Body Temperature in Persons With Tetraplegia When Exposed to Cold

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.

Inclusion Criteria:

- (1) Between 18 and 68 years of age;

- (2) Duration of injury ≥ 1 year; (2) Level of SCI C3-T1;

- (3) Euhydration (subjects will be instructed to avoid caffeine and alcohol, maintain
normal salt and water intake, and avoid strenuous exercise for 24 hours prior to
study)

Exclusion Criteria:

- (1) Known coronary heart, kidney, peripheral vascular or cerebral vascular disease;

- (2) High blood pressure;

- (3) Untreated thyroid disease;

- (4) Diabetes mellitus;

- (5) Acute illness or infection;

- (6) Dehydration;

- (7) Known allergies to midodrine hydrochloride;

- (8) Smoking;

- (9) Pregnancy