Venous Distension ReflexEarly Phase 1VDRNCT03513770
Autonomic Control of the Circulation and VDR
A Early Phase 1 study testing Wrist-to-elbow (W-E) occlusion and ketorolac tromethamine in people with Venous Distension Reflex and Blood Pressure, run by Milton S. Hershey Medical Center at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 21 to 35 yearsHealthy volunteers can take part
- Conditions the study is for
- Venous Distension Reflex, Blood Pressure
- What is being tested?
- Wrist-to-elbow (W-E) occlusion and ketorolac tromethamine
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 18 participants
- Where
- 1 siteUnited States
- Study dates
- 14 Aug 2019to 1 Nov 2027
- Phase
- Early Phase 1
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 21 to 35 years
- All sexes
- Healthy volunteers accepted
- Adult
Who may be able to join
- 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
Who cannot join
- 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)
Show all 13Show fewer
- 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
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
United States1 site, 1 recruiting
- Recruiting
Penn State Milton S. Hershey Medical Center
Hershey, Pennsylvania, 17033
Jian Cui, 7175311799, jcui@pennstatehealth.psu.edu
Kris Gray, 717-531-4589, ksgray@psu.edu
About this study
Official title: Autonomic Control of the Circulation and the Venous Distension Reflex
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.
Read the 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
- Being tested
- Wrist-to-elbow (W-E) occlusion, ketorolac tromethamine, saline control
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Wrist-to-elbow (W-E) occlusionOther
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 tromethamineDrug
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.
saline controlDrug
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.
| Study group | Role | What they receive |
|---|---|---|
| Ketorolac | Experimental | The Wrist-to-Elbow occlusion procedure will be performed followed by 2 ketorolac tromethamine + saline infusions into the occluded arm. Receives: 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. Receives: Other: Wrist-to-elbow (W-E) occlusion; Drug: saline control |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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.
Measured: Recorded continuously during the 3-4 hour study visit
Secondary outcomes (5)
Heart Rate
Heart rate will be continuously monitored using EKG patch electrodes and monitor (Cardiocap, Datex-Ohmeda, GE Healthcare).
Measured: Recorded continuously during the 3-4 hour study visit
Blood Pressure
Systolic and diastolic blood pressure will be monitored using an automatic, non-invasive arm cuff (SureSigns VS3, Philips, Philips Medical Systems), and on the finger with a Finometer (Finapres Medical Systems). Baseline Finometer BP will be adjusted to match the arm cuff BP.
Measured: Recorded continuously during the 3-4 hour study visit
Laser-Doppler flowmetry
Skin blood flow will be monitored non-invasively by laser-Doppler flowmetry using special probes taped to the skin. The skin blood flow may be measured from both arms, and legs (up to 4 probes total).
Measured: Recorded continuously during the 3-4 hour study visit
Strain gauge
The circumference changes of the forearm will be measured with strain gauges (up to 4 gauges on one arm).
Measured: Recorded continuously during the 3-4 hour study visit
Impedance
The electrical impedance or resistance (Zo, in ohms) of a limb segment will be measured, which reflects the total fluid content of the limb. Fluid is an excellent conductor of electricity and the electrical current travels more easily through a ?wet? limb with more blood/fluid volume in the limb. The relative change in Zo will be used as an index for the fluid/blood volume change in a limb segment. By placing 2 pieces of tape with metal strips on the limb, we are able to measure impedance of the limb segment between the tapes.
Measured: Recorded continuously during the 3-4 hour study visit
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted2 May 2018
- Study start14 Aug 2019
- Primary completion1 Nov 2026 (estimated)
- Study completion1 Nov 2027 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Venous Distension ReflexStudies of the same condition, open and under way.
- More trials run by Milton S. Hershey Medical CenterThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Early Phase 1
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- 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
- Triple blind
- Who is masked
- Participant, Investigator, Outcomes assessor
- Enrolment
- 18 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Milton S. Hershey Medical Center
- Sponsor type
- University, hospital or other
- Collaborators
- National Heart, Lung, and Blood Institute (NHLBI)
- Responsible party
- Principal investigator, Jian Cui, Milton S. Hershey Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03513770
- Sponsor's protocol ID
- STUDY00006585
- Other IDs
- R01HL144781
- Acronym
- VDR
- Status last verified
- Jul 2026
- First submitted
- 15 Feb 2018
- Last updated
- 9 Jul 2026
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 9 Jul 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Autonomic Control of the Circulation and the Venous Distension Reflex
- ClinicalTrials.gov ID
- NCT03513770
- Acronym / sponsor ID
- VDR / STUDY00006585
- Conditions
- Venous Distension Reflex, Blood Pressure
- Phase
- Early Phase 1
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 18 participants (estimated)
- Lead sponsor
- Milton S. Hershey Medical CenterUniversity, hospital or other
- Collaborators
- National Heart, Lung, and Blood Institute (NHLBI)
- Study start
- 14 Aug 2019 (actual)
- Primary completion
- 1 Nov 2026 (estimated)
- Study completion
- 1 Nov 2027 (estimated)
- First posted
- 2 May 2018 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Triple blind (participant, investigator, outcomes assessor)
- Number of arms
- 2
- 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.
| Arm | Type | Receives |
|---|---|---|
| Ketorolac | Experimental | Other: Wrist-to-elbow (W-E) occlusion, Drug: ketorolac tromethamineThe Wrist-to-Elbow occlusion procedure will be performed followed by 2 ketorolac tromethamine + saline infusions into the occluded arm. |
| Control | Placebo comparator | Other: Wrist-to-elbow (W-E) occlusion, Drug: saline controlThe Wrist-to-Elbow occlusion procedure will be performed followed by 2 saline only infusions into the occluded arm. |
Who may qualify
- Ages
- 21 to 35 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (7 listed)
- 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
Key exclusion criteria (13 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Wrist-to-elbow (W-E) occlusionAn 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. | Other | Control, Ketorolac |
| ketorolac tromethamineIn 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. | Drug | Ketorolac |
| saline controlIn 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. | Drug | Control |
Primary outcome
Microneurography (MSNA)
Time frame: Recorded continuously during the 3-4 hour study visit
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.
Vein size with MRI
Time frame: Recorded continuously during the 3-4 hour study visit
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.
5 secondary outcomes
Heart Rate
Time frame: Recorded continuously during the 3-4 hour study visit
Blood Pressure
Time frame: Recorded continuously during the 3-4 hour study visit
Laser-Doppler flowmetry
Time frame: Recorded continuously during the 3-4 hour study visit
Strain gauge
Time frame: Recorded continuously during the 3-4 hour study visit
Impedance
Time frame: Recorded continuously during the 3-4 hour study visit
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 9 Jul 2026.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Penn State Milton S. Hershey Medical Center
Hershey, United States
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Early Phase 1 study testing Wrist-to-elbow (W-E) occlusion and ketorolac tromethamine in people with Venous Distension Reflex and Blood Pressure, run by Milton S. Hershey Medical Center at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 13 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 9 Jul 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Early Phase 1 (sometimes called Phase 0) studies give a very small amount of a treatment to a few people, mainly to see how the body handles it.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Each site lists its own contact: choose the nearest one under Trial locations. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Microneurography (MSNA) (time frame: Recorded continuously during the 3-4 hour study visit). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 9 Jul 2026.