Reduction in Splanchnic Capacitance Contributes to Sympathetically Dependent Hypertension in Autonomic Aim 1 of Rare Diseases Clinical Research Network (RDCRN) Project 2
Trial Snapshot
- Phase
- Phase 1
- Status
- Active, not recruiting
- Sponsor
- Vanderbilt University
- Enrollment
- 2
- Locations
- 1
- Primary Endpoint
- The percentage of increase of the y intercept of the P-V relationship
Study Overview
Brief Summary
The purpose of this study is to learn more about the regulation of the veins of the abdomen by the autonomic (involuntary) nervous system, and how this may affect high blood pressure. Normally, the autonomic nervous system controls how much blood flows in the veins. In people with high blood pressure, however, the autonomic nervous system is changed. This change may affect the way blood flows in the veins of the abdomen which may play a role in their high blood pressure. About 32 participants will be screened for the study. The investigators estimate 16 will be eligible to participate in all of the study days.
Detailed Description
The investigators will study male and female subjects, age 40-80 years with possible or probable Multiple System Atrophy, as defined by Consensus Criteria who suffer from supine hypertension defined as SBP≥150, and neurogenic orthostatic hypotension, defined as a ≥30-mmHg decrease in systolic BP within 3 minutes of standing associated with impaired autonomic reflexes determined by autonomic testing in the absence of other identifiable causes. All participants will be able and willing to provide informed consent.
Screening Procedures. Potential participants will be studied in the Vanderbilt Autonomic Dysfunction Center (ADC). Medications affecting BP, blood volume and the autonomic nervous system such as antihypertensives, pressor medications and fludrocortisone will be withdrawn for at least 5 half-lives before studies. Screening procedures can be performed in one or more days depending on the patient's and investigator's availability.
- Patients will undergo a complete history and physical examination, ECG, routine clinical laboratory analysis and a blood pregnancy test for women with childbearing potential.
- Autonomic testing including sinus arrhythmia, Valsalva maneuver and a posture study with plasma catecholamines is then performed to determine if they meet the inclusion/exclusion criteria. During these tests, blood pressure (BP) and heart rate (HR) will be obtained using an automated oscillometric sphygmomanometer, finger photoplethysmography, and continuous ECG. During the orthostatic test, blood samples will be obtained for hormones that regulate BP, such as catecholamines, while patients are supine and upright.
Medical history information and results from any of the screening procedures obtained within the previous 6 months for other studies within this research group may be utilized.
Study Procedures: Study Day 1 and 2
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Crossover
- Primary Purpose
- Basic Science
- Masking
- Single (Participant)
Eligibility Criteria
- Ages
- 40 Years to 80 Years (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Male and female subjects, age 40-80 years, with possible or probable Multiple System Atrophy, as defined by Consensus Criteria.
- •Neurogenic orthostatic hypotension defined as a ≥30-mmHg decrease in systolic blood pressure within 3 minutes of standing associated with impaired autonomic reflexes determined by autonomic testing in the absence of other identifiable causes.
- •Supine hypertension, defined as systolic blood pressure ≥150 mmHg measured on two separate occasions.
- •Subjects able and willing to provide informed consent.
Exclusion Criteria
- •Pregnancy.
- •Systemic illnesses known to produce autonomic neuropathy, including but not limited to diabetes mellitus, amyloidosis, monoclonal gammopathies, and autoimmune neuropathies
- •History of known aortic aneurysms, thoracic, abdominal or pelvic surgery in the past 6 months
- •Symptomatic abdominal or inguinal hernias
- •Severe gastroesophageal reflux
- •Recent fractures or fissures of ribs, thoracic or lumbar spine
- •Medical devices implanted on the abdominal wall or abdomen that would interfere with the abdominal compression
- •Intolerance to any increase in intra-abdominal pressure
- •Clinically unstable coronary artery disease or major cardiovascular or neurological event in the past 6 months, and other factors which in the investigator's opinion would prevent the subject from completing the protocol including clinically significant abnormalities in clinical, mental or laboratory testing.
Arms & Interventions
Trimethaphan
The investigator will measure cardiac output by studying the air the participant breathes in and out. The participant will also wear a facemask to apply a low air pressure to the airway.
After this, the trimethaphan infusion will begin with a small dose and the investigators increase at 1-2 minute intervals for up to five doses. The measurements will be collected again.
Next, a standard blood pressure cuffs will be wrapped around the participant's abdomen. the cuff will inflate to apply pressure for 5 - 15 minutes.
Intervention: Trimethaphan (Drug)
Placebo
The investigator will measure cardiac output by studying the air the participant breathes in and out. The participant will also wear a facemask to apply a low air pressure to the airway.
After this, the placebo (saline) infusion will begin with a small dose and the investigators increase at 1-2 minute intervals for up to five doses. The measurements will be collected again.
Next, a standard blood pressure cuffs will be wrapped around the participant's abdomen. the cuff will inflate to apply pressure for 5 - 15 minutes.
Intervention: Placebo (Drug)
Outcomes
Primary Outcomes
The percentage of increase of the y intercept of the P-V relationship
Time Frame: 5 years
To determine whether autonomic blockade with trimethaphan increases splanchnic capacitance (parallel upward shift in the P-V relationship) compared to placebo.
Secondary Outcomes
No secondary outcomes reported
Investigators
Italo Biaggioni
MD
Vanderbilt University