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Autonomic Control of the Circulation and the Venous Distension Reflex

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ClinicalTrials.gov Identifier: NCT03513770
Recruitment Status : Recruiting
First Posted : May 2, 2018
Last Update Posted : April 16, 2019
Sponsor:
Information provided by (Responsible Party):
Jian Cui, Milton S. Hershey Medical Center

Brief Summary:
This research is being done to determine how the blood pressure control is altered by an increased volume in the veins.

Condition or disease Intervention/treatment Phase
Blood Pressure Drug: Ketorolac Tromethamine Other: Control Early Phase 1

Detailed Description:

In humans, two-thirds of the blood volume is contained within the venous vasculature. Because of this, changes in peripheral blood volume and alterations in the mechanical properties of peripheral veins can greatly impact cardiac filling, cardiac output and blood pressure responses to physiologic stress. Work from our laboratory over the past seven years has showed that local upper limb venous distension via volume infusion into an occluded arm (i.e. volume infusion model) or applying negative pressure to an occluded leg (limb suction experimental model) leads to acute and dramatic increases in Muscle Sympathetic Nerve Activity (MSNA; an index of sympathetic activity directed to skeletal muscle) and blood pressure (BP) in humans. Since this venous distension reflex (VDR) differs physiologically from the other reflex systems and because this system may play a critical role in orthostatic BP control, the investigators believe that it is a significant area of study.

These experimental models "selectively" alter peripheral venous volume as the investigators measure sympathetic reflex responses. This approach is innovative and allows examination of a previously overlooked autonomic reflex in conscious humans. If these studies confirm the hypotheses, the obtained data would challenge the present teaching regarding how the sympathetic nervous system is engaged in humans during postural stress.

A number of thin afferent fibers (Group III and IV) end directly within the adventitia of the small venous vessels. Their discharge can be increased in response to both distention evoked by venous occlusion and the infusion of vasodilatory agents. The investigators postulate that limb venous distension causes the release of substance(s) from vascular walls and/or the surrounding tissues, and in turn stimulates these thin fiber afferents. Previous animal studies show that metabolic products of the cyclooxygenase (COX) enzyme system (i.e. prostaglandins) play an important role in activating Group III and IV afferents during muscle contraction. Of note, colleagues have shown that COX blockade attenuates the rise in BP seen with venous distention in a rat model.

In this protocol, the investigators will examine the role played by metabolic products of arachidonic acid in evoking this reflex. First, the investigators speculate that prostaglandins may cause engagement of the VDR by direct stimulation of afferents as seen during muscle contraction. Second, some of prostaglandins such as prostaglandin I2 (PGI2) and prostaglandin E2 (PGE2) are vasoactive substances, that may induce vasodilation. Thus, the investigators speculate that prostaglandins could cause engagement of the VDR either by direct stimulation of afferents or by inducing vessel dilation, that in turn stimulates afferents. To examine this issue, the investigators propose studies to examine the effects of COX inhibition on venous size measured with 3 Tesla (3T) MRI (Magnetic Resonance Imaging) as peripheral veins are distended in human subjects.

The investigators have published several reports on VDR. However, the investigators have no data regarding if the VDR is still active AFTER COX blockade, if the reflex will be attenuated, or if COX blockade will alter the size of the veins during the venous distension procedure.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 18 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description: The investigators will examine (using a prospective observational design) if a COX blockade will inhibit the Muscle Sympathetic Nerve Activity response to venous distension, and if a COX blockade will alter vein sizes during venous distension using MRI. Each subject will serve as their own control.
Masking: Double (Participant, Outcomes Assessor)
Masking Description: These two trials (A and B) will be performed in random order and in a double-blind fashion for subjects and the data analyzing team. The medical staff who prepare and administrate the drugs and monitor the subject's safety, will not be blinded.
Primary Purpose: Basic Science
Official Title: Autonomic Control of the Circulation and the Venous Distension Reflex
Actual Study Start Date : July 12, 2017
Estimated Primary Completion Date : July 2022
Estimated Study Completion Date : July 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Ketorolac
The Wrist-to-Elbow occlusion procedure will be performed followed by 2 ketorolac tromethamine + saline infusions into the occluded arm.
Drug: Ketorolac Tromethamine
After the Wrist-to-Forearm occlusion is completed, 6 mg ketorolac tromethamine in 10 ml saline will be infused into the forearm over ~ 1 minute. After 10 minutes, a second infusion of ketorolac tromethamine (up to 3 mg) in 5% of the forearm volume of saline (~40-60 ml) will be infused into the occluded forearm via the IV over ~ 1.3 - 2 minutes (at a rate of ~ 30 ml/min). Five minutes of data will then be collected before the upper arm cuff is released.
Other Name: Toradol

Placebo Comparator: Control
The Wrist-to-Elbow occlusion procedure will be performed followed by 2 saline only infusions into the occluded arm.
Other: Control
After the Wrist-to-Forearm occlusion is completed, 10 ml saline will be infused into the forearm over ~ 1 minute. After 10 minutes, a second infusion of 5% of the forearm volume of saline (~40-60 ml) will be infused into the occluded forearm via the IV over ~ 1.3 - 2 minutes (at a rate of ~ 30 ml/min). Five minutes of data will then be collected before the upper arm cuff is released.




Primary Outcome Measures :
  1. Muscle Sympathetic Nerve Activity (MSNA) [ Time Frame: Recorded continuously during the 3-4 hour study visit. ]
    MSNA provides direct recordings of sympathetic nerve activity directed to blood vessels in skeletal muscle.


Secondary Outcome Measures :
  1. Blood pressure in mmHg [ Time Frame: Recorded continuously during the 3-4 hour study visit ]
    Cuffs placed on a finger and arm will monitor blood pressure.

  2. Heart rate in beats per minute [ Time Frame: Recorded continuously during the 3-4 hour study visit ]
    Electrocardiogram (ECG) patches attached to a Cardiocap will monitor heart rate.

  3. Vein size with MRI [ Time Frame: Recorded continuously during the 3-4 hour study visit ]
    Investigators will measure the magnitude of the venous distention during Ketorolac and saline control trials using MRI



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Ages Eligible for Study:   21 Years to 35 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Are capable of giving informed consent
  • Are any race or ethnicity
  • Are fluent in written and spoken English
  • Have a satisfactory history and physical exam to meet inclusion/exclusion criteria
  • Are free of acute or chronic medical conditions
  • Are 21 - 35 years of age (inclusive)
  • Weigh over 50 kg

Exclusion Criteria:

  • Are less than 21 or over 35 years of age
  • Are Pregnant or nursing woman
  • Are prisoner or institutionalized individual or unable to consent
  • Any chronic diseases (hypertension, heart, lung, neuromuscular disease, kidney disease, diabetes or cancer).
  • Are taking medications that may affect their cardiovascular or nervous system
  • Has taken an NSAID within 48 hours of any visit (visit will need to be rescheduled)
  • Has never taken an NSAID and therefore would not know if they were allergic to it
  • Have a supine blood pressure >140/90 mmHg
  • Have known allergy to ibuprofen-like drugs (NSAIDS) or aspirin
  • Have history of asthma or nasal polyps
  • Have history of GI bleeding or ulcers
  • Subjects with ferromagnetic metal implants
  • Subjects who are claustrophobic

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): NCT03513770


Contacts
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Contact: Jian Cui, PhD 717-531-1799 jcui@pennstatehealth.psu.edu
Contact: Kris Gray, MS 717-531-4589 kgray1@pennstatehealth.psu.edu

Locations
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United States, Pennsylvania
Penn State Milton S. Hershey Medical Center Recruiting
Hershey, Pennsylvania, United States, 17033
Contact: Kristen Gray    717-531-4589    kgray1@pennstatehealth.psu.edu   
Contact: Jian Cui    717-531-1799    jcui@pennstatehealth.psu.edu   
Sponsors and Collaborators
Milton S. Hershey Medical Center
Investigators
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Principal Investigator: Jian Cui Penn State College of Medicine

Publications:
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Responsible Party: Jian Cui, Associate Professor of Medicine, Milton S. Hershey Medical Center
ClinicalTrials.gov Identifier: NCT03513770     History of Changes
Other Study ID Numbers: STUDY00006585
First Posted: May 2, 2018    Key Record Dates
Last Update Posted: April 16, 2019
Last Verified: April 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Keywords provided by Jian Cui, Milton S. Hershey Medical Center:
venous distension reflex

Additional relevant MeSH terms:
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Ketorolac
Ketorolac Tromethamine
Dilatation, Pathologic
Pathological Conditions, Anatomical
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Inflammatory Agents
Antirheumatic Agents
Cyclooxygenase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action