Effect of Intermittent Pressure in Patients With PAD

Study Overview
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Brief Summary
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The study will evaluate the effect of intermittent negative pressure (INP) on peripheral arterial disease (PAD) patient vascular function and blood flow. Patients will be given either -40mmHg INP or -10mmHg INP which will act as a placebo. Healthy volunteers will be given -40mmHg INP to evaluate changes in vascular function and blood flow with INP in healthy physiology.

Detailed Description
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Atherosclerosis occurs when blood supply to the lower limbs is restricted upon accumulation of fat in the arteries. Atheroslerosis in the lower limbs is termed peripheral arterial disease (PAD). The initial symptom is pain in the lower limbs followed by ulceration and gangrene. The literature has indicated that intermittent negative pressure (INP) can be used to reduce pain and facilitate wound healing. INP is a non-invasive technique that aims to increase arterial and skin blood flow in lower limbs and foot. This study aims to investigate the underlying mechanisms that are involved in changes in blood flow following application of INP. The Flow-Ox 'boot' will be used to apply INP for periods ranging from 4-8 weeks, for an hour twice per day, to the lower limb to determine the effects of INP on vascular function and blood flow. Specifically, vascular tests such as assessments of endothelial function, arterial stiffness, ankle-brachial pressure index (ABPI) and blood borne metabolic and inflammatory markers will be performed before and after INP application. A pain chart will be employed before and after INP application to determine whether there is any change in perception of pain felt by individuals who suffer from pain associated with lower limb arterial disease.

Official Title
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Mechanistic Insights Into Changes in Blood Flow Following Application of Intermittent Negative Pressure

Conditions
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Peripheral Arterial Disease

Intervention / Treatment
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* Device: Active Intermittent Negative Pressure (INP)
* Device: Placebo Intermittent Negative Pressure (INP)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria PAD Patients: Age ≥ 18 years Attending vascular outpatient clinics or admitted in ward with PAD. ABPI <0.9 Healthy Volunteers: Age ≥ 18 years No current or previous significant cardiovascular illness Able to give written informed consent Exclusion criteria PAD Patients: Unable to give written informed consent Patients with deep venous thrombosis Pregnant women Healthy Volunteers: Positive medical history of: Vascular diseases such as PAD, stroke, IHD, hypertension... etc. Haematological conditions such as hypercoagulability, deep venous thrombosis... etc., Alcohol excess Unable to give written informed consent Pregnant women

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Active PAD group<br>-40mmHg of Intermittent Negative Pressure (INP) for 4-8 weeks. | Device: Active Intermittent Negative Pressure (INP)<br>* Application of -40mmHg negative pressure on the lower limb<br>|
| Experimental: Placebo PAD group<br>-10mmHg of Intermittent Negative Pressure (INP) for 4-8 weeks. | Device: Placebo Intermittent Negative Pressure (INP)<br>* Application of -10mmHg negative pressure on the lower limb<br>|
| Experimental: Healthy Volunteers<br>-40 mmHg of Intermittent Negative Pressure (INP) for 5 days | Device: Active Intermittent Negative Pressure (INP)<br>* Application of -40mmHg negative pressure on the lower limb<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in microvascular blood flow | Microvascular blood flow measurement in foot using laser Dopper imaging. | Baseline, 1 day and 4-8 weeks | 
| Change in microvascular endothelial function | Peak blood perfusion response to acetylcholine (ACh) delivered by iontophoresis will be measured using a laser Doppler imager. | Baseline, 1 day and 4-8 weeks | 
| Change in arterial stiffness | Brachial pulse wave analysis (PWA) augmentation index (Ax) and carotid-femoral pulse wave velocity (m/s) (PWV) as an indication of arterial stiffness. | Baseline, 1 day and 4-8 weeks | 
| Change in macrovascular endothelial function | Brachial endothelial function measured as change in brachial blood vessel diameter (%) upon shear stress. | Baseline, 1 day and 4-8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in pain score | Self-scoring of pain felt by patient on a visual analogue scale with 0 being no pain at all to 10 being the worst pain ever felt. | Baseline, 1 day and 4-8 weeks | 
| Change in concentration of blood borne inflammatory and oxidative stress biomarkers | Concentration of inflammatory and oxidative stress markers of endothelial activation/damage (including IL-1a, IL-6, IL-10, TNF-a, CRP, E-selectin and sICAM-1) measured in serum and plasma collected from patient blood samples. | Baseline, 1 day and 4-8 weeks | 
| Change in Ankle-Brachial Pressure Index (ABPI) | Brachial systolic pressure and ankle (dorsalis pedis) systolic pressure (mmHg) measured using Doppler probe. ABPI calculated as ankle systolic pressure divided by brachial systolic pressure. ABPI <0.9 = PAD, ABPI =>1.0 Normal. | Baseline, 1 day and 4-8 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PAD