Autonomic Control of the Circulation and VDR

NCT03513770 | Recruiting Early Phase 1 FDA Drug

• 1 other identifier: STUDY00006585
• Study Type: interventional
• Target: 18
• Locations: 1 country
• Sites: 1

Brief Summary

The study objective of this project is to examine the mechanisms of the venous distension reflex (VDR) in humans. We hypothesize that COX blockade with ketorolac tromethamine, an intravenous NSAID, will attenuate the muscle sympathetic nerve activity (MSNA) response to limb venous distension. To gain further insight into whether the COX byproducts directly stimulate chemically-sensitive afferents, or enable venodilation and indirectly evoke afferent stimulation, we will measure vein size using 3T MRI during venous distention with and without ketorolac infusions.

Conditions

Venous Distension Reflex; Blood Pressure

Outcome Measures

Primary Outcomes (2)

• Microneurography (MSNA)

  This technique provides direct recordings of sympathetic nerve activity directed to blood vessels in skeletal muscle and will be our primary index of sympathoexcitation. This procedure may be performed in the either leg. External mapping of the peroneal or tibial nerve course (10-60 volts, 1-5msec, 1Hz) will be performed just behind the fibular head of the leg or in the popliteal fossa. A reference electrode will be placed subcutaneously about 2-3 cm away from the recording site. Multiunit recordings of MSNA in the leg will be obtained by transcutaneous placement of a tungsten microelectrode (insulated 200 ?m diameter with a tapered un-insulated 1-5 ?m tip) into C-fiber containing fascicle in the nerve. The electrode will be manipulated to yield a neurogram with characteristic bursts of MSNA, that will be amplified, filtered, rectified and integrated to obtain a mean voltage neurogram. Analysis consists of counting burst frequency and amplitude.

  Recorded continuously during the 3-4 hour study visit

• Vein size with MRI

  Forearm cross sectional images will be obtained in HMC MRI facility. The proton weighted images will be obtained with Siemens Magnetom Trio 3T scanner (Siemens Medical Solutions, Erlangen, Germany). Contrast agents are not required for this completely noninvasive technique. The subject will lie supine inside the MRI scanner, and will be instrumented with an cuffs for the wrist-to-elbow occlusion procedure on one arm, and cuffs for automated BP and HR measurements from the other arm, The images will be obtained before and during the wrist-to-elbow occlusion procedure. The sizes of veins (i.e. cross sectional area) will be measured offline.

  Recorded continuously during the 3-4 hour study visit

Secondary Outcomes (5)

• Heart Rate

  Recorded continuously during the 3-4 hour study visit

• Blood Pressure

  Recorded continuously during the 3-4 hour study visit

• Laser-Doppler flowmetry

  Recorded continuously during the 3-4 hour study visit

• Strain gauge

  Recorded continuously during the 3-4 hour study visit

• Impedance

  Recorded continuously during the 3-4 hour study visit

Other Outcomes (2)

• Forearm volume

  Baseline

• Biochemistry

  3 blood draws during the 3-4 hour study visit.

Study Arms (2)

Ketorolac

EXPERIMENTAL

The Wrist-to-Elbow occlusion procedure will be performed followed by 2 ketorolac tromethamine + saline infusions into the occluded arm.

Other: Wrist-to-elbow (W-E) occlusion; Drug: ketorolac tromethamine

Control

PLACEBO COMPARATOR

The Wrist-to-Elbow occlusion procedure will be performed followed by 2 saline only infusions into the occluded arm.

Other: Wrist-to-elbow (W-E) occlusion; Drug: saline control

Interventions

Wrist-to-elbow (W-E) occlusion OTHER

An IV will be inserted in the antecubital fossa of one arm. The arm will be fitted with occlusion cuffs arranged in a continuous fashion from the wrist to the elbow. A final cuff will be placed on the upper arm. The cuffs from the wrist to the elbow will be inflated to the same pressure of up to 300 mmHg using a pressurized air tank. First, the subject?s arm will be elevated and the subject will make a fist to squeeze blood from the hand. Then the wrist cuff will be inflated. Once that cuff is fully inflated, the next cuff in the sequence will be inflated. Cuffs are inflated in sequence until the elbow cuff is inflated. After a 10-15 second period to allow blood to drain, the upper arm cuff will inflate (up to 250 mmHg) to keep any additional blood from entering the forearm. Next, the cuffs on the forearm will be removed but the upper arm cuff will remain inflated.

Control; Ketorolac

ketorolac tromethamine DRUG

In the COX blockade trial, just after the Wrist-to-elbow occlusion, 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 at a rate of \~ 30 ml/min. Five minutes of data will then be collected before releasing the upper arm cuff. Infusion 1 is to block the COX pathway, while infusion 2 is to induce venous distension.

Ketorolac

saline control DRUG

In the saline control trial performed on a separate day, saline (without ketorolac) in identical volumes as those in the COX blockade trial, will be infused.

Control

Eligibility Criteria

• Age: 21 Years - 35 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Are capable of giving informed consent
• Are any race or ethnicity
• Are fluent in written and spoken English

You may not qualify if:

• Are free of acute or chronic medical conditions
• Are 21 - 35 years of age (inclusive)
• Weigh over 50 kg
• Are less than 21 or over 35 years of age
• Are Pregnant or nursing women
• Are prisoners or institutionalized individuals 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 NSAIDs and therefore would not know if they are allergic to it
• Have a supine BP \>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

Sponsors & Collaborators

• Milton S. Hershey Medical Center: lead

Study Sites (1)

Penn State Milton S. Hershey Medical Center

Hershey, Pennsylvania, 17033, United States

RECRUITING

MeSH Terms

Interventions

Salicylic Acid; Ketorolac Tromethamine

Intervention Hierarchy (Ancestors)

Salicylates; Hydroxybenzoates; Benzoates; Acids, Carbocyclic; Carboxylic Acids; Organic Chemicals; Hydroxy Acids; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Phenols; Indomethacin; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: These two trials (A and B) will be performed in random order and in a doubleblind 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.
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor of Medicine

Model Details: 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.

Study Record Dates

• First Submitted: February 15, 2018
• First Posted: May 2, 2018
• Study Start: August 14, 2019
• Primary Completion: May 1, 2026
• Study Completion (Estimated): May 30, 2026
• Last Updated: September 16, 2025

Record last verified: 2025-09

Locations

US (1)