Autonomic Control of the Circulation and VDR

NCT ID: NCT03513770

Last Updated: 2025-09-16

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: EARLY_PHASE1
• Total Enrollment: 18 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-08-14
• Study Completion Date: 2026-05-30

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.

Detailed Description

We will use a prospective observational design to examine if a COX blockade will inhibit the MSNA response to venous distension (Aim1), and if a COX blockade will alter vein sizes during venous distension (Aim2). Each subject will serve as their own control.

Aim 1:

An IV will be inserted in the antecubital fossa of one arm, and the wrist-to-elbow occlusion will be performed.

To block the COX system, 6 mg ketorolac tromethamine in 10 ml saline will be infused into the forearm over 1 minute (Infusion 1). 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 (Infusion 2). 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.

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

Aim 2:

The subject will lie supine inside the MRI scanner. The subject will be instrumented with 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.

Conditions

Venous Distension Reflex; Blood Pressure

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: TRIPLE

Study Groups

Ketorolac

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

Group Type: EXPERIMENTAL

Wrist-to-elbow (W-E) occlusion

Intervention Type: 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.

ketorolac tromethamine

Intervention Type: 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.

Control

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

Group Type: PLACEBO_COMPARATOR

Wrist-to-elbow (W-E) occlusion

Intervention Type: 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.

saline control

Intervention Type: 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.

Interventions

Wrist-to-elbow (W-E) occlusion

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.

Intervention Type: OTHER

ketorolac tromethamine

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.

Intervention Type: DRUG

saline control

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.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

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

Exclusion Criteria

• 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
• Subjects who are claustrophobic

• Minimum Eligible Age: 21 Years
• Maximum Eligible Age: 35 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Milton S. Hershey Medical Center

OTHER

Sponsor Role: lead

Responsible Party

Jian Cui

Associate Professor of Medicine

Responsibility Role: PRINCIPAL_INVESTIGATOR

Locations

Penn State Milton S. Hershey Medical Center

Hershey, Pennsylvania, United States

Site Status: RECRUITING

Countries

United States

Facility Contacts

Jian Cui

Role: primary

jcui@pennstatehealth.psu.edu

717-531-1799

Kris Gray

Role: backup

ksgray@psu.edu

717-531-4589

Other Identifiers

STUDY00006585

Identifier Type: -

Identifier Source: org_study_id