Local Anesthetic Systemic Toxicity (LAST) - 20 Mark Answer

1. Definition and Introduction

2. Incidence and Risk Factors

• Overall incidence is rare but underreported; estimated at ~0.03% for peripheral nerve blocks
• Higher risk with high-volume blocks (e.g., TAP blocks, intercostal nerve blocks, brachial plexus blocks, epidural anesthesia)
• Patient factors increasing risk:
  • Extremes of age (elderly, neonates)
  • Pregnancy (women in labor have higher LA sensitivity)
  • Low plasma protein (reduced protein binding = more free drug)
  • Hepatic disease (impaired amide metabolism)
  • Cardiac disease (reduced cardiac output, reduced drug redistribution)
  • Acidosis and hypercapnia (increase CNS toxicity threshold lowered; ion trapping of ionized LA in CNS)
• Drug factors: Lipid-soluble, highly potent agents (bupivacaine > ropivacaine > levobupivacaine > lidocaine) carry greater cardiovascular risk
• Technical factors: Absence of ultrasound guidance, lack of incremental dosing/aspiration

3. Pathophysiology and Mechanism

CNS Mechanism

• LAs readily cross the blood-brain barrier
• At low plasma concentrations: inhibit inhibitory interneurons → net excitation
• At higher concentrations: generalized neuronal depression → seizures, coma, respiratory arrest
• CNS toxicity precedes cardiovascular toxicity in most cases (the CNS:CVS toxicity ratio for bupivacaine is ~1:7)

Cardiovascular Mechanism

• LAs block cardiac sodium channels → prolonged PR interval, widened QRS, decreased conduction velocity
• At toxic levels: negative inotropy, bradycardia, heart block, ventricular arrhythmias (VF most feared with bupivacaine)
• Bupivacaine binds cardiac Na+ channels with very high affinity in the inactivated state and dissociates very slowly ("fast in, slow out"), making resuscitation extremely difficult
• LAs also impair CNS regulation of the cardiovascular system (disruption of baroreflex at the brainstem level) and directly affect smooth muscle, producing vasodilation at toxic doses
• Pulmonary vasoconstriction may also occur prior to reduced cardiac output

4. Clinical Features

CNS Signs and Symptoms (in order of progression):

1. Prodromal/excitatory: Circumoral tingling, metallic taste, dizziness, tinnitus, visual disturbances
2. Excitatory CNS: Agitation, confusion, muscle twitching, tremors
3. Seizures (tonic-clonic)
4. CNS depression: Loss of consciousness, coma, respiratory depression/arrest

Cardiovascular Signs and Symptoms:

1. Early: Hypertension, tachycardia (from CNS stimulation)
2. Intermediate: Hypotension, bradycardia, conduction abnormalities (prolonged PR, wide QRS)
3. Severe: Complete heart block, ventricular tachycardia/fibrillation, cardiovascular collapse/asystole

Important Clinical Caveats:

• Atypical presentations are common: Symptoms may begin with cardiovascular instability without preceding CNS signs (especially with bupivacaine and rapid intravascular injection)
• Delayed onset is possible: Toxicity can appear up to 60 minutes after injection
• Sedation may mask early symptoms: In patients under sedation/GA, first sign may be cardiovascular collapse
• LAST should be considered in any patient with altered mental status, seizures, or cardiovascular instability following a local anesthetic injection

5. Prevention

1. Calculate maximum safe dose before injection (weight-based; e.g., bupivacaine ≤2.5 mg/kg plain; ≤3 mg/kg with epinephrine; lidocaine ≤4.5 mg/kg plain; ≤7 mg/kg with epinephrine)
2. Aspirate before every injection to check for inadvertent intravascular placement
3. Incremental injection technique - inject in aliquots of 3-5 mL with 30-second pauses
4. Use epinephrine as intravascular marker (1:200,000) - a tachycardia response of >20 bpm within 60 seconds indicates intravascular injection
5. Ultrasound guidance for peripheral nerve blocks - reduces LAST risk by confirming needle tip position
6. Use lowest effective concentration and volume
7. Choose safer agents when possible (ropivacaine or levobupivacaine instead of bupivacaine for large-volume blocks)
8. Patient monitoring during and after block (ECG, pulse oximetry, verbal contact)
9. Avoid multiple injection sites simultaneously that could summate doses

6. Management of LAST

Step 1: Call for Help

• Activate institutional emergency response at the first sign of LAST
• Alert nearest facility with cardiopulmonary bypass capability

Step 2: Airway Management

• Secure airway and ventilate with 100% oxygen
• Prevent further deterioration by avoiding hypoxia, hypercapnia, and acidosis (all of which worsen LA toxicity by increasing CNS excitability and reducing protein binding)
• Consider early intubation if consciousness is impaired

Step 3: Seizure Management

• Benzodiazepines are first-line (midazolam, diazepam, lorazepam)
• Small doses of propofol may be used (but avoid large doses - may worsen cardiovascular depression)
• Consider small dose succinylcholine for intractable seizures to minimize acidosis and hypoxemia (though it does not stop epileptiform cerebral activity)
• Avoid phenytoin (sodium channel blocker - worsens LA toxicity)

Step 4: 20% Lipid Emulsion Therapy (Lipid Rescue)

• 1.5 mL/kg bolus of 20% lipid emulsion infused over 1 minute
• Followed by infusion at 0.25 mL/kg/min continued for 10 minutes after hemodynamic stability
• Recommended maximum: ~10 mL/kg over first 30 minutes
• Repeat boluses may be given for persistent hemodynamic instability

Step 5: Cardiovascular Resuscitation (Modified ACLS)

• Epinephrine: Use reduced doses (<1 mcg/kg) rather than standard 1 mg boluses - high-dose epinephrine impairs lipid resuscitation and may worsen outcomes
• Amiodarone: Preferred for ventricular arrhythmias
• AVOID:
  • Vasopressin (worsens outcomes in LAST cardiac arrest)
  • Beta-blockers (worsen myocardial depression)
  • Calcium channel blockers (worsen cardiovascular depression)
  • Local anesthetics (lidocaine for arrhythmias - contraindicated)
• Standard ACLS energy for defibrillation
• Consider cardiopulmonary bypass (CPB) / ECMO early for refractory cardiovascular collapse - lipid resuscitation allows meaningful cardiac function to be restored while preparing for bypass

Step 6: Monitoring

• Continue monitoring for at least 2-6 hours after resolution of symptoms
• Extended monitoring recommended for patients with significant cardiovascular comorbidities
• LAST can recur ("resurgence") after apparent recovery

7. Special Situations

Bupivacaine Cardiac Toxicity

• Notoriously difficult to resuscitate because of its slow dissociation from Na+ channels
• Standard resuscitation is often futile without lipid emulsion
• Ropivacaine and levobupivacaine show 30-40% less cardiovascular toxicity than bupivacaine in animal models
• Success rates for resuscitation: lidocaine 100%, ropivacaine 90%, levobupivacaine 70%, bupivacaine 50%

Paediatric LAST

• Children and neonates are at higher risk
• A 2024 systematic review (PMID 38489714) confirmed lipid emulsion therapy is safe and effective across paediatric age groups, though neonatal dosing guidelines remain limited
• Caudal blocks carry particular risk in neonates

Obstetric Patients

• More susceptible to LA toxicity due to enhanced neural sensitivity and reduced protein binding
• TAP blocks in obstetrics have caused LAST - use ≤0.25% bupivacaine, add epinephrine 1:200,000, max 20-25 mL per side, with ultrasound guidance

8. Summary

1. Airway and ventilation (prevent hypoxia/acidosis which worsen toxicity)
2. Seizure control with benzodiazepines
3. 20% lipid emulsion (lipid rescue) as the specific antidote

• Barash, Cullen and Stoelting's Clinical Anesthesia, 9th ed., Ch. 22 (Table 22-11, Table 22-13)
• Tintinalli's Emergency Medicine, 9th ed., Ch. 36
• Neal JM et al. - ASRA 3rd Practice Advisory on LAST, 2018 - Reg Anesth Pain Med 2018;43:113-123
• Lee SH et al. - Lipid emulsion in pediatric LAST (Systematic Review, 2024)
• Lippincott Illustrated Reviews: Pharmacology, 7th ed., Ch. 20