FIG. 1.

The many layers of cerebroprotective cooling: the “Responsivity of Cold Stress Pathways” is an additional (new) concept for optimizing TH. Multiple interdependent factors affect the efficacy of neuroprotective TH in patients. Major variables include the duration of cooling, the device/instrumentation used to induce hypothermia, the time to reach target temperature, the depth of cooling, and the prevention of detrimental side effects. Purple text: the optimal hypothermia protocol(s) that increase tissue/plasma levels of neuroprotective CSHs remain to be elucidated. Nor is it known if TH is able to increase CSPs in the brain in human adults. Age-dependent and other patient-specific differences may alter (increase or decrease) the induction of CSHs/CSPs by TH, which in turn may influence neurological recovery after a CNS injury. Furthermore, additional work is needed to determine if CSHs/CSPs can be optimized (i.e., adjusted) using noncooling interventions such as pharmacological approaches. CNS, central nervous system; CSHs, cold stress hormones; CSPs, cold shock proteins; TH, therapeutic hypothermia.