1. The major excitatory neurotransmitter, glutamate, and the major inhibitory neurotransmitter, gamma-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, including synapse formation, 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, it acts as an excitatory transmitter in the developing CNS.(2)
- 6. During very early stages of normal brain development (i.e. neurogenesis), neurons are produced in excess and elimination of this excess (totaling as much as 50-70% of all of the neurons and progenitor cells produced) is critical for normal brain structure and function. In later stages of normal brain development (i.e. synaptogenesis), neuronal elimination is a very tightly controlled phenomenon during which a very small number of neurons are destined to die.(3)
- 7. The excess cells are eliminated by an inherent cell death program, termed apoptosis.(3)
- 8. In rats and mice, the peak period of synaptogenesis is the first two weeks of life.(4)
- 9. In humans, synaptogenesis starts during the third trimester and rapid brain growth occurs in different brain regions at different ages. By age 2 to 3 years, rapid brain growth in nearly all brain regions is mostly complete.(5)
- 10. In humans, normal brain development also importantly involves formation of neural circuits across different brain regions for functional connectivity. Neural circuit development slows after age 2 to 5 years, but it continues throughout childhood and adolescence.(6-8)
- 11. All anesthetics and sedatives used in infants and children including inhaled agents, benzodiazepines, barbiturates, ketamine, propofol, and etomidate are believed to block NMDA receptors and/or enhance GABA-A receptors to varying degrees.(9)
- 12. When anesthetic and sedative agents are administered to rodents during synaptogenesis or rapid brain growth, they cause widespread neuronal apoptosis, neurodegeneration, and changes in neuron growth and cell structure. In many of these studies, the rodents have subsequent learning and behavioral abnormalities as adults.(10-18)
- 13. In studies in which neonatal rodents are given ketamine in the presence of noxious stimuli, the degree of neuronal apoptosis is much reduced.(19) SmartTots Summary Points (2 of 4) www.smarttots.org
- 14. Limited data are available from non-human primate studies. In neonatal monkeys, ketamine or isoflurane, given during the vulnerable period of rapid brain growth, causes widespread neuronal death and neurodegeneration. In one study, ketamine given to neonatal monkeys resulted in long-term behavioral abnormalities and impairments in learning and memory when the monkeys became adults.(20-23)
- 15. There are no studies that describe neuronal cell abnormalities in children attributed to anesthesia
- 16. Observational studies in humans have been mixed. Several studies report that anesthesia in infants and young children is associated with an increased risk of learning disabilities (with multiple anesthesia exposures, but not single), developmental and behavioral abnormalities, impaired language and abstract reasoning (with both single and multiple anesthetic exposures), and poor academic performance. Other studies do not find any association between anesthesia during early childhood and poor school academic performance or abnormal behavior later in life. Two studies in neonates report that there is no evidence that prolonged sedation, in and of itself, increases the risk of abnormal neurodevelopment.(24-34)
- 17. All of the human observational studies involve analyzing data originally collected for other purposes, either as studies to investigate other questions or data collected for reasons other than specifically for research. These studies use data already available on learning, academic performance, and behavior in children and infants with a history of anesthesia and surgery in the past, usually before age 3 to 4 years. Observational studies have significant weaknesses due to confounding factors that are both known (co-morbidity) and unknown, making interpretation of these studies difficult.
- 18. There are two key research approaches and techniques for detecting potential neuronal toxicity associated with anesthetic exposure, allowing scientists to bridge information between pre-clinical (rodents and non-human primates) and clinical (human) anesthesia projects. In preclinical research, in vivo imaging of rodent and non-human primate models by positron emission tomography (microPET) allows for an objective and quantitative assessment of functional and molecular targets in a longitudinal manner. When combined with cognitive and behavioral studies, PET offers a unique bridging approach allowing insight into “structure and function” issues that are not accessible via other methods. Additionally, scientists are able to use molecular tracers that label apoptotic neurons in the brain of anesthetic-exposed rodents, allowing one the ability to visualize and quantify neurotoxicity in nonhuman primate models of neonatal anesthetic exposure. Applying these tracers in human PET imaging will allow investigations of acute and chronic effects of anesthetics and consequences of potential therapeutic strategies.35,36,37
- 19. Recent advances in our understanding of stem cell biology and neuroscience have opened up new avenues of research for detecting anesthetic-induced neurotoxicity, dissecting underlying mechanisms, and developing potential protection/prevention strategies against anestheticinduced neuronal injury.38 The use of stem cell-derived models, especially human embryonic stem cells (in vitro) with their capacity for proliferation and potential for differentiation, have a great advantage for detecting potential anesthetic-induced neurotoxicity. Studies are currently underway to employ radioactive tracers (PET) designed to target specific stem cell ligands so that the anatomical locations of those cells can be determined and monitored. In addressing critical questions about the relationship between anesthetic-induced neurotoxicity and developmental stage at time of exposure, these molecular imagining tools can be utilized in vivo to monitor endogenous neural stem cell activity following exposure to general anesthetics. SmartTots Summary Points (3 of 4) www.smarttots.org
References
1. Lujan R, Shigemoto R, Lopez-Bendito G. Glutamate and GABA receptor signaling 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. Dobbing J, Sands J. Comparative aspects of the brain growth spurt. Early Hum Dev 1979; 3: 79-83.
5. 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.
6. Huttenlocher, P.R. and A.S. Dabholkar, Regional differences in synaptogenesis in human cerebral cortex. J Comp Neurol 1997. 387(2): p. 167-78.
7. Casey, B.J., et al., Imaging the developing brain: what have we learned about cognitive development? Trends Cogn Sci 2005. 9(3): p. 104-10.
8. Tau, G.Z. and B.S. Peterson, Normal Development of Brain Circuits. Neuropsychopharmacology 2010. 35(1): p. 147-68.
9. Campagna JA, Miller KW, Forman SA. Mechanisms of actions of inhaled anesthetics. N Engl J Med 2003; 348: 2110-24.
10. 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.
11. Mellon RD, Simone AF, Rappaport BA. Use of anesthetic agents in neonates and young children. Anesth Analg 2007; 104: 509-20.
12. 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.
13. 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.
14. Lemkuil, B.P., et al., Isoflurane neurotoxicity is mediated by p75NTR-RhoA activation and actin depolymerization. Anesthesiology 2011. 114(1): p. 49-57.
15. Head, B.P., et al., Inhibition of p75 neurotrophin receptor attenuates isoflurane-mediated neuronal apoptosis in the neonatal central nervous system. Anesthesiology 2009. 110(4): p. 813- 25.
16. Vutskits, L., et al., Effect of ketamine on dendritic arbor development and survival of immature GABAergic neurons in vitro. Toxicol Sci 2006. 91(2): p. 540-9.
17. Stratmann, G., et al., Isoflurane differentially affects neurogenesis and long-term neurocognitive function in 60-day-old and 7-day-old rats. Anesthesiology 2009. 110(4): p. 834-48.
18. Loepke, A.W., et al., The effects of neonatal isoflurane exposure in mice on brain cell viability, adult behavior, learning, and memory. Anesth Analg 2009. 108(1): p. 90-104.
19. Liu, J.R., et al., Noxious stimulation attenuates ketamine-induced neuroapoptosis in the developing rat brain. Anesthesiology,2012. 117(1): p. 64-71.
20. 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.
21. Zou, X., et al., Prolonged exposure to ketamine increases neurodegeneration in the developing monkey brain. Int J Dev Neurosci 2009. 27(7): p. 727-31.
22. Brambrink AM, Evers AS, Avidan MS, Farber NB, Smith DJ, Zhang X, Dissen GA, Creeley CE, Olney SmartTots Summary Points (4 of 4) www.smarttots.org JW. Isoflurane-induced neuroapoptosis in the neonatal rhesus macaque brain. Anesthesiology 2010; 112: 834-41.
23. Paule MG, Li M, Allen RR, Liu F, Zou X, Hotchkiss C, Hanig JP, Patterson TA, Slikker W Jr, Wang C. Ketamine anesthesia during the first week of life can cause long-lasting cognitive deficits in rhesus monkeys. Neurotoxicol Teratol. 2011; 33: 220-30.
24. 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 populationbased birth cohort. Anesthesiology 2009; 110: 796-804.
25. Sprung, J., Flick, R. P., Katusic, S. K., Colligan, R. C., Barbaresi, W. J., Bojanic, K., Welch, T. L., Olson, M. D., Hanson, A. C., Schroeder, D. R., Wilder, R. T. and Warner, D. O. Attentiondeficit/hyperactivity disorder after early exposure to procedures requiring general anesthesia. Mayo Clin Proc 2012; 87: 120-129.
26. Flick, R.P., et al., Cognitive and behavioral outcomes after early exposure to anesthesia and surgery. Pediatrics 2011. 128(5): p. e1053-61.
27. DiMaggio, C., L.S. Sun, and G. Li, Early childhood exposure to anesthesia and risk of developmental and behavioral disorders in a sibling birth cohort. Anesth Analg 2011. 113(5): p. 1143-51.
28. DiMaggio, C., et al., A retrospective cohort study of the association of anesthesia and hernia repair surgery with behavioral and developmental disorders in young children. J Neurosurg Anesthesiol 2009. 21(4): p. 286-91.
29. Ing, C., et al., Long-term Differences in Language and Cognitive Function After Childhood Exposure to Anesthesia. Pediatrics 2012. 130(3): p. e476-85.
30. Block, R.I., et al., Are Anesthesia and Surgery during Infancy Associated with Altered Academic Performance during Childhood? Anesthesiology 2012. 117(3): p. 494-503.
31. Hansen, T.G., et al., Academic performance in adolescence after inguinal hernia repair in infancy: a nationwide cohort study. Anesthesiology 2011. 114(5): p. 1076-85.
32. Bartels, M., R.R. Althoff, and D.I. Boomsma, Anesthesia and cognitive performance in children: no evidence for a causal relationship. Twin Res Hum Genet 2009. 12(3): p. 246-53.
33. Guerra, G.G., et al., Neurodevelopmental outcome following exposure to sedative and analgesic drugs for complex cardiac surgery in infancy. Paediatr Anaesth 2011. 21(9): p. 932-41.
34. Roze, J.C., et al., Prolonged sedation and/or analgesia and 5-year neurodevelopment outcome in very preterm infants: results from the EPIPAGE cohort. Arch Pediatr Adolesc Med 2008. 162(8): p. 728-33.
35. Zhang, X., et al., A minimally invasive, translational biomarker of ketamine-induced neuronal death in rats: microPET Imaging using 18F-annexin V. Toxicol Sci. 2009. 111(2): p. 355-61.
36. Zhang, X., et al., MicroPET imaging of ketamine-induced neuronal apoptosis with radiolabeled DFNSH. J Neural Transm. 2011. 118(2): p. 203-11.
37. Zhang, X., et al., MicroPET/CT imaging of [18F]-FEPPA in the nonhuman primate: a potential biomarker of pathogenic processes associated with anesthetic-induced neurotoxicity. ISRN Anesthesiology. Accepted.
38. Trujillo, C.A., Schwindt, T.T., Martins, A.H., Alves, J.M., Mello, L.E. & Ulrich, H. Novel perspectives of neural stem cell differentiation: from neurotransmitters to therapeutics. Cytometry A 2009. 75(1):38-53.