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Neurotoxicity of Anesthesia in Children: Prevention and Treatment

  • Amy E. Vinson
  • Constance S. Houck
Pediatric Neurology (A Yeshokumar, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Pediatric Neurology

Abstract

Purpose of review

The purpose of this review is to summarize the current evidence regarding the impact of the exposure to anesthetic and sedative agents on neurodevelopment during the period of rapid brain growth in the first 3 years of life. Though much of the definitive data demonstrating anesthesia-induced neurotoxicity has come from studies in young animals, the focus of this review is on emerging human data.

Recent findings

In 2016, the first prospective trials investigating the neurodevelopmental impact of early anesthetic exposure (GAS and PANDA studies) were published, both showing no significant impact on IQ from a single brief anesthetic. More recent population cohort analyses have shown varying, but minimal, impacts from early anesthetic exposure on academic performance and IQ, much smaller than that of maternal education and other environmental factors.

Summary

Animal and human data document that post-anesthetic neurotoxicity is a genuine phenomenon, but its long-term clinical significance is uncertain. Most experts would agree that a single, brief anesthetic likely has no significant impact on neurodevelopment, but it is yet to be determined whether longer exposures or multiple anesthetics are associated with subsequent learning issues. Future research is aimed at determining the mechanisms of neuronal injury from exposure to anesthetic and sedative agents, adjunctive medications that may prevent or ameliorate this injury, and therapeutic approaches such as early intervention that can enhance recovery. While these studies are underway, it is recommended that exposure to anesthetic and sedative agents be minimized in young children and consideration be given to alternative methods of immobilization for nonpainful procedures such as radiologic imaging.

Keywords

Anesthetic neurotoxicity Anesthetic exposure Sedation exposure Pediatric anesthesia neurotoxicity Post-anesthetic neurotoxicity 

Notes

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflicts of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    US Food and Drug Administration. FDA drug safety communication: FDA review results in new warnings about using general anesthetics and sedation drugs in young children and pregnant women. 2016. https://www.fda.gov/drugs/drugsafety/ucm532356.htm. Accessed 20 July 2018.
  2. 2.
    US Food and Drug Administration. FDA drug safety communication: FDA approves label changes for use of general anesthetic and sedation drugs in young children. 2017. https://www.fda.gov/downloads/Drugs/DrugSafety/UCM554644.pdf. Accessed 20 July 2018.
  3. 3.
    Anand KJ, Hickey PR. Pain and its effects in the human neonate and fetus. N Engl J Med. 1987;317(21):1321–9.CrossRefGoogle Scholar
  4. 4.
    van der Griend BF, Lister NA, McKenzie IM, et al. Postoperative mortality in children after 101,885 anesthetics at a tertiary pediatric hospital. Anesth Analg. 2011;112(6):1440–7.CrossRefGoogle Scholar
  5. 5.
    Flick RP, Sprung J, Harrison TE, Gleich SJ, Schroeder DR, Hanson AC, et al. Perioperative cardiac arrests in children between 1988 and 2005 at a tertiary referral center: a study of 92,881 patients. Anesthesiology. 2007;106(2):226–37.CrossRefGoogle Scholar
  6. 6.
    Bhananker SM, Ramamoorthy C, Geiduschek JM, Posner KL, Domino KB, Haberkern CM, et al. Anesthesia-related cardiac arrest in children: update from the pediatric perioperative cardiac arrest registry. Anesth Analg. 2007;105(2):344–50.CrossRefGoogle Scholar
  7. 7.
    Shi Y, Hu D, Rodgers EL, Katusic SK, Gleich SJ, Hanson AC, et al. Epidemiology of general anesthesia prior to age 3 in a population-based birth cohort. Paediatr Anaesth. 2018;28(6):513–9.CrossRefGoogle Scholar
  8. 8.
    Bartels DD, McCann ME, Davidson AJ, Polaner DM, Whitlock EL, Bateman BT. Estimating pediatric general anesthesia exposure: quantifying duration and risk. Paediatr Anaesth. 2018;28(6):520–7.CrossRefGoogle Scholar
  9. 9.
    Ikonomidou C, Bosch F, Miksa M, Bittigau P, Vöckler J, Dikranian K, et al. Blockade of NMDA receptors and apoptotic neurodegeneration in the developing brain. Science. 1999;283(5398):70–4.CrossRefGoogle Scholar
  10. 10.
    Jevtovic-Todorovic V, Hartman RE, Izumi Y, Benshoff ND, Dikranian K, Zorumski CF, et al. Early exposure to common anesthetic agents causes widespread neurodegeneration in the developing rat brain and persistent learning deficits. J Neurosci. 2003;23(3):876–82.CrossRefGoogle Scholar
  11. 11.
    Brambrink AM, Evers AS, Avidan MS, Farber NB, Smith DJ, Zhang X, et al. Isoflurane-induced neuroapoptosis in the neonatal rhesus macaque brain. Anesthesiology. 2010;112(4):834–41.CrossRefGoogle Scholar
  12. 12.
    Paule MG, Li M, Allen RR, Liu F, Zou X, Hotchkiss C, et al. Ketamine anesthesia during the first week of life can cause long-lasting cognitive deficits in rhesus monkeys. Neurotoxicol Teratol. 2011;33(2):220–30.CrossRefGoogle Scholar
  13. 13.
    Stratmann G, Sall JW, May LDV, Bell JS, Magnusson KR, Rau V, et al. Isoflurane differentially affects neurogenesis and long-term neurocognitive function in 60-day-old and 7-day-old rats. Anesthesiology. 2009;110(4):834–48.CrossRefGoogle Scholar
  14. 14.
    Briner A, Nikonenko I, De Roo M, Dayer A, Muller D, Vutskits L. Developmental stage-dependent persistent impact of propofol anesthesia on dendritic spines in the rat medial prefrontal cortex. Anesthesiology. 2011;115(2):282–93.CrossRefGoogle Scholar
  15. 15.
    Lunardi N, Hucklenbruch C, Latham JR, Scarpa J, Jevtovic-Todorovic V. Isoflurane impairs immature astroglia development in vitro: the role of actin cytoskeleton. J Neuropathol Exp Neurol. 2011;70(4):281–91.CrossRefGoogle Scholar
  16. 16.
    Sanchez V, Feinstein SD, Lunardi N, Joksovic PM, Boscolo A, Todorovic SM, et al. General anesthesia causes long-term impairment of mitochondrial morphogenesis and synaptic transmission in developing rat brain. Anesthesiology. 2011;115(5):992–1002.CrossRefGoogle Scholar
  17. 17.
    Jackson WM, Gray CDB, Jiang D, Schaefer ML, Connor C, Mintz CD. Molecular mechanisms of anesthetic neurotoxicity: a review of the current literature. J Neurosurg Anesthesiol. 2016;28(4):361–72.CrossRefGoogle Scholar
  18. 18.
    Yang M, Wei H. Anesthetic neurotoxicity: apoptosis and autophagic cell death mediated by calcium dysregulation. Neurotoxicol Teratol. 2017;60:59–62.CrossRefGoogle Scholar
  19. 19.
    Saito H, Kato R, Hashimoto T, Uchida Y, Hase T, Tsuruga K, et al. Influence of nitrous oxide on granule cell migration in the dentate gyrus of the neonatal rat. Biomed Res. 2018;39(1):39–45.CrossRefGoogle Scholar
  20. 20.
    Jiang S, Li X, Jin W, Duan X, Bo L, Wu J, et al. Ketamine-induced neurotoxicity blocked by N-methyl-d-aspartate is mediated through activation of PKC/ERK pathway in developing hippocampal neurons. Neurosci Lett. 2018;673:122–31.CrossRefGoogle Scholar
  21. 21.
    Yu D, Li L, Yuan W. Neonatal anesthetic neurotoxicity: insight into the molecular mechanisms of long-term neurocognitive deficits. Biomed Pharmacother. 2017;87:196–9.CrossRefGoogle Scholar
  22. 22.
    Sanders RD, Hassell J, Davidson AJ, Robertson NJ, Ma D. Impact of anaesthetics and surgery on neurodevelopment: an update. Br J Anaesth. 2013;110(suppl 1):i53–72.CrossRefGoogle Scholar
  23. 23.
    Zhou Z, Ma D. Anaesthetics-induced neurotoxicity in developing brain: an update on preclinical evidence. Brain Sci Multidisciplinary Digital Publishing Institute. 2014;4(1):136–49.CrossRefGoogle Scholar
  24. 24.
    Shih J, May LDV, Gonzalez HE, Lee EW, Alvi RS, Sall JW, et al. Delayed environmental enrichment reverses sevoflurane-induced memory impairment in rats. Anesthesiology. 2012;116(3):586–602.CrossRefGoogle Scholar
  25. 25.
    Wilder RT, Flick RP, Sprung J, Katusic SK, Barbaresi WJ, Mickelson C, et al. Early exposure to anesthesia and learning disabilities in a population-based birth cohort. Anesthesiology. 2009;110(4):796–804.CrossRefGoogle Scholar
  26. 26.
    DiMaggio C, Sun LS, Kakavouli A, Byrne MW, Li G. 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):286–91.CrossRefGoogle Scholar
  27. 27.
    Bartels M, Althoff RR, Boomsma DI. Anesthesia and cognitive performance in children: no evidence for a causal relationship. Twin Res Hum Genet. 2009;12(3):246–53.CrossRefGoogle Scholar
  28. 28.
    •• Sun LS, Li G, Miller TLK, Salorio C, Byrne MW, Bellinger DC, et al. Association between a single general anesthesia exposure before age 36 months and neurocognitive outcomes in later childhood. JAMA. 2016;315(21):2312–20. This is a sibling matched prospective analysis of children undergoing hernia repair prior to age 36 months. They found no significant difference in behavior or IQ, including subset analysis of IQ.CrossRefGoogle Scholar
  29. 29.
    •• Davidson AJ, Disma N, de Graaff JC, Withington DE, Dorris L, Bell G, et al. Neurodevelopmental outcome at 2 years of age after general anaesthesia and awake-regional anaesthesia in infancy (GAS): an international multicentre, randomised controlled trial. Lancet. 2016;387(10015):239–50. This the first randomized controlled trial investigating post-anesthetic neurotoxicity in the young and represents secondary outcome data at 2 years of age. They found no significant impact from a single brief anesthetic on neurodevelopment as measured.CrossRefGoogle Scholar
  30. 30.
    Graham MR, Brownell M, Chateau DG, Dragan RD, Burchill C, Fransoo RR. Neurodevelopmental assessment in kindergarten in children exposed to general anesthesia before the age of 4 years: a retrospective matched cohort study. Anesthesiology. 2016;125(4):667–77.CrossRefGoogle Scholar
  31. 31.
    •• Glatz P, Sandin RH, Pedersen NL, Bonamy A-K, Eriksson LI, Granath F. Association of anesthesia and surgery during childhood with long-term academic performance. JAMA Pediatr. 2017;171(1):e163470 This large Swedish cohort analysis demonstrated a small difference in exposed vs. non-exposed children at 16 and 18 years of age, but noted that this difference was orders of magnitude less than many environmental factors, such a maternal education level and month of birth.CrossRefGoogle Scholar
  32. 32.
    • Warner DO, Zaccariello MJ, Katusic SK, Schroeder DR, Hanson AC, Schulte PJ, et al. Neuropsychological and behavioral outcomes after exposure of young children to procedures requiring general anesthesia: The mayo anesthesia safety in kids (MASK) study. Anesthesiology. 2018;129(1):89–105. This is a birth cohort study of children who are exposed to anesthesia singly and multiply. They demonstrate parental report of behavioral changes and concerns with executive function and reading in the multiply exposed group.CrossRefGoogle Scholar
  33. 33.
    Schneuer FJ, Bentley JP, Davidson AJ, Holland AJ, Badawi N, Martin AJ, et al. The impact of general anesthesia on child development and school performance: a population-based study. Paediatr Anaesth. 2018;28(6):528–36.CrossRefGoogle Scholar
  34. 34.
    • Orser BA, Suresh S, Evers AS. SmartTots update regarding anesthetic neurotoxicity in the developing brain. Anesth Analg. 2018;126(4):1393–6. This is an update from the SmartTots collaborative outlining the current state of research and goals for continued innovation and understanding. CrossRefGoogle Scholar
  35. 35.
    American Academy of Pediatrics – Section on Perinatal Pediatrics. Five things physicians and patients should question. 2015. http://www.choosingwisely.org/societies/american-academy-of-pediatrics-section-on-perinatal-pediatrics/. Accessed 16 Aug 2018.
  36. 36.
    American Academy of Pediatrics. Neuroimaging (CT, MRI) is not necessary in a child with simple febrile seizures. 2018. http://www.choosingwisely.org/clinician-lists/american-academy-pediatrics-neuroimaging-for-simple-febrile-seizure/. Accessed 16 Aug 2018.

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Anesthesiology, Critical Care and Pain MedicineBoston Children’s Hospital and Harvard Medical SchoolBostonUSA

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