Body Temperature in Persons With Tetraplegia When Exposed to Cold
Condition: Tetraplegia; Hypothermia; Mild Cognitive Impairment
MeSH terms: Quadriplegia; Hypothermia; Cognitive Dysfunction
Study type: Interventional
Phase: Phase 4

Summary: 
      The ability to maintain normal body core temperature (Tcore = 98.6°F) is impaired in persons
      with tetraplegia. Despite the known challenges to the ability of persons with spinal cord
      injury (SCI) to maintain Tcore, and the effects of hypothermia to impair mental function in
      able-bodied (AB) persons, there has been no work to date addressing these issues in persons
      with tetraplegia.

      The aim of this study is to determine if exposure of up to 2 hrs to cool temperatures (64°F)
      causes body core temperature to decrease in persons with tetraplegia and if that decrease is
      related to a decrease in mental performance.

      After sitting in a cool (64°F) room for up to 2 hours the investigators hypotheses are:

      Hypotheses (1): Tcore of most of the persons with tetraplegia will decline approximately
      1.8°F (e.g., 98.6 to 96.8°F) while Tcore of controls will not decline at all; (2) Most of the
      persons with tetraplegia will show a decline in mental performance (memory or
      clear-headedness) while only some of AB controls will show a decline.

      The second aim of this study is to determine if a 10 mg dose of an approved blood pressure
      raising medicine (midodrine hydrochloride) will (1) reduce the decrease in body core
      temperature and (2) prevent or delay the decline in mental performance in the group with
      tetraplegia compared to the exact same procedures performed on the day with no medicine
      (Visit 1) in the same group.

      Hypotheses (3 & 4): The changes in blood flow to the skin caused by taking a one-time dose of
      midodrine will lessen the decline in Tcore and prevent or delay the decline in mental
      performance compared to the changes in Tcore and mental performance during cool temperature
      exposure without midodrine in the group with tetraplegia.
    

Detailed description: 
      This study will investigate the mechanisms contributing to the thermoregulatory fragility in
      persons with tetraplegia when exposed to cool ambient temperatures that are routinely
      encountered during activities of daily living (ADL). Subnormal body core temperatures and
      vulnerability to hypothermia (Tcore<95°F) has been reported in veterans with tetraplegia upon
      exposure to relatively mild environmental temperatures. The impact that a drift in Tcore will
      be expected to have on cognitive performance, specifically working memory and executive
      function, will be demonstrated. These 2 areas of cognitive performance are vital for the
      ability to optimally care for one's self, which persons with higher cord lesions must excel
      at to ensure health, as well as to be able to attain the maximal degree of independence
      possible. Administration of an alpha agonist, midodrine hydrochloride, in an attempt to
      attenuate the drift in Tcore and prevent or delay the expected decline in cognitive
      performance to exposure to cool on cognitive function will be investigated as well.

      Primary Specific Aim: To determine the change in: (1) Tcore and (2) cognitive performance
      (attention, working memory, processing speed, and executive function) in persons with
      tetraplegia after exposure to a cool environment (64°F) for up to 120 min in the seated
      position.

      Primary Hypotheses:(1) 66% of persons with tetraplegia will demonstrate a decline of 1.8°F in
      Tcore while 0% of controls will demonstrate that same thermal decline; (2) 80% of persons
      with tetraplegia will have a decline of at least 1 T-score in Stroop Interference scores
      (executive functioning) while 30% of controls will demonstrate that same magnitude of
      decline.

      Secondary Specific Aims: To determine the change in: (1) the average of distal skin
      temperatures, (2) metabolic rate, and (3) subjective rating of thermal sensitivity after
      exposure to 64°F in the seated position.

      Secondary Hypotheses: Persons with tetraplegia will have less of a percent change in average
      distal skin temperatures and metabolic rate, and report lower thermal sensitivity ratings
      compared with AB.

      Tertiary Specific Aim: To determine if a single, 10 mg dose of midodrine will (1) reduce the
      decrease in Tcore and (2) prevent or delay the decline in cognitive performance in the group
      with tetraplegia.

      Tertiary Hypotheses: Because administration of a peripheral alpha-agonist will address the
      primary thermoregulatory impairment to cool temperature exposure in persons with
      tetraplegia-that is, lack of vasoconstriction, the midodrine-induced peripheral
      vasoconstriction will be anticipated to blunt the decrease in Tcore and prevent or delay the
      decline in cognitive performance compared to cool exposure without drug administration.

      Preparation for Study Visits: The study visits will be separated by a minimum of 1 day and no
      more than 14 days. Subjects will wear minimal clothing (gym shorts, sports bra) during the
      study to maximize bare skin exposure to the cool temperature. Each subject will be asked to
      eat a light, standard meal 2 hours prior to their scheduled visit consisting of either a
      plain bagel or 2 pieces of toast. For each visit they will be asked to empty their bladders
      prior to arrival and again upon arrival, if needed.

      Visit 1: Cold Ambient Challenge: Instrumentation: During Visit 1, all subjects will be
      transferred to a padded table for instrumentation, after which they will be transferred back
      to their own wheelchair or, for controls, to a provided wheelchair. All subjects will use a
      Roho seat cushion for air circulation consistency and decubiti prevention. A rectal probe
      will be placed 4 inches beyond the anal sphincter for core temperature measurement, and skin
      thermal sensors will be taped at 15 sites above and below the level of lesion for collection
      of skin temperatures. A mask will be placed over the subject's nose and mouth for measurement
      of exhaled gases from which resting metabolic rate will be calculated from analysis of
      expired gases (VO2) by a metabolic cart. Laser Doppler flowmetry (LDF) will be used to
      measure changes in microvascular perfusion by taping a doppler probe on the skin in the area
      of the ulnar styloid processes and medial malleoli bilaterally (wrists and ankles) to confirm
      vasoconstriction. A pulse oximeter will be placed on the left second digit to obtain blood
      oxygen saturation and heart rate (HR). An automated blood pressure cuff will be placed above
      the right elbow to measure brachial BP. An intravenous catheter will be placed in the right
      antecubital or nearby vein and secured for sequential blood collection for cortisol and
      norepinephrine.

      Baseline Collection: At the end of the 30 minute acclimation period (81°F), a baseline (BL)
      collection of the following parameters will be performed for 15 minutes with Tcore, skin
      temperatures, and VO2 measured continuously; HR, BP, blood oxygen saturation, subjective
      measures of thermal sensitivity, and 5 minutes of LDF will be measured at 10 minute
      intervals. A venous blood draw will be collected once at baseline for norepinephrine and
      cortisol concentrations. At the end of the BL period, a cognitive performance battery will be
      administered.

      Thermal Challenge: Following completion of the baseline period, subjects will be wheeled into
      an 18°C thermal chamber for 120 minutes or until Tcore ≤ 95°F. Tcore, skin temperatures, and
      VO2 will be continuously monitored to ensure subject safety throughout the protocol; brachial
      BP, HR, blood oxygen saturation, thermal sensitivity, and symptoms of hypothermia and
      autonomic dysreflexia will be assessed at 10 min intervals while LDF will be measured for 5
      minutes every 20 minutes. Venous blood will be collected at 50 minute intervals. A decrease
      in Tcore to ≤ 95°F, or moderate subject discomfort, will result in termination of the
      protocol. The cognitive performance battery will be administered when Tcore has declined
      1.8°F or is ≤ 95.9°F (in subjects with tetraplegia) or after 120 minutes of cold exposure (in
      both groups) on Visits 1 & 2.

      Visit 2: Cold Ambient Challenge with Midodrine: Visit 2 will be completed in subjects with
      tetraplegia who participated in Visit 1 and who had an impaired ability to maintain Tcore.
      Following completion of the BL period, subjects will be orally administered midodrine
      hydrochloride (10 mg tablet). Forty minutes after midodrine administration (for onset of drug
      effect), a second BL collection will be obtained, and subjects will be wheeled into the 64°F
      thermal chamber for 120 minutes or until Tcore ≤ 95°F. Data collection will follow the same
      schedule and be conducted in the seated position as in Visit 1. If brachial BP increases to
      160/90 mmHg, the subject will be removed from the cool room and evaluated by Dr. William A.
      Bauman, who may consider the administration of labetalol (to lower BP), if deemed necessary.
    

Intervention name(s): Midodrine hydrochloride
Intervention type(s): Drug
Intervention description(s): Midodrine hydrochloride is an approved medication used to treat low blood pressure. We are using a standard dose of 10 mg (tablet) only one time to determine if the effects of this drug improve the ability to maintain body core temperature in a cool environment (off-label use). A physician will administer the drug once before the cool thermal challenge in subjects with tetraplegia only(Visit 2)
Other intervention name(s): Midodrine hydrochloride 10 mg tablet; Amatine; ProAmatine; Gutron
Intervention MeSH terms: Midodrine
Allocation: Non-Randomized
Intervention model: Factorial Assignment
Masking: None (Open Label)
Keywords: Quadriplegia; Spinal Cord Injuries; Body Temperature Regulation; Mild Cognitive Impairment