Midodrine for Ischemic Stroke With Penumbra

Acute ischemic stroke (AIS) affects over 700,000 Americans every year and is the leading cause of long-term disability. Early neurological deterioration after AIS typically occurs within 72 hours of stroke onset and affects 30% of all stroke patients, who have a higher rate of death or poor outcome. Several mechanisms account for early neurological deterioration, including hemorrhagic conversion, systemic illness, cerebral edema, and seizure, but the most common cause is extension of the stroke into the "penumbra," a region of salvageable brain tissue surrounding the core of irreversible ischemic infarct. The penumbra is tenuously perfused by collateral blood vessels. AIS management is primarily focused on recanalizing the occluded artery causing the stroke, but an alternative and relatively unexplored approach is optimization of collateral blood flow.

Over 60% of AIS patients present with a transient acute hypertensive response, which is theorized to be the result of either increased sympathoadrenal tone, poorly controlled underlying hypertension, or an unknown stroke-specific mechanism related to augmenting cerebral perfusion through collateral blood flow. Epidemiological data suggests worse stroke outcomes are associated with extremes of sustained hypo- or hypertension, which has led to dozens of clinical trials involving over 20,000 patients to determine if pharmacologically lowering blood pressure after AIS is beneficial. The results have been persistently neutral or negative. In contrast, there have been no major clinical trials on the efficacy of using vasopressor medications to maintain or increase baseline blood pressure after AIS, despite promising preclinical data and pilot studies that showed no increase in cerebral hemorrhage or edema. The only randomized trial of vasopressor use after AIS demonstrated an improvement in clinical outcomes, but there was no difference in mean blood pressure between the control and intervention arms, suggesting the beneficial effect was not exclusively related to induced hypertension. One possibility is that the vasopressor reduced blood pressure variability, which preliminary data has shown to be detrimental after AIS, although that aspect of neurovascular coupling has not been adequately studied in the acute phase after AIS.

The reliance on IV vasopressors, which are only administered in the intensive care unit, is a fundamental limitation of prior research. An alternative, but untested, approach is to use the oral vasopressor midodrine hydrochloride. We hypothesize that frequent midodrine dosing after AIS can optimize collateral blood flow and help salvage the ischemic penumbra. The objective of this study is to develop tools to quantify midodrine's effect on blood pressure and the ischemic penumbra.