The Effects of Normalizing Blood Pressure on Cerebral Blood Flow in Hypotensive Individuals With Spinal Cord Injury
Condition: Spinal Cord Injury; Autonomic Dysreflexia; Baroreceptor Integrity; Sympathetic Integrity; Vagal Integrity; Autonomic Integrity; Hypotensive; Cognitive Function; Cerebral Blood Flow; Blood Pressure
MeSH terms: Spinal Cord Injuries; Autonomic Dysreflexia; Hypotension; Wounds and Injuries
Study type: Interventional
Phase: Phase 2

Summary: 
      Dysregulation of blood pressure (BP), secondary to decentralized autonomic nervous system
      (ANS) control of the cardiovascular system, often results in chronic hypotension and
      orthostatic hypotension (OH) in persons with spinal cord injury (SCI), particularly in those
      with high cord lesions (i.e., above T6). While most hypotensive individuals with chronic SCI
      remain asymptomatic and do not complain of symptoms associated with cerebral hypoperfusion,
      evidence of reduced resting cerebral blood flow (CBF) has been reported in association with
      low systemic BP in the SCI and non-SCI populations. Reduced CBF in hypotensive individuals
      may lead to cognitive dysfunction, and we reported significantly impaired memory and
      marginally impaired attention processing in hypotensive individuals with SCI compared to a
      normotensive SCI cohort. Furthermore, we found that CBF was not increased during cognitive
      testing in individuals with SCI, which may contribute to impaired cognitive function compared
      to non-SCI controls. Although asymptomatic hypotension may have an adverse impact on
      cognitive function and quality of quality of life (QOL) clinical management of this condition
      is extremely low. In fact, we reported that while nearly 40% of Veterans with SCI were
      hypotensive, less than 1% carried the diagnosis of hypotension or were prescribed an
      anti-hypotensive medication. The discrepancy between incidence and treatment of asymptomatic
      hypotension in the SCI population may relate to a paucity of treatment options which are
      supported by rigorous clinical trials documenting safe and effective use of anti-hypotensive
      therapy on BP, CBF and cognitive function. We hypothesize these study medications may
      increase systolic blood pressure to the normal range and improve cerebral blood flow
      velocity. Results and conclusions will not be removed from the record.
    

Detailed description: 
      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.
    

Intervention name(s): Midodrine Hydrochloride; Pyridostigmine Bromide; Mirabegron; Placebo
Intervention type(s): Drug; Drug; Drug; Other
Intervention description(s): study 1 will be single blind. study 2 will be blinded randomized-control trial.; study 1 will be single blind. study 2 will be blinded randomized-control trial.; study 1 will be single blind. study 2 will be blinded randomized-control trial.; placebo will only be used for study arm 2, the randomized blinded phase.
Other intervention name(s): midodrine; pyridostigmine
Intervention MeSH terms: Midodrine; Bromides; Mirabegron; Pyridostigmine Bromide
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment