Clinical trial NCT02379156
Conditions: Tetraplegia Hypothermia Mild Cognitive Impairment
Keywords: Quadriplegia Spinal Cord Injury Body Temperature Regulation Mild Cognitive Impairment
Sponsor: James J. Peters Veterans Affairs Medical Center
Start date: 2015-04-01; Completion date: 2022-12-01
Enrollment: 30 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The ability to maintain normal core body temperature (Tcore = 98.6°F) is impaired in persons with a cervical spinal cord injury (tetraplegia). Despite the known deficits in 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.

Primary Aim: To determine if exposure of up to 2 hours to cool temperatures (64°F) causes Tcore to decrease in persons with tetraplegia, and if that decrease is associated with a decrease in cognitive function.

Primary Hypotheses: Based on our pilot data: (1) 66% of persons with tetraplegia and none of the matched controls will demonstrate a decline of 1.8°F in Tcore; (2) 80% of persons with tetraplegia and 30% of controls will have a decline of at least one T-score in Stroop Interference scores (a measure of executive function).

Secondary Aim: To determine the change in: (1) distal skin temperature, (2) metabolic rate, and (3) thermal sensitivity.

Secondary Hypothesis: 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 controls.

Tertiary Aim: To determine if a 10 mg dose of an approved blood pressure-raising medicine (midodrine hydrochloride) will (1) reduce the decrease in Tcore and (2) prevent or delay the decline in cognitive performance in the group with tetraplegia compared to the exact same procedures performed on the day with no medicine (Visit 1) in that same group.

Tertiary Hypothesis: Through administering a one-time dose of midodrine, the medicine-induced decreased blood flow to the skin will lessen the decline in Tcore and prevent or delay the associated decline in cognitive performance compared to the changes in Tcore and cognitive performance during cool temperature exposure without midodrine in the same group with tetraplegia.

Detailed description:
This study will investigate the mechanisms contributing to thermoregulatory fragility in persons with tetraplegia when exposed to cool ambient temperatures that are routinely encountered during their activities of daily living (ADL). Subnormal body core temperatures and vulnerability to hypothermia (Tcore\<95°F) have 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 and to attain the maximal degree of independence possible. The one-time 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.

Preparation for Study Visits:

The study visits will be at least 1 day apart but no more than 2 weeks apart. Subjects will be provided a light, standard meal which they will be asked to eat 2 hours prior to their scheduled visit time. The meal will be either a plain bagel or 2 pieces of toast. For each visit, subjects will be asked to empty their bladders before their arrival and again upon arrival, if needed. Subjects will be asked to avoid caffeinated and alcoholic beverages and heavy exertion for 24-hours before testing. Subjects will wear minimal clothing (gym shorts, sports bra) during the study to maximize bare skin exposure to the cool temperature.

Visit 1: Cold Ambient Challenge Instrumentation: During the subject's first visit, a thin flexible rectal sensor will be placed 4 inches beyond the anal sphincter for Tcore measurement, and skin thermal sensors will be taped at 15 sites above and below the level of lesion for collection of skin temperature (Tsk). 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 laser doppler probe on the skin in the area of the ulnar styloid processes and medial malleoli bilaterally 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 blood pressure (BP). An intravenous catheter will be placed in the right antecubital or nearby vein and secured for sequential blood collection for blood hormones (cortisol and norepinephrine).

Baseline Collection: At the end of the 30-minute acclimation period (81°F), a 15-minute baseline (BL) collection of the following measures will be performed: Tcore, Tsk, and VO2 will be measured continuously; BP, HR, blood oxygenation, and thermal sensitivity will be measured at 5-minute intervals; 5 minutes of LDF will be measured at 10-minute intervals; a venous blood draw will be collected once for norepinephrine and cortisol concentrations. At the end of the BL period, a cognitive performance battery will be given.

Cool Ambient Challenge: Following the completion of the baseline period, subjects will be wheeled into a 64°F thermal room for 120 minutes or until Tcore ≤ 95°F. Tcore, Tsk, and VO2 will be continuously monitored for safety throughout the study, while BP, HR, blood oxygenation, and thermal sensitivity will be measured every 10 minutes. LDF will be measured for 5 minutes every 25 minutes, and venous blood will be collected every 60 minutes. 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). A decrease in Tcore to ≤ 95°F, or moderate subject discomfort, will result in termination of the protocol. Subjects will be transferred to a warm room (81°F), covered with warming blankets, and given warm fluids. If symptoms continue, Dr. William Bauman will assess the subject and provide the appropriate care.

Visit 2: Cold Ambient Challenge with Midodrine Visit 2 will be completed in the subjects with tetraplegia who participated in Visit 1 and demonstrated an impaired ability to maintain Tcore. All procedures will be conducted in the seated position and will be the same as in Visit 1, with the exception of the oral administration of a 10 mg tablet of midodrine hydrochloride following the completion of the baseline period. Forty minutes after midodrine administration (in order for the medicine's effects to start), a second baseline collection will be performed and subjects will then be placed inside the 64°F thermal room for up to 2 hours or until Tcore ≤ 95°F. Data collection will follow the same schedule and be conducted in the same seated position as in Visit 1. During Visit 2, BP will be continuously monitored after midodrine administration for safety purposes. If subjects' BP increases to 160/90 mmHg, subjects will be seen by Dr. William Bauman, who may consider the administration of labetalol, if necessary.

Arms: arm 1: Subjects are able-bodied (AB) persons, ages 18-65. AB participants were matched to the SCI group by age and gender. Procedure is exposure to cool temperature (64° F) for up to 2 hours in a temperature-controlled room in order to assess the body's temperature-regulating mechanisms and any associated change in cognitive performance (Visit 1). arm 2: Subjects are persons with tetraplegia: spinal cord lesion level C3 to T1, American Spinal Injury Association Impairment Scale (AIS) levels A and B, ages 18-65 years. Procedure is exposure to cool temperature (64° F) for up to 2 hours in a temperature-controlled room in order to assess the body's temperature-regulating mechanisms and any associated change in cognitive performance (Visit 1). arm 3: Subjects are persons with tetraplegia who completed Visit 1 (no drug). Subjects are administered a 10 mg tablet of midodrine hydrochloride by a physician before being exposed to cool temperature (64° F) for up to 2 hours in a temperature-controlled room in order to assess the body's temperature-regulating mechanisms and any associated change in cognitive performance (Visit 2).
Interventions: intervention 1: Midodrine Hydrochloride intervention 2: Cool Temperature
Intervention descriptions: intervention 1: 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 vascular-constricting effects of this drug will help keep warm blood closer to the body's core and improve the ability to maintain Tcore 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). intervention 2: Subjects will be exposed to a routinely encountered cool temperature (64° F) for up to to 2 hours depending on the vital signs (BP, HR, Tcore) and tolerance (comfort).

Protocol documents:
Prot_SAP_000.pdf: 
Thermoregulation and Cognition During Cool Ambient Exposure in Tetraplegia 
NCT02379156 
Most Recent Update / Human Subjects Protection Review Board Approval: 03/07/2023 


RESEARCH PROTOCOL 
1. SPECIFIC AIMS.
Problem Statement: After a cervical spinal cord injury (SCI) the motor, sensory and autonomic 
deficits cause, among other detriments, a blunted ability to maintain a constant core body 
temperature (Tcore). Impaired thermoregulation leaves persons with tetraplegia more susceptible 
to hypothermia than able-bodied persons (AB). In addition, the commonly prescribed medications 
to treat the spasticity, pain, and depression that accompany this injury, raise the vulnerability of 
this population to hypothermia, and its potentially fatal consequences.  
Persons with tetraplegia are routinely exposed to cool ambient temperatures in their homes, work 
environments, and while waiting on or riding in accessible public transportation. The 
thermoregulatory response and cognitive consequences of prolonged exposure to cool 
temperatures have not been investigated in persons with tetraplegia. Preliminary data has 
suggested that even limited exposure to cool temperatures can cause a drift in Tcore to values 
approaching hypothermia. With this lowering of Tcore, cognitive performance may also be 
negatively affected. Such demonstration of mild (or worse) hypothermia and concomitant declines 
in cognitive function would warrant investigations of interventions to mitigate this drift in persons 
with tetraplegia. The International Spinal Cord Injury Skin and Thermoregulation Basic Data Set 
is further evidence of the growing recognition that many people with SCI are affected by 
thermoregulatory dysfunction. 
There has been a paucity of work addressing the thermoregulatory responses of persons with 
SCI to cool ambient temperatures, and even less study of medical interventions to improve 
maintenance of Tcore. Although it is presently unknown as to whether a modest fall in Tcore 
impairs cognition in persons with SCI, one may expect deterioration in cognitive function because 
central neurological function is exquisitely temperature sensitive. As such, cognitive performance 
will be determined after decrement in core body temperature. 
The goals of this study are: 1) to improve our understanding of the thermoregulatory mechanisms 
of individuals with tetraplegia when exposed to cold, 2) to determine if cognitive performance is 
affected after a decrement in Tcore, and 3) to determine if administration of an alpha-adrenergic 
agonist (midodrine) delays or decreases the expected downward drift in Tcore and possible 
deterioration of cognitive performance. 
In order to address our goals, we have designed a study methodology which consists of 
comparing the physiological and subjective responses of the two study groups (tetraplegia versus 
AB controls) from thermoneutral (27°C) to cool (18°C) environments in the seated position. On a 
2nd visit, the subjects with tetraplegia who completed the first visit, will be given midodrine while 
seated prior to being placed in the cool environment to compare their responses with midodrine 
to their responses to the identical challenge without midodrine. 
Overall Objective: The overall objective is to identify and address the physiological and 
cognitive problems that persons with spinal cord injury (SCI) face when exposed to routinely 
encountered cool temperatures.  
- Specific Aims: during exposure to a cool environment (18°C) for up to 120 min in the seated
position:
Primary Specific Aim: To determine the change in: (1) Tcore and to assess (2) cognitive
performance (attention, processing speed, working memory, and executive function) before and


after exposure to cool temperatures. Primary Hypotheses: Based on our pilot data: (1) Sixty-
six percent of persons with tetraplegia and none of the controls will demonstrate a decline of 
1.0°C in Tcore; (2) Eighty percent of persons with tetraplegia and 30% of controls will have a 
decline of at least one T-score in Stroop Interference scores (a measure of executive function). 
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. Secondary 
Hypotheses: Persons with tetraplegia will have less of a percent change in average distal skin 
temperatures and metabolic rate, and report blunted thermal sensitivity ratings compared with 
able-bodied (AB) controls.  
Tertiary Specific Aim: To determine if a 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 Hypothesis: Because the one-time, off-label use of midodrine will address the primary 
systemic impairment to cold exposure in persons with tetraplegia, lack of peripheral 
vasoconstriction, the induced vasoconstriction will serve to reduce cutaneous heat losses and will 
be anticipated to blunt the decrease in Tcore and delay the decline in cognitive performance 
compared to cool exposure without drug administration.    
METHODS 
Research Design and Methods: A prospective, two-group comparative study will be performed to 
determine the effects of cold thermal challenge on Tcore, cognitive performance, distal skin 
temperatures (Tsk), metabolic rate (VO2), and thermal sensitivity (TS) in the seated position in 
individuals with tetraplegia and in a matched AB control group (Visit 1). During Visit 2, a 
prospective, within-group comparative study will be performed to determine the effects of cold 
thermal challenge on Tcore, cognitive performance, Tsk, VO2, and TS only in individuals with 
tetraplegia after midodrine administration compared to their response on Visit 1.  
A prospective, two-group comparative study will be performed to determine the effects of cold 
thermal challenges on core temperature measured by rectal thermocouple (Tre), skin temperature 
by surface thermocouples (Tsk), cognitive performance by [digit span section of the Wechsler 
Adult Intelligence Scale-Fourth Edition (WAIS-IV), Stroop Color and Word tests, Symbol Digit 
Modalities Test (SDMT), memory and delayed recall sections of the Montreal Cognitive 
Assessment (MoCA)], metabolic rate measured by oxygen consumption (VO2), and thermal 
sensation by the thermosensitivity cold scale in the seated position in individuals with tetraplegia 
and in a matched AB control group (Visit 1). During Visit 2 a prospective, within-group comparative 
study will be performed to determine the effects of thermal challenge on Tcore, skin temperature, 
cognitive performance, metabolic rate, and thermal sensation in individuals with tetraplegia who 
have participated in Visit 1 and in those same individuals who repeat the Visit 1 challenge 
identically, except for the administration of midodrine prior to the cold challenge while in the seated 
position (Visit 2).  
Subjects:  Fifteen subjects with tetraplegia (C4-T1) and 15 non-SCI control subjects matched for 
age (± 5 years), and gender will be recruited for study.   
Subject Recruitment: 
Patients referred by their physician following routine physical examinations will be approached for 
possible study enrollment. Physicians will be informed of the inclusion and exclusion criteria for 
this study and will be able to provide us with the assurance that the patient is an appropriate study 
subject and that they were willing to speak with the study coordinators. 
Veterans with SCI responding to IRB approved articles in lay publications and advertisements.  
Veterans with an ongoing relationship with our center, such as through attendance at one of the 
following SCI clinics: (1) Metabolic, (2) Pulmonary, or (3) GI. 


a. Inclusion criteria
1. Between 18 and 68 years of age;
2. Duration of injury ≥ 1 year;
3. Level of SCI C4-T1; (AIS A & B)
4. 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); and
5. Age (± 5 years) and gender matched AB control group.
b. Exclusion criteria
1. Evidence of sympathetic integrity below the lesion level by the skin axon-reflex
vasodilatation (SkARV) test (a distinctly diminished vasodilatory response to
mechanical stimulation of the skin is evident below the lesion level when
sympathetic integrity has been interrupted);
2. Known allergies to midodrine hydrochloride;
Exclusion Criteria shared by subjects with SCI and AB controls
3. PMH of diagnosed heart, kidney, peripheral vascular, or cerebral vascular disease,
or diabetes mellitus;
4. Hypertension (BP>140/90 mmHg);
5. Untreated thyroid disease;
6. Acute illness or infection;
7. Current smoker;
8. Pregnancy.
Preparation for Study Visits: AB controls will be gender- and age-matched (±5 years) to subjects 
with SCI. All 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 to ensure euhydration.  
Subjects will enter the laboratory between 8:00-10:00 AM on each study visit. 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 skin exposure to the cool temperature. Each 
subject will be asked to eat a light, standard meal (plain bagel or 2 pieces of toast) 2 hours prior 
to their visit. Subjects will be asked to empty their bladders prior to each study visit and again 
upon arrival, if needed. 
Visit 1: Cool Ambient Challenge: Instrumentation: During Visit 1, all subjects will be instrumented 
on a padded table, after which they will be transferred back to their wheelchair or, for controls, to 
a provided wheelchair. All subjects will use a Roho seat cushion (high-profile single compartment 
ROHO seat cushion, the Roho Group, Belleville, IL) for air circulation consistency and decubiti 
prevention. A rectal probe will be placed 10 cm beyond the anal sphincter for core temperature 
collection, and skin thermocouples will be secured at 15 sites above and below the level of lesion 
for collection of skin temperatures. A dilution mask will be placed over the subject’s nose and 
mouth for collection 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 placing 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 second digit to obtain blood oxygen 
saturation and heart rate (HR).  A BP cuff will be placed above the right elbow to measure brachial 
BP. An intravenous catheter will be placed in an upper extremity vein for sequential blood draws 
to assess plasma NE and cortisol levels.  


Baseline Collection: At the end of the 30-minute acclimation period (27°C), a baseline (BL) 
collection of the following parameters will be performed for 15 minutes with Tcore, Tsk, and VO2 
measured continuously; HR, BP, blood oxygen saturation, subjective measures of TS, and 5 
minutes of LDF will be measured at 10-minute intervals. A venous blood draw will be collected 
once at baseline for NE and cortisol concentrations. At the end of the BL period, hypertonicity 
(spasticity) will be measured only in subjects with tetraplegia in both upper extremities, at the 
elbows and wrists (flexors and extensors) and both lower extremities, at the knees and ankles 
(flexors and extensors) using the Modified Ashworth Scale. Once the spasticity measurement is 
completed, a cognitive performance battery will be administered. 
Thermal Challenge: Following completion of the BL period, subjects will be wheeled into an 18°C 
thermal chamber for 120 minutes or until Tcore ≤ 35°C. Tcore, Tsk, and VO2 will be continuously 
monitored to ensure subject safety throughout the protocol; brachial BP, HR, blood oxygen 
saturation, TS, and symptoms of autonomic dysreflexia and hypothermia will be assessed at 10- 
minute intervals while LDF will be measured for 5 minutes every 20 minutes. Venous blood will 
be collected at 50-minute intervals. After 1 hour of Cold Challenge, hypertonicity (spasticity) will 
be measured again only in subjects with tetraplegia in both upper extremities, at the elbows and 
wrists (flexors and extensors) and both lower extremities, at the knees and ankles (flexors and 
extensors) using the Modified Ashworth Scale. A decrease in Tcore to ≤ 35°C, or subject 
discomfort, will result in termination of the protocol. The cognitive performance battery will be 
administered when Tcore has declined 1°C or is ≤ 35.5°C (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, hypertonicity (spasticity) will be measured only in subjects with 
tetraplegia in both upper extremities, at the elbows and wrists (flexors and extensors) and both 
lower extremities, at the knees and ankles (flexors and extensors) using the Modified Ashworth 
Scale. Subjects will then be orally administered midodrine hydrochloride (10 mg). Forty minutes 
after midodrine administration (for onset of drug effect), a second BL collection will be obtained, 
and hypertonicity (spasticity) will again be measured only in subjects with tetraplegia in both upper 
and lower extremities. Subjects will then be wheeled into the 18°C thermal chamber for 120 
minutes or until Tcore ≤ 35° C. Data collection will follow the same schedule and be conducted in 
the seated position as in Visit 1. After 1 hour of Cold Challenge, hypertonicity (spasticity) will again 
be measured in both upper and lower extremities.  
 
Statistical Analyses: Visit 1: Depending on the data distribution, parametric or non-parametric 
analyses will be performed. For the within-group comparisons, paired-t and Wilcoxon signed rank 
tests will be conducted to determine intra-group differences in the dependent variables. For the 
between-group comparisons, unpaired-t and Mann-Whitney U tests will be performed to 
determine between-group differences in the percentage change (from thermoneutral to cool) of 
the dependent variables (Tcore, cognitive performance, Tsk, and VO2).  
Visit 2 (with midodrine): Depending on the data distribution, parametric or non-parametric 
analyses will be performed. Within the group with tetraplegia, paired-t or Wilcoxon signed rank 
tests will be used to determine differences in the percentage change (from thermoneutral to cool) 
of the dependent variables (Tcore, cognitive performance, Tsk, VO2), without midodrine (Visit 1) 
compared to with midodrine (Visit 2). 
 
Sample size: The primary outcome variables are Tcore and cognitive performance. For Tcore, 
using our preliminary data obtained post cold exposure in tetraplegic and AB subjects, mean 
Tcores of 35.95±0.63°C and 37.3±0.28°C were demonstrated, respectively. The difference 
between the groups for these values yields a power of 99.9% at an alpha of 0.05 with 8 subjects 


per group (double-sided). Four of the 6 subjects with tetraplegia (66%) had a decrease of ≥ 1.0°C 
while no control demonstrated a decline > 0.297°C in Tcore (0%). Cognitive performance will be 
assessed after a Tcore decline of 1.0°C in subjects with tetraplegia. Using 66% (tetraplegia) 
versus 0% (control) with a count of 15 per group, the power is 99.59% at an alpha of 0.05. We 
are hypothesizing that 66% of subjects in the SCI group will have a decline of 1.0°C in Tcore while 
none of the controls will demonstrate the same decline. We are well-powered to test this endpoint. 
For cognitive performance, preliminary data indicated that 5 of 6 subjects with tetraplegia (83%), 
compared to 2 of 6 AB subjects (33%), demonstrated a decline of ≥ 1 T-score in Stroop 
Interference scores post cold exposure. Using 83% (tetraplegia) versus 33% (control) with a count 
of 15 per group, the power is 82.75% at an alpha of 0.05 (double-sided).76 We hypothesize that 
80% of subjects in the SCI group will have a decline of at least 1 T-score in Stroop Interference 
scores while 30% of controls will demonstrate that same decline. We are well-powered to test this 
outcome.