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Effects of Cold Exposure and Breathing Techniques on Immune Response (EXPOCOL)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03240497
Recruitment Status : Completed
First Posted : August 7, 2017
Last Update Posted : April 1, 2019
Sponsor:
Collaborator:
Erasmus Medical Center
Information provided by (Responsible Party):
Radboud University

Brief Summary:

Inflammatory cytokines play a pivotal role in rheumatoid arthritis (RA) and innovative non-pharmacological therapies aimed at limiting cytokine production are highly warranted. Recently, our group showed that healthy volunteers trained in an intervention developed by 'Iceman' Wim Hof were able to voluntarily attenuate the pro-inflammatory response during experimental human endotoxemia (a model of systemic inflammation elicited by administration of lipopolysaccharide [LPS] in healthy volunteers). Subjects trained in the intervention exhibited profound increases in plasma adrenaline levels, a rapid increase of an anti-inflammatory cytokine and subsequent attenuation of the pro-inflammatory response.

The intervention consists of three elements, namely meditation, exposure to cold and breathing techniques. The meditation element is not likely to be involved. It was a very minor part of the training program and was not practiced during the endotoxemia experiments. Exposure to cold and the subsequent rewarming to normal body temperature may influence the inflammatory response through the release of immunomodulatory molecules like HSP-70. Also, exposure to cold can induce an ischemia-reperfusion-like state in the skin and peripheral tissue that is known to be involved in the downregulation of pro-inflammatory cytokines and upregulation of anti-inflammatory cytokines. The investigators anticipate that the third element, breathing techniques, is the major contributor to the anti-inflammatory effects of the intervention previously observed. The present study aims to explore the effects of the breathing technique ('strength ventilation'), the exposure to cold, and these two elements combined on the immune response during human endotoxemia. Elucidation of the relative contribution of the elements is of importance to establish a feasible, safe, and effective intervention for future use in patients.

Objective: The primary objective of the present study is to determine the effects of the 'strength ventilation' breathing technique and exposure to cold, both separately and in combination, on the inflammatory response during human endotoxemia. To this end, a 2 by 2 design will be employed. Additionally, an evaluation of the influence of the cold exposure and breathing technique on pain thresholds and oxygen tension in the mitochondria will take place.


Condition or disease Intervention/treatment Phase
Cold Exposure Hyperventilation Inflammation Endotoxemia Behavioral: Cold Exposure Behavioral: Strength Ventilation Not Applicable

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 48 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: A parallel randomized controlled explorative study in healthy male volunteers during experimental endotoxemia.
Masking: Single (Outcomes Assessor)
Masking Description: We employ a PROBE design (Prospective Randomized Open Blinded End-point) [41]. All subjects will receive a code number. Almost all of our end-points, especially the most important ones including the primary endpoint, are laboratory measurements, which will be performed blinded for the treatment of the subjects.
Primary Purpose: Basic Science
Official Title: The Influence of Breathing Techniques and Exposure to Cold on Inflammation During Human Endotoxemia, an Explorative Study'
Actual Study Start Date : April 12, 2016
Actual Primary Completion Date : April 2018
Actual Study Completion Date : April 2018

Arm Intervention/treatment
Experimental: Cold Exposure
A group of subjects (n=12) that will receive an extensive course in cold exposure similar in length to our previous study (total of 10 days) before the endotoxemia experiment.
Behavioral: Cold Exposure

The start of the training is scheduled 7 to 12 days before the endotoxemia experiment day. Subjects in this group will participate in a 4 day intensive cold exposure course (see section 5.1). On day 1, venous blood will be sampled directly after ice water immersion. On day 4, venous blood will be sampled before the training procedures on that day and after the last ice water immersion.

After the 4 day course, subjects will continue to practice cold exposure at home using cold showers. The timing and length of this training is analogous to the time spend on training in the cold in our previous study protocol [7].


Experimental: Strength Ventilation
A group of subjects (n=12) that will be trained in the strength ventilation breathing technique before the endotoxemia experiment.
Behavioral: Strength Ventilation
The training is scheduled 2 to 6 days before the endotoxemia experiment day. Subjects in this group will receive a detailed, written instruction about the strength ventilation technique (see section 5.1). In addition, they will receive a 2 hour instruction session during which the research team will supervise the practices and clarify the instructions of needed. Subjects are instructed not to practice the learned techniques at home.

Experimental: Cold Exposure and Strength Ventilation
A group of subjects (n=12) that will receive both the cold exposure course (same as the STV group) as well as the training in the strength ventilation breathing technique (same as the CEX group) before the endotoxemia experiment.
Behavioral: Cold Exposure

The start of the training is scheduled 7 to 12 days before the endotoxemia experiment day. Subjects in this group will participate in a 4 day intensive cold exposure course (see section 5.1). On day 1, venous blood will be sampled directly after ice water immersion. On day 4, venous blood will be sampled before the training procedures on that day and after the last ice water immersion.

After the 4 day course, subjects will continue to practice cold exposure at home using cold showers. The timing and length of this training is analogous to the time spend on training in the cold in our previous study protocol [7].


Behavioral: Strength Ventilation
The training is scheduled 2 to 6 days before the endotoxemia experiment day. Subjects in this group will receive a detailed, written instruction about the strength ventilation technique (see section 5.1). In addition, they will receive a 2 hour instruction session during which the research team will supervise the practices and clarify the instructions of needed. Subjects are instructed not to practice the learned techniques at home.

No Intervention: Control group
A group of subjects (n=12) that will receive no training and will not be exposed to cold before the endotoxemia experiment.



Primary Outcome Measures :
  1. circulating TNF-α [ Time Frame: 8 hours ]
    The main study endpoint is the difference in circulating TNF-α over time following LPS administration between groups


Secondary Outcome Measures :
  1. Cytokines [ Time Frame: 8 hours ]
    Levels of other circulating cytokines (including, but not limited to IL-6, IL-10 and IL-1RA)

  2. Plasma adrenaline levels [ Time Frame: 8 hours ]
    routine analysis methods also used for patient samples (high-performance liquid chromatography with fluorometric detection

  3. Plasma cortisol levels [ Time Frame: 8 hours ]
    routine analysis methods also used for patient samples performed by the Department of Laboratory Medicine of the Radboud University Nijmegen Medical Centre.

  4. - Blood gas parameters [ Time Frame: 8 hours ]
    Blood gas parameters will be analyzed using the i-STAT Blood Gas Analyzer (Abbot, Hoofddorp, The Netherlands).

  5. - Mitochondrial oxygen tension [ Time Frame: 8 hours ]
    The COMET device measures cutaneous mitochondrial oxygen tension (MitoPO2) over time. MitoPO2 is measured by means of delayed fluorescence of mitochondrial protoporphyrin IX (PpIX) [6]. Microcirculatory flow can be stopped by applying pressure with the measuring probe on the skin, enabling the determination of the oxygen disappearance rate (ODR)

  6. - Metabolome [ Time Frame: 8 hours ]

    The metabolome will determined using the 'Kenkodo @home' sampling set, developed by Metabolomic Discoveries GmbH (http://www.metabolomicdiscoveries.com/).

    Using a minimally invasive finger prick we will obtain 10µl (microliter) of blood from the subjects. The used Mitra Sampling Device is a Class 1 medical device (D254956) and complies with FDA good manufacturing practices. Samples will be analyzed at Metabolomic Discoveries GmbH.


  7. - Body temperature [ Time Frame: 8 hours ]
    The course of body temperature will be determined every 30 minutes for the first 8 hours after endotoxine administration using an infrared tympanic thermometer (Sherwood Medical, 's-Hertogenbosch, the Netherlands).

  8. - Illness score [ Time Frame: 8 hours ]
    To monitor the onset and alterations of endotoxine-induced symptoms, all subjects will be asked to score the severity of nausea, headache, shivering, muscle- and backpain every 30 minutes during the course of the experiment. Symptoms are scored on a scale ranging from 0 (symptom not present) to 5 (symptom is worst ever experienced).

  9. heart rate [ Time Frame: 8 hours ]
    Heart rate will be continuously measured by connecting the arterial catheter to an arterial pressure monitoring set. Data will be recorded from the patient monitor every 30 seconds by a custom in-house-developed data recording system.

  10. Blood pressure [ Time Frame: 8 hours ]
    Blood pressure will be continuously measured by connecting the arterial catheter to an arterial pressure monitoring set. Data will be recorded from the patient monitor every 30 seconds by a custom in-house-developed data recording system.

  11. - Leukocyte counts and differentiation [ Time Frame: 8 hours ]
    Measurements of haemoglobin, leukocyte and thrombocyte count, determinations of kidney and liver function, amylase, CRP, cortisol and catecholamines will be performed by the laboratory for clinical chemistry at the Radboud university medical center.

  12. Pain thresholds: PPT [ Time Frame: 8 hours ]
    PPT will be measured on the left and right bodyside once at three locations. Single pulse evoked pain measurement is performed by one pulse at 150% of the EPT and assessed on a VAS. .

  13. Pain thresholds: EPTT [ Time Frame: 8 hours ]
    Electrical Pain Tolerance Thresholds (EPTT) (test stimulation) are assessed and expressed in milli-Ampère on the m. Rectus femoris contralateral to the dominant hand

  14. - Presence of TLR ligands in plasma [ Time Frame: 8 hours ]
    HSP70 will be measured in using ELISA. Presence of other TLR ligands in plasma will be studied using transfected HEK-blue TLR cells (Invivogen).

  15. - HSP70 levels in plasma. [ Time Frame: 8 hours ]
    HSP70 will be measured in using ELISA. Presence of other TLR ligands in plasma will be studied using transfected HEK-blue TLR cells (Invivogen).

  16. - Production of inflammatory mediators by ex vivo-stimulated leukocytes [ Time Frame: 8 hours ]
    Ex vivo leukocyte stimulation by different pathogens will be performed at the Laboratory of General Internal Medicine of the Radboud university medical center. Cytokines in supernatants of stimulated leukocyte cultures will be determined by ELISA. Inflammatory transcriptional pathways will be determined by quantitative PCR/microarrays/RNA sequencing at the Laboratory of General Internal Medicine of the Radboud university medical center and/or the University of Groningen medical center.

  17. - Inflammatory transcriptional pathways sequencing [ Time Frame: 8 hours ]
    by use of qPCR/microarrays/RNA



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 35 Years   (Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Written informed consent
  • Male
  • Healthy

Exclusion Criteria:

  • Prior experience with any of the elements of the intervention developed by Hof
  • Prior experience with other breathing, meditation, or cold exposure techniques
  • Prior experience with mindfulness or yoga
  • Prior experience with exposure to cold showers
  • Frequent visits to sauna facilities (more than 1/month)
  • Use of any medication
  • Smoking
  • History of asthma
  • History of porphyria
  • Previous spontaneous vagal collapse
  • History of atrial or ventricular arrhythmia
  • (Family) history of myocardial infarction or stroke under the age of 65 years
  • Cardiac conduction abnormalities on the ECG consisting of a 2nd degree atrioventricular block or a complex bundle branch block
  • Hypertension (defined as RR systolic > 160 or RR diastolic > 90)
  • Hypotension (defined as RR systolic < 100 or RR diastolic < 50)
  • Renal impairment (defined as plasma creatinin >120 μmol/l)
  • Liver enzyme abnormalities
  • Medical history of any disease associated with immune deficiency
  • CRP > 20 mg/L, WBC > 12x109/L, or clinically significant acute illness, including infections, within
  • 4 weeks before endotoxin administration
  • Participation in a drug trial or donation of blood 3 months prior to the LPS challenge
  • Use of recreational drugs within 7 days prior to endotoxemia experiment day
  • Recent hospital admission or surgery with general anaesthesia (<3 months)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03240497


Locations
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Netherlands
Radboud University Medical Centre, Intensive Care
Nijmegen, Netherlands, 6525 GA
Sponsors and Collaborators
Radboud University
Erasmus Medical Center
Investigators
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Principal Investigator: Jelle Zwaag, MSc Radboud University
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Responsible Party: Radboud University
ClinicalTrials.gov Identifier: NCT03240497    
Other Study ID Numbers: EXPOCOL
First Posted: August 7, 2017    Key Record Dates
Last Update Posted: April 1, 2019
Last Verified: July 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Endotoxemia
Hyperventilation
Inflammation
Pathologic Processes
Respiration Disorders
Respiratory Tract Diseases
Bacteremia
Sepsis
Infection
Toxemia
Systemic Inflammatory Response Syndrome
Signs and Symptoms, Respiratory