Acetylcholinesterase Inhibition and Orthostatic Hypotension in SCI
Condition: Hypotension, Postural
MeSH terms: Hypotension, Orthostatic; Hypotension
Study type: Interventional
Phase: Phase 2

Summary: 
      Due to de-centralized cardiovascular control, persons with spinal cord injury (SCI)
      experience blood pressure (BP) dysregulation which manifests in chronic hypotension with
      exacerbation during orthostatic positioning. Although many individuals with SCI remain
      asymptomatic to hypotension and orthostatic hypotension (OH), we recently reported reduced
      memory and marginally reduced attention and processing speed in hypotensive individuals with
      SCI compared to a normotensive cohort. Thus, we believe that treatment of overtly
      asymptomatic hypotension and OH in the SCI population is clinically warranted. Currently the
      FDA has approved only midodrine hydrochloride for the treatment of dizziness associated with
      OH and proof of efficacy is limited. Acetylcholinesterase inhibition for treatment of OH is a
      novel concept and has gained recent recognition in models of neurogenic OH (multiple system
      atrophy; pure autonomic failure, diabetic neuropathy). The physiological rationale of this
      concept is unique: acetylcholine (AcH) is the pre-ganglionic neurotransmitter of the
      sympathetic nervous system. Inhibition of acetylcholinesterase will limit the breakdown of
      AcH thereby facilitating vascular adrenergic tone and peripheral vasoconstriction.
      Acetylcholinesterase inhibition has been reported to be efficacious in models of both
      pre-ganglionic (multiple system atrophy) and post-ganglionic (pure autonomic failure,
      diabetic neuropathy) origin and persons with SCI reflect a model of a preganglionic disorder.
      In theory, if an individual has a complete autonomic lesion, acetylcholinesterase inhibition
      would not be expected to improve orthostatic BP because little/no neural traffic would be
      transmitted to the pre-synapse. However, individuals with an incomplete autonomic lesion may
      benefit from this class of agent. Researchers are currently investigating the orthostatic BP
      effects of acetylcholinesterase inhibition with pyridostigmine bromide (60 mg) in 10
      individuals with SCI.
    

Detailed description: 
      Due to de-centralized cardiovascular control, persons with spinal cord injury (SCI)
      experience blood pressure (BP) dysregulation which manifests in chronic hypotension with
      exacerbation during orthostatic positioning. Although many individuals with SCI remain
      asymptomatic to hypotension and orthostatic hypotension (OH), we recently reported reduced
      memory and marginally reduced attention and processing speed in hypotensive individuals with
      SCI compared to a normotensive cohort. Thus, we believe that treatment of overtly
      asymptomatic hypotension and OH in the SCI population is clinically warranted. Currently the
      FDA has approved only midodrine hydrochloride for the treatment of dizziness associated with
      OH and proof of efficacy is limited. Acetylcholinesterase inhibition for treatment of OH is a
      novel concept and has gained recent recognition in models of neurogenic OH (multiple system
      atrophy; pure autonomic failure, diabetic neuropathy). The physiological rationale of this
      concept is unique: acetylcholine (AcH) is the pre-ganglionic neurotransmitter of the
      sympathetic nervous system. Inhibition of acetylcholinesterase will limit the breakdown of
      AcH thereby facilitating vascular adrenergic tone and peripheral vasoconstriction.
      Acetylcholinesterase inhibition has been reported to be efficacious in models of both
      pre-ganglionic (multiple system atrophy) and post-ganglionic (pure autonomic failure,
      diabetic neuropathy) origin and persons with SCI reflect a model of a preganglionic disorder.
      In theory, if an individual has a complete autonomic lesion, acetylcholinesterase inhibition
      would not be expected to improve orthostatic BP because little/no neural traffic would be
      transmitted to the pre-synapse. However, individuals with an incomplete autonomic lesion may
      benefit from this class of agent. Researchers are currently investigating the orthostatic BP
      effects of acetylcholinesterase inhibition with pyridostigmine bromide (60 mg) in 10
      individuals with SCI. The primary objectives of this study are to compare the BP response to
      head-up tile (HUT: 45°) between no-drug and drug (pyridostigmine 60 mg) in individuals with
      SCI with documented OH; and to compare the orthostatic BP responses following drug in
      individuals with SCI.

      Subjects will be tested on two separate days. On day 1 of testing, subjects will be
      transferred onto a tilt table and will remain in the supine position for the entirety of the
      test. During the first 60 minutes the subject will remain at the resting supine position.

      Following the 60 minute resting position, a progressive head-up tilt will be utilized in
      which the table will be adjusted to 15°, 25°, 35° for 5 minutes at each angle and then
      maintained at 45° for 45 minutes or until the subjects experiences symptoms of compromised
      cerebral blood flow, which include, but are not limited to, light headedness, blurry vision,
      dizziness and nausea.

      On day 2 of testing, the protocol will be duplicated with the exception of drug
      administration. 60 mg of the study drug, pyridostigmine will be administered at the 30 minute
      mark of the resting supine position. Data for heart rate and blood pressure will be monitored
      continuously during the progressive HUT maneuver and will be recorded at 10 minute intervals
      during the 45° HUT.
    

Intervention name(s): Pyridostigmine Bromide; Tilt table test
Intervention type(s): Drug; Device
Intervention description(s): After being transferred onto a tilt table, subject will lie in a rested, supine position in which the study drug, pyridostigmine bromide will be administered at the 30 minute time point. Following the administration of the study drug, the subject will remain in the supine position for an additional 30 minutes until the tilting protocol commences.; After 60 minutes in supine resting position, a progressive head-up tilt will be utilized in which the table will be adjusted to 15°, 25°, 35° for 5 minutes at each angle and then maintained at 45° for 45 minutes or until the subjects experiences symptoms of compromised cerebral blood flow, which include, but are not limited to, light headedness, blurry vision, dizziness and nausea.
Other intervention name(s): Brand Name: Mestinon; Upright tilt testing
Intervention MeSH terms: Bromides; Pyridostigmine Bromide
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Hypotension, Postural