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Effects of Esmolol Infusion on Hemodynamic Responses to Isometric Handgrip

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04181606
Recruitment Status : Not yet recruiting
First Posted : November 29, 2019
Last Update Posted : May 21, 2020
Sponsor:
Information provided by (Responsible Party):
David N. Proctor, PhD, Penn State University

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.

Condition or disease Intervention/treatment Phase
Peripheral Arterial Disease Aging Drug: Esmolol infusion Drug: Saline infusion Other: Pre exercise baseline Other: Isometric handgrip exercise Other: Post exercise cuff occlusion Other: Recovery Early Phase 1

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 60 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple (Participant, Investigator, Outcomes 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.
Primary Purpose: Basic Science
Official Title: Novel Therapies to Improve Cardiac and Skeletal Muscle O2 Supply-demand Mismatch in Older Adults With Peripheral Arterial Disease: Esmolol Infusion
Estimated Study Start Date : July 2020
Estimated Primary Completion Date : May 2021
Estimated Study Completion Date : January 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: Esmolol Infusion Study Visit
The hemodynamic responses at rest, during isometric handgrip exercise, and post-exercise arm occlusion will be measured during Esmolol infusion.
Drug: Esmolol infusion
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).
Other Name: Esmolol Hydrochloride

Other: Pre exercise baseline
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.

Other: Isometric handgrip exercise
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.

Other: Post exercise cuff occlusion
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.

Other: Recovery
Cuff is released, monitoring continues until heart rate and blood pressure return to baseline.

Placebo Comparator: Saline Infusion Study Visit
The hemodynamic responses at rest, during isometric handgrip exercise, and post-exercise arm occlusion will be measured during Saline infusion.
Drug: Saline infusion
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).
Other Name: Normal saline solution

Other: Pre exercise baseline
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.

Other: Isometric handgrip exercise
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.

Other: Post exercise cuff occlusion
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.

Other: Recovery
Cuff is released, monitoring continues until heart rate and blood pressure return to baseline.




Primary Outcome Measures :
  1. Coronary blood velocity [ Time Frame: Recorded continuously during the 2-3 hour study visit ]
    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.

  2. Rate pressure product [ Time Frame: Recorded continuously during the 2-3 hour study visit ]
    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).

  3. Arterial pulse wave velocity [ Time Frame: Recorded continuously during the 2-3 hour study visit ]
    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 :
  1. Central blood pressure [ Time Frame: Recorded continuously during the 2-3 hour study visit ]
    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).



Information from the National Library of Medicine

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Ages Eligible for Study:   21 Years to 85 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Patients with peripheral arterial disease (PAD)

    1. Capable of giving informed consent
    2. Men and women age 21-85 years
    3. Diagnosed with PAD (i.e., ankle-brachial index below 0.9)
    4. Fontaine stage II or less - no pain while resting
    5. Satisfactory history and physical exam
    6. Fluent in written and spoken English

Healthy adults without PAD

  1. Capable of giving informed consent
  2. Men and women age 21-85 years
  3. Satisfactory medical history and physical exam, as determined by study physician
  4. Not currently taking medications affecting heart rate or contractility (confirmed by study physician)
  5. Fluent in written and spoken English

Exclusion Criteria:

Participants who will not be studied are those who:

  1. Are less than 21 years of age
  2. Are females who are pregnant or lactating
  3. Are prisoners or institutionalized individuals or unable to consent
  4. Diagnosed renal failure (Creatinine >2.0 mg/dl)
  5. Diagnosed liver disease (ALT and AST 2 times normal)
  6. Have uncontrolled diabetes
  7. Have uncontrolled hypertension
  8. Have a left ventricular ejection fraction < 40%
  9. Have a recent history of unstable angina or myocardial infarction (<6 months), unstable angina, or use of nitrate medications within past 2 weeks
  10. Severe lung disease (i.e., on supplemental oxygen or frequently use rescue inhalers)
  11. Diagnosed bleeding or clotting disorder or recent blood transfusion
  12. Have asthma, history of thyroid issues or hyperkalemia

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04181606


Contacts
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Contact: David Proctor, PhD 8145715234 dnp3@psu.edu
Contact: Kris Gray, MS 7175314589 ksgray@psu.edu

Locations
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United States, Pennsylvania
Milton S. Hershey Medical Center
Hershey, Pennsylvania, United States, 17033
Sponsors and Collaborators
David N. Proctor, PhD
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Responsible Party: David N. Proctor, PhD, Professor of Kinesiology, Physiology, and Medicine, Penn State University
ClinicalTrials.gov Identifier: NCT04181606    
Other Study ID Numbers: 10736
First Posted: November 29, 2019    Key Record Dates
Last Update Posted: May 21, 2020
Last Verified: May 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by David N. Proctor, PhD, Penn State University:
Esmolol hydrochloride
Coronary blood flow
Additional relevant MeSH terms:
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Peripheral Arterial Disease
Peripheral Vascular Diseases
Atherosclerosis
Arteriosclerosis
Arterial Occlusive Diseases
Vascular Diseases
Cardiovascular Diseases
Esmolol
Adrenergic beta-1 Receptor Antagonists
Adrenergic beta-Antagonists
Adrenergic Antagonists
Adrenergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs