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Anesthesia induced neurotoxicity in developing · PDF file 2015-10-29 · Anesthesia induced neurotoxicity and organ protection In the 1950s, concerns regarding the debilitating effect

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    Anesthesia induced neurotoxicity and organ protection

    In the 1950s, concerns regarding the debilitating effect of general anesthesia on neurologic function initially reported which was related with personality changes, those were observed especially in younger children following exposure to cyclopropane.1) Several decades later, potentially deleterious effects of anesthetics on young children is ignited initially, first, in a study observing neuronal degeneration following repeated N-methyl-D-aspartate (NMDA) antagonist exposure in neonatal rat pubs.2) The neurotoxic effects observed in animals include apoptotic neuronal cell death, diminished neuronal density, decreased neurogenesis, alterations in dendritic architecture, diminution of neurotrophic factors, mitochondrial degeneration, cytoskeletal destabilization, learning and memory impairment. Because it is impossible to examine brain tissue in infant or children, human studies have relied on observe any prospective data and are obviously interfered by inability to randomize young children to undergo painful procedures without anesthesia and analgesia. Furthermore, exposure to anesthetic agent or sedative, analgesics cannot be justified without a surgery or diagnostic procedure and it is difficult to distinguish the respective contributions of the underlying condition, surgical procedure on the postoperative neurologic outcome. Therefore, to the recently, available human data rely all on postoperative behavioral studies, epidemiologic analysis. Comparisons of long- term neurologic outcomes in children suffering from illness requiring the administration of anesthetics and sedatives during surgery or intensive care hampered gathering meaningful solution. Until proven today, it can be recommended to keep anesthesia and surgery as short as possible, to use short acting agents and/or multimodal therapy to reduce the overall drug dosage.

    What we already knew,

    1. In the developing brain, the major excitatory neurotrans- mitter, glutamate, transmitters play a central role in brain morphogenesis, including synapse formation, proliferation, mi gration, differentiation and survival of neurons.3)

    2. Although gamma-aminobutyric acid (GABA) is an inhibitory neurotransmitter in adults, it acts as an excitatory trans- mitter in the developing CNS.4)

    3. The excess cells are eliminated by an inherent cell death

    program, termed apoptosis. 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.5)

    4. 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.6)

    5. All anesthetics and sedatives used in infants and children including inhaled agents, benzodiazepines, barbiturates, keta- mine, propofol, and etomidate are believed to block NMDA receptors and/or enhance GABA-A receptors to varying degrees.7)

    6. 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, impa- ired 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.8-10)

    What studies in animals or humans in progress are?

    1. 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. PET offers a unique bridging approach allowing insight into “structure and function” issues that are not accessible via other methods.11)

    2. The use of stem cell-derived models, especially human embryonic stem cells (in vitro) with their capacity for proli- feration and potential for differentiation, have a great advantage for detecting potential anesthetic-induced neurotoxicity.12)

    3. FDA launches SAFEKIDS Initiative with Academic and Clinical Partners.The Safety of Key Inhaled and Intravenous

    마취제의 뇌독성과 장기보호 효과

    Anesthesia induced neurotoxicity in developing brain

    Il-Ok Lee

    Department of Anesthesiology and Pain Medicine, Korea University

  • 2015 대한마취통증의학회 제92차 종합학술대회12

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    Bedside to Evidence, Evidence to Bedside

    Drugs in Pediatrics (SAFEKIDS) Initiative is a multi- year project designed to address major gaps in scientific information about the safe use of anesthetics and sedatives received by millions of children each year. • The International Anesthesia Research Society (Cleveland, Ohio): leading the administrative oversight and the over- arching framework

    • Children's Hospital - Harvard University (Boston): regional or general anesthesia as neonates or infants.

    •Arkansas Children's Hospital Research Institute (Little Rock, Ark.): pharmacokinetics, pharmacodynamics, and neurotoxic effects of an anesthetic agent

    • Columbia University (New York): neurocognitive, emotional and behavioral outcomes

    •MASK (Mayo Safety in Kids) (Rochester, Minn.): long- term cognitive development

    •GAS study (National Institute of Health): general anesthesia and spinal

    • PANDA (Pediatric Anesthesia and Neurodevelopment Assessment): multicenter neurodevelopment and cognitive function, NEPSY-II


    Currently, the available evidence does not support a change in clinical practice. However, it is unwise to ignore several epidemiologic human studies have observed an association between anesthesia exposure in younger 3 years and subsequent neurologic sequelae. Practically, it will be recommended that parents must talk to their pediatrician about the risks and benefits of procedures requiring anesthetics and weigh them against the known health risks of not treat ing certain conditions. The SmartTots website (www. remains resources for up-to-date informations.


    1. Eckenhoff JE. Relationship of anesthesia to postoperative per-

    sonality changes in children. AMA Am J Dis Child. 1953 Nov; 86(5):587-91.

    2. Ikonomidou C(1), Bosch F, Miksa M, Bittigau P, Vöckler J, Dikranian K, Tenkova TI, Stefovska V, Turski L, Olney JW. Blockade of NMDA receptors and apoptotic neurodegeneration in the developing brain. Science 1999 Jan 1;283(5398):70-4.

    3. Lujan R, Shigemoto R, Lopez-Bendito G. Glutamate and GABA receptor signaling in the developing brain. Neuroscience 2005;130:567-80.

    4. 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.

    5. 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.

    6. Huttenlocher, P.R. and A.S. Dabholkar, Regional differences in synaptogenesis in human cerebral cortex. J Comp Neurol 1997;387:167-78.

    7. Campagna JA, Miller KW, Forman SA. Mechanisms of actions of inhaled anesthetics. N Engl J Med 2003;348:2110-24.

    8. 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;113:1143-51.

    9. Ing, C., et al., Long-term Differences in Language and Cognitive Function After Childhood Exposure to Anesthesia. Pediatrics 2012;130:e476-85.

    10. Block, R.I., et al., Are Anesthesia and Surgery during Infancy Associated with Altered Academic Performance during Childhood? Anesthesiology 2012;117:494-503.

    11. Zhang, X., et al., MicroPET imaging of ketamine-induced neuronal apoptosis with radiolabeled DFNSH. J Neural Transm 2011;118:203-11.

    12. 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;75:38-53.

  • Friday, N ovem

    ber 6 Saturday, N

    ovem ber 7

    일 반 연 제


    Anesthesia induced neurotoxicity and organ protection


    노인들은 전 신체 기관에 걸쳐 기능적 예비력(functional reserve)이 점진적으로 감소하는데, 뇌를 포함한 중추신경계 도 예외가 아니다. 노화에 따라 각 장기의 기능적 예비력이 감 소함에 따라 마취 및 수술과 같은 스트레스에 대한 대응능력이 떨어지게 되고, 그에 따른 합병증이 발생하기 쉽다. 또한 각 장 기에서 노화에 따라 그 병태 생리가 발현되는 특유의 질환들이 존재한다. 노인에서 특히 잘 발생하는 수술 후 인지기능 장애 (postoperative cognitive dysfunction, POCD)나 섬망(delirium), 혹 은 치매(dementia)는 노화와 관련된 대표적인 뇌기능 이상이나 질환이다.

    전신마취제는 주 작용부위가 중

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