婴儿全身麻醉或清醒局部麻醉后5岁时的神经系统发育：国际性、多中心、随机对照等效试验
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Neurodevelopmental outcome at 5 years of age after general anaesthesia or awake-regional anaesthesia in infancy (GAS): an international, multicentre, randomised, controlled equivalence trial
背景与目的
在动物实验中，大多数全身麻醉剂都会引起神经毒性，表现为神经元细胞死亡、异常的行为和认知。一些大型的人类队列研究显示，年幼时曾行全身麻醉与之后的神经发育缺陷有关，但这些研究存在偏差，其他研究也并未发现任何证据表明二者有关联。本研究旨在确定婴儿早期全身麻醉是否影响其神经发育结果。
方 法
在澳大利亚、意大利、美国、英国、加拿大、荷兰和新西兰的28家医院进行了一项国际性、盲评、等效、随机对照试验，将停经后年龄小于60周并且怀孕26周以后出生，拟行择期腹股沟疝修补术但既往无全身麻醉史或神经损伤危险因素的婴儿作为本试验的纳入标准。采用网络随机分配服务决定患儿（1:1）是进行清醒局部麻醉或七氟醚全身麻醉。麻醉医生知道分组细节，但评估神经发育结果的评审并不知道。根据知情同意要求，婴儿的父母被告知自己孩子的分组情况，但要掩盖评审提供的信息。主要观察指标是5岁时Wechsler学龄前和小学智力量表第三版（WPPSI-III）的全量表智商（FSIQ）。初步分析是按方案进行的，根据出生时和国家标准的胎龄进行调整，并用多次插补来解释缺失的数据。并进行了意向治疗分析。5点平均值的差异定义为临床等效界限。
结 果
对2007年2月9日至2013年1月31日期间的4023名婴儿进行了筛选，最终722名婴儿被纳入试验并随机分组：363名（50%）为清醒局部麻醉组，359名（50%）为全身麻醉组。清醒局部麻醉组有74例违反方案，全身麻醉组有2例违反方案。按照方案分析的主要指标数据来自清醒局部麻醉组的205名婴儿和全身麻醉组的242名婴儿。全身麻醉持续时间的中值为54 min（IQR 41–70）。清醒局部麻醉组的平均FSIQ评分为99.08（SD：18.35），全身麻醉组的平均FSIQ评分为98.97（SD：19.66），平均值的差异（清醒局部麻醉减去全身麻醉）为0.23（95%CI：2.59-3.06），这为等效性提供了有力证据。意向治疗分析结果与方案分析结果相似。
结 论
本次以男婴为主的研究中，与清醒局部麻醉相比，婴儿早期不到1小时的全身麻醉并不会改变5岁时的神经发育结果。
原始文献摘要
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[J].The Lancet. 2019,393(10172):664-677.DOI:10.1016/s0140-6736(18)32485-1.
Background：In laboratory animals, exposure to most general anaesthetics leads to neurotoxicity manifested by neuronal cell death and abnormal behaviour and cognition. Some large human cohort studies have shown an association between general anaesthesia at a young age and subsequent neurodevelopmental deficits, but these studies are prone to bias. Others have found no evidence for an association. We aimed to establish whether general anaesthesia in early infancy affects neurodevelopmental outcomes.
Methods：In this international, assessor-masked, equivalence, randomised, controlled trial conducted at 28 hospitals in Australia, Italy, the USA, the UK, Canada, the Netherlands, and New Zealand, we recruited infants of less than 60 weeks’ postmenstrual age who were born at more than 26 weeks’ gestation and were undergoing inguinal herniorrhaphy, without previous exposure to general anaesthesia or risk factors for neurological injury. Patients were randomly assigned (1:1) by use of a web-based randomisation service to receive either awake-regional anaesthetic or sevoflurane-based general anaesthetic. Anaesthetists were aware of group allocation, but individuals administering the neurodevelopmental assessments were not. Parents were informed of their infants group allocation upon request, but were told to mask this information from assessors. The primary outcome measure was full-scale intelligence quotient (FSIQ) on the Wechsler Preschool and Primary Scale of Intelligence, third edition (WPPSI-III), at 5 years of age. The primary analysis was done on a per-protocol basis, adjusted for gestational age at birth and country, with multiple imputation used to account for missing data. An intention-totreat analysis was also done. A difference in means of 5 points was predefined as the clinical equivalence margin. This completed trial is registered with ANZCTR, number ACTRN12606000441516, and ClinicalTrials.gov, number NCT00756600.
Findings：Between Feb 9, 2007, and Jan 31, 2013, 4023 infants were screened and 722 were randomly allocated: 363 (50%) to the awake-regional anaesthesia group and 359 (50%) to the general anaesthesia group. There were 74 protocol violations in the awake-regional anaesthesia group and two in the general anaesthesia group. Primary outcome data for the per-protocol analysis were obtained from 205 children in the awake-regional anaesthesia group and 242 in the general anaesthesia group. The median duration of general anaesthesia was 54 min (IQR 41–70). The mean FSIQ score was 99.08 (SD 18.35) in the awake-regional anaesthesia group and 98·97 (19.66) in the general anaesthesia group, with a difference in means (awake-regional anaesthesia minus general anaesthesia) of 0.23 (95% CI –2.59 to 3.06), providing strong evidence of equivalence. The results of the intention-to-treat analysis were similar to those of the per-protocol analysis.
Interpretation：Slightly less than 1 h of general anaesthesia in early infancy does not alter neurodevelopmental outcome at age 5 years compared with awake-regional anaesthesia in a predominantly male study population.
麻醉学文献进展分享
贵州医科大学高鸿教授课题组
翻译：冯玉蓉 编辑：何幼芹 审校：王贵龙