低温治疗可使新生儿脑病患儿获益

据5月31日《新英格兰医学杂志》发表的一项纳入190例6~7岁儿童的随访研究报告，全身低温治疗可降低中重度新生儿脑病患儿死亡率，且不增加神经发育缺陷发生率(N. Engl. J. Med. 2012;366:2085-92)。

截止目前，尚没有可用于评估接受低温治疗的新生儿缺氧缺血性脑病患儿2岁后能否持续获益的研究数据。为此，韦恩州立大学新生儿围生儿医学中心主任Seetha Shankaran博士及其同事利用尤妮丝·肯尼迪·施莱佛国立儿童健康和人类发育研究所(NICHD)新生儿研究协作网的资料，评估了2000~2003年出生的190例儿童的远期死亡率、认知障碍和其他神经发育结局。所有受试者均在出生后6 h内被确诊为中至重度脑病，其原因是急性围产期事件所致严重酸中毒或必需接受复苏治疗。新生儿被随机分组，分别接受72 h的全身33.5° C低温治疗(97例)或常规治疗(93例)。

结果显示，低温组和对照组达到主要结局指标(6~7岁时死亡或IQ<70)的比例分别为47%和62%。低温组和对照组分别有27例和41例死亡，IQ<70的儿童比例分别为27%和33%，平均IQ分别为82和75。虽然两组主要复合结局差异未达到统计学显著水平，但结果表明低温治疗对患儿有益。如果将复合结局指标拆分统计，低温治疗可显著改善死亡率，并且幸存者神经发育缺陷风险无显著增加。

低温组次要复合结局(死亡或重度残疾和死亡或大脑性瘫痪)比例明显较低，尤其是大脑性瘫痪和失明发生率，低温组分别为17%和1%，而对照组分别为29%和4%。此外，未发现低温组非残疾儿童运动功能异常风险高于对照组，注意力、执行功能和视觉空间能力也未见显著组间差异。

已知大脑性瘫痪儿童健康状况“明显不佳”，但既往研究显示，无论残疾程度如何，儿童社会心理健康和儿童健康对父母情绪的影响几乎相同。在本项研究中，两组儿童父母对儿童健康或自尊心的评价未见显著差异，儿童幸福对父母情绪影响的评价结果也未见组间差异。

同时担任密歇根儿童医院地区新生儿项目主任的Shankaran博士指出，对于任何旨在减少高危残疾婴儿死亡率的治疗的主要担忧是使残疾幸存者数量增加。然而，本研究结果显示，没有证据表明低温治疗幸存儿童6~7岁时IQ<70、重度残疾或大脑性瘫痪比例增加。上述结果令人欣慰，因为目前低温治疗正在全球范围内广泛应用，并且已得到医疗保健决策者的推荐。

该研究由美国国立卫生研究院和尤妮丝·肯尼迪·施莱佛NICHD新生儿研究协作网资助。Shankaran博士的同事报告与Olympic Medical/Natus等公司存在经济利益关系，并接受多个学会或政府基金资助。

Whole-body hypothermia reduced the rate of death in patients with moderate to severe neonatal encephalopathy without raising the rate of neurodevelopmental deficits in a study that followed 190 children to age 6-7 years, according to a report in the May 31 issue of the New England Journal of Medicine.

Until now, data “have not been available to assess whether the benefits of hypothermia for neonatal hypoxic-ischemic encephalopathy persist after 2 years of age,” said Dr. Seetha Shankaran, director of the division of neonatal-perinatal medicine at Wayne State University, Detroit, and her associates.

“These results are reassuring since hypothermia is being used extensively around the world and currently is recommended by health care policymakers,” they noted.

The investigators used data from the U.S. Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Neonatal Research Network to assess the long-term rates of death, cognitive impairment, and other neurodevelopmental outcomes in 190 children born in 2000-2003. All the study subjects were diagnosed as having moderate to severe encephalopathy within 6 hours of birth, after an acute perinatal event causing severe acidosis or necessitating resuscitation.

The neonates had been randomly assigned either to undergo whole-body hypothermia at 33.5° C for 72 hours (97 patients) or to usual care (93 patients).

The primary outcome measure – a combination of death or an IQ score below 70 at 6-7 years of age – occurred in 47% of the hypothermia group and 62% of the control group. There were 27 deaths in the hypothermia group and 41 in the control group. In the hypothermia group, 27% of the children attained an IQ score below 70, compared with 33% of the control group. The mean IQ score was 82 with hypothermia and 75 in the control group.

These rates showed a benefit with hypothermia, but the difference between the two groups in the composite primary outcome just failed to reach statistical significance.

When the combined outcome was broken down into its individual parts, however, hypothermia was found to significantly improve mortality, “with no appreciable increase in the risk of neurodevelopmental deficits among survivors,” said Dr. Shankaran, who is also director of regional neonatal programs at Children’s Hospital of Michigan, Detroit, and her colleagues.

The secondary composite outcomes of death or severe disability and of death or cerebral palsy were significantly lower in children who had undergone hypothermia. In particular, the rate of cerebral palsy was 17% with hypothermia and 29% in the control group; the rate of blindness was 1% with hypothermia, compared with 4% in the control group, the investigators said (N. Engl. J. Med. 2012;366:2085-92).

“We did not find a decrease in the risk of abnormalities in motor function among nondisabled children in the hypothermia group as compared with those in the control group,” the researchers said.

There also were no significant differences between the two groups in measures of attention, executive function, and visuospatial ability.

Children with cerebral palsy are known to have “markedly poor” health, but previous studies have found that “the psychosocial health of children and the emotional impact of the child’s health on the parents tend to be similar regardless of the level of disability,” they said.

In this study, parents’ assessments of the child’s health or self-esteem did not differ significantly between children who received hypothermia and the control group, and ratings of the emotional impact of the child’s well-being on the parents also were not significantly different, Dr. Shankaran and her associates said.

With any therapy that reduces mortality in infants at high risk of disability, there is a concern that the number who survive with disability will increase. However, “as reported here, there was no evidence of increased rates of an IQ score below 70, severe disability, or cerebral palsy at 6 to 7 years of age among surviving children treated with hypothermia,” the investigators said.

This study was supported by the National Institutes of Health and the Eunice Kennedy Shriver NICHD Neonatal Research Network. Some of Dr. Shankaran’s associates reported ties to Olympic Medical/Natus Corp., MedImmune, Pfeiffer Research Foundation, and the Robertson Foundation, as well as being recipients of various institutional and governmental grants.