Local Anesthetic Toxicity

Adverse effects of local anesthetics are usually caused by high plasma concentrations of the agent, which may result from one of the following:

• Inadvertent intravascular injection
• Excessive dose or rate of injection
• Delayed drug clearance
• Administration into vascular tissue

Patient factors can also affect toxicity. For example, because lidocaine is hepatically metabolized, liver dysfunction increases the risk of toxicity. Because lidocaine is also protein bound, low protein states may also increase risk. Acidosis increases the risk because it favors dissociation of lidocaine from plasma proteins. Interactions with other drugs (eg, cimetidine, beta-blockers) can also affect lidocaine drug levels.

Large doses of lidocaine (up to 55 mg/kg, versus the conventional maximum of 4.5 mg/kg) are used for tumescent anesthesia, in which a dilute local anesthetic solution is injected into subcutaneous tissue until it becomes firm and tense. This technique was developed to facilitate liposuction but its use has expanded to other dermatologic and plastic surgery procedures, as well as to endocrine and vascular surgeries.[3] Larger doses of lidocaine are generally tolerated during tumescent anesthesia for liposuction, probably due to coadministration of epinephrine, the low concentration of lidocaine in tumescent solution, and poor systemic absorption from subcutaneous fat.[4, 5, 6, 7]

Systemic toxicity of anesthetics most often involves the central nervous system (CNS) or the cardiovascular system. Concurrent administration of other drugs, such as benzodiazepines, may mask the development of CNS symptoms but not cardiovascular symptoms.

CNS toxicity is biphasic. The earlier manifestations are due to CNS excitation, with problems such as seizures. Subsequent manifestations include CNS depression with a cessation of convulsions and the onset of unconsciousness and respiratory depression or arrest.

Cardiovascular effects occur at higher serum concentrations of local anesthetics. These effects may include reentrant arrhythmias. Acceleration of the ventricular rate has been reported in patients with atrial arrhythmias. See Presentation.

Relatively rarely (< 1%), local anesthetic agents can affect the immune system, producing an immunoglobulin E (IgE)–mediated allergic reaction. Most cases are associated with the use of amino esters. Some anesthetics, particularly benzocaine, are associated with hematologic effects, namely methemoglobinemia.

 

The onset of action, potency, and duration of action of a local anesthetic are determined by the agent's pKa, lipid solubility, protein binding, and vasodilatory effects, along with tissue pH. Increasing the dose by administering a high concentration shortens onset while increasing duration of action, as well as increasing the possibility for adverse/toxic reactions.

The pKa of an agent is the primary factor that determines its onset of action. A lower pKa increases tissue penetration and shortens onset of action, because of increased lipid solubility of nonionized (uncharged) particles. A pKa that is closer to pH optimizes penetration. In addition, inflammation in the extracellular space may decrease pH and may slow onset of action. Site of administration is also a factor; onset is prolonged in areas with increased tissue or nerve sheath size. Addition of sodium bicarbonate speeds onset of action by increasing the fraction of agent in the nonionized state.

The following factors influence potency:

• High partition coefficients, which are reflective of lipophility, promote passage of the anesthetic into the lipid nerve membrane, enhancing potency

• Vasodilation promotes vascular absorption, thereby reducing locally available drug and decreasing potency

• Addition of sodium bicarbonate increases pH, thereby increasing nonionized particles, which are more lipid soluble, and increases apparent potency

• Most local anesthetic solutions that contain premixed epinephrine contain preservatives; in these solutions, the pH is adjusted lower to maintain the stability of epinephrine and antioxidants

The following factors influence duration of action:

• Addition of epinephrine to local anesthetic solutions prolongs duration of action by causing vasoconstriction and decreasing systemic absorption

• Degree of protein binding primarily determines duration of action; high protein binding increases duration

Anesthetic concentration and dilution

Drug concentration is expressed as a percentage (eg, bupivacaine 0.25%, lidocaine 1%). Percentage is measured in grams per 100 mL (ie, 1% is 1 g/100 mL [1000 mg/100 mL], or 10 mg per mL).

Calculate the mg/mL concentration quickly from the percentage by moving the decimal point 1 place to the right, as in the following examples:

• Bupivacaine 0.25% = 2.5 mg/mL
• Lidocaine 1% = 10 mg/mL

When epinephrine is combined in an anesthetic solution, the result is expressed as a dilution (eg, 1:100,000), as follows:

• 1:1000 means 1 mg per 1 mL (ie, 0.1%)
• 1:10,000 means 1 mg per 10 mL (ie, 0.01%)
• 1:2000 means 1 mg per 2 mL (ie, 0.05%)
• 1:20,000 means 1 mg per 20 mL (ie, 0.005%)
• 0.1 mL of 1:1000 epinephrine added to 9.9 mL of anesthetic solution = 1:100,000 dilution or 0.01 mg/mL

For higher dilutions, see Table 1, below.

Table 1. Epinephrine Content Examples (Open Table in a new window)

Toxicity mechanisms

CNS toxicity from local anesthetics manifests initially as CNS excitation, followed by CNS depression. This biphasic effect occurs because local anesthetics first block inhibitory CNS pathways (resulting in stimulation) and then eventually block both inhibitory and excitatory pathways (resulting in overall CNS inhibition).

Cardiovascular effects occur because these agents block sodium channels through a fast-in, slow-out mechanism that affects impulse conduction through the heart and nerve tissue. In the heart, this depresses Vmax (ie, the rate of depolarization during phase 0 of the cardiac action potential) and may lead to reentrant arrhythmias. Additionally, conduction through the sinus and atrioventricular nodes is suppressed.

Local anesthetics can be divided into 2 groups: the esters and the amides. See Table 2, below.

Table 2. Local Anesthetic Agents Used Commonly for Infiltrative Injection (Open Table in a new window)

The occurrence of numerous fatalities associated with the cardiovascular toxicity of bupivacaine prompted a search for less toxic long-acting local anesthetic agents. This search resulted in the development of levobupivacaine and ropivacaine.

Bupivacaine is a 50:50 racemic mixture of a dextrorotatory R-(+)-enantiomer and a levorotatory S-(-)-enantiomer. Clinical studies demonstrated that the S-(-)-enantiomer, levobupivacaine, has less potential for CNS and cardiovascular toxicity. In particular, the intravascular dose required to cause lethality is almost 78% greater for levobupivacaine compared with the R-(+) enantiomer.

Further clinical trials in the 1990s led to the introduction in 1996 of ropivacaine, a pure S-(-) enantiomer. Ropivacaine, like bupivacaine, has the capacity to produce differential blockade but has a better sensorimotor dissociation at lower doses. This long-acting amide is the first local anesthetic drug developed with initial extensive toxicological studies before its clinical release. Although ropivacaine may be associated with acute CNS and cardiovascular toxicity, the incidence appears to be extremely low.

Local anesthetic toxicity can occur because of inadvertent intravascular injection or dosing error. Intravascular injection can cause toxicity even if the anesthetic was administered within the recommended dose range.

The minimum doses of anesthetics in which adverse reactions have occurred are listed in Table 3, below.

Table 3. Minimum Intravenous Toxic Dose of Local Anesthetic in Humans ^[8] (Open Table in a new window)

In addition to high doses, high injection rates also increase the risk of adverse reactions to local anesthetics. Patient factors that increase risk include the following:

• Kidney or liver compromise
• Metabolic or respiratory acidosis
• Preexisting heart block or heart conditions
• Pregnancy
• Extremes of age
• Hypoxia

The frequency of local anesthetic toxicity is difficult to determine because these agents are used widely in a variety of settings, most reactions probably involve only minor symptoms, and most reactions are not reported. Systemic toxicity from local anesthetics has been estimated to occur in 0.03% of peripheral nerve blocks, or 0.27 episodes per 1,000 blocks.[9]  

In the United States in 2020, according to the American Association of Poison Control Centers (AAPCC), 1885 single exposures to lidocaine were reported, along with 2665 single exposures to other or unknown local and/or topical anesthetics. Of the lidocaine exposures reported by the AAPCC, 576 occurred in children younger than 6 years.[10]

If oxygenation, ventilation, and cardiac output are maintained, patients usually have a full recovery without sequelae. Without treatment, local anesthetic toxicity can result in seizures, respiratory depression or arrest, hypotension, cardiovascular collapse or cardiac arrest, and death. According to the AAPCC National Poison Data System 2019 Annual Report, 319 of the lidocaine exposures had no negative outcome; 244 exposures resulted in a minor outcome;96, in a moderate outcome; and 24, in a major outcome; 3 deaths were reported.[10]

Advise patients with adverse reactions to a specific anesthetic agent to avoid that specific anesthetic agent in the future and to alert medical personnel of the reaction. If a patient has experienced an adverse reaction to one class of anesthetic (ester or amide), risk for adverse reactions is higher for all agents in that class. However, if the episode involved seizures, the patient should be reassured that this does not indicate an increased risk for the development of a seizure disorder in the future.

Manifestations of local anesthetic toxicity typically appear 1-5 minutes after the injection, but onset may range from 30 seconds to as long as 60 minutes.[1] Initial manifestations may also vary widely. Classically, patients experience symptoms of central nervous system (CNS) excitement such as the following:

• Circumoral and/or tongue numbness
• Metallic taste
• Lightheadedness
• Dizziness
• Visual and auditory disturbances (difficulty focusing and tinnitus)
• Disorientation
• Drowsiness

Although cardiac toxicity classically does not occur without preceding CNS toxicity, numerous published case reports describe episodes limited to cardiovascular manifestations. In these cases, onset of symptoms was delayed by 5 minutes or more.[1]

After the use of local anesthetic agents, consider the appearance of new signs or symptoms as a possible sign of toxicity. The manifestation of toxicity depends on the organ system or systems that are affected. Toxicity manifestations can be categorized as follows:

• CNS
• Cardiovascular
• Hematologic
• Allergic
• Local tissue

Central nervous system manifestations

With higher doses, initial CNS excitation is often followed by a rapid CNS depression, with the following features:

• Muscle twitching
• Convulsions
• Unconsciousness
• Coma
• Respiratory depression and arrest

With progression of toxicity, the patient may experience tonic-clonic seizures and, eventually, unconsciousness and coma. CNS symptoms may be masked in patients premedicated with anticonvulsants such as benzodiazepines or barbiturates. The first sign of toxicity in these premedicated patients may be cardiovascular depression.

When blood levels are high enough to block inhibitory and excitatory pathways, convulsions cease and the patient may experience respiratory depression or arrest and cardiovascular depression. Large bolus injections may increase peak anesthetic levels to the point where the CNS and cardiovascular system are affected simultaneously.

Cardiovascular manifestations

Risk of cardiovascular toxicity is somewhat greater with lipophilic local anesthetics such as bupivacaine. Risk of cardiac toxicity is greatest in those patients with underlying cardiac conduction problems or after myocardial infarction.

Toxic doses of local anesthetic agents can cause myocardial depression (tetracaine, etidocaine, bupivacaine), cardiac dysrhythmias (bupivacaine), and cardiotoxicity in pregnancy. Several anesthetics (eg, lidocaine) also alter vascular tone, with low doses having vasoconstrictive effects and higher doses causing relaxation of vascular smooth muscle, possibly leading to hypotension.

The range of signs and symptoms of cardiovascular toxicity include the following:

• Chest pain
• Shortness of breath
• Palpitations
• Lightheadedness
• Diaphoresis
• Hypotension
• Syncope
• Cardiovascular depression and collapse

Effects on cardiac conduction include widened PR interval, widened QRS duration, sinus tachycardia, sinus arrest, and partial or complete atrioventricular dissociation. Cardiac arrest has been reported after intraurethral administration of lidocaine.[11]

Cardiac toxicity is potentiated by acidosis, hypercapnia, and hypoxia, which worsen cardiac suppression and increase the chance of arrhythmia. This is important to consider since seizure makes this metabolic picture more likely.

Hematologic manifestations

Methemoglobinemia has been frequently reported in association with benzocaine use; however, lidocaine and prilocaine have also been implicated. O-toluidine, the liver metabolite of prilocaine, is a potent oxidizer of hemoglobin to methemoglobin. At low levels (1-3%), methemoglobinemia can be asymptomatic, but higher levels (10 - 40%) may be accompanied by any of the following complaints:

• Cyanosis
• Cutaneous discoloration (gray)
• Tachypnea
• Dyspnea
• Exercise intolerance
• Fatigue
• Dizziness and syncope
• Weakness

Allergic manifestations

Amino esters are derivatives of para -aminobenzoic acid (PABA), which have been associated with acute allergic reactions. Previous studies indicate a 30% rate of allergic reactions to procaine, tetracaine, and chloroprocaine. Amino amides are not associated with PABA and do not produce allergic reactions with the same frequency. However, preparations of amide anesthetics may sometimes contain methylparaben, which is structurally similar to PABA and thus may result in allergic reactions.

Allergic manifestations of local anesthetics include rash and urticaria. Anaphylaxis due to local anesthetics is very rare but should be considered if the patient starts to wheeze or suffer respiratory distress after receiving the anesthetic. Patients who report an allergy to lidocaine are likely allergic to the methylparaben preservative in multi-dose vials. Preservative-free lidocaine can be obtained from single-dose ampules of lidocaine or from preservative-free lidocaine used by cardiologists and anesthesiologists.

Local tissue manifestations

In addition to numbness and paresthesias, which is expected with normal doses of local anesthetic, very high doses can produce irreversible conduction block within 5 minutes. Peripheral neurotoxicity, such as prolonged sensory and motor deficits, has also been documented. It is hypothesized that a combination of low pH and sodium bisulfite in the mixture can be partially responsible for these changes. Reversible skeletal muscle damage has also been reported.

Adverse effects of topical application

A variety of anesthetics are available for topical or mucosal application (eg, tetracaine, benzocaine, lidocaine). Adverse effects from these agents typically occur when they are applied to abraded or torn skin, resulting in systemic absorption and high plasma concentrations of the agent. Similarly, absorption of oral viscous lidocaine may cause systemic toxicity, particularly with repeated use in infants or children.

The following systemic reactions may occur with topical anesthetics:

• CNS: High plasma concentration initially produces CNS stimulation (including seizures), followed by CNS depression (including respiratory arrest); CNS stimulatory effects may be absent in some patients, particularly with amides (eg, tetracaine); epinephrine-containing solutions may add to the CNS stimulatory effect

• Cardiovascular: High plasma levels typically depress the heart; effects may include bradycardia, dysrhythmias, hypotension, cardiovascular collapse, and cardiac arrest; epinephrine-containing local anesthetics may cause hypertension, tachycardia, and myocardial ischemia

• Suppression of the gag reflex with oral administration

Other adverse effects include the following:

• Transient local burning or stinging sensation
• Skin discoloration
• Swelling
• Neuritis
• Tissue necrosis and sloughing
• Methemoglobinemia with prilocaine

For more information on topical anesthetics, see Topical Anesthesia.

Adverse effects of cocaine as a topical anesthetic

Various anesthetic mixtures containing cocaine have been used to provide topical anesthesia for suturing of minor skin lacerations, especially on the face or scalp. One such combination that is extemporaneously prepared by hospital pharmacies includes tetracaine 0.5%, epinephrine (adrenaline) 1:2000, and cocaine 11.8% (commonly referred to as "TAC" solution). TAC is particularly useful in patients who are unable to tolerate injections or who have difficulty following instructions or sitting still (eg, children, mentally challenged individuals).

However, serious toxic effects (eg, seizures, cardiac death) have been described after topical cocaine application, particularly in infants and children. Because of this toxicity, as well as expense and federal regulatory issues, cocaine is no longer recommended for topical anesthesia.

Newer compounded mixtures have replaced cocaine with lidocaine 4% solutions (lidocaine, epinephrine, tetracaine) because of its superior safety when applied to injured skin. Still, these solutions should not be applied to wounds with end-arteriolar blood supply.

The evaluation in patients with possible toxicity from a local anesthetic should be guided by the clinical presentation. Blood levels of the anesthetic may be measured, although blood levels may not correlate with toxicity and results are not obtained in a clinically useful time.

Imaging studies are determined by the overall clinical picture. For example, if the patient has a seizure and the etiology of the seizure is not apparent, consider a head computed tomography scan.

Obtain adequate intravenous access. Airway control may require intubation.

In the patient with suspected local anesthetic toxicity, the initial step is stabilization of potential threats to life. If the signs and symptoms develop during administration of the local anesthetic, stop the injection immediately and prepare to treat the reaction. Ensure adequate oxygenation, whether by face mask or by intubation.

Attention to impending respiratory arrest, significant hypotension, dysrhythmias, and seizures takes precedence. Once other possible etiologies of the patient's new symptoms have been excluded, management of the specific symptoms can begin.

Benzodiazepines are the drugs of choice for seizure control. Propofol can be used to control seizures but has the risk of potentiating cardiovascular toxicity; avoid large doses, especially in hemodynamically unstable patients.[2] Refractory seizures may treated with barbiturates or may require neuromuscular blockade (eg, with succinylcholine).

In severe reactions, monitor the cardiovascular system and support the patient with intravenous fluids and vasopressors as required. Small bolus doses of epinephrine (≤1 mcg/kg) are preferred. Avoid vasopressin, calcium channel blockers, beta-blockers, or other local anesthetics.[2]

Hypoxemia and metabolic acidosis may potentiate the cardiovascular toxicity of lidocaine and other local anesthetics. Early control of seizures and aggressive airway management to treat hypoxemia and acidosis may prevent cardiac arrest. Use of sodium bicarbonate may be considered to treat severe acidosis.

Cardiac arrest due to local anesthetic toxicity is a rare but well recognized complication that may occur in cases of large overdose, especially those involving inadvertent intravascular injection. These patients have a favorable prognosis if circulation can be restored before hypoxemic injury occurs. Aggressive resuscitation is therefore indicated in most cases. Cardiopulmonary bypass and veno-arterial extracorporeal membrane oxygenation (VA-ECMO) have been used effectively to treat cardiac arrest due to local anesthetic toxicity.[12]

Current guidelines recommend the intravenous (IV) infusion of lipid emulsion to reverse the cardiac and neurologic effects of local anesthetic toxicity.[2, 13]  Although no blinded studies have been conducted in humans, a systemic review and meta-analysis has confirmed the efficacy of lipid emulsion therapy.[14] Case reports support the early use of lipid emulsion at the first sign of arrhythmia, prolonged seizure activity, or rapid progression of toxic manifestations in patients with suspected local anesthetic toxicity.[1]

Infrequently, local anesthetics may provoke an allergic or hematologic reaction. Allergic reactions can be treated with diphenhydramine and corticosteroids. Anaphylaxis may also require epinephrine administration. Methemoglobinemia should initially be treated symptomatically. Subsequent treatment is guided by blood levels of methemoglobin; methylene blue and hyperbaric oxygen may be required in severe cases. See Methemoglobinemia for specific treatment.

Local ischemic or nerve toxicities may occur, particularly in the extremities with prolonged anesthesia or use of agents containing epinephrine. 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.

Patients with persistent or unresolved significant reactions require admission to a monitored bed for observation, further evaluation, and treatment. Patients who are stable and have minor or easily controlled adverse reactions can be discharged and monitored on an outpatient basis.

Finally, the prevention of local anesthetic toxicity should always be the primary consideration. Although all adverse reactions cannot be anticipated, complications can be minimized 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.

Guidelines

Guidelines for the management of local anesthetic toxicity have been published by the following groups:

• American Society of Regional Anesthesia and Pain Medicine (ASRA) ^[2]
• Association of Anaesthetists of Great Britain and Ireland (AAGBI) ^[13]

Treatment of central nervous system (CNS) complications and toxicity remains controversial. Seizures have been treated successfully with benzodiazepines or barbiturates (eg, phenobarbital); case 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.

The American Society of Regional Anesthesia and Pain Control (ASRA) recommends benzodiazepines as first-line treatment of local anesthetic–induced seizures, because these drugs have limited potential for causing cardiac depression. If benzodiazepines are not available, the ASRA considers propofol an acceptable alternative, but notes that it should be used at the lowest effective dose, because of the potential to worsen hypotension or cardiac depression.[2] In particular, propofol should be avoided in patients showing signs of cardiovascular instability, as it can cause significant bradycardia.

Prolonged PR, QRS, and QT intervals potentiating reentrant tachycardias with aberrant conduction may herald cardiovascular toxicity. 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, some of these patients can be successfully treated with properly conducted cardiopulmonary resuscitation (CPR).

If cardiac arrest occurs, the ASRA recommends standard Advanced Cardiac Life Support (ACLS) with the following modifications:

• If epinephrine is used, small initial doses (10-100 μg boluses in adults) are preferable
• Vasopressin is not recommended
• Avoid calcium channel blockers and beta-blockers
• If ventricular arrhythmias develop, amiodarone is preferable

In patients with cardiac toxicity, avoiding the use of lidocaine and related class IB antidysrhythmic agents (eg, mexiletine, tocainide) is crucial because they may worsen toxicity. Lidocaine has been used successfully in bupivacaine-induced dysrhythmias, but its additive CNS toxicity is still a major concern.

In patients who do not respond to standard resuscitative measures, some case reports have indicated that the use of cardiac pacing and cardiopulmonary bypass may improve the outcome.[8] Cardiopulmonary bypass may serve as a bridging therapy until tissue levels of the local anesthetic have cleared.[2]  Extracorporeal membrane oxygenation (VA-ECMO) has similarly been used to maintain systemic perfusion and oxygenation until local anesthetic cardiovascular toxicity has resolved.[15]

In a Korean study, combined boluses of glucose, insulin, and potassium were successful in reversing bupivacaine-induced cardiovascular collapse.[16] 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. In China, shenfu, an extract of traditional Chinese herbal medicines, was shown to reduce the CNS and cardiovascular toxicity of bupivacaine on rats.[17]

Intravenous infusion of a 20% lipid emulsion (eg, Intralipid 20%) has become an accepted part of treatment for systemic toxicity from local anesthetics, and particularly for cardiac arrest that is unresponsive to standard therapy.[18] ASRA guidelines recommend considering the use of lipid emulsion therapy at the first signs of systemic toxicity from local anesthetics, after airway management.[2]

The proposed mechanism is that lipid infusion creates a lipid phase that extracts the lipid-soluble molecules of the local anesthetic from the aqueous plasma phase (lipid sink hypothesis). An in vitro study demonstrated high solubility of local anesthetics in lipid emulsions and high binding capacity of these emulsions.[19] Other possible mechanisms, which may work in concert with the lipid sink effect, include fatty acid supply, reversal of mitochondrial dysfunction, inotropic effect, glycogen synthase kinase–3β (GSK-3β) phosphorylation, inhibition of nitric oxide release, and reversal of cardiac sodium channel blockade.[14]

In an animal model, Weinberg et al demonstrated the successful application of lipid emulsion infusion in the resuscitation of bupivacaine-induced cardiac arrest.[20, 21] Rosenblatt and colleagues 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.[22]

Subsequent case reports from other researchers documented successful use of lipid emulsion in the treatment of both cardiovascular and neurologic toxicity, including asystole, cardiovascular collapse, and seizures. Local anesthetic agents involved in these cases have included ropivacaine, mepivacaine and prilocaine, and levobupivacaine.[23, 24, 25, 26, 27, 28]

Marwick and colleagues reported 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.[29]

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 either epinephrine or vasopressin.[30, 31] Both of these vasopressors were associated with adverse outcomes.

However, several reports question the efficacy of lipid rescue treatment. Mayr et al, 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.[32] Harvey et al 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.[33]

A range of adverse events have been reported after acute infusion of lipid emulsion. These have included acute kidney injury, cardiac arrest, ventilation-perfusion mismatch, acute lung injury, venous thromboembolism, hypersensitivity, fat embolism, fat overload syndrome, pancreatitis, extracorporeal circulation machine circuit obstruction, allergic reaction, and increased susceptibility to infection.[34]

Recommended dosing regimen

Lipid emulsion therapy is performed with a 20% solution.[35]  The 2020 ASRA guidelines state that the order of administration (bolus or infusion) and the method of infusion are not critical. For patients who weigh less than 70 kg, administer a bolus of 1.5 mL/kg over 2 - 3 minutes.[36, 13, 2]  or an infusion at a rate of 0.25 mL/kg/min.[2]  For patients weighing < 40 kg, consider using a pump for infusion.  For patients who weigh more than 70 kg, administer a bolus of 100 mL over 2-3 minutes or an infusion of 250 mL over 15-20 min.[2]

If this regimen does not provide adequate resuscitation, the bolus can be repeated or the infusion doubled. The recommended upper limit of lipid emulsion is 12 mL/kg over the first 30 minutes; staying within that limit is particularly important in children and small adults. Much smaller doses are typically needed.[2]

Note that propofol 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.[1]

Although allergic reactions to local anesthetics are extremely rare, these are treated according to severity. Mild cutaneous reactions may be treated with oral or intravenous (IV) diphenhydramine (Benadryl, 25 - 50 mg for adults, 1 mg/kg for pediatric patients).

For more serious allergic reactions, administer subcutaneous epinephrine (0.3 mL of 1:1000 dilution) and closely monitor for further decompensation. Corticosteroids (125 mg methylprednisolone IV push, or 60 mg prednisone orally) should be given to the patient with severe allergic reactions (eg, respiratory distress, hypotension).

Consultation with a medical toxicologist or a regional Poison Control Center is warranted in patients with significant cardiovascular or neurologic toxicity due to local anesthetic agents, to aid in guiding management of these critically ill patients. 

The following suggestions may help avoid complications related to local anesthetic use, especially in emergency department patients:

• Consider obtaining and documenting informed consent in individuals with a prior history of anesthetic reactions

• Document the amount and type of anesthetic used during the procedure

• Always obtain an adequate history and physical examination to identify risk factors and allergies

• Do not use class IB antidysrhythmics (including phenytoin) for seizures or dysrhythmias believed to be due to cocaine toxicity

• Consider changes in neurologic signs or symptoms as a possible manifestation of anesthetic toxicity

• Admit patients with serious or unresolved symptoms

Know the toxic dose of the local anesthetic being used. Use the lowest concentration and volume of local anesthetic that still produces good results. Use epinephrine-containing solutions when not contraindicated to slow vascular uptake through vasoconstriction.

Describe the early symptoms of local anesthetic overdose to patients and instruct them to inform the physician if they experience any of these effects. Be sure that patients understand the effects of local anesthetics and that they should tell the physician if symptoms occur.

A careful injection method may help prevent toxic reactions. Perform high-volume (> 5 mL) injections slowly, in 3-mL increments. Stop to aspirate and observe for blood in the syringe after every 3 mL injected. Injecting local anesthetic in this manner reduces the chances of a large-volume intravascular injection.

Maintain verbal contact with the patient during the procedure. This helps detect subtle symptoms, such as dysarthria, as well as more severe ones, such as changes in mental status.

Because benzodiazepines raise the threshold for CNS symptoms but not for cardiovascular symptoms, heavy benzodiazepine premedication is likely to result in a patient progressing directly to cardiovascular toxicity without showing preliminary signs of CNS toxicity.

For more information, see Infiltrative Administration of Local Anesthetic Agents.

Dosage guidelines

Lower concentrations of local anesthetics are typically used for infiltration anesthesia.

Variation in local anesthetic dose depends on the procedure, the degree of anesthesia required, and individual patient circumstances. Use of a reduced dose is indicated in the following patients:

• Debilitated or acutely ill patients

• Very young children or geriatric patients

• Patients with liver disease, atherosclerosis, or occlusive arterial disease

The goals of pharmacologic therapy in patients with neurologic toxicity from local anesthetic agents are to terminate the neuromuscular and cerebral manifestations.

Class Summary

These agents terminate seizures.

Pentobarbital (Nembutal)

A short-acting barbiturate with sedative, hypnotic, and anticonvulsant properties, pentobarbital can produce all levels of CNS mood alteration.

Phenobarbital (Luminal)

Phenobarbital interferes with the transmission of impulses from the thalamus to the cerebral cortex. In the emergent setting, phenobarbital is typically used when benzodiazepines fail to abort status epilepticus.

Class Summary

These agents terminate seizures. By binding to a specific receptor site, these agents appear to potentiate the effects of gamma-aminobenzoic acid (GABA) and to facilitate inhibitory GABA neurotransmission and other inhibitory neurotransmitters.

Diazepam (Valium, Diastat, Diastat AcuDial)

Diazepam depresses all levels of the CNS (eg, limbic and reticular formation), possibly by increasing the activity of GABA. Diazepam diminishes or terminates seizures. Individualize dosage and increase cautiously to avoid adverse effects.

Midazolam

Midazolam depresses all levels of the CNS (eg, limbic and reticular formation), possibly by increasing activity of GABA. It diminishes or terminates seizures. Midazolam is shorter acting and more potent than diazepam. Individualize dosage and increase cautiously to avoid adverse effects.

Class Summary

These agents terminate the neuromuscular manifestations of seizures.

Succinylcholine (Anectine, Quelicin)

Succinylcholine causes paralysis of airway and respiratory muscles; apnea ensues. Establishing and maintaining an airway and ventilation are mandatory prerequisites.