Anaesthesia-Related Neurotoxicity

  • Effect of general anaesthesia on human cognitive development brain is unclear, but probably minor if present
    • No particular agent shown to be superior
  • Effects of anaesthesia are difficult to separate from having surgery/having an illness that requires surgery
  • In general: balance benefits of anaesthesia in children and pregnant women against risks, especially if procedures >3 hours or if multiple procedures are required

General anaesthesia is potentially neurotoxic at both extremes of age. These effects:

Pathophysiology

The developing brain:

  • Has a different structure to adult brain
    • Many more neurones present in early development
  • Has 50-70% of its neurones eliminated by apoptosis, under normal circumstances
    • This allows behaviourally relevant connections to remain
    • 3rd trimester and 1st year of life are the most important

Anaesthetic agents affect several aspects of brain development, including:

  • Inducing neuro-apoptosis
    • Critical factors
      • Stage of brain development at time of exposure
        Different brain regions develop at different points.
      • Degree of exposure
    • Secondary factors
      • Agent used
      • Health status
      • Surgical procedure
  • Reduced neurogenesis
    • Associated with oxidative stress

Effect of anaesthetic agents is difficult to separate from (and may be worsened by)associated factors, including:

  • Surgery
  • Underlying disease

Animal Studies

  • Juvenile animal studies identified that NMDA antagonists and GABA activators/potentiators appeared to ↑ rates of neuronal apoptosis when used for longer than 3 hours
  • Use of anaesthetic drugs during periods of rapid brain growth and synaptogenesis causes neuronal and glial cell loss
  • Primate studies showed ↑ neuronal cell loss with:
    • 24 hours of ketamine
    • 5 hours of isoflurane or 5 hours of propofol
  • Rat and primate studies suggest neuronal cell loss is associated with learning and memory deficits
  • Dose response relationship appears to exist
    • Light surgical plains of anaesthesia were less affected
    • Shorter duration of anaesthesia does not show the same effect
  • Age-related outcome
    Apoptosis is 2.2× greater in monkey foetus as compared to 120 day old monkey.

Human Studies

  • Retrospective cohort studies
    • Wide variety of ages and agents
    • Mostly unable to determine duration of anaesthesia
  • Conflicting data
    However, some dramatic results; e.g. one observational study suggested before the age of 4:
    • 2 Anaesthetics
      1.6× more likely to have learning disability.

    • 3 Anaesthetics
      2.6× more likely to have a learning disability.

    • Note that the magnitude of the risk was small: ~1% difference in school grades
  • Lots of confounders
    • Surgical trauma and pathology are also important
      • Humoral and inflammatory stress
      • Metabolic, haemodynamic, and respiratory events
      • Pathology
      • Sepsis
      • Chromosomal abnormalities
  • Notably no data regarding adverse consequences of human foetal exposure

Key Studies

Neurotoxicity of anaesthesia:

  • GAS (2019)
    • 722 children, multicentre international RCT
    • Awake regional vs. sevoflurane for inguinal hernia repair
    • No difference in development at 2 years of age
      Bayley Scale of Infant and Toddler Development III.
  • PANDA (2016)
    • 105 Children <3 years with an eligible sibling
    • Sibling-matched observational cohort study
    • Evaluating IQ
    • No difference in primary outcome

Summary

  • Single, short anaesthetics in infancy are not associated with developmental delay
  • Requirement for multiple anaesthetics early in life is associated with an ↑ risk of learning disability
    • The magnitude of this disability is small
  • Discuss with surgeons and parents about delaying unnecessary procedures until >3 years of age if feasible

References

  1. Jevtovic-Todorovic V, Absalom AR, Blomgren K, Brambrink A, Crosby G, Culley DJ, et al. Anaesthetic neurotoxicity and neuroplasticity: an expert group report and statement based on the BJA Salzburg Seminar. British Journal of Anaesthesia. 2013 Aug;111(2):143–51. 1 Wilder RT, Flick RP, Sprung J, Katusic SK, Barbaresi WJ, Mickelson C, Gleich SJ, Schroeder DR, Weaver AL, Warner DO. Early exposure to anesthesia and learning disabilities in a population-based birth cohort. Anesthesiology. 2009 Apr; 110(4):796-804.
  2. Brambrink AM, Evers AS, Avidan MS, Farber NB, Smith DJ, Martin LD, Dissen GA, Creeley CE, Olney JW. Ketamine-induced neuroapoptosis in the fetal and neonatal rhesus macaque brain. Anesthesiology. 2012 Feb;116(2):372-84.
  3. Yu CK, Yuen VMY, Wong GT, Irwin MG. The effects of anaesthesia on the developing brain: a summary of the clinical evidence. F1000Research. 2013;2:166.
  4. Andropoulos DB, Greene MF. Anesthesia and Developing Brains - Implications of the FDA Warning. N Engl J Med. 2017 Mar 9;376(10):905-907.
  5. Davidson AJ, Sun LS. Clinical Evidence for Any Effect of Anesthesia on the Developing Brain. Anesthesiology. 2018 Apr;128(4):840-853. Pinyavat T, Warner DO, Flick RP, et al. Summary of the Update Session of Clinical Studies. Journal of neurosurgical anesthesiology. 2016;28(4):356-360.
  6. McCann ME, de Graaff JC, Dorris L, Disma N, Withington D, Bell G, et al. Neurodevelopmental outcome at 5 years of age after general anaesthesia or awake-regional anaesthesia in infancy (GAS): an international, multicentre, randomised, controlled equivalence trial. The Lancet. 2019 Feb;393(10172):664–77.
  7. Sun LS, Li G, Miller TLK, et al. Association Between a Single General Anesthesia Exposure Before Age 36 Months and Neurocognitive Outcomes in Later Childhood. JAMA. 2016;315(21):2312-2320. doi:10.1001/jama.2016.6967