Postoperative Cognitive Effects in NewbornsThe Role of Inflammatory Processes

481 March 2013 M illions of children have surgery under anesthesia each year in the United states. The majority of these children receive volatile anesthetics-based general anesthesia. However, the safety of general anesthetics, especially volatile anesthetics, in children has become an active research field in the last 10 yr because the detrimental effects of general anesthetics on brain cell survival and cognitive functions have been revealed in animals.1 Although evidence for anesthetics-induced neurotoxicity in children has not been clearly demonstrated, some retrospective studies have shown that multiple surgeries under general anesthesia in young children may increase the risk of learning impairment later in life.2,3 Thus, it is important to investigate the detrimental effects of general anesthetics on young brains and the mechanisms for these effects in animal studies so that potential interventions can be designed for humans if the harmful effects of general anesthetics in children are confirmed in future studies. in this issue of Anesthesiology, two studies from Dr. Zhongcong Xie’s laboratory have been provided as examples of the basic research in this field.4,5 The first study by shen et al.4 showed that 6-day-old mice exposed to 3% sevoflurane for 2 h every day for 3 days had cognitive impairment assessed by the Morris Water Maze at 1 month of age. These mice also had neuroinflammation as evidenced by increased interleukin-6, tumor necrosis factor-α, and ionized calcium-binding adaptor molecule 1-positive cells (a marker of microglial activation) in the brain at the end of sevoflurane exposure (8-day-old mice). The cognitive impairment was attenuated by an enriched environment and ketorolac, an antiinflammatory agent. in contrast, exposure of 60-day-old mice to 2% sevoflurane for 2 h every day for 3 days did not induce cognitive impairment and neuroinflammation. Exposure of 6-day-old mice to 3% sevoflurane for 2 h once or to 9% desflurane for 2 h every day for 3 days also did not induce cognitive impairment and neuroinflammation. The brain in the growth-spurt period (up to postnatal 36 months in humans and 3 weeks in rodents)6 is particularly susceptible to various insults. Wilder et al.2 have found that children who had three, but not one, exposures to anesthesia and surgery at an early age (before 4 yr of age) are at an increased risk to develop learning disabilities. The results of shen’s study4 that three, but not one, exposures to sevoflurane anesthesia lead to cognitive impairment in young mice replicate the findings of the study by Wilder et al. in children, and suggest a potential role of sevoflurane anesthesia alone in the clinically observed learning disability in children after anesthesia and surgery. Also, shen et al.4 found that enriched environment reduced sevoflurane-induced cognitive impairment, suggesting that simple behavioral intervention(s) may be used to attenuate this potential detrimental effect of anesthetics on children. The second study from Xie’s group published in this issue of Anesthesiology exposed pregnant mice at gestation stage day 14 to 2.5% sevoflurane for 2 h.5 This exposure increased activated caspase-3 and interleukin-6 levels and reduced the levels of postsynaptic density-95, a synaptic protein, in the brain tissues of the fetal mice. sevoflurane anesthesia in pregnant mice also increased interleukin-6 levels and reduced the levels of postsynaptic density-95 and synaptophysin, another synaptic protein, in the brain tissues of the offspring mice at postnatal day 31. More importantly, exposure of fetal mice to sevoflurane induced cognitive impairment assessed at postnatal day Postoperative Cognitive Effects in Newborns