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Updates: Effect of age on vulnerability to neurotoxicity of anesthesia in children

The age at which the developing human brain may be most vulnerable to neurotoxic effects of anesthetic drugs is unknown. A large retrospective study compared the risk of a mental health diagnosis or developmental delay for children in 11 separate age cohorts (from <28 weeks to 5 years) undergoing minor common surgical procedures with matched controls. Although there was an increased risk for a mental health disorder or developmental delay in children with anesthesia exposure (hazard ratios 1.26 to 1.31), there was no difference in risk between the different age cohorts. There is little support for delaying necessary minor surgery in young children to reduce neurodevelopmental risks. 

The age at which the developing human brain may be most vulnerable to neurotoxic effects of anesthetic drugs is unknown, and is controversial. Whereas brain development extends from the embryonic period until and through adolescence, neurodevelopment may be more susceptible to environmental insult during specific periods depending on the toxicant. In rodent studies, the vulnerable period to anesthesia is thought to correspond to the period of maximal synaptogenesis (ie, approximately two days before birth until two weeks after birth), based solely on findings of induced apoptosis and neurodegeneration during this time period. Translation of this data to humans is debated as synaptogenesis in children peaks at under six months of age in the sensorimotor cortex, at approximately 10 months of age in the parietal and temporal cortices, and at approximately age three years in the prefrontal cortex.

Studies on neurotoxicity have involved children exposed to anesthesia from as early as birth to as late as 10 years of age. While some studies have found varying risk of neurodevelopmental deficit based on the age at exposure to anesthesia, most have not accounted for the fact that children tend to receive different procedures at different ages.

●In one study, children exposed to anesthesia before age three had an increased risk of deficits in language and reasoning, but the same deficits were not present in children exposed between ages three and five, and 5 and 10, suggesting a potential vulnerability at a younger age.

●The opposite result, however, was found in one of the studies from Canada, finding that children exposed between ages two and four years were more likely to have deficits than children exposed from age zero to two years, suggesting vulnerability at an older age. In this study, however, the majority of children exposed at ages two to four years received anesthesia for dental procedures. It is possible that children who require anesthesia for dental procedures have a higher incidence of underlying behavioral problems compared to children who do not require anesthesia for these procedures.

●One other large retrospective study compared the risk of a mental health diagnosis or developmental delay for children in eleven separate age cohorts (from <28 weeks to 5 years) undergoing minor common surgical procedures with matched controls. Although there was an increased risk for a mental health disorder or specifically developmental delay or attention deficit hyperactivity disorder (ADHD) in children with anesthesia exposure (hazard ratios 1.26 to 1.31), there was no difference in risk between the different age cohorts. There is little support for delaying necessary minor surgery in young children to reduce neurodevelopmental risks.

References:
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Environmental toxicology: Sensitive periods of development and neurodevelopmental disorders. Heyer DB, Meredith RM . Neurotoxicology. 2017;58:23. Epub 2016 Nov 4.  PMID 27825840

Comparative aspects of the brain growth spurt. Dobbing J, Sands J . Early Hum Dev. 1979;3(1):79.  PMID 118862

Control of postnatal apoptosis in the neocortex by RhoA-subfamily GTPases determines neuronal density. Sanno H, Shen X, Kuru N, Bormuth I, Bobsin K, Gardner HA, Komljenovic D, Tarabykin V, Erzurumlu RS, Tucker KL . J Neurosci. 2010;30(12):4221.  PMID 20335457

Anesthesia induces neuronal cell death in the developing rat brain via the intrinsic and extrinsic apoptotic pathways. Yon JH, Daniel-Johnson J, Carter LB, Jevtovic-Todorovic V . Neuroscience. 2005;135(3):815. Epub 2005 Sep 8.  PMID 16154281

Imaging the developing brain: what have we learned about cognitive development? Casey BJ, Tottenham N, Liston C, Durston S . Trends Cogn Sci. 2005;9(3):104.  PMID 15737818

Imaging the developing brain: what have we learned about cognitive development? Casey BJ, Tottenham N, Liston C, Durston S . Trends Cogn Sci. 2005;9(3):104.  PMID 15737818

Neurodevelopmental outcomes after initial childhood anesthetic exposure between ages 3 and 10 years. Ing CH, DiMaggio CJ, Whitehouse AJ, Hegarty MK, Sun M, von Ungern-Sternberg BS, Davidson AJ, Wall MM, Li G, Sun LS . J Neurosurg Anesthesiol. 2014;26(4):377. PMID 25144506

Age at Exposure to Surgery and Anesthesia in Children and Association With Mental Disorder Diagnosis. Ing C, Sun M, Olfson M, DiMaggio CJ, Sun LS, Wall MM, Li G . Anesth Analg. 2017;125(6):1988.  PMID 28857799