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| ID | Type | Description | Link |
|---|---|---|---|
| R01HL144781 | U.S. NIH Grant/Contract | View source |
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| Name | Class |
|---|---|
| National Heart, Lung, and Blood Institute (NHLBI) | NIH |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Ketorolac | Experimental | The Wrist-to-Elbow occlusion procedure will be performed followed by 2 ketorolac tromethamine + saline infusions into the occluded arm. |
|
| Control | Placebo Comparator | The Wrist-to-Elbow occlusion procedure will be performed followed by 2 saline only infusions into the occluded arm. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| 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. |
| Measure | Description | Time Frame |
|---|---|---|
| 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 |
| Measure | Description | Time Frame |
|---|---|---|
| Heart Rate | Heart rate will be continuously monitored using EKG patch electrodes and monitor (Cardiocap, Datex-Ohmeda, GE Healthcare). | Recorded continuously during the 3-4 hour study visit |
| Blood Pressure |
| Measure | Description | Time Frame |
|---|---|---|
| Forearm volume | Forearm volume will be measured by the water displacement method. The arm will be placed in the water bath up to the elbow. The baseline limb circumference will also be measured with a tape measure. | Baseline |
| Biochemistry |
Inclusion Criteria
Exclusion Criteria
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Penn State Milton S. Hershey Medical Center | Recruiting | Hershey | Pennsylvania | 17033 | United States |
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| ID | Term |
|---|---|
| D020156 | Salicylic Acid |
| D020911 | Ketorolac Tromethamine |
| ID | Term |
|---|---|
| D012459 | Salicylates |
| D062385 | Hydroxybenzoates |
| D001565 | Benzoates |
| D000146 | Acids, Carbocyclic |
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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.
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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.
|
| 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. |
|
| 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. |
|
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.
| 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). | 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). | 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. | Recorded continuously during the 3-4 hour study visit |
Venous blood samples will be drawn for Thromboxane B2 (TXB2) which will be used as an index for COX blockade, and will be measured in the Pathology laboratory in Hershey Medical Center.
| 3 blood draws during the 3-4 hour study visit. |
| D002264 |
| Carboxylic Acids |
| D009930 | Organic Chemicals |
| D006880 | Hydroxy Acids |
| D001555 | Benzene Derivatives |
| D006841 | Hydrocarbons, Aromatic |
| D006844 | Hydrocarbons, Cyclic |
| D006838 | Hydrocarbons |
| D010636 | Phenols |
| D007213 | Indomethacin |
| D007211 | Indoles |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |