The Effects of Normalizing Blood Pressure on Cerebral Blood Flow in Hypotensive Individuals With Spinal Cord Injury

Study 1: Subjects will visit the laboratory between 3 and 9 times for 4 hours to determine the BP response to each dose of the 3 study medications (midodrine, pyridostigmine, and mirabegron). Upon arrival to the laboratory subjects will be randomized to receive midodrine, pyridostigmine, or mirabegron. Subjects will remain seated in their wheelchair for the duration of testing. Instrumentation will be applied by study personnel while subject is seated quietly, this can take up to 20 minutes. Instrumentation includes placement of 3 ECG electrodes for continuous HR monitoring and finger and brachial BP cuffs. BP, BR and HR will be recorded for 5-minutes before medication administration (baseline). After baseline, a small pill will be given with a glass of water. BP, BR and HR will be monitored for 5-minutes every 30 minutes for 4 hours after drug administration.

Study 2: Twenty will visit the laboratory on 4 occasions to determine the effects of three anti-hypotensive agents, compared to placebo, on BP, CBFv, and cognitive performance on selected neuropsychological tests. Upon arrival to the laboratory for every visit subjects will be randomized to receive midodrine, pyridostigmine, mirabegron, or matching placebo. Neither the study subject nor the investigator will know which is being administered. Subjects will remain seated in their wheelchair throughout the duration of the study session and will be closely monitored by study personnel. Instrumentation will include placement of 3 ECG electrodes for continuous heart rate (HR) monitoring, finger and brachial BP cuffs, and a Doppler ultrasound probe positioned at the left MCA for continuous CBFv monitoring. Subjects will remain quietly seated in their wheelchair for 30-minutes after instrumentation for a 5-minute recording of continuous HR, BP, and CBFv (baseline). Prior to the baseline data collection period, the first battery of cognitive tests will be administered. The study medication will be administered to the subject along with a glass of water approximately 30-minutes after arrival to the laboratory. There will be a 2 hour break period until the second cognitive battery begins.

Inclusion criteria

Spinal Cord Injured

• Any level of injury
• Any ASIA grade of SCI
• Primarily wheelchair dependent for mobility
• Duration of injury ˃ 1 year

Exclusion criteria

• Current illness or infection
• History of severe autonomic dysreflexia (AD: condition where BP increases)
• More than 3 symptomatic events per week; BP elevations above 140/90 mmHg; adverse symptoms reporting (e.g., light headedness, dizziness, goosebumps, chills, nausea, etc.)
• Diagnosis of hypertension
• History of Traumatic Brain Injury (TBI)
• Documented history of traumatic brain injury (TBI)
• Neurological condition other than SCI (Alzheimer's disease, dementia, stroke, multiple sclerosis, Parkinson's disease, etc)
• History of epilepsy or other seizure disorder
• Liver or kidney disease
• Bladder problems including blockage of the urine and/or weak urine stream
• Diagnosis of a psychiatric disorder such as schizophrenia or bipolar disorder
• Diagnosis of artery disease, heart failure, irregular heartbeat, and AV block
• Allergies to aspirin, a yellow dye, pyridostigmine bromide, midodrine hydrochloride, lyethylene oxide, polyethylene glycol, hydroxypropyl cellulose, butylated hydroxytoluene, magnesium stearate, hypromellose, yellow ferric oxide, and red ferric oxide
• Had major surgery in the last 30 days
• Illicit drug abuse within the last 6 months
• Pregnant