Effects of Cold Exposure and Breathing Techniques on Immune Response

NCT03240497 | Completed

• 1 other identifier: EXPOCOL
• Study Type: interventional
• Target: 48
• Locations: 1 country
• Sites: 1

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.

Conditions

Cold Exposure; Hyperventilation; Inflammation; Endotoxemia

Outcome Measures

Primary Outcomes (1)

• circulating TNF-α

  The main study endpoint is the difference in circulating TNF-α over time following LPS administration between groups

  8 hours

Secondary Outcomes (17)

• Cytokines

  8 hours

• Plasma adrenaline levels

  8 hours

• Plasma cortisol levels

  8 hours

• - Blood gas parameters

  8 hours

• - Mitochondrial oxygen tension

  8 hours

Study Arms (4)

Cold Exposure

EXPERIMENTAL

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

Strength Ventilation

EXPERIMENTAL

A group of subjects (n=12) that will be trained in the strength ventilation breathing technique before the endotoxemia experiment.

Behavioral: Strength Ventilation

Cold Exposure and Strength Ventilation

EXPERIMENTAL

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; Behavioral: Strength Ventilation

Control group

NO INTERVENTION

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

Interventions

Cold Exposure BEHAVIORAL

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 \[7\].

Cold Exposure; Cold Exposure and Strength Ventilation

Strength Ventilation BEHAVIORAL

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.

Cold Exposure and Strength Ventilation; Strength Ventilation

Eligibility Criteria

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

You may qualify if:

• Written informed consent
• Male
• Healthy

You may not qualify if:

• 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)

Sponsors & Collaborators

• Radboud University Medical Center: lead
• Erasmus Medical Center: collaborator

Study Sites (1)

Radboud University Medical Centre, Intensive Care

Nijmegen, 6525 GA, Netherlands

Location

Related Publications (2)

• Wefers Bettink MA, Zwaag J, Schockaert B, Pickkers P, Kox M, Mik EG. Measuring mitochondrial oxygenation and respiration during systemic inflammation in humans in vivo. Sci Rep. 2025 Jul 16;15(1):25815. doi: 10.1038/s41598-025-10715-6.

  PMID: 40670486 DERIVED

• Zwaag J, Naaktgeboren R, van Herwaarden AE, Pickkers P, Kox M. The Effects of Cold Exposure Training and a Breathing Exercise on the Inflammatory Response in Humans: A Pilot Study. Psychosom Med. 2022 May 1;84(4):457-467. doi: 10.1097/PSY.0000000000001065. Epub 2022 Feb 23.

  PMID: 35213875 DERIVED

MeSH Terms

Conditions

Hyperventilation; Inflammation; Endotoxemia

Condition Hierarchy (Ancestors)

Respiration Disorders; Respiratory Tract Diseases; Signs and Symptoms, Respiratory; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Pathologic Processes; Bacteremia; Sepsis; Infections; Toxemia; Systemic Inflammatory Response Syndrome

Study Officials

• Jelle Zwaag, MSc

  Radboud University Medical Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Masking Details: 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.
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: A parallel randomized controlled explorative study in healthy male volunteers during experimental endotoxemia.

Study Record Dates

• First Submitted: July 19, 2017
• First Posted: August 7, 2017
• Study Start: April 12, 2016
• Primary Completion: April 1, 2018
• Study Completion: April 1, 2018
• Last Updated: April 1, 2019

Record last verified: 2017-07

Locations

NL (1)