Local Anesthetic Side-Effects /Toxicities and Neurotoxicity

• Overview

  • Primary side effects

    • Allergic reactions

    • Systemic toxicity

      • Secondary to high plasma/tissue local anesthetic concentrations

      • Manifestation:

        •  Seizures

          • Frequency: 1-4/1000 cases

          •   Bupivacaine (Marcaine) -- local anesthetic most likely to cause seizures

• Allergic Reactions:

  • Allergic reactions are considered rare occurrence (< 1% of local anesthetic adverse reactions due to allergic mechanism.)

    • Higher-risk: ester-type local anesthetics (those which are metabolized to p-aminobenzoic acid-related compounds)

  • Allergic reaction following local anesthetic administration may be caused by preservatives (methylparaben or related structures) included in the preparation (preservatives are structurally similar to p-aminobenzoic acid).

    •  Antibody production may have been previously induced by the preservative and is therefore not a reaction to the local anesthetic.

  • Cross Sensitivity

    • May be due to common metabolite profile (i.e. a structure similar to para-aminobenzoic acid.)

    • No cross sensitivity between ester vs. amide local anesthetic classes

      • Patient with allergy to an ester local anesthetic drug may receive an amide local anesthetic

      • The anesthetic agent thought to not produce an allergic reaction should not have preservatives because it is possible that the preservative is the allergen.

  • Basis/evidence for local anesthetic allergies

    1. . Clinical history, intradermal testing.

    2.  Suggestive:

       • Rash, urticaria, laryngeal edema, possible hypotension, bronchospasm.

       • Caution: hypotension with syncope/tachycardia following epinephrine-containing local anesthetic injection; accidental intravascular injection.

    3.  Intradermal testing: must use preservative-free drug.

Local Anesthetic Systemic Toxicity 

• Overview

  • Systemic Toxicity Cause:  Excessively high plasma local anesthetic concentration

  • Plasma concentration -- determinants

    • Rate of entry into systemic circulation balanced by redistribution to tissue sites and clearance

  • Most common cause of toxic plasma local anesthetic concentrations --

    • Accidental direct intravascular injection during peripheral nerve block or epidural anesthesia

  • Other cause of toxic plasma levels: -- excessive absorption from injection site (no intravascular injection)

  • Extent of systemic absorption:  dependencies

    • Initial dose of administered

    • Injection site vascularity

    • Whether or not epinephrine was used to provide local vasoconstriction

    • Properties of the drug itself

•   CNS Toxicity-local anesthetics

  • Symptom development:

    •   Tongue and circumoral numbness (low concentration)

    •   CNS changes with local anesthetic entering the brain

      • Initial symptoms: tinnitus, vertigo, restlessness

      • Subsequent symptoms: slurred speech and skeletal muscle fasciculation (muscle twitching: often immediately precedes seizures)

      •   Tonic-clonic seizures

        •  Presentation: generalized seizure (tonic general muscular contractions) with alternating contractions and relaxations.

        •  Duration: one- two minutes

        •  Consciousness: Loss of Consciousness

  • Factors influencing CNS toxicity

    • Plasma concentration-- specific drug dependent

      •   Lidocaine (Xylocaine), mepivacaine (Carbocaine), prilocaine (Citanest): CNS effects (5-10 ug/ml):

      •   Bupivacaine (Marcaine): CNS effects [seizures] (4-5 ug/ml)

    • Rate of injection -- (i.e. rate of rise of serum concentration): may be more important than total amount of drug injected

    • Lidocaine (Xylocaine) -- must also consider active metabolites, e.g.monoethylglycinexylidide, which may contribute to additive toxicity with lidocaine (Xylocaine) following epidural administration

    • Inverse relationship between PaCO₂ and local anesthetic seizure thresholds (possibly related to variation in cerebral blood flow and drug delivery)

    • Hyperkalemia by promoting depolarization increases local anesthetic toxicity

      • Hypokalemia by promoting membrane hyperpolarization reduces local anesthetic toxicity

    • Increased (probably) lidocaine (Xylocaine) neurotoxicity in patients treated with mexiletine (Mexitil) during perioperative time frame.

      • Treatment: Seizures

        • Assure adequate ventilation with oxygen

          •   Rapid onset of arteriole hypoxemia and metabolic acidosis

          •   Add supplemental oxygen when local anesthetic toxicity first appears

        • Seizure suppression

          •   IV midazolam (Versed) or diazepam (Valium)

•  Neurotoxicity

  • Overview -- Neurotoxicity as a consequence of local anesthetic injection into subarachnoid or epidural spaces

    •  Effects:

      •  Groin numbness

      •  Long-lasting, isolated myotomal (muscle segment) weakness

      •  Cauda equina syndrome

    •  Subarachnoid-space injections:

      • Transient radicular irritation

    •  Permanent neurological injury following regional anesthesia: rare

•  Transient Radicular Irritation

  •  Anatomical Location: lumbosacral nerves

  •  Manifestation: moderate/severe lower back, buttocks, posterior thigh pain

  •  time to onset: by 24 hours following spinal anesthesia complete recovery

    • Type of pain (delayed onset): neural inflammatory

    • Pain treatment: if severe, opioids

  • Time to recovery: within one-week

  • Pharmacological issues:

    • Transient radicular irritation -- may not be dependent on anesthetic concentration {frequency comparable following several lidocaine (Xylocaine) concentrations}

    • Spinal anesthesia with tetracaine (pontocaine): reduced incidence of transient radicular irritation relative to lidocaine (Xylocaine)

  •  Transient ischemia due to lengthened exposure to local anesthetic as a result of concurrent epinephrine or phenylephrine (Neo-Synephrine) use {in the anesthetic solution} may contribute to transient neurological symptoms

•  Cauda equina Syndrome

  • Cauda Equina Syndrome:  Presentation, Risk Factors, & Signs/Symptoms"

    Attribution: Tokoph K Cauda Equina Syndrome:  Presentation, Risk Factors, & Signs/Symptoms. https://www.youtube.com/watch?v=clRT_F8eFn4 (5/2021) Catalyst University YouTube Channel:  https://www.youtube.com/channel/UCIzOHtZa0iOH49ez1O5mReQ

  •  Definition: injuries (diffuse) across lumbosacral plexus causing:

    •  Sensory anesthesia

    •  Bowel and bladder sphincter dysfunction

    •  Paraplegia

  •  Circumstances of clinical occurrence:

    • Microcatheters (28 gauge) delivering hyperbaric 5% lidocaine (Xylocaine) may cause nonhomogeneous local anesthetic distribution-- pooling of high anesthetic concentration on stretched nerves (lithotomy position).

    • Following intrathecal lidocaine (Xylocaine) [100 mg 5% lidocaine (Xylocaine), 25-gauge needle]

    • Intended epidural anesthesia

•  Anterior Spinal Artery Syndrome

  •  Manifestation: lower-extremity paresis (variable sensory deficit following neural blockade resolution)

  •  Possible mechanisms

    • Thrombosis

    • Anterior artery spasm

    • Hypotension/vasoconstrictor drugs

  • Possible Predisposing conditions:

    •  Advanced age

    •  Peripheral vascular disease

  • Differential diagnosis with presenting symptoms similar symptoms to that caused by:

    •  Epidural abscess-mediated or hematoma-mediated spinal cord compression.

Primary Reference: Stoelting, R.K., "Local Anesthetics", in Pharmacology and Physiology in Anesthetic Practice, Lippincott-Raven Publishers, 1999, pp 158-181.

Miller, R.D., Local Anesthesia, in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp 425-433.

White, P. F. "Anesthesia Drug Manual", W.B. Saunders Company, 1996.