Hypotension, Postural Clinical Trial
Official title:
Acetylcholinesterase Inhibition: A Novel Approach in the Treatment of Orthostatic Hypotension in Spinal Cord Injury
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.
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.
;