Local Anesthetic Systemic Toxicity: Risk Factors, Prevention, and Treatment

Local anesthetic systemic toxicity (LAST) is a potentially life-threatening complication and can arise with any local anesthetic (LA) and any route of administration.

LAST primarily affects the central nervous system and cardiovascular system and may have a fatal outcome. Physicians practicing regional anesthesia should be aware of early signs of toxicity and the algorithms for providing emergency care.

LAST may be caused by overdose, rapid absorption, or accidental intravenous administration.

Brief clinical pharmacology of local anesthetics

It is necessary to outline certain points of the LA clinical pharmacology to understand the causes, risk factors, and clinical manifestations of LAST.

Local anesthetics prevent pain transmission from neurons to the brain cortex by binding with voltage-gated sodium channels, blocking the transport of sodium ions into the cell. In addition to blocking nerve impulse conduction, LAs affect various anatomical structures involved in the conduction and transmission of nerve impulses: the central nervous system (CNS), neuromuscular synapses, and autonomic ganglia.

LAs contain hydrophobic and hydrophilic sections linked by either an ester or amide bond, determining the site of metabolism: the liver for amide compounds or blood (with pseudocholinesterase involvement) for ester compounds.

The LA activity and duration of action increase with their lipid solubility (the capacity to pass across lipid membranes), but the toxicity also increases. At equivalent doses (e.g., mg/kg), bupivacaine is more cardiotoxic than lidocaine and ropivacaine due to its greater affinity and duration of binding to cardiac sodium channels.

Local anesthetics bind to plasma and tissue proteins, mainly albumin and alpha-1-acid glycoprotein (AGP), but exert their effect in an unbound form.

The degree of LA protein binding decreases with a reduction in pH, so in acidosis, the toxic effect becomes more severe due to an increased free drug fraction.

The risk of side effects depends on the concentration in the blood, which in turn depends on the dose, absorption rate from the site of administration, the site of injection, and the use of vasoconstrictive adjuvants, as well as the type of local anesthetic.

Most local anesthetics, especially amide types, have two enantiomers (same formula but different atomic orientation), explaining the variations in clinical effects (S-enantiomers, e.g., ropivacaine and levobupivacaine, have less cardiotoxicity than racemic bupivacaine).

Risk factors for LA systemic toxicity

Patient-related risk factors

• Extreme age groups: newborns (with low levels of AGP and decreased hepatic clearance) and the elderly (reduced liver function and lower tissue perfusion, with higher nerve sensitivity to local anesthetics);
• Pregnancy: low AGP increases the free fraction of local anesthetics, hormonal changes increase nerve sensitivity to block, and reduced pseudocholinesterase activity is reported;
• Organ dysfunction: hepatic, renal, or heart failure requires a more cautious approach to the patient, with a need to reduce the dose due to reduced LA clearance;
• Pathological conditions: acidosis, hypoxia, hypercapnia.

Drug-related risk factors

• High total dose;
• High lipophilicity of the drug (bupivacaine is a typical example);
• Combinations of different local anesthetics (cumulative toxicity);
• Prolonged infusion or repeated boluses without considering the cumulative effect.

Technique- and site-related risk factors when applying the block

• Highly vascularized area: intercostal block, caudal and epidural anesthesia, blocks in the interfascial areas of the anterior abdominal wall increase the risk of intravascular injection and systemic absorption;
• Blocks requiring large volumes of local anesthetics: interfascial plane blocks increase the risk of systemic absorption.

Symptoms of local anesthetic systemic toxicity

Cardiovascular and CNS toxicity can occur both alone and simultaneously.

Toxic effect on the central nervous system

The degree of toxic effect depends on the LA plasma concentration. Early symptoms arise due to stimulation of the central nervous system (selective inhibition of inhibitory neurons and uncontrolled increase in the activity of excitatory neurons) and manifest as follows:

Early toxicity

• Excitation or anxiety;
• Dizziness;
• Nausea;
• Disorientation;
• Tinnitus, auditory hallucinations;
• Paresthesia of the oral mucosa.

Late toxicity

• Tremor;
• Myoclonia;
• Involuntary twitching;
• Tonoclonic spasms.

With a further increase in the blood LA concentration, CNS stimulation reverts to CNS depression, manifesting as reduced seizure activity, followed by respiratory depression and arrest.

Toxic effect on the cardiovascular system

The toxic effect on the cardiovascular system develops at higher blood concentrations of local anesthetics. Early symptoms of cardiotoxicity are associated with an increase in cardiac output, heart rate, and blood pressure due to increased sympathetic tone.

A further increase in LA blood concentration causes a decrease in peripheral vascular resistance and cardiac output, leading to hypotension and life-threatening arrhythmia.

Arrhythmias may manifest as:

• Cardiac conduction disturbances: PR interval prolongation, complete AV block, sinoatrial node depression;
• Ventricular arrhythmias: ventricular extrasystoles, ventricular fibrillation.

Ultimately, significant hemodynamic instability can lead to cardiac arrest.

Prevention of regional anesthesia complications

Patient safety is the primary requirement for regional anesthesia, and this starts with workplace organization and awareness of the toxic effects of local anesthetics.

Preparation for regional anesthesia

• Availability of resuscitation equipment (ventilator, defibrillator, etc.);
• Availability of vasoactive drugs and 20% lipid emulsion;
• Venous access prior to procedure;
• Baseline monitoring before the procedure (pulse oximetry, ECG, and blood pressure measurement).

Prevention of LA toxicity

• Dosing of medications considering age and comorbidities;
• Mandatory negative aspiration test before LA administration;
• Repeat the aspiration test after administering 3-5 ml of an LA agent;
• In blocks with large LA volume administration, markers of accidental intravascular administration (5 μL adrenaline per 1 ml of LA solution) should be used;
• Addition of vasoconstrictors to reduce systemic absorption;
• Monitoring of patient’s condition after block;
• Use of ultrasound (US) to monitor block application (ability to visualize the needle and avoid unintentional puncture of structures surrounding the nerve, as well as the ability to visually assess the spread of local anesthetic);
• Continuous LA infusion is preferably performed using an infusion pump.

Mechanism of effect reversibility during lipid emulsion therapy

The positively charged lipophilic LA is first redistributed from tissue to negatively charged lipid particles by lipid emulsion, which quickly moves the LA from high-blood-flow target organs such as the brain and heart to lower-blood-flow organs like skeletal muscles and the liver.

Lipid therapy may also play a direct role in mitigating mitochondrial dysfunction, sodium channel blockade, and vasodilation. In the event of cardiac arrest, the goal is to quickly restore coronary perfusion and reduce the concentration of local anesthetic in the tissues, thereby increasing the contractile capacity of the heart and reducing the manifestations of arrhythmia.

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Treatment

Immediate actions in the event of toxicity

• Discontinue the injection of local anesthetic or stop titration via the infusion pump;
• Call for assistance and inform the medical team about the issue;
• Ventilation with 100% oxygen and maintenance of adequate lung ventilation, avoiding hypercapnia and hypoxia;
• Ensure the intravenous access.

Actions in the event of circulatory arrest

• Initiate cardiopulmonary resuscitation according to standard protocols (bolus dose of adrenaline up to ≤1 µg/kg, to avoid arrhythmogenic effects, as arrhythmia may be resistant to treatment);
• Consider the possibility of assisted circulation, if feasible;
• Immediately administer 20% lipid emulsion simultaneously. Propofol is not a suitable alternative: attempts to reproduce the required dose using propofol (containing 10 mg/mL propofol in a 10% lipid emulsion) would exceed the induction dose for general anesthesia by 10-20 times and lead to serious CNS and cardiovascular side effects. Administer lipid emulsion at 1.5 mL/kg over 2-3 minutes (100 mL for an adult weighing approximately 70 kg), then start an intravenous infusion at a rate of 15 mL/kg/h;
• Repeat bolus administration of 20% lipid emulsion after 5 minutes if necessary, and increase the intravenous infusion rate to 30 mL/kg/h if cardiac output has not improved or sufficient blood circulation has decreased;
• After 10 minutes from the start, if cardiac activity is restored, continue the infusion at 30 mL/kg/h until hemodynamic stability and adequate circulation are achieved or the maximum cumulative dose is reached. If cardiac activity is not restored, administer the maximum third bolus and continue infusion at 30 mL/kg/h until hemodynamic stability and adequate blood circulation are achieved or the maximum cumulative dose is reached;
• Do not exceed a maximum cumulative dose of 12 mL/kg.

LAST treatment measures without circulatory arrest

• Immediate administration of 20% lipid emulsion;
• In case of tachyarrhythmia, use amiodarone as a first-line antiarrhythmic, avoiding lidocaine and other sodium channel blockers (procainamide, quinidine), calcium channel blockers, and beta-blockers;
• In case of hypotension, avoid vasopressin;
• In the event of bradycardia, administer atropine as the first-line agent;
• In the case of methemoglobinemia (with prilocaine and lidocaine use), treat with methylene blue, or if unavailable, ascorbic acid, vitamin C, and hyperbaric oxygen therapy.

Actions required in case of seizures

• First-line medications for the treatment of seizures are benzodiazepines (midazolam 0.1-0.2 mg/kg, up to 10 mg over 4 minutes);
• In the event of their failure, use propofol (in increasing doses with 20 mg increments until effect is achieved) or sodium thiopental, considering reduced cardiac output;
• In the event of uncontrolled seizures, using muscle relaxants (succinylcholine) may be considered to prevent acidosis due to muscle activity.

Post-incident measures

• Transport the patient to the relevant clinical unit with the appropriate equipment and suitable personnel until stable recovery is achieved for further follow-up;
• Monitor the patient for 2 hours post-seizure, 4-6 hours post-hemodynamic instability, and as necessary in the event of circulatory arrest;
• Side effects of lipid emulsion include pancreatitis and deep vein thrombosis: regular clinical examination, daily tests for amylase or lipase levels, and consideration of thromboprophylaxis are necessary;
• Incident documentation.