The Venous Distension Reflex and Orthostatic Hypertension (OH)

April 3, 2024 updated by: Jian Cui, Milton S. Hershey Medical Center
This research is being done to find out whether distension of veins in legs will cause a rise in blood pressure (orthostatic hypertension).

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

In humans, two-thirds of the blood volume is contained within the venous vasculature. Because of this, changes in peripheral blood volume and alterations in the mechanical properties of peripheral veins can greatly impact cardiac filling, cardiac output and blood pressure (BP) responses to physiologic stress. Work from our laboratory over the past seven years has shown that local upper limb venous distension via volume infusion into an occluded arm (i.e. volume infusion model) or applying negative pressure to an occluded leg (limb suction experimental model) leads to an acute and dramatic increase in Muscle Sympathetic Nerve Activity (MSNA; an index of sympathetic activity directed to skeletal muscle) and BP in humans. Since this venous distension reflex (VDR) differs physiologically from the other reflex systems, and since this system may play a critical role in orthostatic BP control, we believe that it is a significant area of study.

The investigators speculate that VDR from lower limbs contributes to the autonomic adjustment to orthostatic stress. To examine the VDR in lower limbs, an arterial occlusion cuff on the mid-thigh was inflated (250 mm mercury; Hg). Then, limb suction (-100 mmHg) was applied ~10-15 cm below the level of arterial occlusion (i.e. below the knee). MSNA was measured in the opposite control limb. When suction was applied below the level of arterial occlusion (i.e. occlusion + suction), both MSNA and mean arterial BP (MAP) increased. In control trials, arterial occlusion without limb suction (i.e. occlusion alone) did not increase MSNA. Plethysmographic data showed calf circumference increased without detectable arterial pulsations. Pilot data suggest that the fluid shifts from the occluded but non-depressurized zone of the limb (i.e. between the cuff and knee) into the occluded and depressurized region of the limb within the tank. Thus, the results suggest that the VDR was engaged with this limb suction experimental model.

These experimental models "selectively" alter peripheral venous volume as the investigators measure sympathetic reflex responses. This approach is innovative and allows examination of a previously overlooked autonomic reflex in conscious humans. If these studies confirm the hypotheses, the obtained data would challenge the present teaching regarding how the sympathetic nervous system is engaged in humans during postural stress.

In ~2.5-10% of the population, BP rises as the person stands. This has been termed orthostatic hypertension, and is different from the "normal" sustained BP response when a person stands. The incidence of orthostatic hypertension may increase with aging (~2.4% for 45-64 years old and ~8.7% for >70 years old). Orthostatic hypertension is a risk factor for the development of stroke, left ventricular hypertrophy, and chronic kidney disease. It is unclear why BP rises with standing in some individuals. Some investigators have speculated that orthostatic hypertension is due to exaggerated baroreceptor withdrawal with standing. Others have speculated that this response is due to an increase in sympathetic output. It has been noted that some patients with orthostatic hypertension have increased venous pooling in their lower legs. Based these data, the investigators postulate that heightened engagement of the VDR reflexly increases MSNA and also serves to reset the aortic baroreflex. In this protocol, the investigators will determine if the MSNA response to leg suction is heightened in the individuals with elevated standing BP, and examine if the baroreflex is altered in these individuals. The investigators will also examine if external pressure on lower limbs, which limits the venous pooling in the lower limbs, will attenuate the increase in BP during standing in those individuals.

Study Type

Interventional

Enrollment (Estimated)

30

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

Yes

Description

Inclusion Criteria:

  • Are capable of giving informed consent
  • Are of any race or ethnicity
  • Are fluent in written and spoken English
  • Whose history and physical exam did not uncover any exclusion criteria
  • Are 18 years of age

For subjects with elevated standing BP

  • Systolic BP (SBP) during standing is at least 10 mmHg > the supine SBP
  • Patients with a diagnosis of stage I hypertension without other chronic diseases may be INCLUDED

For normal subjects without elevated standing BP

  • The change in SBP by standing is within ± 5 mmHg from the supine SBP
  • Matched gender, similar age and BMI (within 10%) to participants with elevated standing BP
  • Free of acute or chronic medical conditions

Exclusion Criteria:

  • Age < 18 years of age
  • Are a pregnant or nursing woman
  • Are a prisoner or institutionalized individual or unable to consent
  • Have chronic diseases (e.g. heart, lung, neuromuscular disease, or cancer) other than stage I hypertension
  • Have orthostatic hypotension or a history of syncope
  • Current smoker
  • History of blood clots

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Basic Science
  • Allocation: Non-Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Single

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Tilt + external pressure
Tilt + external pressure on legs performed in both "BP elevated with standing" and "BP maintained with standing" groups.
Other: Tilt + external pressure
In Visit 1, the anti-shock trousers will be inflated to 20, 40, or 60 mmHg. BP will be measured 3 times from the brachial artery. Then the table will be tilted head up to a maximum of 70o for up to 10 min, while BP will be measured from the brachial artery at 1 min intervals. The tilt table is returned to 0o and the resting supine baseline BP will be collected. Then, the anti-shock trousers will be inflated to a different pressure (20, 40, or 60 mmHg) and the head up tilt will be repeated. Repetitions at the various pressures will be performed in a random order with suitable resting intervals in between the tilting bouts.
Placebo Comparator: Tilt + no external pressure
Tilt + no external pressure performed in both "BP elevated with standing" and "BP maintained with standing" groups.
Other: Tilt + no external pressure.
In Visit 1, the anti-shock trousers will NOT be inflated. Auscultatory BP will be measured 3 times from the brachial artery. Thereafter, the table will be tilted head up to a maximum of 70o for up to 10 min, while BP will be measured from the brachial artery at 1 min intervals.
Experimental: Limb occlusion + negative pressure
Limb occlusion + negative pressure performed in both "BP elevated with standing" and "BP maintained with standing" groups.
Other: Limb occlusion + negative pressure
In Visit 2, a cuff will be placed on the thigh of a leg that is sealed in an airtight pressure tank. After the cuff is inflated to 250 mmHg, the pressure in the tank will be reduced to -100mmHg for 2 minutes. The application of negative pressure creates a suction effect on the leg, and leads to an overall increase in pressure gradient across the blood vessel wall and induces vascular distension.
Placebo Comparator: Limb occlusion + no negative pressure
Limb occlusion + no negative pressure performed in both "BP elevated with standing" and "BP maintained with standing" groups.
Other: Limb occlusion + no negative pressure
In Visit 2, a cuff will be placed on the thigh of a leg that is sealed in an airtight pressure tank. The cuff is inflated to 250 mmHg for 2 minutes, but the pressure in the tank is not changed.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Muscle Sympathetic Nerve Activity (MSNA) in bursts/min or arbitrary units/min
Time Frame: Recorded continuously during Visit 2, the 4-5 hr Negative Pressure study visit.
MSNA provides direct recordings of sympathetic nerve activity directed to blood vessels in skeletal muscle.
Recorded continuously during Visit 2, the 4-5 hr Negative Pressure study visit.

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Blood pressure in mmHg
Time Frame: Recorded continuously during the 4-5 hr visit.
Cuffs placed on a finger and arm will monitor blood pressure.
Recorded continuously during the 4-5 hr visit.
Heart rate in beats per minute
Time Frame: Recorded continuously during the 4-5 hr visit.
Electrocardiogram (ECG) patches attached to a Cardiocap will monitor heart rate.
Recorded continuously during the 4-5 hr visit.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Milton S. Hershey Medical Center

Investigators

  • Principal Investigator: Jian Cui, Penn State College of Medicine

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

March 10, 2020

Primary Completion (Estimated)

June 30, 2025

Study Completion (Estimated)

June 30, 2025

Study Registration Dates

First Submitted

February 15, 2018

First Submitted That Met QC Criteria

April 5, 2018

First Posted (Actual)

April 12, 2018

Study Record Updates

Last Update Posted (Actual)

April 4, 2024

Last Update Submitted That Met QC Criteria

April 3, 2024

Last Verified

April 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • STUDY00007397

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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