Local Anesthetic Toxicity Treatment & Management

In the patient with suspected local anesthetic toxicity, the initial step is stabilization of potential life threats. Impending airway compromise, significant hypotension, and treatment of dysrhythmias and seizures take precedence. Once other possible etiologies of the patient's new symptoms have been excluded, management of the specific symptoms can begin.

Although allergic reactions to local anesthetics are extremely rare, these are treated according to severity. Mild cutaneous reactions may be treated with diphenhydramine (Benadryl 25-50 mg IV/PO for adult doses, 1 mg/kg for pediatric doses); treat patients with more serious reactions with 0.3 (mL) of epinephrine SC (1:1000), and closely monitor for further decompensation. Corticosteroids (125 mg methylprednisolone IVP, or 60 mg prednisone PO) should be given to the patient with severe allergic reactions (eg, respiratory distress, hypotension).

Treatment of CNS complications and toxicity is still very controversial because no single remedy exists. CNS manifestations, such as seizures, have been treated successfully with benzodiazepines and barbiturates (eg, phenobarbital). Recent reports indicate that 1 mg/kg of intravenous propofol (Diprivan) and 2 mg/kg of intravenous thiopental (Pentothal) are successful in stopping local anesthetic-induced seizures and muscle twitching. Clinicians should be aware that propofol can by itself cause significant bradycardia that can further compromise the cardiovascular status of the patient. Avoid use of phenytoin (Dilantin) because it shares pharmacologic properties (ie, sodium channel blockade) with lidocaine and may potentiate toxicity.

Prolonged PR, QRS, and QT intervals potentiating reentrant tachycardias with aberrant conduction may herald cardiovascular toxicity. Expect that cardiac resuscitation of such patients may be difficult and prolonged (30-45 min) because some anesthetics are very lipid soluble and require a long time for redistribution. However, most cases of lidocaine-induced cardiac toxicity can be successfully treated with properly conducted cardiopulmonary resuscitation (CPR) (airway protection and chest compression) due to its relatively short duration of action.

In the setting of anesthetic toxicity, avoiding the use of class IB antidysrhythmic agents, such as phenytoin, mexiletine (Mexitil), and tocainide (Tonocard), is crucial because they may worsen toxicity. Bupivacaine depresses conduction and contractility at low doses. Lidocaine has been used successfully in bupivacaine-induced dysrhythmias, but its additive CNS toxicity is still a major concern. Even though bretylium theoretically should not potentiate CNS toxicity (as does lidocaine), its benefits in cardiovascular resuscitation are unclear. Evidence for use of amiodarone is also lacking at this time. A study performed in a porcine model shows that CPR with a combination of vasopressin and epinephrine resulted in significantly better survival rates than either drug alone.^[2] Human data are currently lacking. Lastly, some recent case reports have indicated that the use of cardiac pacing and cardiopulmonary bypass may improve the outcome in the setting of prolonged resuscitation.^[1]

In a Korean study, combined boluses of glucose, insulin, and potassium were successful in reversing bupivacaine-induced cardiovascular collapse.^[3] However, the 2 units/kg dose of insulin used in this protocol may be challenging to use in clinical practice because of physicians' reluctance to administer such unusually high doses of insulin. In China, shenfu, an extract of traditional Chinese herbal medicines, was shown to reduce the CNS and cardiovascular toxicity of bupivacaine on rats.^[4]

In cases of refractory cardiovascular collapse caused by an overwhelming overdose of local anesthetic, Weinberg et al (1998 and 2003) demonstrated the successful application of lipid emulsion infusion in the resuscitation of bupivacaine-induced cardiac arrest.^{[5, 6]} The proposed mechanism is that lipid infusion accelerates the decline in bupivacaine myocardial content (reduced tissue binding) by creating a lipid phase that extracts the lipid-soluble bupivacaine molecules from the aqueous plasma phase (lipid sink hypothesis). A beneficial energetic-metabolic effect may also occur.^[7] An in vitro study did demonstrate high solubility of local anesthetics in lipid emulsions and high binding capacity of these emulsions.^[8]

To date, the use of lipid infusion in significant local anesthetic toxicity in humans has been documented in 7 successful case reports. Rosenblatt and colleagues (2006) were the first to report use of a 20% lipid infusion to resuscitate a patient from prolonged cardiac arrest that followed an interscalene block with bupivacaine and mepivacaine.^[9] Litz and colleagues (2006 and 2008) published 2 successful case reports, one after ropivacaine-induced asystole and the other after brachial plexus block using mepivacaine and prilocaine.^{[10, 11]} Foxall and colleagues (2007) successfully treated levobupivacaine-induced seizures and cardiovascular collapse.^[12] This case was the first one to demonstrate efficacy of lipid emulsion in a periarrest situation. Zimmer et al, Warren et al, and Ludot et al have continued to demonstrate the clinical efficacy of lipid infusion therapy for local anesthetic toxicity.^{[13, 14, 15]}

Marwick and colleagues are the first to report a case of successful lipid rescue in which systemic toxicity recurred after 40 minutes. Since additional lipid supply was not available, amiodarone was used for the recurrent dysrhythmia. This case highlights the importance of the availability of a sufficient quantity of lipid emulsion (1000 mL) when regional anesthesia is performed.^[16]

In recent studies, Weinberg and colleagues, using an intact animal model of bupivacaine overdose, have shown that lipid emulsion therapy provides superior hemodynamic and metabolic recovery from bupivacaine-induced cardiac arrest than do vasopressors (epinephrine and vasopressin).^{[17, 18]}

However, several reports question the efficacy of lipid rescue treatment. Mayr et al (2008), working with a porcine model of bupivacaine toxicity, reported that vasopressin combined with epinephrine resulted in higher coronary perfusion pressure during CPR and better short-term survival rates than lipid emulsion.^[19] Harvey et al (2009) showed that lipid emulsion/ACLS resulted in lower coronary perfusion pressure and lower rates of spontaneous circulation compared with ACLS alone in a rabbit model of asphyxial cardiac arrest.^[20]

In 2007, the Association of Anaesthetists of Great Britain and Ireland (AAGBI) published guidelines for management of severe local anesthetic systemic toxicity (LAST).^[21] The American Society of Critical Care Anesthesiologists and the American Society of Anesthesiologists Committee on Critical Care Medicine as well as the Resuscitation Council of the UK published protocols in 2008.^{[22, 23, 24]}

Recommended dosing regimen for use in humans^[24]

In cardiac arrest secondary to local anesthetic toxicity that is unresponsive to standard therapy, intravenous administration of a lipid such as Intralipid 20% is recommended in the following regimen:

1. Administer bolus of 20% Lipid, 1.5 mL/kg^{[25, 21, 23]}
2. Then, convert to an infusion at a rate of 0.25 mL/kg/min for 20 minutes,^[21] 30-60 minutes,^[25] or until hemodynamic stability is restored.^[23]
3. If adequate resuscitation is not restored, various regimens have been suggested: bolus doses may be repeated up to 2 times,^[25] up to 2 times at 5-minute intervals,^[21] or at 5-minute intervals until stable rhythm is restored^[23] and the infusion rate may be increased^[25] or increased to 0.5 mL/kg/min for 10 minutes.^[21]

Note that propofol (Diprivan) is not a component of lipid rescue. It is formulated in a 10% lipid emulsion, and, therefore, an overdose of propofol (gram quantities) would be necessary to provide an adequate dose of lipid emulsion. Propofol is contraindicated when any evidence of cardiovascular toxicity is present.

Local ischemic or nerve toxicities may occur, particularly in the extremities with prolonged anesthesia or epinephrine use. Suspected nerve damage should prompt neurologic consultation for urgent peripheral nerve studies. If vascular compromise, such as limb ischemia, is suspected, consult a vascular surgeon immediately. Therapy for extravasation (eg, warm compresses, phentolamine, nitroglycerin cream) should be initiated for localized vascular toxicity.

Methemoglobinemia should initially be treated symptomatically and then guided by blood levels of methemoglobin. Methylene blue and hyperbaric oxygen may be required in severe cases. See Methemoglobinemia for specific treatment.

Finally, the prevention of local anesthetic toxicity should always be the primary consideration. Although all adverse reactions cannot be anticipated, complications can be avoided by strict adherence to the guidelines of anesthetic dosing, identification of patients at increased risk, and implementation of appropriate anesthetic application techniques to avoid unintentional intravascular injection.