Autonomic Nervous Activity During the Systemic Inflammatory Response in Trained and Untrained Healthy Volunteers

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
Bispebjerg Hospital
Information provided by (Responsible Party):
Inge Holm, Rigshospitalet, Denmark
ClinicalTrials.gov Identifier:
NCT01592526
First received: May 2, 2012
Last updated: January 17, 2013
Last verified: January 2013
  Purpose

Critical illness, severe infection, extensive trauma or tissue damage cause an inflammatory (irritative) reaction in the body. This reaction affects the whole body and causes malaise, circulatory and cardiac changes, fever, increases the number of white blood cells in the blood stream and prompts release of signaling proteins. This reaction contributes to the development of considerable organ damage and possibly organ failure. These are serious complications in critical illness which are associated with a high mortality. This inflammatory reaction is affected by the autonomic nervous system. This is the part of the nervous system, which is beyond the control of the free will, and the part that regulates circulation, breathing and digestive functions. The autonomic nervous system works via so-called sympathetic signals, which set the body in a state of alertness to overcome immediate challenges, and parasympathetic (vagal) signals, which are especially active during restitution and rest. It is known, that the balanced activity in the autonomic nervous system affects the body's inflammatory response in critical illness. A study in mice has shown that if parasympathetic (vagal) signals are blocked mortality in critical illness is increased. Reversely, when the autonomic nervous system is medically stimulated towards parasympathetic signaling, the magnitude of the inflammatory response is decreased. Nicotine exerts this stimulatory effect.

Also, we know that individuals in good physical shape have increased parasympathetic tone compared to less trained individuals. However, studies have never addressed whether this shifted balance in the autonomic nervous system affects the inflammatory response related to critical illness.

Over the last 30 years an experimental model mimicking the inflammatory response has been used in studies. Inflammation may be simulated by injecting the drug E.Coli LPS, which induces a controlled, fully reversible, harmless reaction the duration of which is a few hours. Influenza-like symptoms occur and changes in circulatory parameters and concentrations of signaling proteins can be measured.

Using this experimental model, the investigators wish to study whether this shifted balance in the autonomic nervous system in individuals in good physical shape affects the body's reaction to critical illness. Investigators also want to determine how nicotine (using a nicotine patch) affects this reaction.


Condition Intervention Phase
Systemic Inflammatory Response Syndrome
Other: Endotoxin
Other: Endotoxin + Nicotine
Phase 0

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Crossover Assignment
Masking: Open Label
Primary Purpose: Basic Science
Official Title: Autonomic Nervous Activity During the Systemic Inflammatory Response in Trained and Untrained Healthy Volunteers

Resource links provided by NLM:


Further study details as provided by Rigshospitalet, Denmark:

Primary Outcome Measures:
  • Cytokines [ Time Frame: up to 8 hours ] [ Designated as safety issue: No ]

    Cytokines are released into the bloodstream as part of the systemic inflammatory response and allow quantification of the severity of the systemic inflammatory response.

    Cytokines are measured multiple times to record changes from baseline during the intervention.



Secondary Outcome Measures:
  • Heart Rate Variability (HRV) [ Time Frame: up to 8 hours ] [ Designated as safety issue: No ]

    HRV is the variation in the interval between heart beats over a given time period. A higher variability is considered an indirectly marker of increasing vagal acitivity. Low variability contrarily indicates decreasing vagal activity and increased sympathetic activity.

    HRV is calculated from continous, non-invasive monitoring of heart rhytm. Recordings are made at multiple fixed times to track changes from baseline during intervention.



Estimated Enrollment: 24
Study Start Date: June 2012
Estimated Study Completion Date: December 2013
Estimated Primary Completion Date: January 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Untrained, healthy volunteers
Untrained, healthy volunteers (VO2max < 45 ml/kg/min)
Other: Endotoxin
Bolus injection of LPS 2 ng/kg IV at time = 2 hours (Study day 1).
Other Name: Clinical Center Reference Endotoxin
Other: Endotoxin + Nicotine
Transdermal application of nicotine patch applied at time = -8 hours (midnight the day before Study day 2) + bolus injection of LPS 2 ng/kg at time = 2 hours (Study day 2)
Other Names:
  • Clinical Center Reference Endotoxin
  • Nicotine Patch (Nicorette 15mg/16t)
Experimental: Well-trained healthy volunteers
Well-trained health volunteers (VO2max > 60 ml/kg/min).
Other: Endotoxin
Bolus injection of LPS 2 ng/kg IV at time = 2 hours (Study day 1).
Other Name: Clinical Center Reference Endotoxin
Other: Endotoxin + Nicotine
Transdermal application of nicotine patch applied at time = -8 hours (midnight the day before Study day 2) + bolus injection of LPS 2 ng/kg at time = 2 hours (Study day 2)
Other Names:
  • Clinical Center Reference Endotoxin
  • Nicotine Patch (Nicorette 15mg/16t)

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years to 35 Years
Genders Eligible for Study:   Male
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Male
  • Age 18-35 years
  • BMI < 30 kg/m2
  • Healthy
  • Well-trained (N = 12): VO2max > 60 ml/kg/min
  • Untrained (N = 12): VO2max < 45 ml/kg/min

Exclusion Criteria:

  • Daily medicine intake (excl. antihistamines during pollen season)
  • Smoking or use of nicotine substitutes
  • Previous allergic reaction to nicotine pads
  • Previous splenectomy
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01592526

Locations
Denmark
Center for Inflammation and Metabolism, Rigshospitalet
Copenhagen, Copenhagen OE, Denmark, 2100
Sponsors and Collaborators
Rigshospitalet, Denmark
Bispebjerg Hospital
Investigators
Principal Investigator: Susanne Janum, MD Bispebjerg Hospital/Rigshospitalet
Study Director: Kirsten Møller, MD,PhD,DMSc Rigshospitalet, Denmark
  More Information

No publications provided

Responsible Party: Inge Holm, Local administrator, Rigshospitalet, Denmark
ClinicalTrials.gov Identifier: NCT01592526     History of Changes
Other Study ID Numbers: H-3-2012-011
Study First Received: May 2, 2012
Last Updated: January 17, 2013
Health Authority: Denmark: Danish Dataprotection Agency
Denmark: The Regional Committee on Biomedical Research Ethics

Keywords provided by Rigshospitalet, Denmark:
Systemic inflammatory response.
Autonomic nervous regulation.
Cholinergic antiinflammatory pathway

Additional relevant MeSH terms:
Systemic Inflammatory Response Syndrome
Inflammation
Pathologic Processes
Shock
Nicotine
Ganglionic Stimulants
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Pharmacologic Actions
Nicotinic Agonists
Cholinergic Agonists
Cholinergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on September 29, 2014