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

NCT01592526 | Completed Early Phase 1 DMC

• 1 other identifier: H-3-2012-011
• Study Type: interventional
• Target: 23
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Systemic Inflammatory Response Syndrome

Keywords

Systemic inflammatory response.; Autonomic nervous regulation.; Cholinergic antiinflammatory pathway

Outcome Measures

Primary Outcomes (1)

• Cytokines

  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.

  up to 8 hours

Secondary Outcomes (1)

• Heart Rate Variability (HRV)

  up to 8 hours

Other Outcomes (2)

• Pain Pressure Threshold (PPT)

  Baseline, 2 hours, 6 hours

• Heat Pain Perception

  Baseline, 2 hours, 6 hours

Study Arms (4)

Untrained, healthy volunteers A

EXPERIMENTAL

(Endotoxin) before (Endotoxin + Nicotine)

Other: Endotoxin; Other: Endotoxin + Nicotine

Well-trained healthy volunteers A

EXPERIMENTAL

(Endotoxin) before (Endotoxin + Nicotine)

Other: Endotoxin; Other: Endotoxin + Nicotine

Untrained, healthy volunteers B

EXPERIMENTAL

(Endotoxin + Nicotine) before (Endotoxin)

Other: Endotoxin; Other: Endotoxin + Nicotine

Well-trained healthy volunteers B

EXPERIMENTAL

(Endotoxin + Nicotine) before (Endotoxin)

Other: Endotoxin; Other: Endotoxin + Nicotine

Interventions

Endotoxin OTHER

Bolus injection of LPS 2 ng/kg IV at time = 2 hours (Study day A).

Also known as: Clinical Center Reference Endotoxin

Untrained, healthy volunteers A; Untrained, healthy volunteers B; Well-trained healthy volunteers A; Well-trained healthy volunteers B

Endotoxin + Nicotine OTHER

Transdermal application of nicotine patch applied at time = -8 hours (midnight the day before Study day B) + bolus injection of LPS 2 ng/kg at time = 2 hours (Study day 2)

Also known as: Clinical Center Reference Endotoxin, Nicotine Patch (Nicorette 15mg/16t)

Untrained, healthy volunteers A; Untrained, healthy volunteers B; Well-trained healthy volunteers A; Well-trained healthy volunteers B

Eligibility Criteria

• Age: 18 Years - 35 Years
• Sex: male
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Male
• Age 18-35 years
• BMI \< 30 kg/m2
• Healthy
• Well-trained (N = 12): VO2max \> 60 ml/kg/min
• Untrained (N = 12): VO2max \< 47 ml/kg/min

You may not qualify if:

• Daily medicine intake (excl. antihistamines during pollen season)
• Smoking or use of nicotine substitutes
• Previous allergic reaction to nicotine pads
• Previous splenectomy

Sponsors & Collaborators

• Rigshospitalet, Denmark: lead
• Bispebjerg Hospital: collaborator

Study Sites (1)

Center for Inflammation and Metabolism, Rigshospitalet

Copenhagen, Copenhagen OE, 2100, Denmark

Location

MeSH Terms

Conditions

Systemic Inflammatory Response Syndrome

Interventions

Endotoxins; Nicotine; Tobacco Use Cessation Devices; Nicotine Chewing Gum

Condition Hierarchy (Ancestors)

Inflammation; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Shock

Intervention Hierarchy (Ancestors)

Bacterial Toxins; Toxins, Biological; Biological Factors; Solanaceous Alkaloids; Alkaloids; Heterocyclic Compounds; Pyridines; Heterocyclic Compounds, 1-Ring; Therapeutics; Chewing Gum; Plant Gums; Biopolymers; Polymers; Macromolecular Substances; Polysaccharides; Carbohydrates; Candy; Food; Diet, Food, and Nutrition; Physiological Phenomena; Food and Beverages

Study Officials

• Susanne Janum, MD

  Bispebjerg Hospital/Rigshospitalet

  PRINCIPAL INVESTIGATOR

• Kirsten Møller, MD,PhD,DMSc

  Rigshospitalet, Denmark

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Local administrator

Study Record Dates

• First Submitted: May 2, 2012
• First Posted: May 7, 2012
• Study Start: June 1, 2012
• Primary Completion: January 1, 2013
• Study Completion: December 1, 2015
• Last Updated: January 29, 2016

Record last verified: 2016-01

Locations

DK (1)