Sahuquillo Juan, Vilalta Anna
Department of Neurosurgery Vall d'Hebron University Hospital, Barcelona, Spain.
Curr Pharm Des. 2007;13(22):2310-22. doi: 10.2174/138161207781368756.
Neither any neuroprotective drug has been shown to be beneficial in improving the outcome of severe traumatic brain injury (TBI) nor has any prophylactically-induced moderate hypothermia shown any beneficial effect on outcome in severe TBI, despite the optimism generated by preclinical studies. This contrasts with the paradox that hypothermia still is the most powerful neuroprotective method in experimental models because of its ability to influence the multiple biochemical cascades that are set in motion after TBI. The aim of this short review is to highlight the most recent developments concerning the pathophysiology of severe TBI, to review new data on thermoregulation and induced hypothermia, the regulation of core and brain temperature in mammals and the multiplicity of effects of hypothermia in the pathophysiology of TBI. Many experimental studies in the last decade have again confirmed that moderate hypothermia confers protection against ischemic and non-ischemic brain hypoxia, traumatic brain injury, anoxic injury following resuscitation after cardiac arrest and other neurological insults. Many posttraumatic adverse events that occur in the injured brain at a cellular and molecular level are highly temperature-sensitive and are thus a good target for induced hypothermia. The basic mechanisms through which hypothermia protects the brain are clearly multifactorial and include at least the following: reduction in brain metabolic rate, effects on cerebral blood flow, reduction of the critical threshold for oxygen delivery, blockade of excitotoxic mechanisms, calcium antagonism, preservation of protein synthesis, reduction of brain thermopooling, a decrease in edema formation, modulation of the inflammatory response, neuroprotection of the white matter and modulation of apoptotic cell death. The new developments discussed in this review indicate that, by targeting many of the abnormal neurochemical cascades initiated after TBI, induced hypothermia may modulate neurotoxicity and, consequently, may play a unique role in opening up new therapeutic avenues for treating severe TBI and improving its devastating effects. Furthermore, greater understanding of the pathophysiology of TBI, new data from both basic and clinical research, the good clinical results obtained in randomized clinical trials in cardiac arrest and better and more reliable cooling methods have given hypothermia a second chance in treating TBI patients. A critical evaluation of hypothermia is therefore mandatory to elucidate the reasons for previous failures and to design further multicenter randomized clinical trials that would definitively confirm or refute the potential of this therapeutic modality in the management of severe traumatic brain injuries.
尽管临床前研究带来了乐观情绪，但尚无任何神经保护药物被证明对改善重度创伤性脑损伤（TBI）的预后有益，预防性诱导的中度低温对重度TBI的预后也未显示出任何有益效果。这与低温在实验模型中仍是最强大的神经保护方法这一矛盾现象形成对比，因为它能够影响TBI后启动的多种生化级联反应。这篇简短综述的目的是强调重度TBI病理生理学的最新进展，回顾体温调节和诱导低温的新数据、哺乳动物核心体温和脑温的调节以及低温在TBI病理生理学中的多种作用。过去十年中的许多实验研究再次证实，中度低温可对缺血性和非缺血性脑缺氧、创伤性脑损伤、心脏骤停复苏后的缺氧损伤及其他神经损伤起到保护作用。在受伤大脑的细胞和分子水平上发生的许多创伤后不良事件对温度高度敏感，因此是诱导低温的良好靶点。低温保护大脑的基本机制显然是多因素的，至少包括以下方面：降低脑代谢率、对脑血流量的影响、降低氧输送的临界阈值、阻断兴奋性毒性机制、钙拮抗作用、维持蛋白质合成、减少脑热蓄积、减少水肿形成、调节炎症反应、对白质的神经保护以及调节凋亡细胞死亡。本综述中讨论的新进展表明，通过针对TBI后启动的许多异常神经化学级联反应，诱导低温可能调节神经毒性，因此可能在开辟治疗重度TBI的新治疗途径和改善其破坏性影响方面发挥独特作用。此外，对TBI病理生理学的更深入了解、基础研究和临床研究的新数据、心脏骤停随机临床试验中获得的良好临床结果以及更好、更可靠的降温方法，使低温在治疗TBI患者方面有了第二次机会。因此，必须对低温进行批判性评估，以阐明先前失败的原因，并设计进一步的多中心随机临床试验，以最终证实或反驳这种治疗方式在重度创伤性脑损伤管理中的潜力。
