the most commonly accepted theory is that of the “lipid sink”,
whereby lipid-soluble drugs (such as bupivacaine) dissolve into lipid micelles of the emulsion within the
systemic circulation. The micelles are metabolized by the liver, thus eliminating the toxic agent.
In summary, LAST is a complex adverse drug event with variable clinical presentation and lack of clinical
data. However, in the event of severe, life-threatening cardiac toxicity, recommendations have been
established. Treatment of cardiac arrest from bupivacaine should include initiation of lipid emulsion
therapy, a small dose of epinephrine, in combination with chest compressions and ventilation with 100%
oxygen. The addition of intravenous lipid emulsion therapy to standard ACLS seems to render
resuscitative medications, chest compressions and airway management more effective. Early use of lipid
emulsion in suspected LAST may also help prevent CNS symptoms from progressing to more severe
events such as seizures or cardiac arrest.6
References
1
Butterworth JF. Models and mechanisms of local anesthetic toxicity. Reg Anesth Pain Manag.
2010:35:167-76.
2
Neal JM, Bernards CM, Butterworth JF, et al. ASRA practice advisory on local anesthetic systemic
toxicity. Reg Anesth Pain Med. 2010;35(2):152-61.
3
Wolfe JW, Buttterworth JF. Local anesthetic systemic toxicity: update on mechanisms and treatment.
Curr Opin Anesthesiol. 2011;24:561-6.
4
Weinberg GL. Treatment of local anesthetic systemic toxicity (LAST). Reg Anesth Pain Med.
2010;35(2):188-93.
5
Litz RJ, Roessel T, Heller AR, et al. Reversal of central nervous system and cardiac toxicity after local
anesthetic intoxication by lipid emulsion injection. Anesth Analg. 2008;106:1575-77.
6
Spence AG. Lipid reversal of central nervous system symptoms of bupivacaine toxicity. Anesthesiology.
2007;17:516-7.