Inclusion Criteria1. 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
Exclusion Criteria1. 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.