Stress and the Nervous System

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Stress, Physiological; Autonomic Nervous System; Baroreflex
• Intervention / Treatment: Drug: Cosyntropin; Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 23
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Brigham and Women's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Cosyntropin; Subjects will receive cosyntropin infusion at 70 mcg/hr for two sessions of 2.5 hours each on day 2 of a three day admission to our research center.	Drug: Cosyntropin; 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.; Other Names: ACTH
Placebo Comparator: Normal saline (Placebo); Subjects will receive normal saline infusion for two sessions of 2.5 hours each on day 2 of a three day admission to our research center.	Drug: Placebo; 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.; Other Names: Normal Saline

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Baseline, 4-hours after infusion, 24-hours after infusion

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	1 day after ACTH
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.	1 day after ACTH

Collaborators and Investigators

• Sponsor: Brigham and Women's Hospital
• Collaborators: Beth Israel Deaconess Medical Center
• Investigators: Principal Investigator: Gail Adler, MD, PhD, Brigham and Women's Hospital

Publications and helpful links

General Publications

• Zaheer S, Meyer K, Easly R, Bayomy O, Leung J, Koefoed AW, Heydarpour M, Freeman R, Adler GK. Effect of adrenocorticotropic hormone infusion on circulating sclerostin levels. Endocr Connect. 2021 Dec 14;10(12):1607-1614. doi: 10.1530/EC-21-0263.
• van der Boom T, Jia C, Lefrandt JD, Connelly MA, Links TP, Tietge UJF, Dullaart RPF. HDL Cholesterol Efflux Capacity is Impaired in Severe Short-Term Hypothyroidism Despite Increased HDL Cholesterol. J Clin Endocrinol Metab. 2020 Sep 1;105(9). pii: dgaa411. doi: 10.1210/clinem/dgaa411.
• Leung JH, Bayomy OF, Bonyhay I, Celli J, White J, Freeman R, Adler GK. ACTH Infusion Impairs Baroreflex Sensitivity-Implications for Cardiovascular Hypoglycemia-Associated Autonomic Failure. J Clin Endocrinol Metab. 2020 Jul 1;105(7):2345-53. doi: 10.1210/clinem/dgaa221.

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2015
• Primary Completion (Actual): October 1, 2016
• Study Completion (Anticipated): December 1, 2023

Study Registration Dates

• First Submitted: January 6, 2015
• First Submitted That Met QC Criteria: January 12, 2015
• First Posted (Estimate): January 15, 2015

Study Record Updates

• Last Update Posted (Actual): July 25, 2022
• Last Update Submitted That Met QC Criteria: July 18, 2022
• Last Verified: July 1, 2022

More Information

Terms related to this study

• Keywords: stress; ACTH; baroreflex sensitivity; cosyntropin; cardiovagal
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Cosyntropin
• Other Study ID Numbers: 2014P002423