Thermoregulation and Cognition During Cool Ambient Exposure in Tetraplegia

NCT ID: NCT02379156

Last Updated: 2025-03-21

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 30 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-04-30
• Study Completion Date: 2022-12-31

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.

Conditions

Tetraplegia; Hypothermia; Mild Cognitive Impairment

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: SUPPORTIVE_CARE
• Blinding Strategy: NONE

Study Groups

Able-bodied Control Cool Temperature Exposure / No Drug

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).

Group Type: OTHER

Cool Temperature

Intervention Type: OTHER

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).

SCI Cool Temperature Exposure / No Drug

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).

Group Type: EXPERIMENTAL

Cool Temperature

Intervention Type: OTHER

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).

SCI Cool Temperature Exposure with Drug

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).

Group Type: EXPERIMENTAL

Midodrine Hydrochloride

Intervention Type: DRUG

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).

Cool Temperature

Intervention Type: OTHER

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).

Interventions

Midodrine Hydrochloride

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 Type: DRUG

Cool Temperature

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).

Intervention Type: OTHER

Other Intervention Names

Gutron; ProAmatine; Amatine; Orvaten; Midodrine hydrochloride 10 mg tablet; 64° F

Eligibility Criteria

Inclusion Criteria

• Duration of SCI ≥1 year;
• Level of SCI C3-T1, AIS A & B;
• Age between 18 and 68 years.

Exclusion Criteria

• Evidence of sympathetic integrity below the lesion level by the skin axon-reflex vasodilatation (SkARV) test;
• Known allergies to midodrine hydrochloride;
• Past Medical History (PMH) of diagnosed heart, kidney, peripheral vascular, or cerebral vascular disease, or diabetes mellitus;
• Hypertension (BP>140/90 mmHg);
• Untreated thyroid disease;
• Acute illness or infection;
• Current smoker;
• Pregnancy.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 68 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

The Craig H. Neilsen Foundation

OTHER

Sponsor Role: collaborator

James J. Peters Veterans Affairs Medical Center

FED

Sponsor Role: lead

Responsible Party

John Handrakis, PT, DPT, EdD

Research Health Science Specialist

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

John P Handrakis, PT, DPT, EdD

Role: PRINCIPAL_INVESTIGATOR

James J. Peters VAMC

Locations

Center of Excellence for the Medical Consequences of SCI, James J Peters VAMC

The Bronx, New York, United States

Countries

United States

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Related Links

http://www.scirc.org/

Link to Research Center website. Look under Research tab to find Thermoregulation program.

Other Identifiers

315696

Identifier Type: OTHER_GRANT

Identifier Source: secondary_id

01589

Identifier Type: OTHER

Identifier Source: secondary_id

HAN-14-045

Identifier Type: -

Identifier Source: org_study_id