Lower Body Muscle Pre-activation in Initial Orthostatic Hypotension (IOH)

April 28, 2021 updated by: University of Calgary

Lower Body Muscle Pre-activation in Initial Orthostatic Hypotension: Effects on Orthostatic Tolerance

This study is aimed primarily at providing a simple and effective form of treatment to reduce the symptoms of Initial Orthostatic Hypotension (IOH) and prevent syncope. We will first characterize the physiology of IOH, and then we will study four sit-to-stand maneuvers, each with a different stress tests to identify the role of sympathetic activity vs. simple muscle contraction in IOH. Then we will complete an additional two sit-to-stands with interventions designed to decrease the blood pressure drop (and hopefully symptoms) with initial stand. These consist of physical counter maneuvers, which may be a possible treatment that can be used to mitigate the drop in blood pressure (BP) seen in IOH during a stand and relieve presyncope symptoms.

Study Overview

Status

Active, not recruiting

Conditions

Intervention / Treatment

Detailed Description

IOH is a form of orthostatic intolerance defined by a transient decrease in systolic blood pressure (SBP) by 40mmHg or diastolic blood pressure (DBP) by 20mmHg within the first 15-30 seconds of assuming a standing position from a supine or seated position. IOH commonly occurs in teenagers and young adults and is associated with presyncope symptoms such as nausea, light-headedness, and blurred vision and may sometimes lead to full syncope. These symptoms are a consequence of cerebral hypoperfusion caused by a rapid reduction in BP and are often present only during an active stand, and not with a passive tilt-table test. This suggests that a muscle activation reflex may play an important role underlying IOH. Identifying the refractory period of leg muscle activation will allow future investigators to accurately determine a common baseline seated period to allow hemodynamic recovery in patients after a stand. This will allow investigators to observe the physiological effects of repeated stands without any interference from a prior stand.

Upon standing there is a large shift of blood (approximately 500 mL) towards the lower extremities and abdomen. With this shift there is a decrease in venous return which results in a drop in BP. Subsequently, the decrease in BP activates the baroreceptors to increase sympathetic activity and reduce parasympathetic activity, which functions to restore BP by increasing heart rate (HR) and total peripheral resistance (TPR).

The underlying physiological mechanism behind the large decrease in blood pressure upon standing in IOH patients has not yet been confirmed. The most widely accepted explanation at this time involves rapid vasodilation localized to the contracting leg muscles during a stand. Research in both human and animal models from the past couple of decades have shown that skeletal muscle resistance vessels can dilate rapidly in response to, as well as in proportion to, a singular brief muscle contraction. This effect may be exaggerated in IOH patients, which could explain the decrease in TPR in IOH patients upon a stand and thus their subsequent drop in blood pressure. Current treatments of IOH include non-pharmacological interventions and physical counter-maneuvers such as standing up slowly or sitting up first before fully standing.

Physical counter-measures function to oppose the gravitational pull experienced on systemic circulation during a stand. During a stand, a large percentage of circulating blood shifts towards the lower extremities and abdomen resulting in blood pooling. Gravitational venous pooling can be minimized and opposed by performing a physical countermeasure such as a lower-body muscle contraction to translocate blood centrally. Sustained tensing of the lower-body muscles prevents further peripheral pooling in the legs and abdomen.

The investigators hypothesize that pre-activation of lower body muscles prior to standing, will attenuate the drop in SBP seen in IOH patients upon a stand, and alleviate symptoms of IOH, compared to an active stand without muscle pre-activation. The study participant will complete 14 active stands in total within a single day. The first 8 stands will be in an attempt to define the refractoriness of leg muscle activation. The next 4 stands will involve stress tests prior to standing to isolate the roles of sympathetic activity vs. simple muscle contraction. The final 2 stands will involve physical counter-maneuvers intended to mitigate the large drop in BP seen in IOH patients upon a stand.

The first 8 stands will be performed from a seated position. They will begin at a 20 minute seated baseline before the first stand, then in a random order perform stands after baseline durations of 30 sec, 2 min, 3 min, 4 min, 5 min, 7 min, and 10 min.

The next 4 stands will also be performed from a seated position. The interventions that will be performed in a random order are: (1) free stand with no intervention, (2) Serial 7's mental arithmetic stress test, (3) Cold Pressor stress test, (4) functional electrical stimulation.

The final 2 stands will be performed from a seated position as well. The interventions that will be performed in a random order are: (1) supine knee raises and tensing prior to standing and (2) leg crossing and tensing after standing. The entire study will take approximately 3-4 hours.

The study participant will be instrumented in a fasting state and on an empty bladder. The investigators will apply skin electrodes to continuously monitor heart rate and record an ECG. BP will be monitored continuously using finger volume clamp photoplethysmography and calibrated with intermittent brachial cuff measurements. From the continuous BP waveform, the investigators can obtain an estimate of stroke volume, cardiac output, and systemic vascular resistance (Modelflow). Oxygen saturation will be assessed from a finger probe. Middle cerebral blood flow velocity will be assessed using transcranial doppler (TCD).

Study Type

Interventional

Enrollment (Anticipated)

64

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 Locations

  • Canada
    • Alberta
      • Calgary, Alberta, Canada, T2N4N1
        • University Of Calgary

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 to 50 years (Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Either have initial orthostatic hypotension or are a healthy volunteer
  • 18-50 years old
  • Male or Female
  • Ability to travel to Libin Cardiovascular Institute of Alberta Autonomic Research Testing Lab in the Teaching, Research & Wellness Building at the University of Calgary, Calgary, AB
  • Able and willing to provide informed consent

Exclusion Criteria:

  • Inability to stand up or perform leg exercises without assistance
  • Sustained orthostatic hypotension past 3 minutes of standing
  • Pregnant

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: Treatment
  • Allocation: Randomized
  • Interventional Model: Crossover Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
No Intervention: No Physical Intervention
The participant will actively stand up from a seated position without performing any physical counter-maneuvers either prior to or following the stand.
Experimental: Supine Knee Raises
The participant will perform 30 seconds of raising their knees to their chest while sitting down before actively standing.
Other: Physical Counter-maneuver
Physical counter-maneuver targeted at minimizing the large drop in BP seen in IOH patients.
Experimental: Leg Crossing
The participant will actively stand and then immediately cross their legs and tense their leg muscles for 60 seconds.
Other: Physical Counter-maneuver
Physical counter-maneuver targeted at minimizing the large drop in BP seen in IOH patients.
Experimental: Cold Pressor Test
The participant will submerge their hands in ice water for approximately 45 seconds.
Other: Stress Test
Stress test involving submerging your hand in ice water or performing mental arithmetic to increase sympathetic activity.
Other Names:
  • Cold Pressor Test, Serial 7's Stress Test
Experimental: Serial 7's Stress Test
The participant will perform a mental arithmetic stress test for 30 seconds prior to standing.
Other: Stress Test
Stress test involving submerging your hand in ice water or performing mental arithmetic to increase sympathetic activity.
Other Names:
  • Cold Pressor Test, Serial 7's Stress Test
Experimental: Functional Electrical Stimulation
The participant will have their quadriceps passively contracted using mild electrical stimulation for approximately 30 seconds prior to standing.
Other: Functional Electrical Stimulation
A mild electrical stimulus to passively induce a leg muscle contraction with minimal sympathetic activation.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Magnitude of change in SBP from sitting to stand with a physical intervention
Time Frame: < 5 minutes
The magnitude of change in SBP from sitting to stand when the participant performs muscle pre-activation before a stand compared to no intervention at all.
< 5 minutes

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Differences in Vanderbilt Orthostatic Symptoms Score (VOSS) Symptom Rating
Time Frame: < 5 minutes

Subjective symptom scoring as reported by participant during each study arm. The VOSS evaluates 9 symptoms on a 0 to 10 scale with 0 being no symptom to 10 being worst ever symptom. The total score ranges from 0-90, with a higher score being more severe symptoms.

The 9 symptoms are mental clouding, blurred vision, shortness of breath, rapid heartbeat, tremulousness, chest discomfort, headache, lightheadedness, and nausea. The participant's VOSS score will be compared across the 4 arms of this study.

The VOSS score has been previously used in multiple publications
< 5 minutes
Nadir SBP
Time Frame: < 5 minutes
Nadir systolic blood pressure when standing during each study arm.
< 5 minutes
Peak HR
Time Frame: < 5 minutes
Peak heart rate when standing during each study arm.
< 5 minutes
Cerebral Blood Flow Velocity (CBFV)
Time Frame: < 5 minutes
CBFV when standing during each study arm.
< 5 minutes

Collaborators and Investigators

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

Sponsor

University of Calgary

Investigators

  • Principal Investigator: Satish R Raj, MD, MSCI, University Of Calgary

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)

July 1, 2019

Primary Completion (Anticipated)

December 31, 2023

Study Completion (Anticipated)

December 31, 2023

Study Registration Dates

First Submitted

May 24, 2019

First Submitted That Met QC Criteria

May 29, 2019

First Posted (Actual)

May 31, 2019

Study Record Updates

Last Update Posted (Actual)

April 29, 2021

Last Update Submitted That Met QC Criteria

April 28, 2021

Last Verified

April 1, 2021

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • REB19-0792

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

IPD Plan Description

I will not be sharing individual participant data.

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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