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Anesthetics and the Developing Brain: The Yin and Yang

  • Pediatric Anesthesia (J Lerman, Section Editor)
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Abstract

Millions of children undergo surgical operations and painful interventions with general anesthesia every year. Animal research has demonstrated structural and functional consequences following exposure early in life. Epidemiological studies have associated early childhood anesthetic exposure for surgery with subsequent neurobehavioral abnormalities. Combined, these findings have raised substantial concerns that anesthetics may interfere with brain development in humans. However, several important questions remain unresolved, such as whether structural abnormalities occur in humans, the exact neurocognitive phenotype following exposure, whether age during exposure affects vulnerability, and if there even exists a safe age after which the brain becomes resistant to long-term alterations by anesthetics. Complicating this discussion is the fact that anesthetics also protect the immature brain from the noxious effects of stress, pain, and ischemia. Accordingly, this review discusses the current state of research into this ambiguity, the yin and yang of anesthetic effects on the developing brain.

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References

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  1. DeFrances CJ, Cullen KA, Kozak LJ. National hospital discharge survey: 2005 annual summary with detailed diagnosis and procedure data. Vital Health Stat. 2007;13:1–209.

    Google Scholar 

  2. Weiser TG, Regenbogen SE, Thompson KD, et al. An estimation of the global volume of surgery: a modelling strategy based on available data. Lancet. 2008;372:139–44.

    Article  PubMed  Google Scholar 

  3. Loepke AW, Davidson AJ. Surgery, anesthesia, and the developing brain. In: Coté CJ, Lerman J, Anderson B, editors. A practice of anesthesia for infants and children: expert consult—online and print. 5th ed. Philadelphia: W. B. Saunders; 2012. p. 492–509.

    Google Scholar 

  4. Ward CG, Loepke AW. Anesthetics and sedatives: toxic or protective for the developing brain? Pharmacol Res. 2011;65:271–4.

    Article  PubMed  CAS  Google Scholar 

  5. Lin EP, Soriano SG, Loepke AW. Anesthetic neurotoxicity. Anesthesiol Clin. 2014;32:133–55.

    Article  PubMed  Google Scholar 

  6. • Deng M, Loepke AW. Anesthetic neurotoxicity: preclinical and clinical research. J Perioper Sci. 2014;1:1–49. Most recent, exhaustive literature review regarding laboratory and clinical studies into anesthetic neurotoxicity, documenting a 5-fold increase in the number of articles within the past 7 years.

  7. • Rappaport BA, Suresh S, Hertz S, et al. Anesthetic neurotoxicity: clinical implications of animal models. N Engl J Med. 2015;372:796–7. Editorial statement including researchers at the Food and Drug Administration (FDA) delineating the concerns regarding the adverse effects of anesthetic agents on neurological development in young children.

    Article  CAS  Google Scholar 

  8. Loepke AW, Soriano SG. An assessment of the effects of general anesthetics on developing brain structure and neurocognitive function. Anesth Analg. 2008;106:1681–707.

    Article  PubMed  Google Scholar 

  9. Penn AA, Shatz CJ. Brain waves and brain wiring: the role of endogenous and sensory-driven neural activity in development. Pediatr Res. 1999;45:447–58.

    Article  PubMed  CAS  Google Scholar 

  10. de Lima AD, Opitz T, Voigt T. Irreversible loss of a subpopulation of cortical interneurons in the absence of glutamatergic network activity. Eur J Neurosci. 2004;19:2931–43.

    Article  PubMed  Google Scholar 

  11. Bayer SA, Altman J, Russo RJ, et al. Timetables of neurogenesis in the human brain based on experimentally determined patterns in the rat. Neurotoxicology. 1993;14:83–144.

    PubMed  CAS  Google Scholar 

  12. Kuida K, Zheng TS, Na S, et al. Decreased apoptosis in the brain and premature lethality in cpp32-deficient mice. Nature. 1996;384:368–72.

    Article  PubMed  CAS  Google Scholar 

  13. Kuan CY, Roth KA, Flavell RA, et al. Mechanisms of programmed cell death in the developing brain. Trends Neurosci. 2000;23:291–7.

    Article  PubMed  CAS  Google Scholar 

  14. Kerr JF, Wyllie AH, Currie AR. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer. 1972;26:239–57.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Crain B, Cotman C, Taylor D, et al. A quantitative electron microscopic study of synaptogenesis in the dentate gyrus of the rat. Brain Res. 1973;63:195–204.

    Article  PubMed  CAS  Google Scholar 

  16. De Felipe J, Marco P, Fairen A, et al. Inhibitory synaptogenesis in mouse somatosensory cortex. Cereb Cortex. 1997;7:619–34.

    Article  PubMed  Google Scholar 

  17. Huttenlocher PR, Dabholkar AS. Regional differences in synaptogenesis in human cerebral cortex. J Compd Neurol. 1997;387:167–78.

    Article  CAS  Google Scholar 

  18. Istaphanous GK, Howard J, Nan X, et al. Comparison of the neuroapoptotic properties of equipotent anesthetic concentrations of desflurane, isoflurane, or sevoflurane in neonatal mice. Anesthesiology. 2011;114:578–87.

    Article  PubMed  CAS  Google Scholar 

  19. Lu LX, Yon JH, Carter LB, et al. General anesthesia activates bdnf-dependent neuroapoptosis in the developing rat brain. Apoptosis. 2006;11:1603–15.

    Article  PubMed  CAS  Google Scholar 

  20. Head BP, Patel HH, Niesman IR, et al. Inhibition of p75 neurotrophin receptor attenuates isoflurane-mediated neuronal apoptosis in the neonatal central nervous system. Anesthesiology. 2009;110:813–25.

    Article  PubMed  CAS  Google Scholar 

  21. Pontén E, Fredriksson A, Gordh T, et al. Neonatal exposure to propofol affects bdnf but not camkii, gap-43, synaptophysin and tau in the neonatal brain and causes an altered behavioural response to diazepam in the adult mouse brain. Behav Brain Res. 2011;223:75–80.

    Article  PubMed  CAS  Google Scholar 

  22. Sanchez V, Feinstein SD, Lunardi N, et al. General anesthesia causes long-term impairment of mitochondrial morphogenesis and synaptic transmission in developing rat brain. Anesthesiology. 2011;115:992–1002.

    Article  PubMed  Google Scholar 

  23. Boscolo A, Milanovic D, Starr JA, et al. Early exposure to general anesthesia disturbs mitochondrial fission and fusion in the developing rat brain. Anesthesiology. 2013;118:1086–97.

    Article  PubMed  CAS  Google Scholar 

  24. Brambrink A, Back SA, Riddle A, et al. Isoflurane-induced apoptosis of oligodendrocytes in the neonatal primate brain. Ann Neurol. 2012;72:525–35.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Lunardi N, Hucklenbruch C, Latham JR, et al. Isoflurane impairs immature astroglia development in vitro: the role of actin cytoskeleton. J Neuropathol Exp Neurol. 2011;70:281–91.

    Article  PubMed  CAS  Google Scholar 

  26. Lunardi N, Ori C, Erisir A, et al. General anesthesia causes long-lasting disturbances in the ultrastructural properties of developing synapses in young rats. Neurotox Res. 2010;17:179–88.

    Article  PubMed  CAS  Google Scholar 

  27. Briner A, Nikonenko I, De Roo M, et al. Developmental stage-dependent persistent impact of propofol anesthesia on dendritic spines in the rat medial prefrontal cortex. Anesthesiology. 2011;115:282–93.

    Article  PubMed  CAS  Google Scholar 

  28. Ma D, Williamson P, Januszewski A, et al. Xenon mitigates isoflurane-induced neuronal apoptosis in the developing rodent brain. Anesthesiology. 2007;106:746–53.

    Article  PubMed  CAS  Google Scholar 

  29. Cattano D, Williamson P, Fukui K, et al. Potential of xenon to induce or to protect against neuroapoptosis in the developing mouse brain. Can J Anaesth. 2008;55:429–36.

    Article  PubMed  Google Scholar 

  30. Sanders RD, Sun P, Patel S, et al. Dexmedetomidine provides cortical neuroprotection: impact on anaesthetic-induced neuroapoptosis in the rat developing brain. Acta Anaesthesiol Scand. 2010;54:710–6.

    Article  PubMed  CAS  Google Scholar 

  31. Wei H, Liang G, Yang H. Isoflurane preconditioning inhibited isoflurane-induced neurotoxicity. Neurosci Lett. 2007;425:59–62.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Zou X, Sadovova N, Patterson TA, et al. The effects of l-carnitine on the combination of, inhalation anesthetic-induced developmental, neuronal apoptosis in the rat frontal cortex. Neuroscience. 2008;151:1053–65.

    Article  PubMed  CAS  Google Scholar 

  33. Yon JH, Carter LB, Reiter RJ, et al. Melatonin reduces the severity of anesthesia-induced apoptotic neurodegeneration in the developing rat brain. Neurobiol Dis. 2006;21:522–30.

    Article  PubMed  CAS  Google Scholar 

  34. Wang QJ, Li KZ, Yao SL, et al. Different effects of isoflurane and sevoflurane on cytotoxicity. Chin Med J. 2008;121:341–6.

    Article  PubMed  CAS  Google Scholar 

  35. Wang C, Sadovova N, Patterson TA, et al. Protective effects of 7-nitroindazole on ketamine-induced neurotoxicity in rat forebrain culture. Neurotoxicology. 2008;29:613–20.

    Article  PubMed  CAS  Google Scholar 

  36. Turner CP, Gutierrez S, Liu C, et al. Strategies to defeat ketamine-induced neonatal brain injury. Neuroscience. 2012;210:384–92.

    Article  PubMed  CAS  Google Scholar 

  37. Lemkuil BP, Head BP, Pearn ML, et al. Isoflurane neurotoxicity is mediated by p75NTR-rhoa activation and actin depolymerization. Anesthesiology. 2011;114:49–57.

    Article  PubMed  CAS  Google Scholar 

  38. Boscolo A, Ori C, Bennett J, et al. Mitochondrial protectant pramipexole prevents sex-specific long-term cognitive impairment from early anaesthesia exposure in rats. Br J Anaesth. 2013;110(Suppl 1):i47–52.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Pellegrini L, Bennis Y, Velly L, et al. Erythropoietin protects newborn rat against sevoflurane-induced neurotoxicity. Paediatr Anaesth. 2014;24:749–59.

    Article  PubMed  Google Scholar 

  40. Straiko MM, Young C, Cattano D, et al. Lithium protects against anesthesia-induced developmental neuroapoptosis. Anesthesiology. 2009;110:862–8.

    Article  PubMed  CAS  Google Scholar 

  41. Edwards DA, Shah HP, Cao W, et al. Bumetanide alleviates epileptogenic and neurotoxic effects of sevoflurane in neonatal rat brain. Anesthesiology. 2010;112:567–75.

    Article  PubMed  CAS  Google Scholar 

  42. Jevtovic-Todorovic V, Hartman RE, Izumi Y, et al. Early exposure to common anesthetic agents causes widespread neurodegeneration in the developing rat brain and persistent learning deficits. J Neurosci. 2003;23:876–82.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. •• Paule MG, Li M, Allen RR, et al. Ketamine anesthesia during the first week of life can cause long-lasting cognitive deficits in rhesus monkeys. Neurotoxicol Teratol. 2011;33:220–30. First study demonstrating long-standing impairments in cognitive abilities and motivation in non-human primates following a neonatal, albeit prolonged, exposure to ketamine.

  44. Rozé JC, Denizot S, Carbajal R, 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;162:728–33.

    Article  PubMed  Google Scholar 

  45. Kalkman CJ, Peelen L, Moons KG, et al. Behavior and development in children and age at the time of first anesthetic exposure. Anesthesiology. 2009;110:805–12.

    Article  PubMed  Google Scholar 

  46. Wilder RT, Flick RP, Sprung J, et al. Early exposure to anesthesia and learning disabilities in a population-based birth cohort. Anesthesiology. 2009;110:796–804.

    Article  PubMed  Google Scholar 

  47. Sprung J, Flick RP, Wilder RT, et al. Anesthesia for cesarean delivery and learning disabilities in a population-based birth cohort. Anesthesiology. 2009;111:302–10.

    Article  PubMed  Google Scholar 

  48. DiMaggio CJ, Sun LS, Kakavouli A, 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;21:286–91.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Bartels M, Althoff RR, Boomsma DI. Anesthesia and cognitive performance in children: no evidence for a causal relationship. Twin Res Hum Genet. 2009;12:246–53.

    Article  PubMed  Google Scholar 

  50. DiMaggio C, Sun L, Li G. Early childhood exposure to anesthesia and risk of developmental and behavioral disorders in a sibling birth cohort. Anesth Analg. 2011;113:1143–51.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Flick RP, Lee K, Hofer RE, et al. Neuraxial labor analgesia for vaginal delivery and its effects on childhood learning disabilities. Anesth Analg. 2011;112:1424–31.

    Article  PubMed  Google Scholar 

  52. Flick RP, Katusic SK, Colligan RC, et al. Cognitive and behavioral outcomes after early exposure to anesthesia and surgery. Pediatrics. 2011;128:e1053–61.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Garcia Guerra G, Robertson CM, Alton GY, et al. Neurodevelopmental outcome following exposure to sedative and analgesic drugs for complex cardiac surgery in infancy. Paediatr Anaesth. 2011;21:932–41.

    Article  Google Scholar 

  54. Hansen TG, Pedersen JK, Henneberg SW, et al. Academic performance in adolescence after inguinal hernia repair in infancy: a nationwide cohort study. Anesthesiology. 2011;114:1076–85.

    Article  PubMed  Google Scholar 

  55. • Ing C, DiMaggio C, Whitehouse A, et al. Long-term differences in language and cognitive function after childhood exposure to anesthesia. Pediatrics. 2012;130:e476–8. Epidemiological study demonstrating abnormalities in language development and cognition following a single anesthetic exposure under 3 years of age.

    Article  PubMed  Google Scholar 

  56. Block RI, Thomas JJ, Bayman EO, et al. Are anesthesia and surgery during infancy associated with altered academic performance during childhood? Anesthesiology. 2012;117:494–503.

    Article  PubMed  Google Scholar 

  57. Filan PM, Hunt RW, Anderson PJ, et al. Neurologic outcomes in very preterm infants undergoing surgery. J Pediatr. 2012;160:409–14.

    Article  PubMed  Google Scholar 

  58. Hansen TG, Pedersen JK, Henneberg SW, et al. Educational outcome in adolescence following pyloric stenosis repair before 3 months of age: a nationwide cohort study. Paediatr Anaesth. 2013;23:883–90.

    Article  PubMed  Google Scholar 

  59. Fan Q, Cai Y, Chen K, et al. Prognostic study of sevoflurane-based general anesthesia on cognitive function in children. J Anesth. 2013;27:493–9.

    Article  PubMed  Google Scholar 

  60. Andropoulos DB, Ahmad HB, Haq T, et al. The association between brain injury, perioperative anesthetic exposure, and 12-month neurodevelopmental outcomes after neonatal cardiac surgery: a retrospective cohort study. Paediatr Anaesth. 2014;24:266–74.

    Article  PubMed  PubMed Central  Google Scholar 

  61. Garcia Guerra G, Robertson CM, Alton GY, et al. Neurotoxicity of sedative and analgesia drugs in young infants with congenital heart disease: 4-year follow-up. Paediatr Anaesth. 2014;24:257–65.

    Article  PubMed  Google Scholar 

  62. •• Ing CH, DiMaggio CJ, Malacova E, et al. Comparative analysis of outcome measures used in examining neurodevelopmental effects of early childhood anesthesia exposure. Anesthesiology. 2014;120:1319–32. Important comparison of different outcomes measures assessing neurological function following surgery with anesthesia in early childhood.

    Article  PubMed  CAS  Google Scholar 

  63. • Stratmann G, Lee J, Sall JW, et al. Effect of general anesthesia in infancy on long-term recognition memory in humans and rats. Neuropsychopharmacology. 2014;39:2275–87. First clinical study demonstrating abnormalities in memory tasks in children prospectively tested following surgery with anesthesia prior to their second birthday.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  64. Yon JH, Daniel-Johnson J, Carter LB, et al. Anesthesia induces neuronal cell death in the developing rat brain via the intrinsic and extrinsic apoptotic pathways. Neuroscience. 2005;135:815–27.

    Article  PubMed  CAS  Google Scholar 

  65. •• Hofacer RD, Deng M, Ward CG, et al. Cell age-specific vulnerability of neurons to anesthetic toxicity. Ann Neurol. 2013;73:695–704. Animal study demonstrating that isoflurane exposure induces neuronal cell death in young and adult rodents, suggesting that neuronal age, rather than simply age of the individual affects vulnerability to anesthetic neurotoxicity.

    Article  PubMed  PubMed Central  Google Scholar 

  66. •• Krzisch M, Sultan S, Sandell J, et al. Propofol anesthesia impairs the maturation and survival of adult-born hippocampal neurons. Anesthesiology. 2013;118:602–10. Laboratory study proving deleterious effects of propofol exposure on neuronal maturation and survival in adult rodents.

    Article  PubMed  CAS  Google Scholar 

  67. • Deng M, Hofacer RD, Jiang C, et al. Brain regional vulnerability to anaesthesia-induced neuronal cell death shifts with age during exposure and extends into adulthood for some regions. Br J Anaesth. 2014;113:443–51. Rodent study introducing the concept that brain regions are differentially affected by anesthesia-induced neurodegeneration dependent on their relative peaks in neurogenesis.

  68. Taliaz D. Skills development in infants: a possible role for widespread neurogenesis? Front Behav Neurosci. 2013;7:178.

    Article  PubMed  PubMed Central  Google Scholar 

  69. Bardin J. Neurodevelopment: unlocking the brain. Nature. 2012;487:24–6.

    Article  PubMed  CAS  Google Scholar 

  70. Davidson AJ, McCann ME, Morton NS, et al. Anesthesia and outcome after neonatal surgery: the role for randomized trials. Anesthesiology. 2008;109:941–4.

    Article  PubMed  Google Scholar 

  71. Sun L. Early childhood general anaesthesia exposure and neurocognitive development. Br J Anaesth. 2010;105(Suppl 1):i61–8.

    Article  PubMed  PubMed Central  Google Scholar 

  72. Nemergut ME, Aganga D, Flick RP. Anesthetic neurotoxicity: what to tell the parents? Paediatr Anaesth. 2014;24:120–6.

    Article  PubMed  Google Scholar 

  73. Anand KJ, Garg S, Rovnaghi CR, et al. Ketamine reduces the cell death following inflammatory pain in newborn rat brain. Pediatr Res. 2007;62:283–90.

    Article  PubMed  CAS  Google Scholar 

  74. Reynolds ML, Fitzgerald M. Long-term sensory hyperinnervation following neonatal skin wounds. J Compd Neurol. 1995;358:487–98.

    Article  CAS  Google Scholar 

  75. LaPrairie JL, Johns ME, Murphy AZ. Preemptive morphine analgesia attenuates the long-term consequences of neonatal inflammation in male and female rats. Pediatr Res. 2008;64:625–30.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  76. Bhutta AT, Rovnaghi C, Simpson PM, et al. Interactions of inflammatory pain and morphine in infant rats: long-term behavioral effects. Physiol Behav. 2001;73:51–8.

    Article  PubMed  CAS  Google Scholar 

  77. Anand KJ, Coskun V, Thrivikraman KV, et al. Long-term behavioral effects of repetitive pain in neonatal rat pups. Physiol Behav. 1999;66:627–37.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  78. Ruda MA, Ling QD, Hohmann AG, et al. Altered nociceptive neuronal circuits after neonatal peripheral inflammation. Science. 2000;289:628–31.

    Article  PubMed  CAS  Google Scholar 

  79. Sternberg WF, Scorr L, Smith LD, et al. Long-term effects of neonatal surgery on adulthood pain behavior. Pain. 2005;113:347–53.

    Article  PubMed  Google Scholar 

  80. LaPrairie JL, Murphy AZ. Female rats are more vulnerable to the long-term consequences of neonatal inflammatory injury. Pain. 2007;132(Suppl 1):S124–33.

    Article  PubMed  PubMed Central  Google Scholar 

  81. Helmeke C, Ovtscharoff W Jr, Poeggel G, et al. Imbalance of immunohistochemically characterized interneuron populations in the adolescent and adult rodent medial prefrontal cortex after repeated exposure to neonatal separation stress. Neuroscience. 2008;152:18–28.

    Article  PubMed  CAS  Google Scholar 

  82. Rokyta R, Yamamotova A, Slamberova R, et al. Prenatal and perinatal factors influencing nociception, addiction and behavior during ontogenetic development. Physiol Res. 2008;57(Suppl 3):S79–88.

    Article  PubMed  CAS  Google Scholar 

  83. Boasen JF, McPherson RJ, Hays SL, et al. Neonatal stress or morphine treatment alters adult mouse conditioned place preference. Neonatology. 2009;95:230–9.

    Article  PubMed  Google Scholar 

  84. Anand KJ, Brown MJ, Causon RC, et al. Can the human neonate mount an endocrine and metabolic response to surgery? J Pediatr Surg. 1985;20:41–8.

    Article  PubMed  CAS  Google Scholar 

  85. Anand KJ, Hansen DD, Hickey PR. Hormonal-metabolic stress responses in neonates undergoing cardiac surgery. Anesthesiology. 1990;73:661–70.

    Article  PubMed  CAS  Google Scholar 

  86. Grunau RE, Haley DW, Whitfield MF, et al. Altered basal cortisol levels at 3, 6, 8 and 18 months in infants born at extremely low gestational age. J Pediatr. 2007;150:151–6.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  87. Taddio A, Katz J, Ilersich AL, et al. Effect of neonatal circumcision on pain response during subsequent routine vaccination. Lancet. 1997;349:599–603.

    Article  PubMed  CAS  Google Scholar 

  88. Grunau RE, Whitfield MF, Petrie-Thomas J, et al. Neonatal pain, parenting stress and interaction, in relation to cognitive and motor development at 8 and 18 months in preterm infants. Pain. 2009;143:138–46.

    Article  PubMed  PubMed Central  Google Scholar 

  89. Anand KJ, Sippell WG, Aynsley-Green A. Randomised trial of fentanyl anaesthesia in preterm babies undergoing surgery: effects on the stress response. Lancet. 1987;1:62–6.

    Article  PubMed  CAS  Google Scholar 

  90. Anand KJ, Sippell WG, Schofield NM, et al. Does halothane anaesthesia decrease the metabolic and endocrine stress responses of newborn infants undergoing operation? Br Med J. 1988;296:668–72.

    Article  CAS  Google Scholar 

  91. Wolf AR, Eyres RL, Laussen PC, et al. Effect of extradural analgesia on stress responses to abdominal surgery in infants. Br J Anaesth. 1993;70:654–60.

    Article  PubMed  CAS  Google Scholar 

  92. Rao SC, Pirie S, Minutillo C, et al. Ward reduction of gastroschisis in a single stage without general anaesthesia may increase the risk of short-term morbidities: results of a retrospective audit. J Paediatr Child Health. 2009;45:384–8.

    Article  PubMed  Google Scholar 

  93. Anand KJ, Hickey PR. Halothane-morphine compared with high-dose sufentanil for anesthesia and postoperative analgesia in neonatal cardiac surgery. N Engl J Med. 1992;326:1–9.

    Article  PubMed  CAS  Google Scholar 

  94. Stang HJ, Gunnar MR, Snellman L, et al. Local anesthesia for neonatal circumcision. Effects on distress and cortisol response. JAMA. 1988;259:1507–11.

    Article  PubMed  CAS  Google Scholar 

  95. Keelan J, Bates TE, Clark JB. Heightened resistance of the neonatal brain to ischemia-reperfusion involves a lack of mitochondrial damage in the nerve terminal. Brain Res. 1999;821:124–33.

    Article  PubMed  CAS  Google Scholar 

  96. Hövels-Gürich HH, Seghaye MC, Schnitker R, et al. Long-term neurodevelopmental outcomes in school-aged children after neonatal arterial switch operation. J Thorac Cardiovasc Surg. 2002;124:448–58.

    Article  PubMed  Google Scholar 

  97. Hövels-Gürich HH, Bauer SB, Schnitker R, et al. Long-term outcome of speech and language in children after corrective surgery for cyanotic or acyanotic cardiac defects in infancy. Eur J Paediatr Neurol. 2008;12:378–86.

    Article  PubMed  Google Scholar 

  98. Kurth CD, Priestley M, Watzman HM, et al. Desflurane confers neurologic protection for deep hypothermic circulatory arrest in newborn pigs. Anesthesiology. 2001;95:959–64.

    Article  PubMed  CAS  Google Scholar 

  99. Loepke AW, Priestley MA, Schultz SE, et al. Desflurane improves neurologic outcome after low-flow cardiopulmonary bypass in newborn pigs. Anesthesiology. 2002;97:1521–7.

    Article  PubMed  CAS  Google Scholar 

  100. Zhao P, Zuo Z. Isoflurane preconditioning induces neuroprotection that is inducible nitric oxide synthase-dependent in neonatal rats. Anesthesiology. 2004;101:695–703.

    Article  PubMed  CAS  Google Scholar 

  101. Zhao P, Peng L, Li L, et al. Isoflurane preconditioning improves long-term neurologic outcome after hypoxic-ischemic brain injury in neonatal rats. Anesthesiology. 2007;107:963–70.

    Article  PubMed  CAS  Google Scholar 

  102. McAuliffe JJ, Joseph B, Vorhees CV. Isoflurane-delayed preconditioning reduces immediate mortality and improves striatal function in adult mice after neonatal hypoxia-ischemia. Anesth Analg. 2007;104:1066–77.

    Article  PubMed  CAS  Google Scholar 

  103. Luo Y, Ma D, Leong E, et al. Xenon and sevoflurane protect against brain injury in a neonatal asphyxia model. Anesthesiology. 2008;109:782–9.

    Article  PubMed  CAS  Google Scholar 

  104. McAuliffe JJ, Loepke AW, Miles L, et al. Desflurane, isoflurane, and sevoflurane provide limited neuroprotection against neonatal hypoxia-ischemia in a delayed preconditioning paradigm. Anesthesiology. 2009;111:533–46.

    Article  PubMed  CAS  Google Scholar 

  105. • Lin EP, Miles L, Hughes EA, et al. A combination of mild hypothermia and sevoflurane affords long-term protection in a modified neonatal mouse model of cerebral hypoxia-ischemia. Anesth Analg. 2014;119:1158–73. Report of a novel animal model of neonatal brain ischemia, using a protective strategy of mild hypothermia and sevoflurane to improve long-term neurocognitive outcome.

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Anesthesiology, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH, 45229, USA

    Erica P. Lin, Jeong-Rim Lee & Andreas W. Loepke

  2. Departments of Anesthesiology and Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, 45229, USA

    Erica P. Lin & Andreas W. Loepke

  3. Department of Anesthesiology and Pain Medicine, Yonsei University College of Medicine, Seoul, 120-752, Korea

    Jeong-Rim Lee

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  1. Erica P. Lin
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Correspondence to Andreas W. Loepke.

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This article is part of the Topical Collection on Pediatric Anesthesia.

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Lin, E.P., Lee, JR. & Loepke, A.W. Anesthetics and the Developing Brain: The Yin and Yang. Curr Anesthesiol Rep 5, 177–189 (2015). https://doi.org/10.1007/s40140-015-0107-8

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