Fetal Physiology and Neuroscience Group, Department of Physiology, University of Auckland, Private Bag 92019, Auckland, New Zealand.
Semin Fetal Neonatal Med. 2010 Oct;15(5):253-60. doi: 10.1016/j.siny.2010.05.007. Epub 2010 Jun 19.
Cerebral hypothermia reduces brain injury and improves behavioral recovery after hypoxia-ischemia (HI) at birth. However, using current enrolment criteria many infants are not helped, and conversely, a significant proportion of control infants survive without disability. In order to further improve treatment we need better biomarkers of injury. A 'true' biomarker for the phase of evolving, 'treatable' injury would allow us to identify not only whether infants are at risk of damage, but also whether they are still able to benefit from intervention. Even a less specific measure that allowed either more precise early identification of infants at risk of adverse neurodevelopmental outcome would reduce the variance of outcome of trials, improving trial power while reducing the number of infants unnecessarily treated. Finally, valid short-term surrogates for long term outcome after treatment would allow more rapid completion of preliminary evaluation and thus allow new strategies to be tested more rapidly. Experimental studies have demonstrated that there is a relatively limited 'window of opportunity' for effective treatment (up to about 6-8h after HI, the 'latent phase'), before secondary cell death begins. We critically evaluate the utility of proposed biochemical, electronic monitoring, and imaging biomarkers against this framework. This review highlights the two central limitations of most presently available biomarkers: that they are most precise for infants with severe injury who are already easily identified, and that their correlation is strongest at times well after the latent phase, when injury is no longer 'treatable'. This is an important area for further research.
脑低温可减少出生时缺氧缺血（HI）后的脑损伤并改善行为恢复。然而，使用当前的入组标准，许多婴儿并未从中受益，相反，很大一部分对照婴儿在没有残疾的情况下存活下来。为了进一步改善治疗效果，我们需要更好的损伤生物标志物。一个用于“正在发展的、可治疗的”损伤的“真正”生物标志物不仅可以帮助我们确定婴儿是否有受损的风险，还可以确定他们是否仍能从干预中受益。即使是一个不太具体的措施，如果可以更精确地早期识别有不良神经发育结局风险的婴儿，也可以减少试验结果的变异性，提高试验效能，同时减少不必要的治疗婴儿数量。最后，治疗后长期结局的有效短期替代指标将允许更快速地完成初步评估，从而允许更快地测试新策略。实验研究表明，在继发性细胞死亡开始之前，有效的治疗（HI 后约 6-8 小时，即“潜伏期”）有一个相对有限的“机会窗口”。我们根据这一框架对提出的生化、电子监测和影像学生物标志物的实用性进行了批判性评估。这篇综述突出了目前大多数可用生物标志物的两个核心局限性：它们对已经很容易识别的严重损伤婴儿最精确，而且它们的相关性在潜伏期过后很久的时间最强，此时损伤不再“可治疗”。这是进一步研究的重要领域。
