High-dose albumin for neuroprotection in acute ischemic stroke: From basic investigations to multicenter clinical trial

Abstract

Albumin (ALB), the plasma's most abundant protein, is a multifunctional molecule with potent antioxidant and intravascular actions. Albumin is in widespread clinical use to provide circulatory support in the settings of shock, burns, and surgery. More recently, we have shown that albumin when administered in high doses acts as a powerful neuroprotective agent in acute ischemic stroke and brain injury. In experimental studies of focal cerebral ischemia conducted in physiologically monitored rats, animals treated with ALB (typically 25% solution in doses of 1.25 g/kg and above) showed improved neurological score, substantial reductions of infarct volume, and markedly reduced brain swelling compared to saline placebo-treated rats, with a therapeutic window of 4-5 h. In mechanistic studies, ALB improved local blood flow in the ischemic penumbra; antagonized postischemic microvascular thrombosis; improved perfusion distal to microvascular thrombi; and facilitated delivery of fatty acids to the postischemic brain. In a two-center dose-escalation human pilot clinical trial, ALB was generally well tolerated; the chief adverse event was mild-to-moderate pulmonary edema in 13% of subjects, which could be readily managed. A major phase III multicenter clinical efficacy trial-the ALIAS (Albumin in Acute Stroke) Trial-is now underway in the U.S., Canada, and Israel, employing ALB at the 2 g/kg dose shown in experimental studies to be neuroprotective.