Can subcutaneous lidocaine cause seizures due to systemic toxicity?

Mechanism of Lidocaine-Induced Seizures

Subcutaneous lidocaine causes seizures through systemic absorption leading to toxic plasma concentrations that directly affect the central nervous system by blocking inhibitory pathways before excitatory pathways, resulting in unopposed neuronal excitation. 1

Pathophysiology of CNS Toxicity

Lidocaine has an extremely narrow therapeutic window, with CNS toxicity beginning at plasma levels only slightly above therapeutic concentrations (>6 mcg/mL). 2, 1 The mechanism involves:

• Concentration-dependent receptor blockade: At therapeutic levels, lidocaine blocks muscarinic and NMDA receptors, but at near-toxic concentrations, multiple additional receptor systems become affected including Nav1.8/1.7, nicotinic cholinergic receptors, and voltage-gated calcium channels. 3

• Differential CNS pathway inhibition: Lidocaine preferentially blocks inhibitory cortical pathways before excitatory pathways, leading to unopposed excitatory activity and seizures. 1

• Threshold for convulsive activity: Arterial blood levels of 18-21 mcg/mL represent the threshold for convulsive activity in animal models, though objective adverse manifestations become apparent at venous plasma levels above 6 mcg/mL. 1

Why Subcutaneous Administration Can Cause Toxicity

Subcutaneous lidocaine can achieve toxic systemic levels through several mechanisms:

• Excessive total dose: The maximum safe dose is 4-4.4 mg/kg without epinephrine or 7 mg/kg with epinephrine. 4 Exceeding these limits dramatically increases seizure risk, as demonstrated in a case where 38 mg/kg (nine times the recommended maximum) caused seizures with toxic serum levels of 8.7 mg/L. 5

• Inadvertent intravascular injection: Direct injection into blood vessels bypasses first-pass hepatic metabolism and immediately achieves toxic plasma levels, even with appropriate doses. 3, 1

• Delayed absorption and accumulation: Subcutaneous tissue can act as a depot, with slow absorption into systemic circulation causing delayed toxicity 3-4 hours after administration, particularly in patients with altered tissue perfusion. 6, 7

• Highly vascular injection sites: Areas with rich blood supply (oral cavity, head and neck) facilitate rapid systemic absorption. 3

Clinical Progression of Toxicity

Early warning signs (plasma levels 6-10 mcg/mL): 2, 1

• Perioral numbness and tingling of tongue/lips
• Tinnitus
• Metallic taste
• Lightheadedness and dizziness
• Visual and auditory disturbances

Intermediate manifestations (plasma levels 10-15 mcg/mL): 2, 1

• Muscle twitching (critical early warning sign)
• Slurred speech and confusion
• Tremors
• Drowsiness

Severe toxicity (plasma levels >15 mcg/mL): 1, 8

• Tonic-clonic seizures
• Respiratory depression and arrest
• Cardiovascular collapse
• Loss of consciousness

Patient-Specific Risk Factors

The following conditions increase seizure risk even at therapeutic doses: 4, 2

• Hepatic dysfunction: Reduces lidocaine metabolism, prolonging half-life from 1.5-2 hours to >4 hours. 2, 1
• Cardiac failure: Extends half-life to >4 hours. 2
• Cardiogenic shock: Extends half-life to >20 hours. 2
• Acidemia: Increases free (unbound) lidocaine concentration, accelerating toxicity onset. 2, 1
• Hypoalbuminemia: Increases free drug in plasma, making toxicity more likely. 2
• Concurrent medications: Beta-blockers and amiodarone enhance toxicity risk. 2

Critical Management Principles

Immediate treatment of lidocaine-induced seizures: 9, 4

1. Discontinue lidocaine immediately 4

2. Airway management: Intubate and ventilate with 100% oxygen to prevent hypoxia and acidemia, which lower the seizure threshold. 4, 5

3. Seizure control: Administer benzodiazepines (intravenous midazolam 0.1-0.2 mg/kg) as first-line therapy. 9, 4

4. Intravenous lipid emulsion (ILE): Administer 20% ILE for local anesthetic systemic toxicity, even if serum levels are undetectable, as toxicity can occur despite therapeutic dosing. 9, 10

5. Supportive care: Monitor cardiovascular status, as bradycardia, hypotension, and cardiac arrest may follow CNS toxicity. 9, 1

Prevention Strategies

Key measures to prevent lidocaine-induced seizures: 4, 3, 1

• Always aspirate before injection to avoid intravascular administration. 3
• Use the lowest effective dose and never exceed maximum recommended doses. 4
• Calculate doses using ideal body weight rather than actual body weight in obese patients. 9, 2
• Have lipid emulsion 20% immediately available wherever lidocaine is used. 3
• Monitor patients for 30-120 minutes after administration, as delayed toxicity can occur up to 3.5 hours later. 2, 6