Local anesthetic agents

Local anesthetics (LAs) are drugs that block the sensation of pain in the region where they are administered. LAs act by reversibly blocking the sodium channels of nerve fibers, thereby inhibiting the conduction of nerve impulses. Nerve fibers that carry pain sensation have the smallest diameter and are the first to be blocked by LAs. Loss of motor function and sensation of touch and pressure follow, depending on the duration of action and dose of the LA used. LAs can be infiltrated into skin/subcutaneous tissues to achieve local anesthesia or into the epidural/subarachnoid space to achieve regional anesthesia (e.g., spinal anesthesia, epidural anesthesia). Some LAs (lidocaine, prilocaine, tetracaine) are effective on topical application and are used before minor invasive procedures (venipuncture, bladder catheterization, endoscopy/laryngoscopy). LAs are divided into two groups based on their chemical structure. The amide group (lidocaine, prilocaine, mepivacaine, etc.) is safer and, hence, more commonly used in clinical practice. The ester group (procaine, tetracaine) has a higher risk of causing allergic reactions or systemic toxicity and is therefore reserved for patients with known allergies to drugs of the amide group. Local anesthetic systemic toxicity may result from intravascular injection or administration of LA that exceeds the maximum recommended local anesthetic dose. Toxicity may affect the CNS (e.g., tinnitus, seizures) or cardiovascular system (e.g., arrhythmias, cardiac arrest).

See “Local anesthesia” and “Regional anesthesia” for the clinical applications of these agents.

• Clinical applications: See “Local anesthesia” and “Regional anesthesia” for details.
  • Topical anesthesia (e.g., lidocaine, tetracaine, prilocaine)
  • Infiltration anesthesia
    • Skin surgery (e.g., skin biopsy)
    • Epidural anesthesia
    • Spinal anesthesia
• Pharmacology ^[1]
  • LAs have a lipophilic group linked with a hydrophilic group by a hydrocarbon chain
  • Bind to the inner portion of voltage-gated sodium channels of the nerve fibers → reversible blockage of sodium channels → inhibition of nerve excitation and impulse conduction (pain signals)
• Adverse effects ^[2]
  • Allergy (acute anaphylaxis or delayed pruritic rash)
    • Cross-reactivity between amide group and ester group agents is very rare.
    • If a patient has an allergy to one group, prescribe agents from the other group.
  • Local anesthetic systemic toxicity (LAST)
  • Methemoglobinemia (mostly with benzocaine)

Amide LAs (e.g., lidocaine, bupivacaine) contain an "i" in their name preceding “-caine.” Ester LAs do not.

• Pain pathway: thermal, mechanical, or chemical stimuli → nociceptor stimulation → conversion of stimulus to an electric signal (action potential) → neural conduction of electric signal to the CNS → perception of pain
• LAs bind to the inner portion of voltage-gated sodium channels of the nerve fibers; → reversible blockage of sodium channels → inhibition of nerve excitation and impulse conduction (pain signals) → local anesthesia in the area supplied by the nerve
• LAs with 3° amine structure infiltrate membranes in their uncharged form, then bind to ion channels in their charged form.
• The susceptibility of nerve fibers to LA depends on their firing rate, size, and myelination.
  • Rapidly firing neurons are blocked more effectively than slow-firing neurons.
  • Small diameter nerves are the first to be anesthetized.
  • Myelinated nerves are blocked faster than unmyelinated nerves.
  • Because size is thought to outweigh myelination, nerve fibers are blocked in the following order:
    1. Small myelinated fibers
    2. Small unmyelinated fibers
    3. Large myelinated fibers
    4. Large unmyelinated fibers
  • Loss of sensation occurs in the following order:
    1. Pain
    2. Temperature
    3. Touch
    4. Pressure
• Factors that affect the efficacy of LA
  • Use of vasoconstrictors (e.g., epinephrine) reduces bleeding and systemic absorption of LAs, leading to a prolonged anesthetic effect.
  • Inflamed/infected tissue: decreased efficacy of LAs
    • LAs are composed of a lipophilic group and a hydrophilic group, and permeability depends on which group is predominant.
    • Because inflamed tissue has an acidic environment, alkaline anesthetics are charged; and the hydrophilic group predominates → ↓ ability to penetrate the nerve cell membranes → ↓ efficacy

References:^{[3][4][5][6][7]}

Complications are generally uncommon.

Local anesthetic systemic toxicity (LAST) ^[8][9][10]

LAST is a potentially fatal adverse event caused by dose-dependent LA blockade of sodium channels in the CNS and cardiovascular system (CVS). ^[8][9]

Etiology

• Iatrogenic causes
  • Local anesthetic overdose
  • Inadvertent intravascular administration of infiltration anesthesia
• Patient risk factors for LAST ^[9][11]
  • Extremes of age (e.g., < 4 months or > 70 years)
  • Low body weight and/or frailty
  • Heart, liver, or kidney disease
  • Hypoxia and/or acidosis

Clinical features ^[8][9]

• Onset: typically within minutes of LA injection but may occur hours later ^[12][13]
• Prodrome: Minor CNS symptoms often precede major toxicity. ^[9][13][14]
• CNS manifestations
  • Prodromal symptoms: tinnitus, metallic taste, perioral paresthesias, agitation and/or confusion
  • Seizures (most common single CNS feature)
  • CNS depression (e.g., somnolence, coma)
• Cardiovascular manifestations (especially with bupivacaine): initial cardiac excitation followed by cardiac depression
  • Tachycardia, hypertension; , tachyarrhythmia (especially with cocaine)
  • Bradycardia; , atrioventricular block , asystole
  • Decreased cardiac contractility; , hypotension, cardiogenic shock

Be vigilant for symptoms of LAST when administering moderate to large doses of local anesthetics. ^[9]

Management ^[9][12][15]

• Primary survey
  • Call for help.
  • Secure the airway and start 100% oxygen therapy.
  • Treat acute seizures preferentially with benzodiazepines.
• Hemodynamic instability: Start lipid emulsion therapy.
  • LAST-induced cardiac arrest: Provide ACLS with the following modifications. ^[16]
    • Administer low-dose epinephrine (≤ 1 mcg/kg).
    • Treat shockable rhythms with amiodarone; avoid lidocaine.
    • Consider cardiopulmonary bypass or ECMO early in refractory arrest. ^[9][15]
  • Shock: Low-dose epinephrine is the preferred vasopressor; avoid vasopressin.
  • Tachyarrhythmias
    • Amiodarone is the preferred antiarrhythmic.
    • Avoid lidocaine, procainamide, CCBs, and beta blockers.
• Disposition
  • Continuous cardiac monitoring for a minimum of: ^[15]
    • 4–6 hours following resolution of arrhythmia or shock
    • 2 hours following seizure termination
  • Admit all patients with ROSC after cardiac arrest to ICU.

Consider lipid emulsion therapy early for all patients with LAST.

Intravenous lipid emulsion therapy ^[15][17]

• Indications
  • LAST
  • Life-threatening, refractory toxicity from other lipid-soluble drugs
• Contraindications: known egg allergy, chronic liver disease, fat metabolism disorders
• Administration protocol
  • Lipid emulsion 20% bolus followed by lipid emulsion 20% infusion ^[15][17][18]
  • Consider a repeat bolus and doubling the infusion if the patient remains unstable after 5 minutes. ^[12]
  • Continue lipid emulsion infusion for ≥ 15 minutes once hemodynamically stable.
  • Maximum lipid dose: 12 mL/kg

Prevention ^[9]

• Do not exceed the maximum local anesthetic dose. ^[8][9]
• Reduce the dose by 20–25% in patients with risk factors for LAST. ^[9][11]
• Use a proper technique for infiltration anesthesia.

Aspirate the syringe prior to each injection to avoid intravascular injection.

Other adverse effects

• Allergy
  • Acute: anaphylaxis (rare)
  • Delayed: pruritic rash with blisters at site of LA injection within 72 hours of administration
• Vasovagal syncope
• Methemoglobinemia: hematologic; toxicity following local anesthetic administration (most commonly following benzocaine) ^[19][20]
• Possible risk of ischemic complications if LA with a vasoconstrictor is used in areas supplied by end arteries (e.g., digits, ears, penis) ^[8][21][22]

We list the most important adverse effects. The selection is not exhaustive.

• Perform ABCDE assessment and call for help.
• Prioritize airway management and administer 100% oxygen.
• Treat acute seizures with benzodiazepines.
• Begin lipid emulsion therapy if there is hemodynamic instability.
• Treat LAST-induced cardiac arrest with modified ACLS.
• Support blood pressure with epinephrine at a reduced dose.
• Treat arrhythmias with amiodarone.
• Consider ECMO or cardiopulmonary bypass for refractory cardiac instability.