General anesthetics and the developing brain: friends or foes?
General anesthetics and the developing brain: friends or foes?
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全身麻醉与大脑发育：是朋友还是敌人？
DOI：
10.1097/01.ana.0000178111.26972.16
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发表时间：
2005
期刊：
影响因子：
--
通讯作者：
Jevtovic-Todorovic,Vesna
中科院分区：
文献类型：
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作者：
Jevtovic-Todorovic,Vesna
在过去 50-60 年间，幼儿麻醉干预的数量呈指数级增长。它们越来越复杂，因此需要积极且高技能的麻醉管理。此外，由于早产率迅速上升（占总出生率的 12%）1, 2，并且由于新生儿重症监护病房 (NNICU) 中早产儿（受孕后 20 周）的存活率稳步上升，麻醉专业人员经常参与在人类发育的早期阶段提供麻醉护理（例如多次手术干预、在 NNICU 中长时间镇静等）。人类的中枢神经系统（CNS）在出生时尚未完全发育，并在出生后经历剧烈的成熟。出生时大脑重约 300 克，6 个月时体积增加一倍，12 个月时几乎增加两倍。 3 这被称为大脑生长突增期或突触发生期。 4 人类的突触发生既是产前现象，也是产后现象（从怀孕六个月到出生后几年）。在此期间，神经元迁移到最终目的地，并通过大幅扩展其树突表面以适应传入的轴突接触，形成数万亿个突触连接，从而为同步形成有意义的神经元回路奠定了基础。无情的本性对不成功的神经元没有同情心；它认为那些在突触发生过程中没有形成相应连接的细胞是多余的，并注定它们会通过称为“生理性细胞死亡”（即细胞凋亡）的细胞死亡过程而死亡。细胞凋亡的病理组织学标志是独特的，需要几个不同的、定时精确且协调良好的步骤（“程序性细胞死亡”）。神经元凋亡的一个重要特征是缺乏神经胶质反应。与兴奋性毒性神经元死亡不同，没有吞噬作用的迹象；凋亡小体的生物降解不会发生类似“炎症”的反应。 5 早期病理学家创造了“神经元自杀”这个术语，表示这种死亡过程不涉及周围看似正常的神经元。尽管神经元“修剪”是在生理上发生的，但在正常突触发生过程中，只有极少数神经元死亡（1%）。中枢神经系统中神经元兴奋和抑制之间的良好平衡似乎至关重要，不仅对于神经元的存活，而且对于它们的正常成熟和功能也至关重要，这表明过度抑制，就像过度兴奋一样，可能对发育中的神经元有毒。事实上，研究表明，谷氨酸（中枢神经系统中主要的兴奋性神经递质）的过度阻断和/或中枢神经系统中主要抑制性神经递质（GABA）的过度激活，会引发广泛的细胞凋亡性神经变性，影响发育中大脑的几个主要区域的许多神经元。 6-8这对麻醉师来说重要吗？事实上，如果突触发生过程中神经元活动的过度抑制（“过度抑制”）可能构成正在发育的神经元自杀的一般信号，那么，普遍使用的全身麻醉剂（诱导神经元抑制的药物的一个主要例子）可能具有潜在的神经毒性，这难道不是直观的吗？尽管尚未清楚地了解全身麻醉剂如何使患者失去知觉和忘记疼痛，但有一些有希望的线索表明可能涉及两种主要机制：通过 GABAA 受体的抑制性传递增加和……
Over the last 50–60 years, there has been an exponential increase in the number of anesthetic interventions in very young children. They are increasingly complex and therefore require aggressive and highly skilled anesthetic management. In addition, because premature birth rates are rapidly rising (. 12% of the overall birth rate) 1, 2 and because the survival rate of premature babies in the neonatal intensive care unit (NNICU)(as young as 20 weeks post conception) is steadily increasing, the anesthesia professionals are frequently involved in providing anesthesia care (eg, multiple surgical interventions, prolonged sedation in NNICU, etc.) in very early stages of human development. The central nervous system (CNS) in humans is not fully developed at birth and undergoes intense postnatal maturation. The brain weighs approximately 300 g at birth, doubles in size by 6 months, and almost triples by 12 months. 3 This is known as the brain growth spurt period or the period of synaptogenesis. 4 The synaptogenesis in humans is both a pre-and a postnatal phenomenon (from sixth month of gestation to a couple of years after birth). During this period, neurons migrate to their final destination and form trillions of synaptic connections by vastly expanding their dendritic surfaces to accommodate incoming axonal contacts, thus setting the stage for a synchronized formation of meaningful neuronal circuitries. The relentless nature has no sympathy for unsuccessful neurons; it considers ones that did not form consequential connections during synaptogenesis redundant and destines them to die by the cell death process referred to as ‘‘physiologic cell death’’(ie, apoptosis). The pathohistologic hallmarks of apoptosis are unique and entail several distinct, precisely timed, and well coordinated steps (‘‘programmed cell death’’). An important feature of neuronal apoptosis is the lack of the glial reaction. Unlike the excitotoxic neuronal death, there are no signs of phagocytosis; the biodegradation of the apoptotic bodies occurs without an ‘‘inflammatory’’-like reaction. 5 Early pathologists coined the term ‘‘neuronal suicide’’to signify the fact that this dying process does not involve surrounding, otherwise normal-looking, neurons. Although the neuronal ‘‘pruning’’occurs physiologically, a very small percentage of neurons die during normal synaptogenesis (, 1%). It appears that a very fine balance between neuronal excitation and inhibition in the CNS is crucial, not only for neuronal survival, but for their proper maturation and functioning, suggesting that overinhibition, just like overexcitation, may be toxic to a developing neuron. Indeed, it has been shown that the excessive blockade of glutamate, the major excitatory neurotransmitter in the CNS, and/or the excessive activation of g-aminobutyric acid (GABA), a major inhibitory neurotransmitter in the CNS, trigger widespread apoptotic neurodegeneration, affecting many neurons in several major regions of the developing brain. 6–8Could this be important to the anesthesiologist? If, indeed, the excessive depression of neuronal activity (‘‘overinhibition’’) during synaptogenesis may constitute a generic signal for a developing neuron to commit suicide, then would it not be intuitive to propose that commonly used general anesthetics, a prime example of pharmacologic agents that induce neuronal depression, could be potentially neurotoxic? Although a clear understanding of how general anesthetics render a patient unconscious and oblivious to pain has not been achieved, there are some promising clues suggesting that two main mechanisms may be involved: an increase in inhibitory transmission through GABAA receptors and a …