Fibrinolytic treatment of acute stroke: are we treating reversible cerebral ischemia?

With increased understanding of the underlying pathophysiology of acute ischemic stroke, advances in imaging and interventional techniques, and the development of new fibrinolytic and neuroprotective agents, potential therapeutic options in the treatment of patients with acute ischemic stroke have became available recently (1–10). Animal studies have indicated that each minute of ischemia is harmful (11). It is generally believed that the sooner we begin to treat the brain after ischemic stroke, the better are our chances of minimizing the damage: the “time is brain” theory (National Stroke Association newsletter, 1993, 10:1). This has stimulated the drive to treat ischemic stroke as an emergency (“brain attack”). Emergency treatment focuses on the first 6 hours after the onset of ischemic stroke symptoms. It generally is agreed that the 6-hour time period provides a therapeutic window of opportunity during which medical intervention can be initiated to limit brain damage. Within this window (6 hours), it is presumed that most, if not all, ischemic tissue will remain viable and, theoretically, can be revived. Furthermore, the purpose in choosing a therapeutic window for early intervention is not only to rescue the reversible ischemic tissue but also to avoid complications caused by the reperfusion of irreversibly damaged or necrotic tissue. The article by Lanzieri et al (12) in this issue reports that the urgent application of thrombolysis in eight patients with middle cerebral artery occlusion using intraarterial urokinase within 6 hours of the onset of symptoms resulted in a statistically significant positive change in National Institutes of Health (NIH) score by at least five points compared with 26 untreated patients with middle cerebral artery occlusion. A statistically significant benefit of intraarterial urokinase initiated within the therapeutic window was noted. Although the NIH stroke scale is one of impairment, not of disability or outcome, their data suggest that the therapeutic benefit of fibrinolysis in treating acute ischemic stroke is real. They conclude such techniques can be cost-effective in the treatment of patients with acute ischemic stroke. Also in this issue, Jansen et al (13) report different results. They studied 32 patients with acute internal carotid artery occlusion treated with intravenous recombinant tissue plasminogen activator (rtPA, alteplase) and intraarterial alteplase or urokinase within the first 6 hours after the onset of symptoms. Their data showed no significant benefit from either intraarterial or intravenous thrombolytic treatment even when fibrinolysis was initiated within the therapeutic window. Their data further suggest that thrombolytic therapy did not work and may even have made the patient’s condition worse. They suggested that more-potent pharmaceutical agents or other means such as mechanical thrombectomy may improve outcome. They also speculated that the existence of sufficient collateral circulation before the onset of ischemic stroke is an essential factor that may affect outcome. The inconsistency between the two articles and many previous reports regarding the efficacy of fibrinolysis in the treatment of acute ischemic stroke was not unexpected (14–17) (Haley EC, Levy D, Sheppard G, et al, “A DoseEscalation Safety Study of Intravenous Tissue Plasminogen Activator in Patients Treated from 90 to 180 Minutes from Onset of Acute Ischemic Stroke,” Ann Neurol 1990;28:225 [Ab-