Acetylcholinesterase Inhibition and Orthostatic Hypotension in SCI

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.

After being transferred onto a tilt table, subject with complete SCI will lie in a rested, supine position in which the study drug, pyridostigmine bromide (60 mg) 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 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.

Average systolic blood pressure of 10 minutes supine rest before pyridostigmine and after 45 minutes at 45 degrees after pyridostigmine administration compared to 10 minutes supine rest before tilt and at 45 degrees during no-drug head-up tilt maneuver.

Average diastolic blood pressure of 10 minutes supine rest before pyridostigmine and after 45 minutes at 45 degrees after pyridostigmine administration compared to 10 minutes supine rest before tilt and at 45 degrees during no-drug head-up tilt maneuver.

Average heart rate of 10 minutes supine rest before pyridostigmine and after 45 minutes at 45 degrees following pyridostigmine administration compared to 10 minutes supine rest before tilt and at 45 degrees during no-drug head-up tilt maneuver.

Inclusion Criteria: Age 18-65 years old Spinal cord injury with American Spinal Injury Association Impairment Scale (AIS) level of Grade A, B, C or D 9non-ambulatory) Neurological level of injury C3-T2 Duration of injury greater than 1 year Exclusion Criteria: Currently taking medications with known blood pressure raising or lowering effects. Taking over-the-counter medications for allergies or cold symptoms 24-hours prior to testing. I have a C3 level of injury and I am ventilator dependent. History of cardiovascular arrhythmias (especially slow heart rate, less than 45 bpm), block in the electrical signal within the heart, cardiac arrest. History of convulsions or seizures. Currently taking medication to treat active asthma. Thyroid problems. Current smoker. Known coronary heart and/or artery disease. High blood pressure Diabetes Current illness or infection Major surgery in the last 30 days Hypersensitivity to pyridostigmine, bromides, or any component of the formulation; (as determined by review of known drug allergies reported in the medical history intake form and confirmed by the study physician) Pregnancy