Anaesthesia for the Growing Brain

Author(s): Divya Raviraj*, Thomas Engelhardt, Tom G. Hansen.

Journal Name: Current Pharmaceutical Design

Volume 25 , Issue 19 , 2019


Despite the long history of paediatric anaesthesia, there is still much to be discovered regarding how exposure to anaesthesia affects the developing brain. Given that commonly used anaesthetic agents are thought to exert their effect via N-Methyl-D-Aspartate (NMDA) and gamma-aminobutyric acid A (GABAA) receptors, it is biologically plausible that exposure during periods of vulnerable brain development may affect long term outcome. There are numerous animal studies which suggest lasting neurological changes. However, whether this risk also applies to humans is unclear given the varying physiological development of different species and humans. Human studies are emerging and ongoing and their results are producing conflicting data. The purpose of this review is to summarize the currently available evidence and consider how this may be used to minimize harm to the paediatric population undergoing anaesthesia.

Keywords: Paediatric anaesthesia, neurotoxicity, neurocognition, gamma-aminobutyric acid, brain development, N-Methyl-D-Aspartate.

FDA drug safety communication: FDA review results in new warnings about using general anesthetics and sedation drugs in young children and pregnant women
Disma N, Hansen TG. Pediatric anesthesia and neurotoxicity: Can findings be translated from animals to humans? Minerva Anestesiol 2016; 82(7): 791-792-6.
Sinner B, Becke K, Engelhard K. General anaesthetics and the developing brain: an overview. Anaesthesia 2014; 69(9): 1009-22.
[] [PMID: 24829066]
Hansen TG, Engelhardt T. Long-term neurocognitive outcomes following surgery and anaesthesia in early life. Curr Opin Anaesthesiol 2018; 31(3): 297-301.
[] [PMID: 29432291]
Kuida K, Zheng TS, Na S, et al. Decreased apoptosis in the brain and premature lethality in CPP32-deficient mice. Nature 1996; 384(6607): 368-72.
[] [PMID: 8934524]
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.
[] [PMID: 21701379]
Brambrink AM, Evers AS, Avidan MS, et al. Ketamine-induced neuroapoptosis in the fetal and neonatal rhesus macaque brain. Anesthesiology 2012; 116(2): 372-84.
[] [PMID: 22222480]
Zhu C, Gao J, Karlsson N, et al. Isoflurane anesthesia induced persistent, progressive memory impairment, caused a loss of neural stem cells, and reduced neurogenesis in young, but not adult, rodents. J Cereb Blood Flow Metab 2010; 30(5): 1017-30.
[] [PMID: 20068576]
Yon JH, Daniel-Johnson J, Carter LB, Jevtovic-Todorovic V. Anesthesia induces neuronal cell death in the developing rat brain via the intrinsic and extrinsic apoptotic pathways. Neuroscience 2005; 135(3): 815-27.
[] [PMID: 16154281]
Lin EP, Lee JR, Lee CS, Deng M, Loepke AW. Do anesthetics harm the developing human brain? An integrative analysis of animal and human studies. Neurotoxicol Teratol 2017; 60: 117-28.
[] [PMID: 27793659]
Hofacer RD, Deng M, Ward CG, et al. Cell age-specific vulnerability of neurons to anesthetic toxicity. Ann Neurol 2013; 73(6): 695-704.
[] [PMID: 23526697]
Creeley C, Dikranian K, Dissen G, Martin L, Olney J, Brambrink A. Propofol-induced apoptosis of neurones and oligodendrocytes in fetal and neonatal rhesus macaque brain. Br J Anaesth 2013; 110(1)(Suppl. 1): i29-38.
[] [PMID: 23722059]
Creeley CE, Dikranian KT, Dissen GA, Back SA, Olney JW, Brambrink AM. Isoflurane-induced apoptosis of neurons and oligodendrocytes in the fetal rhesus macaque brain. Anesthesiology 2014; 120(3): 626-38.
[] [PMID: 24158051]
Johnson SA, Young C, Olney JW. Isoflurane-induced neuroapoptosis in the developing brain of nonhypoglycemic mice. J Neurosurg Anesthesiol 2008; 20(1): 21-8.
[] [PMID: 18157021]
Briner A, De Roo M, Dayer A, Muller D, Habre W, Vutskits L. Volatile anesthetics rapidly increase dendritic spine density in the rat medial prefrontal cortex during synaptogenesis. Anesthesiology 2010; 112(3): 546-56.
[] [PMID: 20124985]
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(3): 876-82.
[] [PMID: 12574416]
Cattano D, Young C, Straiko MMW, Olney JW. Subanesthetic doses of propofol induce neuroapoptosis in the infant mouse brain. Anesth Analg 2008; 106(6): 1712-4.
[] [PMID: 18499599]
Slikker W Jr. Zou X, Hotchkiss CE, et al. Ketamine-induced neuronal cell death in the perinatal rhesus monkey. J Toxicol Sci 2007; 98(1): 145-58.
Scallet AC, Schmued LC, Slikker W Jr, et al. Developmental neurotoxicity of ketamine: Morphometric confirmation, exposure parameters, and multiple fluorescent labeling of apoptotic neurons. Toxicol Sci 2004; 81(2): 364-70.
[] [PMID: 15254342]
Sinner B, Friedrich O, Zausig Y, Bein T, Graf BM. Toxic effects of midazolam on differentiating neurons in vitro as a consequence of suppressed neuronal Ca2+-oscillations. Toxicology 2011; 290(1): 96-101.
[] [PMID: 21920406]
Bittigau P, Sifringer M, Genz K, et al. Antiepileptic drugs and apoptotic neurodegeneration in the developing brain. Proc Natl Acad Sci USA 2002; 99(23): 15089-94.
[] [PMID: 12417760]
Vutskits L, Xie Z. Lasting impact of general anaesthesia on the brain: Mechanisms and relevance. Nat Rev Neurosci 2016; 17(11): 705-17.
[] [PMID: 27752068]
Mutch WAC, El-Gabalawy RM, Graham MR. Postoperative delirium, learning, and anesthetic neurotoxicity: Some perspectives and directions. Front Neurol 2018; 9(9): 177.
[] [PMID: 29615969]
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): 1143-51.
[] [PMID: 21415431]
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
[] [PMID: 27820621]
Wilder RT, Flick RP, Sprung J, et al. Early exposure to anesthesia and learning disabilities in a population-based birth cohort. Anesthesiology 2009; 110(4): 796-804.
[] [PMID: 19293700]
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.
[] [PMID: 27655179]
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(5): 1076-85.
[] [PMID: 21368654]
Hansen TG, Pedersen JK, Henneberg SW, Morton NS, Christensen K. Educational outcome in adolescence following pyloric stenosis repair before 3 months of age: A nationwide cohort study. Paediatr Anaesth 2013; 23(10): 883-90.
[] [PMID: 23863116]
Davidson AJ, Disma N, de Graaff JC, 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.
[] [PMID: 26507180]
McCann ME, de Graaff JC, Dorris L, et al. Neurodevelopmental outcome at 5 years of age after general anaesthesia or awake-regional anaesthesia in infancy (GAS): An international, multicentre, randomised, controlled equivalence trial. Lancet 2019; 393(10172): 664-77.
[] [PMID: 30782342]
Sun LS, Li G, Miller TL, 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.
[] [PMID: 27272582]
Warner DO, Zaccariello MJ, Katusic SK, 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.
[] [PMID: 29672337]
Szmuk P, Andropoulos D, McGowan F, et al. An open label pilot study of a dexmedetomidine-remifentanil-caudal anesthetic for infant lower abdominal/lower extremity surgery: The T REX pilot study. Paediatr Anaesth 2019; 29(1): 59-67.
[] [PMID: 30428151]
Clausen NG, Kähler S, Hansen TG. Systematic review of the neurocognitive outcomes used in studies of paediatric anaesthesia neurotoxicity. Br J Anaesth 2018; 120(6): 1255-73.
[] [PMID: 29793593]
Weiss M, Vutskits L, Hansen TG, Engelhardt T. Safe Anesthesia For Every Tot - The SAFETOTS initiative. Curr Opin Anaesthesiol 2015; 28(3): 302-7.
[] [PMID: 25887194]

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2019
Page: [2165 - 2170]
Pages: 6
DOI: 10.2174/1381612825666190702151030
Price: $58

Article Metrics

PDF: 31
PRC: 1