Zhang Tao, Lee Yulim, Ju Xianshu, Park Jiho, Hong Boohwi, Cui Jianchen, Kim Yeonsu, Kim Seongeun, Choi Chul Hee, Heo Jun Young, Chung Woosuk
Department of Medical Science, Chungnam National University School of Medicine, Daejeon, Korea.
Brain Korea 21 FOUR Project for Medical Science, Chungnam National University, Daejeon, Korea.
Korean J Anesthesiol. 2025 Aug;78(4):382-394. doi: 10.4097/kja.24768. Epub 2025 Apr 9.
Despite strong preclinical evidence, clinical studies have reported minimal effects of early anesthesia on neurodevelopment. This discrepancy may be due to limitations of preclinical studies, including the absence of clear criteria for appropriate anesthetic depth, lack of physiological monitoring, and absence of a surgical insult. Therefore, we aimed to evaluate the effects of sevoflurane in a more clinically relevant setting by addressing these known limitations.
After confirming robust burst suppression (BS) at 2.5% sevoflurane, postnatal day 17 (PND17) mice were assigned to three groups: a Control group, no intervention; BS (-) group, surgery with 1.4% sevoflurane; and a BS (+) group, surgery with 1.4%-2.5% sevoflurane. Total duration of anesthesia was 2 h, and blood pressure was non-invasively measured in a subset of mice. Long-term behavioral changes were evaluated from PND56 to PND62 at a two-day interval.
We found subtle but significant changes in anxiety and sociability only in BS (+) group mice. Change in anxiety level was observed in the light/dark box test, with the number of transitions between chambers significantly lower in the BS (+) group (P = 0.025). Reduced sociability was observed in the three-chamber test, as mice in the BS (+) group did not significantly prefer the chamber containing a stranger mouse (P = 0.065).
Both surgery and excessive anesthesia depth are necessary to induce subtle yet long-term behavioral changes in young mice. Future preclinical studies should reconsider sevoflurane concentration and account for surgical trauma as a significant factor when investigating anesthesia-induced neurotoxicity.
尽管临床前证据充分，但临床研究报告称早期麻醉对神经发育的影响微乎其微。这种差异可能是由于临床前研究的局限性，包括缺乏明确的合适麻醉深度标准、缺乏生理监测以及没有手术创伤。因此，我们旨在通过解决这些已知的局限性，在更符合临床实际的环境中评估七氟醚的影响。
在确认2.5%七氟醚可产生稳定的爆发抑制（BS）后，将出生后第17天（PND17）的小鼠分为三组：对照组，不进行干预；BS（-）组，使用1.4%七氟醚进行手术；BS（+）组，使用1.4%-2.5%七氟醚进行手术。麻醉总时长为2小时，对部分小鼠进行无创血压测量。在PND56至PND62期间，每隔两天评估长期行为变化。
我们发现仅在BS（+）组小鼠中焦虑和社交能力出现了细微但显著的变化。在明暗箱试验中观察到焦虑水平的变化，BS（+）组在不同箱体间的转换次数显著减少（P = 0.025）。在三室试验中观察到社交能力下降，因为BS（+）组小鼠对含有陌生小鼠的箱体没有明显偏好（P = 0.065）。
手术和过度的麻醉深度对于在幼鼠中诱导细微但长期的行为变化都是必要的。未来的临床前研究在调查麻醉诱导的神经毒性时，应重新考虑七氟醚浓度，并将手术创伤作为一个重要因素加以考虑。
