A Dose Response Trial Using 5 and 10 Mg of Midodrine Hydrochloride
Condition: Orthostatic Hypotension; Spinal Cord Injury
MeSH terms: Spinal Cord Injuries; Hypotension, Orthostatic; Hypotension
Study type: Interventional
Phase: Phase 2

Summary: 
      With upright postures, there is an immediate redistribution of blood to the dependent
      circulation; venous return and central venous filling pressure are reduced, resulting in
      diminution of cardiac output and blood pressure. These hemodynamic alterations stimulate the
      baroreceptor reflex, which is mediated via the central nervous system to increase peripheral
      sympathetic vasomotor tone, restoring blood pressure and cardiac output within
      seconds-to-minutes of the assumption of the upright position. Following SCI, individuals
      often experience the inability to adjust to postural changes due to disruption of central
      command of the baroreceptor reflex and reduction in efferent sympathetic neural pathways;
      consequently, orthostatic hypotension (OH) and symptoms of cerebral hypo-perfusion may ensue.
      OH is a well-documented phenomenon, which is characterized by a fall in systolic blood
      pressure of >20 mmHg or diastolic BP of > 10 mmHg within 3 minutes of assumption of an
      upright posture. As a consequence of OH, many individuals experience symptoms of cerebral
      hypo-perfusion which include lightheadedness, dizziness, blurry vision, fatigue, nausea,
      ringing in the ears, cognitive impairment and heart palpitations. Although several
      investigators have reported increased prevalence of OH during the acute phase of spinal cord
      injury (SCI), individuals with chronic injury also experience significant falls in blood
      pressure with seated upright postures. This investigation will examine the effects of an
      alpha-agonist, midodrine hydrochloride, during head-up tilt on systemic blood pressure,
      cerebral blood flow and cerebral oxygenation compared to placebo administration in persons
      with chronic SCI who demonstrate significant orthostatic hypotension during a 24-hour
      observation study. This is the first study to determine the dose response and efficacy of
      midodrine to improve orthostatic blood pressure and cerebral blood flow and oxygenation in
      the SCI population.
    

Detailed description: 
      In individuals with SCI, blood pressure regulation is altered compared to the non-SCI
      population and relates to the degree of sympathetic vascular denervation. The inadequate
      release of norepinephrine with postural change is a primary component of OH and several
      reports have documented significantly reduced plasma norepinephrine levels in individuals
      with tetraplegia. Ephedrine sulfate and midodrine hydrochloride, both 1 receptor agonists,
      are recommended for the treatment of postural hypotension in this population. Although there
      are case reports documenting improved blood pressure regulation in persons with SCI treated
      with an 1 receptor agonist, this pharmacological treatment for OH has not been adequately
      studied in this population. A dose response trial will be used to determine the efficacy of
      midodrine hydrochloride (5 and 10 mg) compared to no drug at improving systemic blood
      pressure, cerebral blood flow and oxygenation and at reducing symptomatic hypotension during
      tilt-table testing in 16 individuals with SCI who manifest significant orthostatic
      hypotension (total time [minutes] spent with hypotension [ 20% fall in mean arterial pressure
      from supine laboratory observation] over a 24-hour observation.

      Subjects will receive, in an increasing dose manner and on separate days: no drug, 5 and 10
      mg of oral midodrine hydrochloride. Oral ingestion of the pill (placebo or midodrine) will be
      at 30 minutes during the 60 minute supine rest period prior to the head-up tilt maneuver.

      A progressive head-up tilt will be utilized in which the table will be adjusted to 15 , 25 ,
      35 for 5 minutes at each angle and then will be maintained at 45 for 45 minutes or until the
      subjects experiences symptoms of compromised cerebral blood flow, which include, but are not
      limited to, light headedness, blurry vision, dizziness and nausea. Throughout each test day,
      measurements of heart rate, blood pressure, middle cerebral blood flow velocity, and cerebral
      oxygenation will be obtained. In addition, blood draws will be completed to capture humoral
      factors responsible for blood pressure regulation.
    

Intervention name(s): Midodrine Hydrochloride
Intervention type(s): Drug
Intervention description(s): Alpha1-agonist, exerts its actions via activation of the alpha-adrenergic receptors of the arteriolar and venous vasculature, producing an increase in vascular tone and elevation of blood pressure.
Intervention MeSH terms: Midodrine
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Blood pressure; Orthostatic hypotension; Spinal Cord Injury; Sympathetic vascular control; Midodrine