CHAPTER 27 – The Concept of the Therapeutic Window: A Synthesis of Critical Issues*

The therapeutic window is the time-frame within which successful therapy may be initiated prior to the onset of irreversible injury. This chapter explores the criteria used to define the therapeutic window for treating ischemic brain injury, and the characteristics of this window as determined by the type of ischemic insult (focal vs global) and the nature of the therapy. Therapeutic hypothermia is used to illustrate the influence of model-dependent factors and of treatment delay, and intensity and duration of therapy on outcome. The therapeutic window for successful reperfusion therapy of focal ischemia is considered. The great weight of evidence obtained from animal studies of focal ischemia is that the therapeutic window is narrow and that therapy to avert irreversible injury must be instituted within 2 to 4 hours of stroke onset. By contrast, in global ischemia, instances of successful tissue rescue have been obtained with treatment delays of up to 24 hours, depending on the class of agent employed. Consistent observations derived from laboratory experimentation should be regarded seriously in the construction of clinical trials of stroke therapy. The concept of the therapeutic window for the treatment of cerebral ischemia has been refined in the context of intense current effort directed at developing efficacious therapies for focal and global ischemic insults to the central nervous system prior to the onset of irreversible cellular alterations. At first glance, the concept of the therapeutic window has simplistic appeal, fueled by the seductive belief that therapy to avert ischemic brain injury would be possible only if instituted quickly enough following the onset of the ictus. In reality, however, this concept is quite complex, embracing a number of issues whose exegesis forms the substance of this overview.