Neurotoxicity of Anesthetics in the Developing Brain: Summary Points

  1. The major excitatory neurotransmitter, glutamate, and the major inhibitory neurotransmitter, y-aminobutyric acid (GABA), are generally associated with neuronal communication in the adult brain.(1)
  2. In the developing brain, these transmitters play a central role in brain morphogenesis, in some cases prior to synapse formation, including proliferation, migration, differentiation and survival of neurons.(1)
  3. Different types of glutamate and GABA receptors need to be expressed at the right time and place in the developing brain to produce normal brain structure and function.(1)
  4. N-methyl-D-aspartate (NMDA)-type glutamate receptors are widely distributed in the CNS and play a key role in brain development including proliferation, migration, survival, and differentiation of neurons.(1)
  5. Although GABA is an inhibitory neurotransmitter in adults, in acts as an excitatory transmitter in the developing CNS.(2)
  6. During normal brain development, neurons are produced in excess and elimination of this excess (totaling as much as 50-70% all of the neurons and progenitor cells produced) is critical for normal brain structure and function.(3)
  7. The excess cells are eliminated by an inherent cell death program, termed apoptosis.(3)
  8. In humans, synaptogenesis starts during the third trimester and rapid brain growth continues for up to 2 to 3 years.(4)
  9. In rats and mice, the comparable period of brain development is the first two weeks of life.(5)
  10. All anesthetics and sedatives used in infants and children including inhaled agents, benzodiazepines, barbiturates, ketamine, propofol, and etomidate block NMDA receptors and/or enhance GABA-A receptors to varying degrees.(6)
  11. When administered during rapid brain growth in rodents, all of the anesthetics and sedatives commonly used in infants and children as well as non-anesthetic agents with comparable effects at NMDA and GABA receptors cause widespread neurodegeration and/or subsequent behavioral abnormalities.(7-10)
  12. Limited data are available from non-human primate studies. One study showed neurotoxicity in neonatal monkeys given ketamine.(11)
  13. There are no studies that describe neurodegerative abnormalities in children attributed to anesthesia. One study describes learning disabilities after multiple anesthetics but not a single anesthetic administered in infants and children prior to 4 years of age.(12)

References

  1. Lujan R, Shigemoto R, Lopez-Bendito G. Glutamate and GABA receptor signalling in the developing brain. Neuroscience 2005;130:567-80.
  2. Ben-Ari Y, Khazipov R, Leinekugel X, Caillard O, Gaiarsa JL. GABAA, NMDA and AMPA receptors: a developmentally regulated 'menage a trois'. Trends Neurosci 1997;20:523-9.
  3. Blaschke AJ, Weiner JA, Chun J. Programmed cell death is a universal feature of embryonic and postnatal neuroproliferative regions throughout the central nervous system. J Comp Neurol 1998;396:39-50.
  4. Dekaban AS. Changes in brain weights during the span of human life: relation of brain weights to body heights and body weights. Ann Neurol 1978;4:345-56.
  5. Dobbing J, Sands J. Comparative aspects of the brain growth spurt. Early Hum Dev 1979;3:79-83.
  6. Campagna JA, Miller KW, Forman SA. Mechanisms of actions of inhaled anesthetics. N Engl J Med 2003;348:2110-24.
  7. Fredriksson A, Archer T, Alm H, Gordh T, Eriksson P. Neurofunctional deficits and potentiated apoptosis by neonatal NMDA antagonist administration. Behav Brain Res 2004;153:367-76.
  8. Jevtovic-Todorovic V, Hartman RE, Izumi Y, Benshoff ND, Dikranian K, Zorumski CF, Olney JW, Wozniak DF. Early exposure to common anesthetic agents causes widespread neurodegeneration in the developing rat brain and persistent learning deficits. J Neurosci 2003;23:876-82.
  9. Young C, Jevtovic-Todorovic V, Qin YQ, Tenkova T, Wang H, Labruyere J, Olney JW. Potential of ketamine and midazolam, individually or in combination, to induce apoptotic neurodegeneration in the infant mouse brain. Br J Pharmacol 2005;146:189-97.
  10. Mellon RD, Simone AF, Rappaport BA. Use of anesthetic agents in neonates and young children. Anesth Analg 2007;104:509-20.
  11. Slikker W, Jr., Zou X, Hotchkiss CE, Divine RL, Sadovova N, Twaddle NC, Doerge DR, Scallet AC, Patterson TA, Hanig JP, Paule MG, Wang C. Ketamine-induced neuronal cell death in the perinatal rhesus monkey. Toxicol Sci 2007;98:145-58.
  12. 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;110:796-804.