Local Anesthetic Systemic Toxicity (LAST) Under Anesthesia 

Updated: Jul 31, 2018
  • Author: Wendy Ma, MD; Chief Editor: Sheela Pai Cole, MD  more...
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Practice Essentials

Local anesthetic systemic toxicity (LAST) is a rare but serious critical event. Minimizing the risk of LAST, recognizing it early when it occurs, and initiating prompt treatment are imperative for safe use of perioperative local anesthetics.

Anesthesiologists must be vigilant for signs and symptoms of impending LAST, which include cardiovascular and neurologic toxicity. General anesthesia or deep sedation may obscure the initial warning signs, and sudden severe hemodynamic instability or seizures may be presenting symptoms.

If systemic toxicity is suspected, immediately call for help. Initiate hemodynamic support according to Advanced Cardiac Life Support (ACLS) protocols, but exclude calcium channel blockers, beta blockers, and lidocaine. Administer benzodiazepines for seizure prophylaxis or cessation, and support the airway as necessary.

Intravenous (IV) lipid emulsion 20% (Intralipid; Fresenius Kabi, Uppsala, Sweden) is definitive therapy for severe LAST. The initial bolus dose is followed by continuous infusion until 10 minutes after return of spontaneous circulation (ROSC), with subsequent intensive care unit (ICU) monitoring for 12 hours in case of recurrence.

In patients with severe cardiac toxicity, prolonged resuscitation, full cardiopulmonary support on extracorporeal membrane oxygenation (ECMO) or cardiopulmonary bypass (CPB), or both may be necessary, particularly in cases of bupivacaine toxicity.

Other complications of local anesthetic use include neural toxicity, allergic reactions, and metabolic abnormalities, including methemoglobinemia (not covered in this article).

Key points for minimizing risk include the following:

  • Use the minimum effective dose for every patient (ie, the lowest effective volume at the lowest appropriate concentration)
  • Incremental injections with aspiration (eg, 3- to 5-mL aliquots every 30-45 seconds) minimizes but does not eliminate the risk of LAST
  • Addition of intravascular markers (eg, epinephrine, fentanyl) may warn of unintended intravascular injection
  • Certain patient populations are at higher risk for LAST - These populations include neonates and infants (< 4 months), geriatric patients, patients with underlying cardiac conduction disorders or severe cardiac disease, and patients with impaired hepatic, renal, or metabolic systems
  • Certain blocks entail a higher risk of LAST than other blocks do - Intercostal and IV regional techniques have the highest potential rates of systemic absorption; alternative techniques should be considered in patients at high risk for toxicity
  • Close monitoring should continue for 30 minutes after injection of a local anesthetic in patients receiving potentially toxic doses of the anesthetic

Key points for recognizing LAST include the following:

  • Signs and symptoms of LAST may be cardiovascular or neurologic
  • Generally, symptoms can be categorized as typical (mild symptoms followed by severe) or atypical and can range from mild to severe
  • Initial neurologic symptoms include perioral numbness and a metallic taste
  • An excitatory phase ensues with tinnitus, agitation and seizures, followed by neurologic depression with respiratory arrest, coma, or both
  • Cardiovascular symptoms may include an initial hypertensive and tachycardic excitatory phase with ventricular arrhythmias, as well as subsequent cardiac depression with bradycardia, myocardial depression, conduction block, asystole and cardiac arrest
  • Atypical presentations are common and include initial cardiac toxicity with arrhythmias (notably with bupivacaine toxicity), heart block, and/or asystole without preceding central nervous system (CNS) signs
  • Patients may also initially present with seizures or with simultaneous severe neurologic and cardiovascular toxicity
  • Patients may present with mixed pictures, particularly when under deep sedation or general anesthesia

Key points for treating LAST include the following:

  • Prompt initiation of ACLS, IV lipid emulsion administration, and advanced hemodynamic support are the cornerstones of therapy for established LAST [1]
  • Primary physiologic goals are to maintain coronary and cerebral perfusion, stop or prevent seizures, reverse hypoxia, and treat acidosis
  • If cardiac arrest occurs, commence ACLS with the following modifications: (1) Do not administer calcium channel blockers or beta blockers, because these drugs may potentiate LAST-induced conduction block; (2) consider smaller initial doses of epinephrine (10-100 μg IV bolus in adults); (3) vasopressin may be used safely (minimal risk of dysrhythmias that may occur with epinephrine); and (4) amiodarone is the preferred first-line agent to treat malignant arrhythmias (do not use local anesthetics or phenytoin)
  • Administration of lipid emulsion 20% should be initiated with a 1.5 mL/kg IV bolus followed by IV infusion at 0.25 mL/kg/min (patients < 70 kg) or with a 100 mL bolus followed by infusion of 200-250 mL over 15-20 minutes (patients >70 kg), which is continued until 10 minutes after ROSC; the bolus may be repeated once or twice and the infusion rate doubled if cardiovascular collapse persists; total dose should not exceed 12 mL/kg
  • In cases of refractory cardiac arrest, mechanical circulatory support with CPB or ECMO may be required until toxicity subsides
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Problem

Local anesthetics are a cornerstone of anesthesia and perioperative medicine and may be used in a variety of techniques, including infiltration (subcutaneous, intradermal, and tumescent), IV regional anesthesia, peripheral neural blockade, central neuraxial blockade, and topical anesthesia. Despite overall good safety profiles, individual agents vary with regard to metabolism, maximum recommended doses, and preponderance for neurologic versus cardiac toxicity.

Mechanisms of LAST

Pharmacology of local anesthetics

Some basic knowledge of channel physiology is necessary to understand the mechanism of local anesthetics. [2] These drugs bind to voltage-gated sodium channels (VGSCs) in the cell membrane of nerves, blocking transmission of action potentials by preventing depolarization. These VGSCs exist in the resting or closed state at the normal resting membrane potential of –60 to –70 mV.

With a stimulus—which may be chemical, electrical, or mechanical—a conformational change occurs in the VGSCs, causing them to open and allowing an intracellular influx of sodium ions down an electrochemical gradient. Milliseconds later, the resting membrane potential is restored, and the VGSCs are inactivated.

Local anesthetics prevent transmission of nerve impulses via direct reversible binding to VGSCs. These agents exist in equilibrium in a balance of ionized and nonionized states, with the nonionized form capable of crossing nerve membranes and then ionizing inside the cell and binding directly to the intracellular portion of the channel. This prevents channel opening and causes indiscriminate blockade of the propagation of nerve impulses.

Local anesthetics are weak bases with a pKa higher than 7.4. They are classified according to their chemical structure as either aminoamides or aminoesters. The two classes differ broadly from each other with respect to their metabolism and metabolites.

Aminoamides, the more commonly used class, include lidocaine, bupivacaine, mepivacaine, ropivacaine, and articaine. They are metabolized in the liver via enzymatic degradation by cytochrome P450. Aminoamides have a very low incidence of allergic reactions. Aminoesters include benzocaine, procaine, chloroprocaine, cocaine, and tetracaine. They are metabolized via hydrolysis by plasma cholinesterase. Aminoester local anesthetics have a para-aminobenzoic acid (PABA) metabolite, which may induce allergic reactions in some patients.

Two exceptions to the metabolism-by-class trend are cocaine, an ester that is metabolized by hepatic carboxylesterase, and articaine, an amide that is metabolized by plastma carboxylesterase.

Maximum recommended doses for local anesthetics vary in accordance with the specific agent chosen, the addition or exclusion of epinephrine, and the regional anesthetic technique employed (see Table 1 below). It is important to note that there are no formally published toxic doses for humans; the maximum doses cited in the literature are recommended on the basis of animal studies, human case reports of systemic toxicity, pharmacokinetic data, and clinical experience. [3]

Table 1. Maximum Recommended Local Anesthetic Doses in Perioperative Setting (Open Table in a new window)

Drug Usual Concentration Max Dose Without Epinephrine Max Dose With Epinephrine Max Dose in 70-kg Adult Without Epinephrine Max Dose in 70-kg Adult With Epinephrine
Lidocaine

1-2%

10-20 mg/mL
3 mg/kg 7 mg/kg 200 mg 500 mg
Bupivacaine

0.25-0.5%

2.5-5 mg/mL
2 mg/kg 2.5 mg/kg 150 mg 150 mg

Levobupivacaine

(not available in US)

0.5-0.75%

5-7.5 mg/mL
2 mg/kg NA* 150 mg 150 mg
Ropivacaine

0.2-1%

2-10 mg/mL
3 mg/kg 4 mg/kg* 225 mg 225 mg
Prilocaine

1%

10 mg/mL
6 mg/kg 9 mg/kg* 600 mg 600 mg

Etidocaine

(not available in US)

0.5-1%

5-10 mg/mL
5.5 mg/kg 5.5 mg/kg* 400 mg 400 mg
Mepivacaine

2-3%

20-30 mg/mL
5 mg/kg 7 mg/kg 400 mg 500 mg

*Epinephrine is not routinely added to these anesthetics, and it does not increase the maximum recommended dose. Addition of epinephrine may still prolong the duration of blockade of these anesthetics and reduce systemic absorption through local vasoconstriction.

In considering these maximum recommended doses, it must be kept in mind that there are many factors capable of causing variations in the rate of systemic absorption (see below), and thus, an individually tailored anesthetic plan and individualized dosing are essential for optimizing patient analgesia and anesthesia, as well as safety. [2, 3, 4]

Generally speaking, these maximum doses apply to the ideal young adult nonparturient patient who weighs approximately 70 kg and has no renal, hepatic, metabolic, or cardiopulmonary disease. Many patients do not fit this stereotype, and they should receive reduced doses of local anesthetics when undergoing regional anesthesia.

Toxic dose accumulation

Systemic absorption of local anesthetics and the potential for LAST depend on many factors. [2, 5, 3] Specific drugs differ significantly with respect to pharmacokinetics and pharmacodynamics. In addition, the site of injection can have a considerable effect on the rate of systemic absorption (see the image below).

Systemic absorption of local anesthetics in relati Systemic absorption of local anesthetics in relation to injection site.

The total dose given, various patient factors (eg, age and comorbidities), and the use of nonanesthetic additives cause further variation in the rates of systemic absorption (see Tables 2 and 3 below). An understanding of these factors is crucial for efforts to minimize the risk of LAST. [2, 4]

Table 2. Factors Affecting Systemic Absorption of Local Anesthetics (Open Table in a new window)

Category Factor Effect
Drug-specific factors Lipophilicity Increased lipophilicity increases binding to cell membranes, decreasing the amount of unbound anesthetic available for systemic absorption
Total dose Total dose is the product of concentration and volume; an increased total dose increases plasma concentration, decreases onset time, and increases duration of anesthesia, as well as increases risk of systemic absorption
Metabolism and excretion Whereas ester-type local anesthetics undergo hydrolysis in plasma via pseudocholinesterase enzymes, amide-type local anesthetics are primarily metabolized in the liver via cytochrome P450 enzymes, which play critical roles in drug-drug interactions; excretion of these subsequent metabolites occurs via the kidney
Technique-specific factors Site of injection Local vascular supply causes significant variation in systemic absorption on the basis of the site of injection
Additives Coadministration of vasoconstrictors and other additives will have varying effects on local anesthetics (see Table 3)
Patient-specific factors Age

Newborns have decreased circulating levels of alpha1-acid glycoprotein (a plasma protein that binds free local anesthetic), and this increases the risk of toxicity in newborns as compared with adults

In elderly patients, lower clearance rates of local anesthetics may occur because of decreased creatinine clearance and cytochrome P450 activity; elderly patients are more likely to have significant other comorbidities; elderly patients may also have weakened nerve conduction, requiring less anesthetic dose for an effective block

pH Systemic acidosis results in a higher ratio of local anesthetic in its protonated form, which penetrates local tissues more slowly and increases the free fraction for systemic absorption
Organ dysfunction Hepatic, renal, and cardiac dysfunction reduces total body clearance of local anesthetics and some of their metabolites
Pregnancy Progesterone increases the sensitivity of axons to local anesthetic effects; in addition, in the late stages of pregnancy the high cardiac output increases the systemic absorption of local anesthetics, and the epidural and subarachnoid spaces have smaller volumes that require lower doses of local anesthetics

Table 3. Common Additives to Regional Anesthetic Techniques (Open Table in a new window)

Additive Effects
Epinephrine

Causes vasoconstriction to counteract vasodilating effects of local anesthetics

Reduces systemic absorption of local anesthetics

Prolongs duration of action, increases intensity of blockade

In neuraxial techniques, direct alpha2-adrenergic activity potentiates analgesia

Bicarbonate

Alkalinizes local anesthetic solutions

May speed block onset by promoting nonionized (lipophilic) form

Reduces discomfort during injection

Opioids

Insufficient evidence regarding benefits of using opioids in peripheral nerve blocks

In neuraxial techniques, provides synergistic analgesia coadministered with local anesthetics

Alpha2-adrenergic agonists (eg, clonidine)

Supraspinal and spinal adrenergic effects

Increases analgesic effects of local anesthetics in neuraxial and peripheral block techniques (by ~2 hr)

Steroids In IV or perineural techniques, variable prolongation of analgesic duration (eg, by 50% in brachial plexus blocks) 

Clinical manifestations of LAST

Generally, the CNS is more susceptible to systemic local anesthetics than the cardiovascular system is; consequently, the local anesthetic dose required to cause severe neurologic toxicity is usually lower than that required to cause severe cardiovascular toxicity. The notable exception to this is bupivacaine toxicity, which may manifest with initial cardiac toxicity and life-threatening conduction abnormalities and cardiac arrest. [6, 7]

A systems-based description of signs and symptoms of LAST is presented in Table 4.

Table 4. Signs and Symptoms of Local Anesthetic Systemic Toxicity (Open Table in a new window)

Severity Cardiovascular Signs/Symptoms CNS Signs/Symptoms Recommended Actions
Mild Hypertension Lightheadedness, dizziness

Immediately stop administration of local anesthetic

Continue monitoring

Be ready for escalation of care
Tachycardia Tinnitus, perioral tingling
ECG changes (QRS widening, PR prolongation, PVCs) Disorientation, drowsiness
Severe Hypotension (vasodilation in peripheral vasculature) Muscle twitching, shivering, tremors

Immediately call for help

Initiate chest compressions and ACLS protocol

Consider escalation to ECMO or CPB in cases of bupivacaine toxicity

Conduction abnormalities

Bradycardia, sinus arrest

Heart block (1º, 2º, or 3º)

Generalized tonic-clonic seizures
Depressed myocardial contractility

VT

VF

Respiratory depression

Respiratory arrest

Cardiac arrest

PEA

Obtundation, coma
ACLS = advanced cardiac life support; CNS = central nervous system; CPB = cardiopulmonary bypass; ECG = electrocardiography; ECMO = extracorporeal membrane oxygenation; PEA = pulseless electrical activity; PVC = premature ventricular contraction; VF = ventricular fibrillation; VT = ventricular tachycardia.

Toxicity may present within several minutes of administration of local anesthetic, or it may be substantially delayed. Because LAST can occur in any clinical setting where local anesthetic agents are used, practitioners should have a low threshold for considering this diagnosis. [6]

It should be noted that systemic acidosis exacerbates local anesthetic toxicity by means of several factors, including ion trapping, increased cerebral blood flow bringing more drug to the brain, and an increased fraction of free drug resulting from decreased protein binding. Early and aggressive management of acidosis is a key component in the management of LAST.

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Management

Addressing the problem

Prevention 

Minimizing the total dose of local anesthetic is crucial for prevention of LAST. The minimum effective dose (ie, the lowest effective volume at the lowest appropriate concentration) of local anesthetic should be used. In addition, ultrasound-guided techniques may facilitate the use of smaller doses of local anesthetic and thereby reduce the risk of LAST. [8]

Patients who have certain associated conditions and comorbidities are at higher risk for LAST. Broadly, these include patients at the extremes of age (neonates and infants younger than 4 months, as well as geriatric patients), those with renal or hepatic dysfunction, those with heart failure and conduction abnormalities, and pregnant patients. [7, 5] In addition, the risk of LAST is increased with techniques in which large total doses of local anesthetic are administered or injection is performed at sites characterized by rapid systemic absorption.

Finally, techniques involving the administration of test doses containing intravascular markers (eg, epinephrine or fentanyl) should be employed when appropriate, and injection technique should include incremental injections with intermittent aspiration.

Even when all these safety measures are followed, some risk of LAST will remain. Accordingly, it is vital to be able to recognize the syndrome immediately and escalate care promptly.

Treatment 

Effective treatment of LAST requires quick recognition and anticipation of the toxic side effects of local anesthetics, as discussed above. Mild CNS symptoms, including tinnitus, may be closely monitored without intervention. Because hypoxia and acidosis can exacerbate the neurologic and cardiovascular toxicities, maintenance of adequate oxygenation and circulation with ACLS is crucial to ensure perfusion of critical organs.

Benzodiazepines and propofol may be used to treat seizures, though the risk of hemodynamic instability with propofol must be taken into account and cautiously balanced against the expected benefit. Additional doses of lidocaine should not be given for management of ventricular arrhythmias.

Early initiation of IV lipid emulsion 20% is key in the management of established LAST. [6]  In patients weighing less than 70 kg, it should be administered initially in a 1.5 mL/kg bolus rapidly over 2-3 minutes, then infused at a rate of 0.25 mL/kg/min until at least 10 minutes after ROSC. In patients weighing more than 70 kg, it should be administered in a 100 mL bolus rapidly over 2-3 minutes, then infused at a rate of 200-250 mL over 15-20 minutes.

If the patient remains unstable, the bolus may be repeated once or twice and the infusion rate doubled. [6] The maximum recommended dose in the first 30 minutes of therapy is 12 mL/kg. Monitoring in an ICU for a minimum of 12 hours after the resolution of toxicity is necessary; symptoms may recur, and additional lipid emulsion may be needed.

Hemodynamic support should include chest compressions in cases with nonperfusing rhythms, supplemented by vasoactive boluses and infusions (eg, epinephrine and vasopressin). Calcium channel blockers, beta blockers, and lidocaine, though included in routine ACLS protocols, are absolutely contraindicated in this setting because of the additional conduction block, hemodynamic instability, and toxicity. Amiodarone may safely be administered, but not in lieu of lipid emulsion therapy.

If LAST proves refractory to these treatments, CPB or ECMO may be required. If severe cardiac toxicity is present, appropriate consultation with a cardiac anesthesiologist and a cardiac surgeon should be initiated at an early stage.

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Case Example 1

Clinical scenario

A 70-year-old woman with nonischemic cardiomyopathy and recurrent ventricular tachycardia (VT) is admitted to the ICU after undergoing VT ablation under general anesthesia. The case was complicated by refractory VT that necessitated multiple rounds of chest compressions, ACLS, multiple boluses of lidocaine, and an IV lidocaine infusion, at the request of the electrophysiology team. At the conclusion of the procedure, the patient remained intubated and sedated, and she was in normal sinus rhythm with an ongoing lidocaine infusion on transfer to the ICU.

When the patient arrives at the ICU, sedation is turned off, and she remains hemodynamically stable in normal sinus rhythm. Return of spontaneous ventilatory effort with good gas exchange is noted, but she remains unresponsive overnight and is sent for emergency computed tomography (CT) of the head, which shows no acute intracranial pathology.

The differential diagnosis for failure to emerge from general anesthesia in this case is broad. In view of the systemic heparinization and the use of ACLS and chest compressions during the procedure, it should include embolic or ischemic stroke and intracerebral hemorrhage. The effects of residual anesthetic agents, including sedatives and neuromuscular blockers, must be excluded.

Encephalopathic or severely deranged metabolic processes seem unlikely in this case, because the patient was systemically well and neurologically intact before the procedure (on the assumption of normal-trending metabolic, renal, and hepatic function tests). On the basis of her clinical history, there appears to be no likelihood of a drug withdrawal syndrome. Other drug toxicities are possible, however, including neurologic toxicity related to the local anesthesia required for suppression of her refractory VT.

Resolution

Neurologic toxicity related to the lidocaine infusion was suspected, and the infusion was stopped. About 6 hours later, the patient began responding to painful stimuli and subsequently became appropriately responsive, neurologically intact, and capable of following commands. She remained hemodynamically stable and was extubated. Extreme care was taken to maintain continuous telemetry monitoring and immediate bedside availability of defibrillation equipment. The patient resumed her home antiarrhythmic regimen before leaving the ICU and was then discharged home.

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Case Example 2

Clinical scenario

A 65-year-old 55-kg man with end-stage renal disease (ESRD) is undergoing a brachiocephalic arteriovenous fistula (AVF) revision under regional anesthesia and sedation. He has received an axillary brachial plexus block with 20 mL of 0.75% ropivacaine along with 10 mL of 0.5% ropivacaine for musculocutaneous nerve coverage. Sedation in the operating room (OR) is achieved with IV infusion of propofol at a rate of 50 μg/kg/hr. Because of pain experienced on initiation of the propofol infusion, lidocaine 40 mg is administered IV, with good effect.

After administration of the lidocaine, the patient reaches toward his lips. Additional restraint of the nonoperative arm is thus required, and the propofol infusion is restarted. Several minutes later, intermittent airway obstruction is noted, which seems to resolve after placement of a nasopharyngeal airway. The patient is completely unresponsive during placement of the airway but is maintaining spontaneous ventilation with gentle jaw thrust. Subsequently, he is seen to be shivering, with intermittent jerks of his extremities. Local anesthetic toxicity is suspected.

Resolution

The anesthesiologist called for help, alerted the surgeon, and asked the OR circulator to get the local anesthetic toxicity cart. The anesthesiologist then started hyperventilating the patient on 100% oxygen via manual bag-mask ventilation. A colleague arrived and was directed to administer midazolam 5 mg IV and to prepare drugs for induction and intubation, as well as hemodynamic support.

The patient's hemodynamic status remained stable during this time, with the blood pressure cuff cycling every 1 minute. While hyperventilation was continued, the colleague placed an additional peripheral IV line and an arterial line. No electrocardiographic (ECG) changes were noted. After hyperventilation and administration of a benzodiazepine, the patient's shivering and twitching stopped, and he began to open his eyes to jaw thrust.

This is an illustration of rescue from local anesthetic toxicity. As a result of clinical vigilance, appropriate actions were taken and escalated when evidence of systemic toxicity occurred. Reaching toward or touching the mouth may be a mild early warning sign of neurologic toxicity from local anesthetics, particularly in nonverbal or lightly sedated patients. Because any acidosis will potentiate toxicity, early and aggressive hyperventilation is vital for minimizing the impact of respiratory acidosis. Administration of benzodiazepines will decrease the risk of seizures.

In this case, the local anesthetic toxicity resolved without advanced maneuvers, but if the symptoms of toxicity had not resolved after the rescue maneuvers, escalation to lipid emulsion administration and ACLS would have been essential. Note that in situations where the airway is unstable or ACLS is ongoing, intubation is likely to be necessary, but administration of neuromuscular blockade as part of the intubation process will impede  the detection of seizures and hinder the ongoing assessment of neurologic status.

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