As we have discussed, hypothermic studies performed in the laboratory have led to clinical investigations for cerebral ischemia. Significant enthusiasm for this approach still exists in the scientific community. A number of preliminary clinical trials (mostly phase I) to confirm the feasibility and safety of induced mild hypothermia for stroke patients have been completed, and several phase II clinical trials are currently in progress (http://clinicaltrials.gov/
). However, whether mild-to-moderate hypothermia can be successfully translated clinically or, if successful, how long this will take has yet to be determined.
The purpose of our basic research using animal models is to provide the rationale for clinical translation, although we cannot directly extrapolate settings from the laboratory to clinical trials. As discussed, our laboratory experiment is limited due to the short 3-hour duration of hypothermia, which contrasts to human clinical trials where hypothermia may last a few days. In addition, our study used infarct size as the criteria for evaluating the protective effects of hypothermia and not neurological function, as is often the case in clinical studies. Despite these limitations, our results serve as a warning of the persistent challenges we must confront as we seek to translate hypothermia to the clinic.
First of all, the most strikingly disappointing results from our studies are the limited protective effects of hypothermia, including mild hypothermia, and the short therapeutic time window of moderate hypothermia. If these observations are true, successful clinical translation of induced hypothermia may prove to be more difficult than anticipated to achieve.
For example, we demonstrated that even intraischemic mild hypothermia (33°C) induced before ischemic onset failed to reduce infarct size in a focal ischemia model with permanent distal MCA occlusion and partial reperfusion upon bilateral CCA release. This model may be more severe than the model of MCA suture occlusion with reperfusion used by most laboratories, but we have no reason to believe it is more severe than strokes in humans. As previously discussed, many stroke patients suffer from permanent cerebral artery occlusion without reperfusion. To achieve protection, even our experimental ischemic models required reducing intraischemic hypothermia to 30°C or prolonging intraischemic mild hypothermia beyond CCA release. However, applying intraischemic hypothermia before stroke onset in clinical trials is nearly impossible, and inducing hypothermia in stroke patients beyond 33°C to 30°C is very difficult. Clinical trials often use mild rather than moderate hypothermia, and it takes significantly longer to reach the target temperature compared to experimental stroke in animal models.
Nevertheless, as we reviewed previously [6
], other groups have shown that intraischemic mild hypothermia elicits protection even in permanent MCA occlusion models, in contrast to our recent studies. Our negative findings may simply reflect our specific setting and use of a unique model.
Second, the therapeutic time window for moderate hypothermia is extremely narrow after stroke onset, even in the 1-hour transient focal ischemic model. To achieve protection, 3 hours of moderate hypothermia must be induced as early as 45 minutes after stroke onset; a 30-minute delay rendered the moderate hypothermia ineffective. Again, it is highly unlikely that most stroke patients can receive hypothermic treatment within 1 hour of stroke onset. In most clinical studies, mild-to-moderate hypothermia was initiated as late as 5 to 6 hours after stroke, and one to several hours were required to reach target temperatures [37
]. In addition, patients may not have reperfusion, or if there is reperfusion, it may occur at a very late stage.
Our studies on the underlying protective mechanisms may also offer some alternative clues or applications for clinical trials. For instance, we demonstrated that hypothermia reduces infarct size by preserving Akt activity and PTEN phosphorylation and by inhibiting ROS activity. If possible, pharmacological agents may be developed that improve Akt activity while inhibiting PTEN activity, or attenuating ROS production, and such pharmacological agents may be used in combination with induced hypothermia.
In summary, despite confounding issues, laboratory studies have provided strong rationale for clinical application of hypothermia for acute stroke treatment. In clinical settings, a number of crucial variables need to be considered, including the onset time of hypothermia, its depth, and whether the strokes studied include reperfusion. Early reperfusion and rapid hypothermia initiation should be used to achieve maximal protection.