Lower Body Muscle Pre-activation in Initial Orthostatic Hypotension

Brief Title

Lower Body Muscle Pre-activation in Initial Orthostatic Hypotension

Official Title

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

Brief Summary

      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.

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

      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

      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


Primary Outcome

Magnitude of change in SBP from sitting to stand with a physical intervention

Secondary Outcome

 Differences in Vanderbilt Orthostatic Symptoms Score (VOSS) Symptom Rating


Orthostatic Intolerance


Physical Counter-maneuver

Study Arms / Comparison Groups

 No Physical Intervention
Description:  The participant will actively stand up from a seated position without performing any physical counter-maneuvers either prior to or following the stand.


* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information

Recruitment Status


Estimated Enrollment


Start Date

July 1, 2019

Completion Date

December 31, 2023

Primary Completion Date

December 31, 2023

Eligibility Criteria

        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




18 Years - 50 Years

Accepts Healthy Volunteers

Accepts Healthy Volunteers


Satish R Raj, MD, MSCI, , 

Location Countries


Location Countries


Administrative Informations



Organization ID


Responsible Party


Study Sponsor

University of Calgary

Study Sponsor

Satish R Raj, MD, MSCI, Principal Investigator, University of Calgary

Verification Date

April 2021