Increasing Plasma Adrenaline Levels Through Breathing Techniques - an Explorative Study (INADRI)

November 9, 2015 updated by: Radboud University Medical Center
Inflammatory cytokines play a pivotal role in rheumatoid arthritis (RA) and innovative non-pharmacological therapies aimed at limiting cytokine production are highly warranted. Adrenaline, a neurotransmitter of the autonomic sympathetic nervous system, attenuates cytokine production. Along these lines, endogenous modulation of sympathetic activity could limit inflammation and therefore represent a treatment modality that would empower RA patients to exert self-control over disease activity. However, both the autonomic nervous system and the inflammatory response are regarded as systems that cannot be voluntarily influenced. Nevertheless, results from two recent studies demonstrate that this is possible through techniques developed by 'iceman' Wim Hof, namely meditation, exposure to cold, and breathing exercises. Hof himself and healthy volunteers trained by him were able to voluntarily activate the sympathetic nervous system, resulting in adrenaline release and subsequent suppression of the inflammatory response during experimental human endotoxemia (a model of systemic inflammation elicited by administration of lipopolysaccharide [LPS] in healthy volunteers). Interestingly, while having been taught all three techniques, during the endotoxemia experiment the trained subjects (like Hof himself) predominantly practiced the breathing exercises consisting of two different techniques. A 'hyper/hypoventilation' technique, characterized by cycles of hyperventilation followed by breath retention and a 'strength ventilation' technique consisting of deep inhalations and exhalations followed by breath holding. These techniques resulted in intermittent hypoxia and cyclic shifts in acid-base balance. Based on these observations and previous studies, the investigators hypothesize that these breathing techniques account for the increased production of adrenaline and thus for the suppressed inflammatory response but it is unclear which of these two techniques is most important.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

The main objective of the study is to compare the increase in plasma adrenaline levels during the two different breathing techniques in a group of healthy volunteers trained by Hof. Also, the investigators investigate whether it is necessary to be trained by Hof and if a relatively short instruction instead of the extensive training is sufficient. Additionally, the investigators want to evaluate the influence of the training and breathing techniques on pain thresholds.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
40

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Netherlands
    • Gelderland
      • Nijmegen, Gelderland, Netherlands, 6500 HB
        • Intensive Care Medicine, Radboud University Nijmegen Medical Centre

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

18 years to 35 years (Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

Male

Description

Inclusion Criteria:

  • Age ≥18 and ≤35 yrs
  • Male
  • Healthy

Exclusion Criteria:

  • Experience with the methods of Wim Hof or other breathing techniques
  • Use of any medication
  • Smoking
  • Use of recreational drugs within 21 days prior to the experiment day
  • Use of caffeine or alcohol within 1 day prior to the experimental day.
  • Surgery or trauma with significant blood loss or blood donation within 3 months prior to the experimental day.
  • Participation in another clinical trial within 3 months prior to the experimental day.
  • History, signs, or symptoms of cardiovascular disease
  • History of atrial or ventricular arrhythmia
  • Hypertension (RR systolic >160 or RR diastolic >90)
  • Hypotension (RR systolic <100 or RR diastolic <50)
  • Conduction abnormalities on the ECG consisting of a 1st degree atrioventricular block or a complex bundle branch block
  • History of asthma, or any other pulmonary disease
  • C reactive protein (CRP) > 20 mg/L, White blood count (WBC) > 12x109/L, or clinically significant acute illness, including infections, within 4 weeks before the experimental day.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Basic Science
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Experimental: HTR
The 'Hoftraining' group (HTR): a group of subjects (n=10) that will be trained extensively by mr. Hof and his team in both hyper/hypoventilation and strength ventilation breathing techniques. Total time training is 8 days.
Behavioral: Hyper/hypoventilation
Subjects are asked to hyperventilate for an average of 30 breaths. Subsequently, the subjects exhaled and hold their breath for approximately 2 minutes ("retention phase"). The duration of breath retention will be entirely at the discretion of the subject himself. Breath retention is followed by a deep inhalation breath, that will be held for 10 s. Subsequently a new cycle of hyper/hypoventilation begins.
Behavioral: Strength ventilation
This exercise consists of deep inhalations and exhalations in which every inhalation and exhalation is followed by breath holding for 10 s, during which the subject tightens all his body muscles.
Active Comparator: EIN
The 'extensive instruction' group (EIN): a group of subjects (n=10) that will receive an extensive instruction course supervised by the research team (in absence of Mr. Hof) in both hyper/hypoventilation and strength ventilation breathing techniques.
Behavioral: Hyper/hypoventilation
Subjects are asked to hyperventilate for an average of 30 breaths. Subsequently, the subjects exhaled and hold their breath for approximately 2 minutes ("retention phase"). The duration of breath retention will be entirely at the discretion of the subject himself. Breath retention is followed by a deep inhalation breath, that will be held for 10 s. Subsequently a new cycle of hyper/hypoventilation begins.
Behavioral: Strength ventilation
This exercise consists of deep inhalations and exhalations in which every inhalation and exhalation is followed by breath holding for 10 s, during which the subject tightens all his body muscles.
Active Comparator: STR
The 'short training' group (STR): a group of subjects (n=10) that will receive only a short training of 1 hour (immediately prior to the study) by Mr. Hof and his team in both hyper/hypoventilation and strength ventilation breathing techniques.
Behavioral: Hyper/hypoventilation
Subjects are asked to hyperventilate for an average of 30 breaths. Subsequently, the subjects exhaled and hold their breath for approximately 2 minutes ("retention phase"). The duration of breath retention will be entirely at the discretion of the subject himself. Breath retention is followed by a deep inhalation breath, that will be held for 10 s. Subsequently a new cycle of hyper/hypoventilation begins.
Behavioral: Strength ventilation
This exercise consists of deep inhalations and exhalations in which every inhalation and exhalation is followed by breath holding for 10 s, during which the subject tightens all his body muscles.
Active Comparator: SIN
The 'short instruction' group (SIN): a group of subjects (n=10) that will receive no training, but only an short instruction course of 1 hour (immediately prior to the study) supervised by the research team (in absence of Mr. Hof) in both hyper/hypoventilation and strength ventilation breathing techniques.
Behavioral: Hyper/hypoventilation
Subjects are asked to hyperventilate for an average of 30 breaths. Subsequently, the subjects exhaled and hold their breath for approximately 2 minutes ("retention phase"). The duration of breath retention will be entirely at the discretion of the subject himself. Breath retention is followed by a deep inhalation breath, that will be held for 10 s. Subsequently a new cycle of hyper/hypoventilation begins.
Behavioral: Strength ventilation
This exercise consists of deep inhalations and exhalations in which every inhalation and exhalation is followed by breath holding for 10 s, during which the subject tightens all his body muscles.

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Concentration of plasma adrenaline within arm 1
Time Frame: 1 day
Our primary endpoint is the difference between plasma adrenaline levels during the hyper/hypoventilation technique and the strength ventilation technique within the HTR group.
1 day

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Concentration of plasma adrenaline within arms 2, 3, 4
Time Frame: 1 day
Blood will be collected into chilled lithium-heparin tubes and will immediately be placed on ice and centrifuged at 2.000 x g for 10 min at 4 degrees celsius after which plasma will be stored at -80 degrees celsius until analysis. Plasma adrenaline is measured using High Performance Liquid Chromatography (HPLC) with fluorometric detection. The investigators will compare levels during the hyper/hypoventilation technique and plasma adrenaline levels during the strength ventilation technique within the EIN, STR and SIN groups.
1 day
concentration of plasma adrenaline between arms 1, 2, 3, 4
Time Frame: 1 day
Blood will be collected into chilled lithium-heparin tubes and will immediately be placed on ice and centrifuged at 2.000 x g for 10 min at 4 degrees celsius after which plasma will be stored at -80 degrees celsius until analysis. Plasma adrenaline is measured using HPLCy with fluorometric detection. The investigators will compare differences in plasma adrenaline levels during hyper/hypoventilation or strength ventilation between HTR, EIN, STR and SIN groups.
1 day
Plasma interleukine 10 concentration
Time Frame: 1 day
EDTA (ethylenediaminetetraacetic acid) anticoagulated blood will centrifuged immediately at 2.000 x g for 10 min at 4 degrees calcium after which plasma will be stored at -80 degrees until analysis. Concentration of [cytokine] will be measured using a simultaneous Luminex assay according to the manufacturer's instructions (Milliplex; Millipore). The investigators will compare differences between hyper/hypoventilation and strength ventilation within HTR, EIN, STR and SIN groups as well as differences during hyper/hypoventilation or strength ventilation between HTR, EIN, and SIN groups.
1 day
Body temperature
Time Frame: 1 day
Body temperature will be measured using an infrared tympanic thermometer (FirstTemp Genius 2; Sherwood Medical). The investigators will compare differences between hyper/hypoventilation and strength ventilation within HTR, EIN, STR and SIN groups as well as differences during hyper/hypoventilation or strength ventilation between HTR, EIN, and SIN groups.
1 day
Heart rate, blood pressure
Time Frame: 1 day
Heart rate will be recorded with a three-lead electrocardiogram on a Philips MP50 patient monitor. The investigators will compare differences between hyper/hypoventilation and strength ventilation within HTR, EIN, STR and SIN groups as well as differences during hyper/hypoventilation or strength ventilation between HTR, EIN, and SIN groups.
1 day
Blood pressure
Time Frame: 1 day
Blood pressure will be measured on a Philips MP50 patient monitor through a 20-gauge arterial catheter. The investigators will compare differences between hyper/hypoventilation and strength ventilation within HTR, EIN, STR and SIN groups as well as differences during hyper/hypoventilation or strength ventilation between HTR, EIN, and SIN groups.
1 day
Leukocyte counts and differentiation
Time Frame: 1 day
Analysis of leukocyte counts and differentiation will be performed in EDTA anticoagulated blood using routine analysis methods also used for patient samples (flow cytometric analysis on a Sysmex XE-5000). The investigators will compare differences between hyper/hypoventilation and strength ventilation within HTR, EIN, STR and SIN groups as well as differences during hyper/hypoventilation or strength ventilation between HTR, EIN, and SIN groups.
1 day
Cortisol (plasma)
Time Frame: 1 day
Blood will be collected in serum-separating tubes and allowed to clot at room temperature for a minimum of 30 min. Subsequently, samples are centrifuged at 2,000 × g for 10 min at 4 °C, after which serum is stored at -80 °C until analysis. Cortisol levels will be determined using a routine analysis method also used for patient samples (electrochemiluminescent immunoassay on a Modular Analytics E170 (Roche Diagnostics). The investigators will compare differences between hyper/hypoventilation and strength ventilation within HTR, EIN, STR and SIN groups as well as differences during hyper/hypoventilation or strength ventilation between HTR, EIN, and SIN groups.
1 day
Noradrenaline
Time Frame: 1 day
Blood will be collected into chilled lithium-heparin tubes and will immediately be placed on ice and centrifuged at 2.000 x g for 10 min at 4 degrees celsius after which plasma will be stored at -80 degrees celsius until analysis. Plasma noradrenaline is measured using HPLCy with fluorometric detection. The investigators will compare differences between hyper/hypoventilation and strength ventilation within HTR, EIN, STR and SIN groups as well as differences during hyper/hypoventilation or strength ventilation between HTR, EIN, and SIN groups.
1 day
Blood gas parameters
Time Frame: 1 day
Blood gas parameters are analyzed in lithium heparin anticoagulated arterial blood using CG4+ cartridges and a point-of-care i-STAT blood gas analyzer (Abbott). The investigators will compare differences between hyper/hypoventilation and strength ventilation within HTR, EIN, STR and SIN groups as well as differences during hyper/hypoventilation or strength ventilation between HTR, EIN, and SIN groups.
1 day
Pain threshold
Time Frame: 1 day
Pain thresholds before start training/instruction, during each of the breathing techniques, and at the end of the experimental day, objectified with Quantitive Sensory Testing by a dedicated, trained member of the studyteam.
1 day

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Radboud University Medical Center

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

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Study Major Dates

Study Start

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
November 1, 2014

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
July 1, 2015

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
October 1, 2015

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
December 2, 2014

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
April 10, 2015

First Posted (Estimate)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
April 15, 2015

Study Record Updates

Last Update Posted (Estimate)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
November 10, 2015

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
November 9, 2015

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
November 1, 2015

More Information

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Keywords

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Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • INADRI

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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