Back to resultsEffects of Esmolol Infusion on Hemodynamic Responses to Isometric Handgrip
Primary Purpose
Peripheral Arterial Disease, Aging
Status
Withdrawn
Phase
Early Phase 1
Locations
United States
Study Type
Interventional
Intervention
Esmolol infusion
Saline infusion
Pre exercise baseline
Isometric handgrip exercise
Post exercise cuff occlusion
Recovery
Sponsored by
About this trial
This is an interventional basic science trial for Peripheral Arterial Disease focused on measuring Esmolol hydrochloride, Coronary blood flow
Eligibility Criteria
Inclusion Criteria:
Patients with peripheral arterial disease (PAD)
- Capable of giving informed consent
- Men and women age 21-85 years
- Diagnosed with PAD (i.e., ankle-brachial index below 0.9)
- Fontaine stage II or less - no pain while resting
- Satisfactory history and physical exam
- Fluent in written and spoken English
Healthy adults without PAD
- Capable of giving informed consent
- Men and women age 21-85 years
- Satisfactory medical history and physical exam, as determined by study physician
- Not currently taking medications affecting heart rate or contractility (confirmed by study physician)
- Fluent in written and spoken English
Exclusion Criteria:
Participants who will not be studied are those who:
- Are less than 21 years of age
- Are females who are pregnant or lactating
- Are prisoners or institutionalized individuals or unable to consent
- Diagnosed renal failure (Creatinine >2.0 mg/dl)
- Diagnosed liver disease (ALT and AST 2 times normal)
- Have uncontrolled diabetes
- Have uncontrolled hypertension
- Have a left ventricular ejection fraction < 40%
- Have a recent history of unstable angina or myocardial infarction (<6 months), unstable angina, or use of nitrate medications within past 2 weeks
- Severe lung disease (i.e., on supplemental oxygen or frequently use rescue inhalers)
- Diagnosed bleeding or clotting disorder or recent blood transfusion
- Have asthma, history of thyroid issues or hyperkalemia
Sites / Locations
- Milton S. Hershey Medical Center
Arms of the Study
Arm 1
Arm 2
Arm Type
Active Comparator
Placebo Comparator
Arm Label
Esmolol Infusion Study Visit
Saline Infusion Study Visit
Arm Description
The hemodynamic responses at rest, during isometric handgrip exercise, and post-exercise arm occlusion will be measured during Esmolol infusion.
The hemodynamic responses at rest, during isometric handgrip exercise, and post-exercise arm occlusion will be measured during Saline infusion.
Outcomes
Primary Outcome Measures
Coronary blood velocity
Blood velocity in the distal left anterior descending coronary artery (coronary blood velocity, CBV, in cm/sec), an index of myocardial oxygen supply, will be measured using transthoracic Doppler echocardiography (apical four-chamber view). The participant will lie on an exam bed in the supine or left lateral position. CBV will be calculated as the peak diastolic velocity (average of 3 or more cardiac cycles) as measured manually by Prosolv 3.0. Because coronary velocity waveforms will be quantified manually, the person who performs this analysis will be blinded to the treatment until all analyses are complete.
Rate pressure product
Rate pressure product, an index of myocardial oxygen demand, will be obtained by multiplying heart rate by systolic blood pressure. Heart rate will be measured using a three-lead EKG. Peripheral blood pressure will be measured using a finger blood pressure cuff (Finometer, FMS).
Arterial pulse wave velocity
Pulse wave velocity (PWV) will be measured by pressing a sensor (SphygmoCor, AtCor Medical) against one of the participant's neck (carotid) arteries and against one of their groin (femoral) arteries. Carotid-to-femoral PWV, the non-invasive gold standard for assessing central arterial (aortic) stiffness, will be calculated by dividing the estimated distance between the carotid and femoral arteries (i.e. carotid artery to sternal notch + sternal notch to femoral artery) by the pulse transit time between the two sites.
Secondary Outcome Measures
Central blood pressure
Peripheral artery pressure waveforms will be recorded via applanation tonometry of the radial pulse in one wrist using using the SphygmoCor system (AtCor Medical). Peripheral artery pressure waveforms are then used to estimate central blood pressures (systolic, diastolic, and mean) using a generalized transfer function (SphygmoCor, AtCor Medical).
Full Information
NCT ID
NCT04181606
First Posted
November 26, 2019
Last Updated
October 21, 2021
Sponsor
David N. Proctor, PhD
1. Study Identification
Unique Protocol Identification Number
NCT04181606
Brief Title
Effects of Esmolol Infusion on Hemodynamic Responses to Isometric Handgrip
Official Title
Novel Therapies to Improve Cardiac and Skeletal Muscle O2 Supply-demand Mismatch in Older Adults With Peripheral Arterial Disease: Esmolol Infusion
Study Type
Interventional
2. Study Status
Record Verification Date
October 2021
Overall Recruitment Status
Withdrawn
Why Stopped
Organizational Changes and Covid-related delays
Study Start Date
December 2021 (Anticipated)
Primary Completion Date
May 2022 (Anticipated)
Study Completion Date
May 2023 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
David N. Proctor, PhD
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
This study will test the hypothesis that Esmolol hydrochloride, a beta-1 selective blocker, improves myocardial oxygen (O2) supply-demand balance at rest and during isometric (handgrip) stress in adults with peripheral artery disease (PAD) and healthy controls.
Detailed Description
This study will test the hypothesis that infusion of Esmolol, a fast-acting β1 selective antagonist, will acutely improve oxygen (O2) supply to the heart during small muscle mass exercise in adults with and without peripheral artery disease (PAD). β1 selective antagonists (or "β1 blockers") are used to lower heart rate and improve O2 supply-to-demand balance in patients with coronary artery disease. It was recently reported that coronary exercise hyperemia (in response to fatiguing handgrip or plantar flexion exercise) is attenuated in patients with PAD. Preliminary data further show that in healthy young subjects, Esmolol infusion lessens the rise in the rate pressure product (an index of myocardial O2 demand) during handgrip exercise without negatively affecting coronary artery blood velocity. The current project will evaluate how Esmolol infusion affects coronary blood velocity (an index of coronary blood flow) and myocardial demand at rest, during handgrip exercise, and during post-exercise cuff occlusion in 1) young healthy adults, 2) older healthy adults and 3) older adults with PAD. Understanding how beta-1 selective blockade influences coronary and systemic vascular function may aid in the development of therapies to reduce myocardial ischemia in this population, which is a population at heightened coronary event risk both at rest and during blood pressure-raising tasks.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Peripheral Arterial Disease, Aging
Keywords
Esmolol hydrochloride, Coronary blood flow
7. Study Design
Primary Purpose
Basic Science
Study Phase
Early Phase 1
Interventional Study Model
Crossover Assignment
Masking
ParticipantInvestigatorOutcomes Assessor
Masking Description
The participants, investigators, and data analysts (outcomes assessors) will be blinded to the treatment (drug) order. The care providers (research nurse and physician) will be aware of the treatment order for safety reasons i.e., they will be assessing heart rate, blood pressure and symptoms before, during, and after the infusion.
Allocation
Randomized
Enrollment
0 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Esmolol Infusion Study Visit
Arm Type
Active Comparator
Arm Description
The hemodynamic responses at rest, during isometric handgrip exercise, and post-exercise arm occlusion will be measured during Esmolol infusion.
Arm Title
Saline Infusion Study Visit
Arm Type
Placebo Comparator
Arm Description
The hemodynamic responses at rest, during isometric handgrip exercise, and post-exercise arm occlusion will be measured during Saline infusion.
Intervention Type
Drug
Intervention Name(s)
Esmolol infusion
Other Intervention Name(s)
Esmolol Hydrochloride
Intervention Description
The Esmolol loading dose will be 0.4 mg/kg body mass/min administered over the first 3 minutes, followed by a maintenance dose of 0.2 mg/kg body mass/min for the remainder of the protocol (maximum of 60 minutes).
Intervention Type
Drug
Intervention Name(s)
Saline infusion
Other Intervention Name(s)
Normal saline solution
Intervention Description
The Saline loading dose will be 0.4 mg/kg body mass/min administered over the first 3 minutes, followed by a maintenance dose of 0.2 mg/kg body mass/min for the remainder of the protocol (maximum of 60 minutes).
Intervention Type
Other
Intervention Name(s)
Pre exercise baseline
Intervention Description
Subject rests quietly while drug infusion begins (3 min loading dose followed by 10 min of maintenance dose) until heart rate and blood pressure stabilize.
Intervention Type
Other
Intervention Name(s)
Isometric handgrip exercise
Intervention Description
The subject will grip at 40% of their maximum and maintain that grip until fatigue i.e. inability to maintain required force despite verbal encouragement from a member of the research team who is blinded to the infusion order.
Intervention Type
Other
Intervention Name(s)
Post exercise cuff occlusion
Intervention Description
At the point of handgrip fatigue, the subject stops gripping as the cuff is inflated and keeps their arm relaxed for 3 minutes of occlusion.
Intervention Type
Other
Intervention Name(s)
Recovery
Intervention Description
Cuff is released, monitoring continues until heart rate and blood pressure return to baseline.
Primary Outcome Measure Information:
Title
Coronary blood velocity
Description
Blood velocity in the distal left anterior descending coronary artery (coronary blood velocity, CBV, in cm/sec), an index of myocardial oxygen supply, will be measured using transthoracic Doppler echocardiography (apical four-chamber view). The participant will lie on an exam bed in the supine or left lateral position. CBV will be calculated as the peak diastolic velocity (average of 3 or more cardiac cycles) as measured manually by Prosolv 3.0. Because coronary velocity waveforms will be quantified manually, the person who performs this analysis will be blinded to the treatment until all analyses are complete.
Time Frame
Recorded continuously during the 2-3 hour study visit
Title
Rate pressure product
Description
Rate pressure product, an index of myocardial oxygen demand, will be obtained by multiplying heart rate by systolic blood pressure. Heart rate will be measured using a three-lead EKG. Peripheral blood pressure will be measured using a finger blood pressure cuff (Finometer, FMS).
Time Frame
Recorded continuously during the 2-3 hour study visit
Title
Arterial pulse wave velocity
Description
Pulse wave velocity (PWV) will be measured by pressing a sensor (SphygmoCor, AtCor Medical) against one of the participant's neck (carotid) arteries and against one of their groin (femoral) arteries. Carotid-to-femoral PWV, the non-invasive gold standard for assessing central arterial (aortic) stiffness, will be calculated by dividing the estimated distance between the carotid and femoral arteries (i.e. carotid artery to sternal notch + sternal notch to femoral artery) by the pulse transit time between the two sites.
Time Frame
Recorded continuously during the 2-3 hour study visit
Secondary Outcome Measure Information:
Title
Central blood pressure
Description
Peripheral artery pressure waveforms will be recorded via applanation tonometry of the radial pulse in one wrist using using the SphygmoCor system (AtCor Medical). Peripheral artery pressure waveforms are then used to estimate central blood pressures (systolic, diastolic, and mean) using a generalized transfer function (SphygmoCor, AtCor Medical).
Time Frame
Recorded continuously during the 2-3 hour study visit
10. Eligibility
Sex
All
Minimum Age & Unit of Time
21 Years
Maximum Age & Unit of Time
85 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria:
Patients with peripheral arterial disease (PAD)
Capable of giving informed consent
Men and women age 21-85 years
Diagnosed with PAD (i.e., ankle-brachial index below 0.9)
Fontaine stage II or less - no pain while resting
Satisfactory history and physical exam
Fluent in written and spoken English
Healthy adults without PAD
Capable of giving informed consent
Men and women age 21-85 years
Satisfactory medical history and physical exam, as determined by study physician
Not currently taking medications affecting heart rate or contractility (confirmed by study physician)
Fluent in written and spoken English
Exclusion Criteria:
Participants who will not be studied are those who:
Are less than 21 years of age
Are females who are pregnant or lactating
Are prisoners or institutionalized individuals or unable to consent
Diagnosed renal failure (Creatinine >2.0 mg/dl)
Diagnosed liver disease (ALT and AST 2 times normal)
Have uncontrolled diabetes
Have uncontrolled hypertension
Have a left ventricular ejection fraction < 40%
Have a recent history of unstable angina or myocardial infarction (<6 months), unstable angina, or use of nitrate medications within past 2 weeks
Severe lung disease (i.e., on supplemental oxygen or frequently use rescue inhalers)
Diagnosed bleeding or clotting disorder or recent blood transfusion
Have asthma, history of thyroid issues or hyperkalemia
Facility Information:
Facility Name
Milton S. Hershey Medical Center
City
Hershey
State/Province
Pennsylvania
ZIP/Postal Code
17033
Country
United States
12. IPD Sharing Statement
Learn more about this trial
Effects of Esmolol Infusion on Hemodynamic Responses to Isometric Handgrip
We'll reach out to this number within 24 hrs