Question 19

Describe toxicity of local anaesthetic agents.

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College Answer

Most questions lacked a systematic approach to the question and specific detail. The relationship between systemic toxicity (CNS and CVS) and plasma levels should be described. Many candidates did not clearly state that CNS toxicity occurs at lower plasma levels that CVS toxicity. Factors that affect toxicity (e.g. drug factors, patient factors, interactions) needed to be elaborated with some detail. Patient factors such as age, pregnancy, acidosis, hyperkalaemia, hepatic failure were often omitted. Finally, marks were also awarded for noting methaemoglobinaemia as possible toxicity and the existence of specific therapy (intralipid).

Discussion

  • Clinical features of local anaesthetic toxicity:
    • Central nervous system effects:
      • Occur at lower concentration than cardiovascular effects
      • At lower doses:
        • Visual disturbances (resembling nystagmus)
        • Perioral numbness
      • At increasing doses:
        • Slurred speach
        • Incoherent conversation
        • Confusion and decreased level of consciousness
      • With very large doses:
        • Seizures
        • Coma with EEG features of non-convusove status or burst suppression
    • Cardiovascular effects:
      • Require approximately 3 times as much dose as CNS effects
      • Some agents (eg. bupivacaine) are particularly cardiotoxic
      • Lower dose effects are sympathomimetic:
        • Hypertension
        • Vasoconstriction
        • Tachycardia
      • Higher dose effects:
        • Hypotension (systemic vasodilation) 
        • Bradycardia and heart block
        • QRS prolongation, arrhythmias, cardiac arrest
    • Other effects:
      • Methaemoglobinaemia (prilocaine only)
      • Allergy (to ester metabolites or preservative excipents)
      • Myonecrosis from IM injection
  • Patient risk factors for local anaesthetic toxicity:
    • Acidosis (decreased protein binding, increased availability of active ionised form of agent)
    • Old age: slower clearance, more cardiofragile
    • Young age: lower α1-acid glycoprotein level, higher free fraction
    • Pregnant patients: lower α1-acid glycoprotein level, better perfusion of blocked tissue
    • Hyperkalemia (decreased toxic dose of agent)
  • Pharmacological factors which contribute to local anaesthetic toxicity:
    • Dose (obviously)
    • Choice of agent (some drugs, eg. bupivacaine, have a lower CC/CNS ratio)
    • Site of administration (eg. closer to large vessels, hyperaemic site, epidural)
    • Coadministration of vasoconstrictor (slows systemic absorption)
    • Slower dissociation from sodium channels (eg. bupivacaine)
    • Drug interactions:
      • displacement from protein binding (eg. by phenytoin)
      • decreased metabolism (eg. by cimetidine)
  • Management of local anaesthetic toxicity:
    • Alkalinise or hyperventilate:
      • Increase protein binding
      • Decrease charged fraction (active and capable of binding sodium channels)
    • Increase the distribution into lipid:
      • Give intralipid emulsion to increase lipid-bound fraction and decrease free fraction

References

Finucane, Brendan T. Complications of regional anesthesia. New York: Springer, 2007.

Scott, D. B. "Toxic effects of local anaesthetic agents on the central nervous system." BJA: British Journal of Anaesthesia 58.7 (1986): 732-735.

Shibata, Masatoshi, et al. "Tetraphasic actions of local anesthetics on central nervous system electrical activities in cats." Regional Anesthesia and Pain Medicine 19.4 (1994): 255-263.

Ladd, Leigh A., et al. "Effects of CNS site-directed carotid arterial infusions of bupivacaine, levobupivacaine, and ropivacaine in sheep." The Journal of the American Society of Anesthesiologists 97.2 (2002): 418-428.

Blair, M. R. "Cardiovascular pharmacology of local anaesthetics." BJA: British Journal of Anaesthesia 47 (1975): 247-252.

Newton, D. J., et al. "Mechanisms influencing the vasoactive effects of lidocaine in human skin." Anaesthesia 62.2 (2007): 146-150.

Christie, Linsey E., John Picard, and Guy L. Weinberg. "Local anaesthetic systemic toxicity." Bja Education 15.3 (2015): 136-142.

Mauch, J., et al. "Electrocardiographic changes during continuous intravenous application of bupivacaine in neonatal pigs." British journal of anaesthesia 105.4 (2010): 437-441.

Nancarrow, C., et al. "The influence of acidosis on the distribution of lidocaine and bupivacaine into the myocardium and brain of the sheep." Anesthesia and analgesia 66.10 (1987): 925-935.

Avery, Pamela, et al. "The influence of serum potassium on the cerebral and cardiac toxicity of bupivacaine and lidocaine." Anesthesiology 61.2 (1984): 134-138.

Dillane, Derek, and Brendan T. Finucane. "Local anesthetic systemic toxicity." Canadian Journal of Anesthesia/Journal canadien d'anesthésie 57.4 (2010): 368-380.

Garg, Divya, Shikha Soni, and Rakesh Karnawat. "Local Anesthetic Systemic Toxicity." Topics in Local Anesthetics. IntechOpen, 2020.

Naguib, Mohamed, et al. "Adverse effects and drug interactions associated with local and regional anaesthesia." Drug safety 18.4 (1998): 221-250.