Published Mar 1, 2021

Yi Tian  

Peiyu Liu

Weisong Liu

Qiaojing Xu

Xiangkun Zhao


General anesthesia is necessary for patients to undergo surgery and invasive procedures. However, numerous preclinical studies have demonstrated widespread developmental neurotoxicity of the commonly used anesthetics and sedatives for the immature brain. Clinical studies also suggest a strong correlation between childhood anesthesia exposure and subsequent behavioral or cognitive impairment in adulthood. These findings have attracted increasing attention of anesthesiologists, pediatricians, and caregivers about the safety of anesthesia exposure in children, especially during early childhood. Herein, the aim of this review was to present the molecular mechanism of general anesthesia and its effects on the developing brain and introduce the recent clinical evidence of changes in cognition function post-childhood general anesthesia exposure. More importantly, some of the spots will be importantly discussed to scrutinize the phenomena; only in this way, it may help minimize or eliminate relevant risk factors.



Anesthesia, General, Mental Disorders Diagnosed in Childhood, Cognition Disorders, Preventive Medicine, Environment Exposure

Supporting Agencies

This work was supported in part by the National Natural Scientific Foundation of China (NSFC, 81660195).

1. Rappaport BA, Suresh S, Hertz S, Evers AS, Orser BA. Anesthetic neurotoxicity-clinical implications of animal models. N Engl J Med 2015; 372(9):796-797. DOI: https://doi.org/10.1056/nejmp1414786

2. Disma N, Mondardini M, Terrando N, Absalom A, Bilotta F. A systematic review of the methodology applied during preclinical anesthetic neurotoxicity studies: Critical issues and lessons relevant to the design of future clinical research. Paediatr Anaesth 2016; 26(1):6-36. DOI: https://doi.org/10.1111/pan.12786

3. McCann ME, Graaff JC, Dorris L, Disma N, Withington DE, Bell G, Grobler A, Stargatt R, Hunt RW, Sheppard SJ, Marmor J, Giribaldi G, Bellinger DC, Hartmann PL, Hardy P, Frawley G, Izzo F, von Ungern Sternberg BS, Lynn A, Wilton N, Mueller M, Polaner DM, Absalom AR, Szmuk P, Morton N, Berde C, Soriano S, Davidson AJ. Neurodevelopmental outcome at five years of age after general anesthesia or awake-regional anesthesia in infancy (GAS): An international, multicentre, randomized controlled equivalence trial. Lancet 2019;393(10172):664-677. DOI: https://doi.org/10.1016/s0140-6736(18)32485-1

4. Rappaport B, Mellon RD, Simone A, Woodcock J. Defining safe use of anesthesia in children. N Engl J Med 2011; 364(15):1387-1390. DOI: https://doi.org/10.1056/nejmp1102155

5. Communication FDS. FDA review results in recent warnings about using general anesthetics and sedation drugs in young children and pregnant women. Available from http://www.fda.gov/drugs/drugsafety/ucm532356.htm (accessed 8 January 2017), 2016.

6. O'Leary JDWarner DO. What do recent human studies tell us about the association between anaesthesia in young children and neurodevelopmental outcomes? Br J Anaesth 2017; 119(3):458-464. DOI: https://doi.org/10.1093/bja/aex141

7. Lin E, Soriano S, Loepke A. Anesthetic neurotoxicity. Anesthesiol Clin 2014; 32(1):133-155. DOI: https://doi.org/10.1016/j.anclin.2013.10.003

8. Olsen RWLi GD. GABAA receptors as molecular targets of general anesthetics: identification of binding sites provides clues to allosteric modulation. Can J Anaesth 2011; 58(2):206-215. DOI: https://doi.org/10.1007/s12630-010-9429-7

9. Nelson LE, Guo TZ, Lu J, Saper CB, Franks NP, Maze M. The sedative component of anesthesia is mediated by GABAA receptors in an endogenous sleep pathway. Nat Neurosci 2002; 5(10):979-984. DOI: https://doi.org/10.1038/nn913

10. Arhem P, Klement G, Nilsson J. Mechanisms of anesthesia: towards integrating network, cellular, and molecular level modeling. Neuropsychopharmacology 2003; 28 Suppl 1:S40-S47. DOI: https://doi.org/10.1038/sj.npp.1300142

11. Sato Y, Kobayashi E, Murayama T, Mishina M, Seo N. Effect of N-methyl-D-aspartate receptor epsilon1 subunit gene disruption of the action of general anesthetic drugs in mice. Anesthesiology 2005; 102(3):557-561. DOI: https://doi.org/10.1097/00000542-200503000-00013

12. Lee SN, Li L, Zuo Z. Glutamate transporter type 3 knockout mice have a decreased isoflurane requirement to induce loss of righting reflex. Neuroscience 2010; 171(3):788-793. DOI: https://doi.org/10.1016/j.neuroscience.2010.09.044

13. Jevtovic-Todorovic V. Exposure of Developing Brain to General Anesthesia: What Is the Animal Evidence? Anesthesiology 2018; 128(4):832-839. DOI: https://doi.org/10.1097/aln.0000000000002047

14. Zhou X, Lu DH, Li WD, Chen XH, Yang XY, Chen X, Zhou ZB, Ye JH, Feng X. Sevoflurane affects oxidative stress and alters apoptosis status in children and cultured neural stem cells. Neurotox Res 2018; 33:790-800. DOI: https://doi.org/10.1007/s12640-017-9827-5

15. Franks NLieb W. Molecular and cellular mechanisms of general anaesthesia. Nature 1994; 367(6464):607-614. DOI: https://doi.org/10.1038/367607a0

16. 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(1):145-158. DOI: https://doi.org/10.1093/toxsci/kfm084

17. Ikonomidou C, Bosch F, Miksa M, Bittigau P, Vockler J, Dikranian K, Tenkova TI, Stefovska V, Turski L, Olney JW. Blockade of NMDA receptors and apoptotic neurodegeneration in the developing brain. Science 1999; 283(5398):70-74. DOI: https://doi.org/10.1126/science.283.5398.70

18. Boscolo A, Milanovic D, Starr JA, Sanchez V, Oklopcic A, Moy L, Ori CC, Erisir A, Jevtovic-Todorovic V. Early exposure to general anesthesia disturbs mitochondrial fission and fusion in the developing rat brain. Anesthesiology 2013; 118(5):1086-1097. DOI: https://doi.org/10.1097/aln.0b013e318289bc9b

19. Boscolo A, Starr JA, Sanchez V, Lunardi N, DiGruccio MR, Ori C, Erisir A, Trimmer P, Bennett J, Jevtovic-Todorovic V. The abolishment of anesthesia-induced cognitive impairment by timely protection of mitochondria in the developing rat brain: the importance of free oxygen radicals and mitochondrial integrity. Neurobiol Dis 2012; 45(3):1031-1041. DOI: https://doi.org/10.1016/j.nbd.2011.12.022

20. Ringler SL, Aye J, Byrne E, Anderson M, Turner CP. Effects of disrupting calcium homeostasis on neuronal maturation: early inhibition and later recovery. Cell Mol Neurobiol 2008; 28(3): 389-409. DOI: https://doi.org/10.1007/s10571-007-9255-9

21. Ramanantsoa N, Fleiss B, Bouslama M, Matrot B, Schwendimann L, Cohen-Salmon C, Gressens P, Gallego J. Bench to curbside: the path for developing a neuroprotectant. Transl Stroke Res 2013; 4(2):258-277. DOI: https://doi.org/10.1007/s12975-012-0233-2

22. Jia JK, Zhu JP, Yang QT, Wang YL, Zhang ZZ, Chen C.The role of histone acetylation in the sevoflurane-induced inhibition of neurogenesis in the hippocampi of young mice. Neuroscience 2020; 432:73-83. DOI: https://doi.org/10.1016/j.neuroscience.2020.02.023

23. Brambrink A, Back S, Riddle A, Gong X, Moravec M, Dissen G, Creeley C, Dikranian K, Olney J. Isoflurane-induced apoptosis of oligodendrocytes in the neonatal primate brain. Ann Neurol 2012; 72(4):525-535. DOI: https://doi.org/10.1002/ana.23652

24. Culley D, Cotran E, Karlsson E, Palanisamy A, Boyd J, Xie Z, Crosby G. Isoflurane affects the cytoskeleton but not survival, proliferation, or synaptogenic properties of rat astrocytes in vitro. Br J Anaesth 2013; 110 Suppl 1:i19-i28. DOI: https://doi.org/10.1093/bja/aet169

25. Jevtovic-Todorovic V, Hartman R, Izumi Y, Benshoff N, Dikranian K, Zorumski C, Olney J, Wozniak D. Early exposure to common anesthetic agents causes widespread neurodegeneration in the developing rat brain and persistent learning deficits. J Neurosci 2003; 23(3):876-882. DOI: https://doi.org/10.1523/jneurosci.23-03-00876.2003

26. Sanchez V, Feinstein S, Lunardi N, Joksovic P, Boscolo A, Todorovic S, Jevtovic-Todorovic V. General anesthesia causes long-term impairment of mitochondrial morphogenesis and synaptic transmission in developing rat brain. Anesthesiology 2011; 115(5):992-1002. DOI: https://doi.org/10.1097/aln.0b013e3182303a63

27. Walters JLPaule MG. Review of preclinical studies on pediatric general anesthesia-induced developmental neurotoxicity. Neurotoxicol Teratol 2017; 60:2-23. DOI: https://doi.org/10.1016/j.ntt.2016.11.005

28. Lee J, Zhang J, Wei L, Yu S. Neurodevelopmental implications of the general anesthesia in neonate and infants. Exp Neurol 2015; 272:50-60. DOI: https://doi.org/10.1016/j.expneurol.2015.03.028

29. O'Leary JD, Janus M, Duku E, Wijeysundera DN, To T, Li P, Maynes JT, Crawford MW. A population-based study evaluating the association between surgery in early life and child development at primary school entry. Anesthesiology 2016; 125(2):272-279. DOI: https://doi.org/10.1097/aln.0000000000001200

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):667-677. DOI: https://doi.org/10.1097/aln.0000000000001245

31. Glatz P, Sandin RH, Pedersen NL, Bonamy AK, Eriksson LI, Granath F. association of anesthesia and surgery during childhood with long-term academic performance. JAMA Pediatr 2017; 171(1):e163470. DOI: https://doi.org/10.1097/aln.0000000000001972

32. Davidson AJ, Disma N, de Graaff JC, Withington DE, Dorris L, Bell G, Stargatt R, Bellinger DC, Schuster T, Arnup SJ, Hardy P, Hunt RW, Takagi MJ, Giribaldi G, Hartmann PL, Salvo I, Morton NS, von Ungern Sternberg BS, Locatelli BG, Wilton N, Lynn A, Thomas JJ, Polaner D, Bagshaw O, Szmuk P, Absalom AR, Frawley G, Berde C, Ormond GD, Marmor J, McCann ME. Neurodevelopmental outcome at 2 years of age after general anaesthesia and awake-regional anaesthesia in infancy (GAS): An international multicentre, randomized controlled trial. Lancet 2016; 387(10015):239-250. DOI: https://doi.org/10.1016/s0140-6736(15)00608-x

33. Sun LS, Li G, Miller TL, Salorio C, Byrne MW, Bellinger DC, Ing C, Park R, Radcliffe J, Hays SR, DiMaggio CJ, Cooper TJ, Rauh V, Maxwell LG, Youn A, McGowan FX. Association between a single general anesthesia exposure before age 36 months and neurocognitive outcomes in later childhood. JAMA 2016; 315(21):2312-2320. DOI: https://doi.org/10.1001/jama.2016.6967

34. Wang X, Xu Z, Miao CH. Current clinical evidence on the effect of general anesthesia on neurodevelopment in children: An updated systematic review with meta-regression. PLoS One 2014; 9(1):e85760. DOI: https://doi.org/10.1371/journal.pone.008760

35. Backeljauw B, Holland SK, Altaye M, Loepke AW. Cognition and brain structure following early childhood surgery with anesthesia. Pediatrics 2015; 136(1):e1-e12. DOI: https://doi.org/10.1542/peds.2014-3526

36. Ing C, Wall MM, DiMaggio CJ, Whitehouse AJO, Hegarty MK, Sun M, von Ungern-Sternberg BS, Li G, Sun LS. Latent class analysis of neurodevelopmental deficit after exposure to anesthesia in early childhood. J Neurosurg Anesthesiol 2017; 29(3):264-273. DOI: https://doi.org/10.1097/ana.0000000000000303

37. Schneuer FJ, Bentley JP, Davidson AJ, Holland AJ, Badawi N, Martin AJ, Skowno J, Lain SJ, Nassar N. The impact of general anesthesia on child development and school performance: A population-based study. Paediatr Anaesth 2018; 28(6):528-536. DOI: https://doi.org/10.1111/pan.13390

38. Hofacer RD, Deng M, Ward CG, Joseph B, Hughes EA, Jiang C, Danzer SC, Loepke AW. Cell age-specific vulnerability of neurons to anesthetic toxicity. Ann Neurol 2013; 73(6):695-704. DOI: https://doi.org/10.1002/ana.23892

39. Stratmann G, Sall JW, May LD, Bell JS, Magnusson KR, Rau V, Visrodia KH, Alvi RS, Ku B, Lee MT, Dai R. Isoflurane differentially affects neurogenesis and long-term neurocognitive function in 60-day-old and 7-day-old rats. Anesthesiology 2009; 110(4):834-848. DOI: https://doi.org/10.1097/aln.0b013e31819c463d

40. 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):282-293. DOI: https://doi.org/10.1097/aln.0b013e318221fbbd

41. Huttenlocher PRDabholkar AS. Regional differences in synaptogenesis in human cerebral cortex. J Comp Neurol 1997; 387(2):167-178. DOI: https://doi.org/10.1002/(sici)1096-9861(19971020)387

42. Ing C, Sun M, Olfson M, DiMaggio CJ, Sun LS, Wall MM, Li G. Age at exposure to surgery and anesthesia in children and association with mental disorder diagnosis. Anesth Analg 2017; 125(6):1988-1998. DOI: https://doi.org/10.1213/ane.0000000000002423

43. Ing CH, DiMaggio CJ, Whitehouse AJ, Hegarty MK, Sun M, von Ungern-Sternberg BS, Davidson AJ, Wall MM, Li G, Sun LS. Neurodevelopmental outcomes after initial childhood anesthetic exposure between ages 3 and 10 years. J Neurosurg Anesthesiol 2014; 26(4):377-386. DOI: https://doi.org/10.1097/ana.0000000000000121

44. Kokubun H, Hisayo Jin H, Komita M, Aoe T. Conflicting Actions of inhalational anesthetics, neurotoxicity and neuroprotection, mediated by the unfolded protein response. Int J Mol Sci 2020; 21(450): In press. DOI: https://doi.org/10.3390/ijms21020450

45. Garcia Guerra G, Robertson CM, Alton GY, Joffe AR, Cave DA, Yasmin F, Dinu IA, Creighton DE, Ross DB, Rebeyka IM. Neurotoxicity of sedative and analgesia drugs in young infants with congenital heart disease: 4-year follow-up. Paediatr Anaesth 2014; 24(3):257-265. DOI: https://doi.org/10.1111/pan.12257

46. Andropoulos DB, Ahmad HB, Haq T, Brady K, Stayer SA, Meador MR, Hunter JV, Rivera C, Voigt RG, Turcich M, He CQ, Shekerdemian LS, Dickerson HA, Fraser CD, Dean McKenzie E, Heinle JS, Blaine Easley R. 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(3):266-274. DOI: https://doi.org/10.1111/pan.12350

47. Block RI, Thomas JJ, Bayman EO, Choi JY, Kimble KK, Todd MM. Are anesthesia and surgery during infancy associated with altered academic performance during childhood? Anesthesiology 2012; 117(3):494-503. DOI: https://doi.org/10.1097/aln.0b013e3182644684

48. 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(4):796-804. DOI: https://doi.org/10.1097/01.anes.0000344728.34332.5d

49. Ing C, Hegarty MK, Perkins JW, Whitehouse AJO, DiMaggio CJ, Sun M, Andrews H, Li G, Sun LS, von Ungern-Sternberg BS. Duration of general anaesthetic exposure in early childhood and long-term language and cognitive ability. Br J Anaesth 2017; 119(3):532-540. DOI: https://doi.org/10.1093/bja/aew413

50. Naumann H, Haberkern C, Pietila K, Birgfeld C, Starr J, Kapp-Simon K, Hopper R, Speltz M. Duration of exposure to cranial vault surgery: Associations with neurodevelopment among children with single-suture craniosynostosis. Paediatr Anaesth 2012; 22(11):1053-1061. DOI: https://doi.org/10.1111/j.1460-9592.2012.03843.x

51. Ing C, DiMaggio C, Whitehouse A, Hegarty MK, Brady J, von Ungern-Sternberg BS, Davidson A, Wood AJ, Li G, Sun LS. Long-term differences in language and cognitive function after childhood exposure to anesthesia. Pediatrics 2012; 130(3):e476-485. DOI: https://doi.org/10.1542/peds.2011-3822

52. Bong CL, Allen JC, Kim JT. The effects of exposure to general anesthesia in infancy on academic performance at age 12. Anesth Analg 2013; 117(6):1419-1428. DOI: https://doi.org/10.1213/ane.0b013e318299a7c2

53. Taghon T, Masunga A, Small R, Kashou N. A comparison of functional magnetic resonance imaging findings in children with and without a history of early exposure to general anesthesia. Paediatr Anaesth 2015; 25(3):239-246. DOI: https://doi.org/10.1111/pan.12606

54. DiMaggio C, Sun LS, Li G. Early childhood exposure to anesthesia and risk of developmental and behavioral disorders in a sibling birth cohort. Anesth Analg 2011; 113(5):1143-1151. DOI: https://doi.org/10.1213/ane.0b013e3182147f42

55. Flick RP, Katusic SK, Colligan RC, Wilder RT, Voigt RG, Olson MD, Sprung J, Weaver AL, Schroeder DR, Warner DO. Cognitive and behavioral outcomes after early exposure to anesthesia and surgery. Pediatrics 2011; 128(5):e1053-e1061. DOI: https://doi.org/10.1542/peds.2011-0351

56. Sprung J, Flick RP, Katusic SK, Colligan RC, Barbaresi WJ, Bojanic K, Welch TL, Olson MD, Hanson AC, Schroeder DR, Wilder RT, Warner DO. Attention-deficit/hyperactivity disorder after early exposure to procedures requiring general anesthesia. Mayo Clin Proc 2012; 87(2):120-129. DOI: https://doi.org/10.1016/j.mayocp.2011.11.008

57. Hu D, Flick RP, Zaccariello MJ, Colligan RC, Katusic SK, Schroeder DR, Hanson AC, Buenvenida SL, Gleich SJ, Wilder RT, Sprung J, Warner DO. Association between exposure of young children to procedures requiring general anesthesia and learning and behavioral outcomes in a population-based birth cohort. Anesthesiology 2017; 127(2):227-240. DOI: https://doi.org/10.1097/aln.0000000000001735

58. Warner DO, Zaccariello MJ, Katusic SK, Schroeder DR, Hanson AC, Schulte PJ, Buenvenida SL, Gleich SJ, Wilder RT, Sprung J, Hu D, Voigt RG, Paule MG, Chelonis JJ, Flick RP. 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. DOI: https://doi.org/10.1097/aln.0000000000002232

59. Shen X, Liu Y, Xu S, Zhao Q, Guo X, Shen R, Wang F. Early life exposure to sevoflurane impairs adulthood spatial memory in the rat. Neurotoxicology 2013; 39:45-56. DOI: https://doi.org/10.1016/j.neuro.2013.08.007

60. Yu D, Jiang Y, Gao J, Liu B, Chen P. Repeated exposure to propofol potentiates neuroapoptosis and long-term behavioral deficits in neonatal rats. Neurosci Lett 2013; 534:41-46. DOI: https://doi.org/10.1016/j.neulet.2012.12.033

61. Warner D, Shi Y, Flick R. Anesthesia and neurodevelopment in children: Perhaps the end of the beginning. Anesthesiology 2018; 128(4):700-703. DOI: https://doi.org/10.1097/aln.0000000000002121
How to Cite
Tian, Y., Liu, P., Liu, W., Xu, Q., & Zhao, X. (2021). Is Childhood General Anesthesia Exposure An Etiological Contributor to Cognitive Impairment?. Science Insights, 36(3), 251–259. https://doi.org/10.15354/si.21.re005