AcknowledgementsWe wish to thank Ana Maria de Lucas, Tipifarnib CAS and Gema Atienza, for excellent technical assistance, and Rosario Madero for statistical analysis. This work was supported partially by a grant from Plan Nacional I+D+I (SAF 2008-05347) and from Fundaci��n Mutua Madrile?a de Investigaci��n M��dica to Francisco Arnalich (IP 2007) and to Carmen Montiel (IP 2008).
Although initial return of spontaneous circulation (ROSC) from cardiac arrest is achieved in about 30 to 40% of cases, only 10 to 30% of the patients admitted to the hospital will be discharged with good outcome [1]. One third of those who survive, suffer persistent neurological impairments [2]. Mild therapeutic hypothermia has emerged as the most effective strategy to reduce neurological impairment after successful cardiopulmonary resuscitation (CPR) [3].

The precise mechanisms by which mild hypothermia protects brain cells remain to be elucidated, but it is very likely that hypothermia acts upon multiple pathways including reduction in cerebral metabolism and oxygen consumption, attenuation of neuronal damage, and inhibition of excitatory neurotransmitter release [4].There is growing evidence on the damaging nature of the inflammatory response following brain ischemia. Various inflammatory cytokines have been implicated as important mediators of ischemia/reperfusion injury following both focal and global cerebral ischemia [5]. Most of the previous experimental studies induced global cerebral ischemia by bilateral carotid artery occlusion as a correlate of cardiac arrest, but inflammatory response mechanisms following carotid artery occlusion and anti-inflammatory mechanisms of hypothermia may be different from those observed after cardiac arrest and manual CPR.

Thus, it is unknown whether cardiac arrest also triggers the release of cerebral inflammatory molecules, and whether therapeutic hypothermia alters this inflammatory response.Neuronal injury may also result in necrotic and apoptotic cell death. In contrast to necrosis (cell death by acute injury), apoptosis is a well-regulated physiological process. Cells undergoing apoptosis are characterized by cytoplasmic shrinkage, nuclear condensation, and formation of membrane-bound vesicles. Key elements of the apoptotic pathway include changes in the gene expression of the pro-apoptotic protein Bax and the apoptosis-suppressing protein Bcl-2.

The extent to which GSK-3 hypothermia affects cerebral apoptosis-related proteins after successful CPR is not clear [4].The mismatch between early survival and final outcome after CPR emphasizes the importance of further research on potential adjuvants in addition to mild hypothermia. Specifically, pharmacological post-conditioning may offer an attractive opportunity to further ameliorate damage to the brain in the post-resuscitation period.