Increasing plasma adrenaline levels through breathing techniques - an explorative study

Auto-immune diseases are characterized by an inappropriate inflammatory
response against tissues in the body. These diseases, of which rheumatoid
arthritis (RA) is the most well-known, represent a major health care burden.
Pro-inflammatory cytokines such as TNF-α, IL-6 and IL-1β are central in the
pathophysiology of many auto-immune diseases [1, 2], and biologics that
antagonize inflammatory cytokines or their receptors, e.g. anti-TNF-α, soluble
TNF-α-receptor, anti-IL-6 receptor, and IL-1 receptor antagonist, are very
effective treatments [3, 4]. However, they are very expensive and can have
serious side effects [5, 6]. Therefore, innovative therapies aimed at limiting
inflammatory cytokine production in a more physiological manner are warranted.

The sympathetic nervous system, a part of the autonomic nervous system (ANS),
can limit the inflammatory response via activation of β2-adrenoceptors by
catecholamines such as (nor)epinephrine [7, 8]. In addition, as part of a
stress response increased levels of catecholamines are often accompanied by
elevations of the well-known immunodepressant cortisol (via activation of the
hypothalamic-pituitary-adrenal [HPA] axis)[9, 10]. Next to pharmacological
modulation of the sympathetic nervous system, for instance by administration of
catecholamines [7, 8], it can be envisioned that endogenous modulation of
sympathetic activity may also result in attenuation of the inflammatory
response. Which in turn could represent a treatment modality that would empower
RA patients to exert self-control over their disease activity. However, both
the ANS and the inflammatory response are generally regarded as systems that
cannot be voluntarily influenced. Nevertheless, results from two of our recent
endotoxemia studies into the effects of techniques developed by *iceman* Wim
Hof (cold exposure, meditation and breathing techniques) demonstrate that
through these techniques it is indeed possible to voluntarily activate the
sympathetic nervous system [11, 12]. This is reflected by profound increases in
plasma adrenaline levels, a rapid increase of the anti-inflammatory cytokine
IL-10, and subsequent attenuation of the pro-inflammatory response [11].

Ultimately, we want to translate these findings into novel treatment options
for autoimmune diseases such as RA. However, it would be of major benefit if
patients would only have to learn/practice one of the techniques instead of all
three. For instance, the cold exposure is very demanding, might exposure
patients to unnecessary risk, or may not be suitable for patients at all.
Furthermore, it remains to be determined whether the techniques can only be
taught by Hof and if an extensive training is necessary at all. Answering these
questions is pivotal because identification of the optimal technique(s) as well
as objectifying and standardizing Hof*s methods will aid future research in
this field and ultimately facilitate development of clinical protocols.

Strikingly, although having been taught all three techniques, in both studies
subjects predominantly practiced a hyper/hypoventilation technique during the
endotoxemia experiment, characterized by cycles of hyperventilation followed by
breath retention [11, 12]. This resulted in intermittent hypoxia and profound
shifts in acid/base balance. However, approximately 1 hour after LPS
administration the subjects also practiced another breathing technique
consisting of deep inhalations and exhalations in which every in- and
exhalation was followed by breath holding for 10 seconds during which all
muscles were tightened (*strength ventilation*).

Based on these observations, we hypothesize that these breathing techniques are
responsible for the increase in plasma adrenaline levels and the subsequent
dampened immune response, because during the endotoxemia experiments the
subjects solely practiced these techniques, and were not exposed to cold or
practiced meditation [11, 12]. More specifically, we suspect that the
hyper/hypoventilation technique accounts for the observed effects. This is
supported by studies that have shown that both hyperventilation [13, 14] as
well as hypoxia [15, 16] (which occurred in our subjects during the
hypoventilation phase [11]) result in increased plasma adrenaline levels.
However, effects of the strength ventilation on adrenaline induction cannot be
ruled out.

Therefore, the primary objective of the present study is to investigate whether
the hyper/hypoventilation or the strength ventilation technique accounts for
the observed increase in plasma adrenaline levels. Furthermore, we want to
determine whether it is mandatory that subjects are trained by Hof and whether
extensive training is necessary at all.

A parallel randomized study in 36 healthy male volunteers

Subjects will be randomized to either
1. The `hoftraining` group (HTR): a group of subjects (n=12) that will be
trained extensively by Hof and his team in both hyper/hypoventilation and
strength ventilation breathing techniques.
2. The `extensive instruction` group (EIN): a group of subjects (n=12) that
will receive an extensive instruction course supervised by the research team in
both hyper/hypoventilation and strength ventilation breathing techniques.
3. The `short instruction` group (SIN): a group of subjects (n=12) that is
trained for 1 hour on the day before the experiment by the research team in
both hyper/hypoventilation and strength ventilation breathing techniques.

The burden of auto-immune diseases is enormous, both from a clinical and
economical perspective. The most well-known auto-immune disease, rheumatoid
arthritis, is characterized by pain and swelling, joint damage and progressive
disability, which greatly affects quality of life. In the Netherlands in 2007,
approximately 165000 patients suffered from rheumatoid arthritis, of which the
healthcare costs were more than 200 million Euros (source: Nationaal kompas
volksgezondheid). The estimated revenue loss due to working incapactity and
sick leave for rheumatoid arthritis are estimated at several billion Euros. Due
to population growth and increasing age of the population, the prevalence of
rheumatoid arthritis is estimated to increase considerably over the next
decades (source: Nationaal kompas volksgezondheid). Novel therapies for
autoimmune diseases like rheumatoid arthritis are therefore highly warranted.
The therapy investigated in this study could represent a novel, non-invasive,
cheap method to reduce disease progression. Furthermore, it is a therapy that,
if effective, greatly increases self-management of autoimmune diseases. An
increase in patient empowerment is highly warranted, especially in chronic
autoimmune diseases.

Results from two of our 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).
Also, the reported subjective symptom score was lower which further supports
the beneficiary effects of the learned techniques.

The burden of the study procedures consists of the time investment related to
the training procedures and a maximum of three visits to the hospital. All
subjects will visit the hospital for a screening visit in which a medical
interview, physical examination, and blood withdrawal by vena puncture will be
carried out (30 minutes). For the baseline measurements before start of the
training program/instruction (QST, catecholamine*s/cortisol, cytokines, heart
rate variability), subjects will visit the hospital for 50 minutes. During the
experiment day, subjects will be hospitalized for approximately 7 hours. An
arterial line will be placed under local anaesthesia using 2% lidocaine.
Furthermore, a venous cannula will be placed.

We feel that the risk to, and burden for the subjects are in proportion to the
potential value of the research.