Robertson Nicola J, Iwata Osuke
EGA UCL Institute for Women's Health, University College London, London, UK.
Early Hum Dev. 2007 Dec;83(12):801-11. doi: 10.1016/j.earlhumdev.2007.09.015. Epub 2007 Oct 26.
Therapeutic hypothermia gathers impetus in the developed world as a safe and effective therapy for term asphyxial encephalopathy. Although many questions still remain about the optimal application of hypothermic neuroprotection it is difficult to ignore the developing world where the prevalence of asphyxial encephalopathy is much higher. Experimental studies to optimize high tech cooling need to run in parallel with trials to determine the possible benefits of therapeutic hypothermia in low resource settings.
We used a validated newborn piglet model of transient HI to determine (i) whether optimal neuroprotection occurs at different temperatures in the cortical and deep grey matter; (ii) the effect of body size on regional brain temperature under normothermia and hypothermia; (iii) the effect of insult severity on the therapeutic window duration; (iv) whether cooling using a water bottle is feasible. In this model hypoxia-ischaemia is induced by reversible occlusion of the common carotid arteries by remotely controlled vascular occluders and simultaneous reduction in the inspired oxygen fraction to 0.12. Intensive care can be administered to the piglet maintaining metabolic and physiological homeostasis throughout the experiment, and cerebral energy metabolism is monitored continuously providing quantitative measures of the HI insult, latent phase and secondary energy failure using phosphorus-31 ((31)P) magnetic resonance spectroscopy (MRS).
(i) The optimal temperature for cooling was lower in the cortex than deep grey matter. (ii) Cerebral temperatures were body-weight dependent: a smaller body weight led to a lower brain temperature especially with selective head cooling. (iii) Latent-phase duration is inversely related to insult severity. (iv) Low tech, simple cooling methods using a water bottle can induce and maintain moderate hypothermia.
Small shifts in brain temperature critically influence the survival of neuronal cells and body size critically influences brain-temperature gradients - smaller subjects have a larger surface area to brain volume and hence more heat is lost. The clinical implication is that smaller infants may require higher cap or body temperatures to avoid detrimental effects of over-zealous cooling. Latent-phase brevity may explain less effective neuroprotection following severe HI in some clinical studies. "Tailored" treatments which take into account individual and regional characteristics may increase the effectiveness of therapeutic hypothermia in the developed world. Low tech cooling methods using water bottles may be feasible although adequate staffing and monitoring would be required.
治疗性低温作为足月窒息性脑病的一种安全有效的治疗方法，在发达国家正得到广泛应用。尽管关于低温神经保护的最佳应用仍存在许多问题，但窒息性脑病患病率高得多的发展中国家却难以忽视这一疗法。优化高科技降温的实验研究需要与确定治疗性低温在资源匮乏环境中可能带来的益处的试验同时进行。
我们使用经过验证的新生仔猪短暂性缺氧缺血模型来确定：（i）皮质和深部灰质在不同温度下是否能实现最佳神经保护；（ii）常温及低温状态下体重对局部脑温的影响；（iii）损伤严重程度对治疗窗持续时间的影响；（iv）使用水瓶进行降温是否可行。在该模型中，通过遥控血管闭塞器可逆性阻断双侧颈总动脉，并同时将吸入氧分数降至0.12来诱导缺氧缺血。在整个实验过程中可对仔猪进行重症监护以维持代谢和生理稳态，并使用磷-31（³¹P）磁共振波谱（MRS）连续监测脑能量代谢，以提供缺氧缺血损伤、潜伏期和继发性能量衰竭的定量指标。
（i）皮质降温的最佳温度低于深部灰质。（ii）脑温取决于体重：体重越小，脑温越低，尤其是在进行选择性头部降温时。（iii）潜伏期持续时间与损伤严重程度呈负相关。（iv）使用水瓶这种低技术、简单的降温方法可诱导并维持中度低温。
脑温的微小变化对神经元细胞的存活至关重要，体重对脑温梯度有重要影响——体型较小的个体脑表面积与脑体积之比更大，因此散热更多。临床意义在于，较小的婴儿可能需要更高的帽温或体温，以避免过度降温带来有害影响。潜伏期短暂可能解释了在一些临床研究中重度缺氧缺血后神经保护效果较差的原因。考虑个体和局部特征的“个性化”治疗可能会提高发达国家治疗性低温的有效性。使用水瓶的低技术降温方法可能可行，不过需要充足的人员配备和监测。
