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Effects of Heating on Exercise Pressor Reflex in Peripheral Artery Disease: Exercise Ability (EPR)

Primary Purpose

PAD

Status
Recruiting
Phase
Early Phase 1
Locations
United States
Study Type
Interventional
Intervention
Without Heating
Warm Bath
Neutral Bath
Heating Suit
Lower limb warm water immersion
Gardner walking protocol
Sponsored by
Milton S. Hershey Medical Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional basic science trial for PAD focused on measuring exercise, blood pressure response, heating

Eligibility Criteria

21 Years - 85 Years (Adult, Older Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria:

All subjects

  • Capable of giving informed consent
  • Any race or ethnicity
  • Men and women age 21- 85 years (inclusive)
  • Fluent in written and spoken English

Patients with peripheral arterial disease (PAD)

  • 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

Healthy subjects

  • Satisfactory history and physical examination
  • Free of acute medical conditions

Exclusion Criteria:

For patients with PAD and Healthy subjects

  • Age < 21 years
  • Pregnant or nursing women
  • Decisional impairment
  • Prisoners

For patients with PAD

  • History of CAD with symptoms of unstable angina or myocardial infarction (<6 months)
  • History of epilepsy or seizure disorders

For healthy subjects

• Any other chronic diseases (heart, lung, neuromuscular disease or diabetes)

Sites / Locations

  • Penn State Milton S. Hershey Medical CenterRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm 7

Arm 8

Arm 9

Arm 10

Arm Type

Placebo Comparator

Experimental

Placebo Comparator

Experimental

Experimental

Placebo Comparator

Experimental

Placebo Comparator

Experimental

Experimental

Arm Label

PAD without heating

PAD warm bath

PAD neutral bath

PAD heating suit

PAD lower limb warm water immersion

Healthy subjects without heating

Healthy subjects warm bath

Healthy subjects neutral bath

Healthy subjects heat suit

Healthy subjects lower limb immersion

Arm Description

Subjects will walk on a treadmill using the Gardner protocol until the patient says they want to stop. BP, HR and NIRS will be continuously measured during Gardner protocol. Skin blood flow, skin temperature and BP will be measured in the supine position before and after the Gardner protocol.

Subjects will take a warm bath. Then, subjects will walk on a treadmill using the Gardner protocol until the patient says they want to stop. BP, HR and NIRS will be continuously measured during Gardner protocol. Skin blood flow, skin temperature and BP will be measured in the supine position before and after the Gardner protocol.

Subjects will take a neutral bath. Then, subjects will walk on a treadmill using the Gardner protocol until the patient says they want to stop. BP, HR and NIRS will be continuously measured during Gardner protocol. Skin blood flow, skin temperature and BP will be measured in the supine position before and after the Gardner protocol.

Whole body heating with the suit will be performed. Then, subjects will walk on a treadmill using the Gardner protocol until the patient says they want to stop. BP, HR and NIRS will be continuously measured during Gardner protocol. Skin blood flow, skin temperature and BP will be measured in the supine position before and after the Gardner protocol.

Subjects will place their lower legs in warm water. Then, subjects will walk on a treadmill using the Gardner protocol until the patient says they want to stop. BP, HR and NIRS will be continuously measured during Gardner protocol. Skin blood flow, skin temperature and BP will be measured in the supine position before and after the Gardner protocol.

Subjects will walk on a treadmill using the Gardner protocol until the patient says they want to stop. BP, HR and NIRS will be continuously measured during Gardner protocol. Skin blood flow, skin temperature and BP will be measured in the supine position before and after the Gardner protocol.

Subjects will take a warm bath. Then, subjects will walk on a treadmill using the Gardner protocol until the patient says they want to stop. BP, HR and NIRS will be continuously measured during Gardner protocol. Skin blood flow, skin temperature and BP will be measured in the supine position before and after the Gardner protocol.

Subjects will take a neutral bath. Then, subjects will walk on a treadmill using the Gardner protocol until the patient says they want to stop. BP, HR and NIRS will be continuously measured during Gardner protocol. Skin blood flow, skin temperature and BP will be measured in the supine position before and after the Gardner protocol.

Whole body heating with the suit will be performed. Then, subjects will walk on a treadmill using the Gardner protocol until the patient says they want to stop. BP, HR and NIRS will be continuously measured during Gardner protocol. Skin blood flow, skin temperature and BP will be measured in the supine position before and after the Gardner protocol.

Subjects will place their lower legs in warm water. Then, subjects will walk on a treadmill using the Gardner protocol until the patient says they want to stop. BP, HR and NIRS will be continuously measured during Gardner protocol. Skin blood flow, skin temperature and BP will be measured in the supine position before and after the Gardner protocol.

Outcomes

Primary Outcome Measures

Walking time in minutes
Walking time on treadmill using Gardner protocol
Blood pressure in mmHg
Cuffs placed on a finger and arm will monitor blood pressure.
Heart Rate in beats per minute
Electrocardiogram (ECG) patches attached to a Cardiocap will monitor heart rat

Secondary Outcome Measures

Internal Temperature in degrees C
The internal temperature (Tcore) will be measured from the stomach/intestines via a telemetry pill swallowed by subjects.
Near infrared spectroscopy (NIRS) in arbitrary units
This system is designed specifically for non-invasive measurements of muscle tissue. The system measures the tissue saturation of the investigated muscle, called the 'tissue saturation index' (TSI).

Full Information

First Posted
March 29, 2019
Last Updated
April 10, 2023
Sponsor
Milton S. Hershey Medical Center
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1. Study Identification

Unique Protocol Identification Number
NCT03900832
Brief Title
Effects of Heating on Exercise Pressor Reflex in Peripheral Artery Disease: Exercise Ability
Acronym
EPR
Official Title
Effects of Heating on Exercise Pressor Reflex in Peripheral Artery Disease: Exercise Ability
Study Type
Interventional

2. Study Status

Record Verification Date
April 2023
Overall Recruitment Status
Recruiting
Study Start Date
May 15, 2019 (Actual)
Primary Completion Date
July 2024 (Anticipated)
Study Completion Date
July 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Milton S. Hershey Medical Center

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
The study objectives of this projects are to examine the hypothesis that the sympathetic and blood pressure responses to exercise will be attenuated during and after heat exposure in patients with peripheral artery disease, via altering the sensitivity of the muscle afferent receptors.
Detailed Description
Peripheral arterial disease (PAD) affects 8-12 million Americans and its cardinal symptom is leg pain during exercise, termed "intermittent claudication". The diagnosis of PAD involves measuring the ankle-brachial index (ABI, i.e. the systolic pressure in the ankle divided by the systolic pressure in the arm); values below 0.9 are indicative of large vessel obstruction. Intermittent claudication is the most common symptom of this disease and it regularly occurs during exercise/physical activity but is relieved promptly by rest. Previous studies suggest that as the exercise pressor reflex is activated in patients with PAD, BP and heart rate (HR) are exaggerated. The BP rises during walking in the PAD patients were significantly greater than that seen in healthy control subjects. A recent human study from our group further indicates that an early BP response occurred during plantar flexion exercise before claudication was noted by the subjects, which may suggest that the accentuated BP response was due to an augmented muscle mechanoreflex in PAD. Moreover, another recent study from our group also showed that PAD patients have augmented renal vasoconstriction during plantar flexion exercise. It has been shown that exercise has benefits for patients with PAD. However, exercise becomes limited due to the pain and fatigue associated with the disease. Moreover, the augmented pressor response to exercise in PAD may increase the risk for the end organ damage (e.g. brain and/or heart). Thus, finding alternate/complimentary interventions that modulate the cardiovascular system and autonomic nervous system, and can be tolerated by the patients, would be beneficial. One possible intervention is heat exposure, since acute bouts of exercise and acute heat exposure have similar acute effects on both the autonomic and cardiovascular systems. For example, both exercise and heat exposure increase body temperature, increase HR, increase cardiac output (CO), increase left ventricular ejection fraction (EF), and enhance myocardial function. In the peripheral circulation, both exercise and heat exposure increase limb blood flow , muscle blood flow, and skin blood flow. Moreover, recent studies suggest that whole body exposure improves the endothelium function in PAD patients (e.g. activates endothelial progenitor cells CD34+). However, the effect of heat treatment on the ability of walking of PAD patients has not been examined. Moreover, it is unknown if heating can normalize/decrease the accentuated the pressor responses to exercise in PAD patients.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
PAD
Keywords
exercise, blood pressure response, heating

7. Study Design

Primary Purpose
Basic Science
Study Phase
Early Phase 1
Interventional Study Model
Crossover Assignment
Model Description
The investigators will examine (using a prospective observational design) if heating will affect walking ability, blood pressure and heart rate responses in PAD patients. Each subject will serve as their own control. Additionally, we will compare these responses between PAD patients and healthy controls subjects.
Masking
Outcomes Assessor
Masking Description
Subjects will be aware if they are being heated or not, but data analysis process is blinded.
Allocation
Randomized
Enrollment
32 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
PAD without heating
Arm Type
Placebo Comparator
Arm Description
Subjects will walk on a treadmill using the Gardner protocol until the patient says they want to stop. BP, HR and NIRS will be continuously measured during Gardner protocol. Skin blood flow, skin temperature and BP will be measured in the supine position before and after the Gardner protocol.
Arm Title
PAD warm bath
Arm Type
Experimental
Arm Description
Subjects will take a warm bath. Then, subjects will walk on a treadmill using the Gardner protocol until the patient says they want to stop. BP, HR and NIRS will be continuously measured during Gardner protocol. Skin blood flow, skin temperature and BP will be measured in the supine position before and after the Gardner protocol.
Arm Title
PAD neutral bath
Arm Type
Placebo Comparator
Arm Description
Subjects will take a neutral bath. Then, subjects will walk on a treadmill using the Gardner protocol until the patient says they want to stop. BP, HR and NIRS will be continuously measured during Gardner protocol. Skin blood flow, skin temperature and BP will be measured in the supine position before and after the Gardner protocol.
Arm Title
PAD heating suit
Arm Type
Experimental
Arm Description
Whole body heating with the suit will be performed. Then, subjects will walk on a treadmill using the Gardner protocol until the patient says they want to stop. BP, HR and NIRS will be continuously measured during Gardner protocol. Skin blood flow, skin temperature and BP will be measured in the supine position before and after the Gardner protocol.
Arm Title
PAD lower limb warm water immersion
Arm Type
Experimental
Arm Description
Subjects will place their lower legs in warm water. Then, subjects will walk on a treadmill using the Gardner protocol until the patient says they want to stop. BP, HR and NIRS will be continuously measured during Gardner protocol. Skin blood flow, skin temperature and BP will be measured in the supine position before and after the Gardner protocol.
Arm Title
Healthy subjects without heating
Arm Type
Placebo Comparator
Arm Description
Subjects will walk on a treadmill using the Gardner protocol until the patient says they want to stop. BP, HR and NIRS will be continuously measured during Gardner protocol. Skin blood flow, skin temperature and BP will be measured in the supine position before and after the Gardner protocol.
Arm Title
Healthy subjects warm bath
Arm Type
Experimental
Arm Description
Subjects will take a warm bath. Then, subjects will walk on a treadmill using the Gardner protocol until the patient says they want to stop. BP, HR and NIRS will be continuously measured during Gardner protocol. Skin blood flow, skin temperature and BP will be measured in the supine position before and after the Gardner protocol.
Arm Title
Healthy subjects neutral bath
Arm Type
Placebo Comparator
Arm Description
Subjects will take a neutral bath. Then, subjects will walk on a treadmill using the Gardner protocol until the patient says they want to stop. BP, HR and NIRS will be continuously measured during Gardner protocol. Skin blood flow, skin temperature and BP will be measured in the supine position before and after the Gardner protocol.
Arm Title
Healthy subjects heat suit
Arm Type
Experimental
Arm Description
Whole body heating with the suit will be performed. Then, subjects will walk on a treadmill using the Gardner protocol until the patient says they want to stop. BP, HR and NIRS will be continuously measured during Gardner protocol. Skin blood flow, skin temperature and BP will be measured in the supine position before and after the Gardner protocol.
Arm Title
Healthy subjects lower limb immersion
Arm Type
Experimental
Arm Description
Subjects will place their lower legs in warm water. Then, subjects will walk on a treadmill using the Gardner protocol until the patient says they want to stop. BP, HR and NIRS will be continuously measured during Gardner protocol. Skin blood flow, skin temperature and BP will be measured in the supine position before and after the Gardner protocol.
Intervention Type
Other
Intervention Name(s)
Without Heating
Intervention Description
Subject will complete walking protocol without any heating procedure
Intervention Type
Other
Intervention Name(s)
Warm Bath
Intervention Description
Subjects will sit in a warm bathtub with water up to their shoulders, while one arm will be out of water for BP and HR measurement. The water temperature and internal temperature (Tcore), BP and HR will be measured throughout the bath. The water temperature will be controlled between 38-41°C. Subjects will remain in the tub for ≤ 30 minutes. If the HR increases more than 15 -20 bpm, or a significant BP drop occurs (e.g. BP >20 mmHg), the subject will be removed from the bath even if the time is <30 min.
Intervention Type
Other
Intervention Name(s)
Neutral Bath
Intervention Description
Subjects will sit in a warm bathtub with water up to their shoulders, while one arm will be out of water for BP and HR measurement. The water temperature and internal temperature (Tcore), BP and HR will be measured throughout the bath. The water temperature will be controlled between 35 - 37°C. Subjects will remain in the tub for ≤ 30 minutes.
Intervention Type
Other
Intervention Name(s)
Heating Suit
Intervention Description
The mean skin temperature Tsk will be controlled with a water-perfused suit worn by subjects. Whole-body heating will be accomplished by perfusing warm water (~ 45 - 50 °C) through the suit to elevate the Tsk to ≤ 38 °C (100 oF). Warm water is through plastic tubes, and subjects' skin will not directly touch warm water. The heating will be continued until the ∆Tcore reaches ~ 0. 6 - 1.0 °C. This may take approximately 60 - 90 min.
Intervention Type
Other
Intervention Name(s)
Lower limb warm water immersion
Intervention Description
Subjects will sit on a chair and put their lower legs and feet in a bucket with warm water. The water level will be just below the knees (depth of approximately 40 cm). The water temperature will be monitored and controlled at ~38 - 42 °C throughout the 30 minutes. BP, HR, Tcore, the skin temperature and skin blood flow (e.g. on a thigh and/or forearm) will be measured before, during and after the lower limbs warm water immersion.
Intervention Type
Other
Intervention Name(s)
Gardner walking protocol
Intervention Description
The Gardner protocol begins at 2 mph and 0% grade for 2 minutes. The grade increases by 2% every 2 minutes (the speed remains 2 mph) until the subject says they want to stop or 22 minutes maximum. BP and HR will also be measured throughout the protocol.
Primary Outcome Measure Information:
Title
Walking time in minutes
Description
Walking time on treadmill using Gardner protocol
Time Frame
Recording walking time to fatigue (up to 22 minutes maximum) during of every 3-4 hour study visit.
Title
Blood pressure in mmHg
Description
Cuffs placed on a finger and arm will monitor blood pressure.
Time Frame
Recorded continuously during the 3-4 hour study visit
Title
Heart Rate in beats per minute
Description
Electrocardiogram (ECG) patches attached to a Cardiocap will monitor heart rat
Time Frame
Recorded continuously during the 3-4 hour study visit
Secondary Outcome Measure Information:
Title
Internal Temperature in degrees C
Description
The internal temperature (Tcore) will be measured from the stomach/intestines via a telemetry pill swallowed by subjects.
Time Frame
Recorded continuously during the 3-4 hour study visit
Title
Near infrared spectroscopy (NIRS) in arbitrary units
Description
This system is designed specifically for non-invasive measurements of muscle tissue. The system measures the tissue saturation of the investigated muscle, called the 'tissue saturation index' (TSI).
Time Frame
Recorded continuously during the 3-4 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: All subjects Capable of giving informed consent Any race or ethnicity Men and women age 21- 85 years (inclusive) Fluent in written and spoken English Patients with peripheral arterial disease (PAD) 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 Healthy subjects Satisfactory history and physical examination Free of acute medical conditions Exclusion Criteria: For patients with PAD and Healthy subjects Age < 21 years Pregnant or nursing women Decisional impairment Prisoners For patients with PAD History of CAD with symptoms of unstable angina or myocardial infarction (<6 months) History of epilepsy or seizure disorders For healthy subjects • Any other chronic diseases (heart, lung, neuromuscular disease or diabetes)
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Jian Cui, PhD
Phone
7175311799
Email
jcui@pennstatehealth.psu.edu
First Name & Middle Initial & Last Name or Official Title & Degree
Kris Gray, MS
Phone
7175314589
Email
kgray1@pennstatehealth.psu.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jian Cui
Organizational Affiliation
Penn State College of Medicine
Official's Role
Principal Investigator
Facility Information:
Facility Name
Penn State Milton S. Hershey Medical Center
City
Hershey
State/Province
Pennsylvania
ZIP/Postal Code
17033
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Kristen Gray
Phone
717-531-4589
Email
kgray1@pennstatehealth.psu.edu
First Name & Middle Initial & Last Name & Degree
Jian Cui
Phone
717-531-1799
Email
jcui@pennstatehealth.psu.edu

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
27763873
Citation
Cui J, Blaha C, Sinoway LI. Whole body heat stress attenuates the pressure response to muscle metaboreceptor stimulation in humans. J Appl Physiol (1985). 2016 Nov 1;121(5):1178-1186. doi: 10.1152/japplphysiol.00212.2016. Epub 2016 Oct 7.
Results Reference
background
PubMed Identifier
16873399
Citation
Cui J, Blaha C, Moradkhan R, Gray KS, Sinoway LI. Muscle sympathetic nerve activity responses to dynamic passive muscle stretch in humans. J Physiol. 2006 Oct 15;576(Pt 2):625-34. doi: 10.1113/jphysiol.2006.116640. Epub 2006 Jul 27.
Results Reference
background
PubMed Identifier
28330967
Citation
Cui J, Boehmer J, Blaha C, Sinoway LI. Muscle sympathetic nerve activity response to heat stress is attenuated in chronic heart failure patients. Am J Physiol Regul Integr Comp Physiol. 2017 Jun 1;312(6):R873-R882. doi: 10.1152/ajpregu.00355.2016. Epub 2017 Mar 22.
Results Reference
background
PubMed Identifier
26265752
Citation
Cui J, Muller MD, Blaha C, Kunselman AR, Sinoway LI. Seasonal variation in muscle sympathetic nerve activity. Physiol Rep. 2015 Aug;3(8):e12492. doi: 10.14814/phy2.12492.
Results Reference
background

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Effects of Heating on Exercise Pressor Reflex in Peripheral Artery Disease: Exercise Ability

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