Autonomic Control of the Circulation and VDR

Official title

Autonomic Control of the Circulation and the Venous Distension Reflex

Overview

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.

Interventions

• Other 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
• Drug 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
• 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.

Primary outcome measures

• Microneurography (MSNA) [Time frame: Recorded continuously during the 3-4 hour study visit]
• Vein size with MRI [Time frame: Recorded continuously during the 3-4 hour study visit]

Secondary outcome measures (5)

• 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]

Eligibility 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 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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Allocation

Randomized

Model

Crossover

Masking

Triple blind

Primary purpose

Basic science

Study locations

United States · 1 center

• Penn State Milton S. Hershey Medical Center — Hershey

Identifiers

NCT: NCT03513770 · STUDY00006585 · R01HL144781

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗