Salt Lake City,
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
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.
1. Adult patients, ≥ 18 years old, with anterior circulation acute ischemic stroke on
diffusion-weighted imaging (DWI) MRI, defined as predominant stroke burden in the
frontal, parietal, or temporal lobes.
2. Demonstrable neurologic deficit due to stroke at randomization.
3. Within 12 hours of randomization, measured on CT or MR perfusion: a cerebral blood
flow (CBF)/DWI ratio ≥1.25, an absolute difference between the CBF and DWI lesions of
≥15 mL, and a DWI volume between 20-100 mL. (Quantified with the Olea software)
4. Enrollment within 24 hours from stroke onset
1. Endovascular therapy or intravenous tPA treatment for stroke
2. Acute myocardial infarction on ECG or troponin T >0.01 ng/mL.
3. History of cardiac disease, including myocardial infarction or unstable angina within
the last 3 months, any history of clinically significant arrhythmia, symptomatic
valvular disease, dilated cardiomyopathy, hypertrophic obstructive cardiomyopathy,
left-ventricular assist device, or known ejection fraction < 25%.
4. Glomerular filtration rate < 50, serum creatinine >1.5 mg/dl, severe urinary
retention, or end-stage renal disease on dialysis.
5. Coagulopathy, including INR >1.5, PTT >40, platelet count <75, or use of a novel
anticoagulant in the last 3 days (e.g. dabigatran, rivaroxaban, apixaban).
6. Positive pregnancy test.
7. Clinical and laboratory evidence of thyrotoxicosis.
8. Severe Peripheral Vascular Disease or Raynaud's syndrome.
9. Systolic blood pressure (SBP) >180 or diastolic blood pressure (DBP) >100 immediately
prior to randomization.
10. Allergy or history of adverse reaction to IV phenylephrine or midodrine.
11. Hemorrhage within the area of DWI lesion on MRI.
12. Indication for anticoagulation within 5 days of stroke onset.
13. Arterial dissection or cerebral aneurysm.
14. Pre-stroke modified Rankin score of >2.
15. Evidence of bacterial endocarditis.
16. Indication for carotid endarterectomy or stenting in next 5 days.
17. Inability or unwillingness of subject or legal guardian/representative to give
written informed consent.
18. Failure of post-stroke swallow evaluation and no alternative enteric access (e.g.
nasogastric feeding tube, percutaneous endoscopic gastrostomy tube).
19. Active drug or alcohol use or dependence that, in the opinion of the site
investigator, would interfere with adherence to study requirements.