亚低温治疗中重度新生儿缺氧缺血性脑病系统评价/Meta分析

Clinical efficacy and safety of hypothermia for neonates with hypoxic ischemic encephalopathy:A systematic review and meta-analysis

背景2012年前有多项亚低温治疗中重度HIE的系统评价/Meta分析发表,之后又有多项RCT相继完成,本文是《足月儿缺氧缺血性脑病循证实践治疗指南(2022版)》的临床问题之一的系统评价/Meta分析。目的评估中重度HIE经亚低温及其联合其他治疗后的远期随访结局。设计系统评价/Meta分析。方法检索英文数据库:PubMed、Embase、Cochrane、CINAHL;中文数据库:中国生物医学文献服务系统(SinoMed);中文和英文文献检索截止时间分别为2021年11月12日和12月6日。通过阅读文题和摘要进行初筛,之后阅读全文进行二筛。二筛排除标准(满足以下条件之一):①新生儿合并有先天畸形;②亚低温治疗开始时间超过生后12 h;③治疗时新生儿核心温度不在33.0℃~35℃或未持续治疗至72 h;④对症支持治疗联合亚低温治疗随访时间<18个月,或亚低温联合其他治疗随访时间<12个月;⑤干预组为非亚低温治疗的其他治疗。运用GRADE对证据体进行评价,采用RevMan 5.4和R语言对提取的数据进行Meta整合。主要结局指标随访18个月后的死亡和神经系统伤残发生率。结果①亚低温治疗14篇文献,其中RCT 13篇,NRSI 1篇;全身低温8篇,选择性头部低温6篇;随访时间18~30月龄13篇,6~7岁1篇;亚低温组1091例,对照组(对症支持)1087例。亚低温组较对照组降低了27%的死亡和神经系统伤残风险(RR=0.73,95%CI:0.67~0.80,P<0.01),其中中重度HIE死亡和神经系统伤残风险分别降低了41%和19%,脑瘫发生率降低了36%,但不降低听力和视力障碍的发生率;亚低温组与对照组(对症支持)心律失常、严重低血压、凝血功能异常、血小板减少、持续肺动脉高压、败血症、静脉血栓形成和皮肤破损发生率差异均无统计学意义。②亚低温联合药物治疗10篇(联合促红细胞生成素4篇,氙气和干细胞各2篇,褪黑素和托吡酯各1篇),3篇RCT随访≥18个月,亚低温联合或褪黑素、或托吡酯、或氙气较亚低温治疗死亡和神经系统伤残发生率差异无统计学意义(RR=1.08,95%CI:0.59~1.98,P=0.80)。结论亚低温治疗降低了27%中重度HIE死亡和神经系统伤残风险,亚低温联合药物治疗有进一步研究的前景。

Background Most of systematic review or meta-analysis of neonates with moderate-to-severe hypoxic ischemic encephalopathy(HIE) treated with therapeutic hypothermia were published before 2012, and then several RCT studies have been completed.This systematic review and meta-analysis is part of Evidence-based Treatment Guidelines for Hypoxic and Ischemic Encephalopathy in Full-term Children(2022).Objective To study the long-term neurological outcomes of hypothermia alone and hypothermia plus agents for moderate to severe HIE.Design Systematic review and meta-analysis.Methods English literature was searched in PubMed, Embase, Cochrane and CINAHL from the establishment of databases to November 12, 2021 and Chinese literature was searched in Sino Med from the establishment to December 6, 2021.Literature was selected through preliminary screening by reading titles and abstracts and re-screening by reading full texts.Exclusion criteria for re-screening(meeting one of the following option) included: a.Neonates were with congenital malformations;b.Hypothermia occurred beyond 12 h after birth;c.The core temperature was not between 33℃-35.0℃ during the treatment or hypothermia did not last for 72 hours;d.The followup was less than 18 months in the hypothermia group or less than 12 months in the hypothermia plus agents group.e.Hypothermia is not taken as the intervention.GRADE was used to evaluate the evidence system.Meta-analysis was performed using Revman 5.4 and R.Publication bias was analyzed for the evidence body with more than 10 articles.Main outcome measuresThe incidence of death and long-term major neurodevelopmental outcome after the 18-month follow-up.ResultsFourteen articles of hypothermia were enrolled in the analysis, including 13 RCTs and 1 NRSI, involving 1 091 neonates in the intervention group(hypothermia) and 1 087 neonates in the control group(supportive care).Selective head cooling(SHC) and whole body cooling(WBC) were in 6 articles and 8 articles respectively.Follow-up were completed from 18 to 30 months in 13 articles, and 6 to 7 years in 1 article.Hypothermia significantly decreased the incidence of death and/or moderate to severe disability by 27%(RR=0.73,95%CI:0.67-0.80,I2= 0,P<0.01), including moderate encephalopathy(by 41%), severe encephalopathy(by 19%), SHC(by 30%), WBC(by 25%), cerebral palsy(by 36%), but did not reduce the incidence of hearing and visual impairment.There was no significant difference in the incidence of adverse effects including arrhythmia, severe hypotension, abnormal coagulation, thrombocytopenia, persistent pulmonary hypertension, sepsis, venous thrombosis and skin breakage without deleterious consequences.Ten articles of hypothermia plus agents were enrolled in the analysis, including EPO(4 articles), xenon( 2 articles), stem cells(2 articles), melatonin(1 article) and topiramate(1 article).Follow-up were completed more than 18 months in 3 articles between the hypothermia and the control group(supportive care).There was no significant difference in the incidence of death and disability between hypothermia plus melatonin or topiramate or xenon and hypothermia alone(RR = 1.08, 95%CI: 0.59-1.98, P= 0.80).ConclusionTherapeutic hypothermia reduced the risk of death and neurological disability of neonates with moderate to severe hypoxic ischemic encephalopathy by 27%.Further research of hypothermia combined with agents is needed.