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Reduction in Splanchnic Capacitance Contributes to Sympathetically Dependent Hypertension in Autonomic

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ClinicalTrials.gov Identifier: NCT02726711
Recruitment Status : Recruiting
First Posted : April 4, 2016
Last Update Posted : February 4, 2019
Sponsor:
Information provided by (Responsible Party):
Italo Biaggioni, Vanderbilt University

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.

Condition or disease Intervention/treatment Phase
Multiple System Atrophy Orthostatic Hypotension Supine Hypertension Drug: Trimethaphan Drug: Placebo Phase 1

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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volume and the autonomic nervous system such as antihypertensives, pressor medications and fludrocortisone will be withdrawn for at least 5 half-lives before studies.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

Eligible Multiple System Atrophy patients with supine hypertension will be studied twice in a randomized, single blind, crossover design, once with trimethaphan and once with placebo. The order of administration is randomized. The placebo day will have identical interventions, but saline will be infused instead of trimethaphan to provide a time control. Studies will be conducted in a postvoid state and ≥2 hours after meals. Each study day will last 2-3 hours. The following procedures will be conducted:

Patients will be instrumented to measure blood pressure continuously with photoplethysmography, and intermittently with an automated oscillometric device. Heart rate will be monitored continuously with ECG. Electrodes will be placed on thorax and abdomen to measure segmental impedance. Skin blood flow will be measured in the forearm with a laser Doppler. Cardiac output will be measured by the inert gas rebreathing technique and/or by impedance cardiography. An IV will be placed in one arm for drug administration.

After instrumentation baseline measurements will be recorded, including cardiac output and splanchnic venous capacitance. Venous capacitance will be estimated using an adaptation of the method of Schmitt et al. In this technique, segmental impedance is monitored, while continuous positive airway pressure (CPAP) is applied sequentially at 0, 4, 8, 12 and 16 cm water (H20) for 1-2 minute each.

Patients will then receive either placebo (time control) or trimethaphan, to induce complete withdrawal of residual sympathetic tone. Intravenous infusion of trimethaphan camsylate (Cambridge Labs) will be started at 0.5-1 mg/min and increased by 1.0 mg/min in 2-6 minute intervals to one of the following endpoints: presyncopal symptoms, no further decrease in blood pressure with increased infusion rates, or an infusion rate of 4 mg/min. Once a stable decrease in blood pressure is obtained, outcome measurements will be repeated.

Abdominal compression will be applied to a sustained 40 mm Hg pressure while supine with an inflatable binder. Outcome measurements will be repeated 5-15 minutes later. The investigator may decide not to perform this procedure (due to a longer than anticipated study day duration / drug infusion). In this case, the study will include only the outcome measurements during the drug infusion.

The infusion of trimethaphan is then stopped and patient monitored until blood pressure is restored to baseline values.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 32 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Single (Participant)
Primary Purpose: Basic Science
Official Title: Reduction in Splanchnic Capacitance Contributes to Sympathetically Dependent Hypertension in Autonomic Aim 1 of Rare Diseases Clinical Research Network (RDCRN) Project 2
Study Start Date : April 2016
Estimated Primary Completion Date : March 2021
Estimated Study Completion Date : March 2021


Arm Intervention/treatment
Experimental: 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.

Drug: Trimethaphan
Trimethaphan will be infused (0.5 - 4.0 mg IV)
Other Name: Trimethaphan Camsylate

Placebo Comparator: 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.

Drug: Placebo
0.5 - 4.0 mg IV to be infused
Other Name: saline




Primary Outcome Measures :
  1. 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.



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Ages Eligible for Study:   40 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02726711


Contacts
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Contact: Emily C Smith, RN 615.875.1516 autonomics@vumc.org
Contact: Bonnie K Black, RN 615-343-6862 autonomics@vumc.org

Locations
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United States, Tennessee
Vanderbilt University Medical Center Recruiting
Nashville, Tennessee, United States, 37232
Contact: Emily C Smith, RN    615-875-1516    autonomics@vumc.org   
Contact    615-322-3304    autonomics@vumc.org   
Principal Investigator: Italo Biaggioni, MD         
Sub-Investigator: Alfredo Gamboa, MD         
Sub-Investigator: Luis E Okamoto, MD         
Sub-Investigator: Cyndya A Shibao, MD         
Sub-Investigator: Andre Diedrich, MD/PhD         
Sub-Investigator: David H Robertson, MD         
Sub-Investigator: Emily C Smith, RN         
Sponsors and Collaborators
Vanderbilt University
Investigators
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Principal Investigator: Italo Biaggioni, M.D. Vanderbilt University

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Responsible Party: Italo Biaggioni, MD, Vanderbilt University
ClinicalTrials.gov Identifier: NCT02726711     History of Changes
Other Study ID Numbers: 151947
First Posted: April 4, 2016    Key Record Dates
Last Update Posted: February 4, 2019
Last Verified: February 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Additional relevant MeSH terms:
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Hypertension
Atrophy
Hypotension
Hypotension, Orthostatic
Multiple System Atrophy
Shy-Drager Syndrome
Vascular Diseases
Cardiovascular Diseases
Pathological Conditions, Anatomical
Orthostatic Intolerance
Primary Dysautonomias
Autonomic Nervous System Diseases
Nervous System Diseases
Basal Ganglia Diseases
Brain Diseases
Central Nervous System Diseases
Movement Disorders
Neurodegenerative Diseases
Trimethaphan
Trimethaphan camsylate
Adjuvants, Anesthesia
Antihypertensive Agents
Ganglionic Blockers
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Nicotinic Antagonists
Cholinergic Antagonists
Cholinergic Agents
Neurotransmitter Agents