Effects of Different Target Temperatures on Angiogenesis and Neurogenesis Following Resuscitation in a Porcine Model After Cardiac Arrest

Objective: The optimal effective temperature of targeted temperature management (TTM) used to prevent cerebral injury following cardiopulmonary resuscitation (CPR) is undetermined. In this study, we compared the mortality, neurologic deficits, and cerebral protein levels of two target temperatures.

Methods: Fifty 4-month-old female domestic pigs were randomized to sham, TTM at 33°C ± 0.5°C (T33), TTM at 35°C ± 0.5°C (T35), and normothermic (NT) groups. In the NT and TTM groups, untreated ventricular fibrillation was induced electrically in animals for 10 min, followed by 6 min of CPR. Target core temperatures (Tc) of TTM groups were induced and maintained (6 h) using an endovascular hypothermia device, and rewarmed to 37.5 ± 0.5°C in the next 6 h. Tc of the NT group was maintained at 37.5 ± 0.5°C. The survival outcomes and neurological function were evaluated every 24 h for 72 h.

Results: All animals were successfully resuscitated with no significant differences in baseline characteristics or hemodynamic indexes. Survival rates and neurological outcomes were significantly improved in the TTM groups, with T33 showing the most significant effect. Compared with NT-treated animals, TTM-treated animals had higher expressions of angiopoietin-1, transforming growth factor-alpha , vascular endothelial growth factor, metallopeptidase inhibitor (TIMP)-1, TIMP-2, and platelet-derived growth factor-BB. Macrophage migration inhibitory factor and IL-17F levels were markedly upregulated after resuscitation in the NT group but inhibited in the TTM groups. Neuron-specific enolase staining data was also consistent with our conclusion that hypothermia can reduce reperfusion-induced brain injuries.

Conclusion: Lower target temperature showed greater protective effects against cerebral injuries after CPR, and the improved neurological outcomes after TTM may be associated with decreased expression of pro-inflammatory cytokines and increased expression of blood-brain barrier and neurogenesis regulatory factors in this porcine model of CA following resuscitation.