亚低温治疗胎龄大于35周龄新生儿缺氧缺血性脑病效果及安全性的荟萃分析

Meta-analysis of mild hypothermia for gestational age over 35-week newborns with hypoxic- ischemic encephalopathy

目的荟萃分析（Meta分析）综合评价亚低温治疗对重度窒息导致的缺氧缺血性脑病（HIE）新生儿病死率和远期神经发育障碍的影响和安全性。方法采用Cochrane图书馆新生儿综述组制定的标准文献检索策略，获得亚低温治疗HIE的临床文献。采用RevMan5．1软件对满足纳入标准的有关亚低温治疗胎龄I〉35周新生儿HIE的随机对照研究（RCT）进行Meta分析。以18—24个月龄的死亡和严重神经系统伤残联合发生率为主要观察指标，以病死率、神经运动发育延迟、脑瘫、失明、耳聋和严重不良反应事件发生率作为次要观察指标进行定性、定量综合评价和分析。结果共检索出276篇符合条件文献，对符合纳人标准的11项RCT进入Meta分析。治疗性低温可显著降低随访至18～24个月龄时的死亡及严重神经系统伤残联合发生率，与对照组差异有统计学意义（RR=0．76，95％CI：0．68—0．84，P〈0．01）。次要观察指标中病死率（RR=0．76，95％CI：0．65～0．90），神经运动落后（RR=0．69，95％C1：0．55～0．87），神经发育迟缓（RR=0．66，95％C1：0．53—0．83），脑瘫（RR=0．70，95％CI：0．54～0．91）和存活者失明（RR=0．54，95％CI：0．33—0．90）的发生率在两组间差异均有统计学意义（均P〈0．05），而两组间存活者耳聋差异无统计学意义（RR=0．69，95％CI：0．35～1．34，P=0．3000）。亚低温治疗与对照组比较，可明显降低血小板数量（P=0．0400）且未见明显的不良结局；其他如心律失常发生率、凝血功能异常发生率、低血压需要血管活性药物治疗、败血症发生率、肺动脉高压发生率等差异均无统计学意义（均P〉0．05）。结论亚低温治疗可降低中重度HIE患儿病死率、改善神经系统发育障碍，并无严重不良反应发生。对于出生后数小时内有可能发展为中重度HIE患儿推荐在有条件医院开展亚低温治疗。

Objective To determine the effects of therapeutic hypothermia（TH） in encephalopathic asphyxiated newborn infants on mortality, long-term neurodevelopmental disability and side effects by summarizing the data of hypoxic-ischemic eneephalopathy （ HIE ） newborns undergoing mild hypothermia using recta-analysis. Methods The standard searching strategy of the Neonatal Review Group as outlined in the Cochrane Library was used to retrieve all clinical literatures about TH on HIE. RevMan 5.1 software was used to perform the recta-analysis of target papers. The primary outcome measure was a combination of death and severe major neurodevelopmental disabilities at 18 -24 months of age. Secondary outcomes included mortality, cerebral palsy （CP）, neurodevelopmental delay, blindness, deafness and main side effects of cooling therapy. Results A total of 276 papers fulfilled the search strategy and 11 trials were included. Overall TH resulted in a statistically significant and clinically important reduction in the combined outcome of death or major neurodevelopmental disabilities to 18 -24 months of age （RR = 0.76, 95% CI： O. 68 -0. 84, P 〈0.01 ）. Moreover, as compared with the control group, TH significantly decreased the incidence of mortality（RR =0. 76, 95% CI：0. 65 -0. 90, P 〈0. 01 ）, psychomotor development index（RR =0. 69, 95% CI：0. 55 -0. 87, P 〈 0. 01 ）, mental development index （RR = 0. 66, 95% CI：0. 53 - 0. 83, P 〈 0. 01 ）, CP（RR =0.70, 95%CI：0.54 -0.91, P〈0.01） and blindness（RR =0. 54, 95% CI：0.33 -0.90, P〈0. 05） except for severe hearing loss （deafness） （RR = 0. 69, 95% CI： 0. 35 - 1. 34, P= 0. 3000） in survivors. Adverse effects included significant thrombocytopenia in the TH group （ P = 0. 0400 ） but without deleterious consequences. There were no significant differences in arrhythmia, coagulopathy, hypotension requiring inotropic supports, sepsis and pulmonary hypertension between the TH and control groups（ all P 〉 0.05 ）. Conelttsions Mild hypothermia is effective in reducing death and major disabilities in infants with moderate-to-severe HIE without significant side effects. Infants presenting within the first hours after birth with the signs and symptoms of moderate-to-severe encephalopathy should be cooled in accordance with the established protocols of previous randomized controlled trials.