Autonomic Nervous System, Baroreflex, Stress, Physiological
Conditions
Keywords
stress, ACTH, cosyntropin, baroreflex sensitivity, cardiovagal
Brief summary
Models of stress such as hypoglycemia have identified that stress results the next day in decreased baroreflex sensitivity. This project will test the hypothesis that these delayed changes in autonomic nervous system function are secondary to a rise in ACTH. The investigators will infuse cosyntropin versus placebo in a double-blind, crossover study in healthy adults and measure the delayed effects on the autonomic system as measured by cardiovagal baroreflex sensitivity.
Detailed description
Stress has complex effects on the body's physiology. Models of stress such as hypoglycemia have identified that stress activates the hypothalamic-pituitary-adrenal (HPA) axis and sympathoadrenal system acutely. Additionally, there are delayed effects of prior exposure to hypoglycemia. The day after being exposed to a hypoglycemic stimulus there are: 1) decreases in the catecholamine release to a new hypoglycemic stress; 2) decreases in the muscle sympathetic nerve activity (MSNA) response to either a new hypoglycemic challenge or transient hypotension; 3) decreases in cardiac vagal baroreflex sensitivity (BRS); and 4) increases in sensitivity to thermal pain and altered temporal summation (decreased tolerance to a repeated minimally painful stimulus). This project will test the hypothesis that these delayed changes in autonomic nervous system function are secondary to a rise in ACTH that occurs in response to stress. Primary Aim. Infusion of ACTH (cosyntropin) will lead the next day to decreased cardiovagal baroreflex sensitivity in healthy subjects.
Interventions
DRUGCosyntropin
Subjects will receive cosyntropin at 70 mcg/hr for two sessions of 2.5 hours each on day 2 of a three day admission to our research center.
DRUGPlacebo
Subjects will receive placebo (normal saline infusion) for two sessions of 2.5 hours each on day 2 of a three day admission to our research center.
Sponsors
Beth Israel Deaconess Medical Center
Brigham and Women's Hospital
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
OTHER
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
Subjects must be currently healthy, BMI 18-32 kg/m2, and not be on any medications. This study will recruit men and women. Due to concerns about estrogen's effects on hormone levels and possible contributions of menstrual symptoms on pain sensing thresholds, we will schedule the inpatient studies to avoid the early follicular phase in normally cycling women. Subjects must have normal laboratory values for: 1. Complete blood count 2. Serum creatinine, sodium, potassium, glucose, liver enzymes 3. Urinalysis 4. Urine pregnancy test (if female) 5. Normal ECG
Exclusion criteria
We will exclude individuals with: * Systolic blood pressure \> 140 or \< 90 mm Hg * Diastolic blood pressure \> 90 mm Hg * Creatinine clearance ≤ 60 mL/min, as calculated by MDRD formula * Known DM, CHF, CAD, PVD, CVA, MI, asthma * Known or history of Cushing's disease or adrenal insufficiency * Known neurologic disease * Known psychiatric disease * Steroid use (oral or inhaled, local or systemic injections, within the past 6 months) * Significant concomitant medical illnesses * Current excessive alcohol (\>10oz ethanol/week) * Current use of recreational drugs * Current smokers * Current pregnancy * Chronic use of non-steroidal anti-inflammatory or narcotic medications * Evidence of ischemia or heart block on screening electrocardiogram (greater than type I-second degree heart block, left bundle branch block, or ST-T wave changes in 2 or more contiguous leads) * Subjects taking any prescription medications (other than oral birth control pills) or herbal medications will be excluded.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cardiovagal Baroreflex Sensitivity (Modified Oxford Technique) | Baseline, 4-hours after infusion, 24-hours after infusion | Cardiovagal baroreflex sensitivity will be measured with the Modified Oxford Technique before, during, and after drug infusions, to evaluate the effects of cosyntropin infusions. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Pain (Quantitative Sensory Testing Using a Thermal Pain Testing Device) | 1 day after ACTH | Alterations in pain sensing will be evaluated pre and post with quantitative sensory testing using a thermal pain testing device, to evaluate the delayed effect of cosyntropin infusions. |
| Hippocampal Memory (Paired Associative Learning Task) | 1 day after ACTH | Hippocampal memory will be evaluated pre and post with a paired associative learning task. Face Name Associative Memory Exam (FNAME) composite score on a scale from 0-36, with 36 being the best possible score. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Healthy Control | 23 |
| Total | 23 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Period 1 (Placebo or Cosyntropin) | Withdrawal by Subject | 0 | 1 |
| Washout (Period 2) | Withdrawal by Subject | 2 | 0 |
Baseline characteristics
| Characteristic | Healthy Control |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 23 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 22 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants |
| Race (NIH/OMB) Black or African American | 6 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 14 Participants |
| Sex: Female, Male Female | 12 Participants |
| Sex: Female, Male Male | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 22 | 0 / 21 |
| other Total, other adverse events | 2 / 22 | 0 / 21 |
| serious Total, serious adverse events | 0 / 22 | 0 / 21 |
Outcome results
Primary
Cardiovagal Baroreflex Sensitivity (Modified Oxford Technique)
Cardiovagal baroreflex sensitivity will be measured with the Modified Oxford Technique before, during, and after drug infusions, to evaluate the effects of cosyntropin infusions.
Time frame: Baseline, 4-hours after infusion, 24-hours after infusion
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cosyntropin | Cardiovagal Baroreflex Sensitivity (Modified Oxford Technique) | Baseline | 17.75 ms/mmHg | Standard Deviation 5.47 |
| Cosyntropin | Cardiovagal Baroreflex Sensitivity (Modified Oxford Technique) | 4-hours after infusion | 14.42 ms/mmHg | Standard Deviation 5.89 |
| Cosyntropin | Cardiovagal Baroreflex Sensitivity (Modified Oxford Technique) | 24-hours after infusion | 14.76 ms/mmHg | Standard Deviation 5.83 |
| Normal Saline (Placebo) | Cardiovagal Baroreflex Sensitivity (Modified Oxford Technique) | Baseline | 16.90 ms/mmHg | Standard Deviation 8.63 |
| Normal Saline (Placebo) | Cardiovagal Baroreflex Sensitivity (Modified Oxford Technique) | 4-hours after infusion | 17.27 ms/mmHg | Standard Deviation 6.79 |
| Normal Saline (Placebo) | Cardiovagal Baroreflex Sensitivity (Modified Oxford Technique) | 24-hours after infusion | 18.90 ms/mmHg | Standard Deviation 8.4 |
Other Pre-specified
Hippocampal Memory (Paired Associative Learning Task)
Hippocampal memory will be evaluated pre and post with a paired associative learning task. Face Name Associative Memory Exam (FNAME) composite score on a scale from 0-36, with 36 being the best possible score.
Time frame: 1 day after ACTH
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cosyntropin | Hippocampal Memory (Paired Associative Learning Task) | Baseline | 27.8 score on a scale | Standard Deviation 3.7 |
| Cosyntropin | Hippocampal Memory (Paired Associative Learning Task) | 1 day after infusion | 25.6 score on a scale | Standard Deviation 4.1 |
| Normal Saline (Placebo) | Hippocampal Memory (Paired Associative Learning Task) | Baseline | 29.3 score on a scale | Standard Deviation 2.8 |
| Normal Saline (Placebo) | Hippocampal Memory (Paired Associative Learning Task) | 1 day after infusion | 25.9 score on a scale | Standard Deviation 4.1 |
Other Pre-specified
Pain (Quantitative Sensory Testing Using a Thermal Pain Testing Device)
Alterations in pain sensing will be evaluated pre and post with quantitative sensory testing using a thermal pain testing device, to evaluate the delayed effect of cosyntropin infusions.
Time frame: 1 day after ACTH