Is Reperfusion Injury a Largely Intra-Ischemic Injury?

Reperfusion injury (RI) refers to an array of detrimental cellular and biochemical processes that are widely believed to be triggered by reperfusion following focal cerebral ischemia and to contribute to infarct extension and poor outcome despite complete recanalization. Accordingly, it is widely recommended that therapies targeting RI be administered after recanalization. The present topical review demonstrates, however, that the vast majority of, and possibly all, processes considered part of RI are not actually provoked by reperfusion but develop during the ischemic phase. This notion has significant implications for clinical trials. Thus, for optimal efficacy, treatments targeting RI should accordingly be started before recanalization. Conversely, interventions aimed at protecting the ischemic penumbra, either pharmacological or nonpharmacological, during arterial occlusion are likely to also benefit RI-related processes and should probably be continued after recanalization. Overall, RI is largely an intra-ischemic process that has important ramifications for drug development and clinical trials and more broadly for the management of patients with hyperacute ischemic stroke before, and following, recanalization.