The effects of concentration/meditation on the innate immune response during human endotoxemia

The innate immune response is the first line of defense against invading
pathogens. Ideally, this inflammatory response is tightly regulated leading to
both adequate protection to invading pathogens as well as limitation of an
exuberant or unwanted immune response such as seen in sepsis or auto-immune
diseases. Certain individuals master a concentration/meditation technique
involving a special breathing pattern which allows them to achieve remarkable
feats, such as withstanding extreme coldness. This technique might influence
the autonomic nervous system (ANS), since the ANS has a major influence on
thermoregulation. This could represent a novel, non-pharmacological mechanism,
to modulate the immune system since the ANS plays an important role in the
regulation of the innate immune response. Activation of the sympathetic
division of ANS dampens inflammation via β2-adrenoceptors. The parasympathetic
branch of the ANS modulates the inflammatory response as well, since it was
discovered that electrical stimulation of the efferent vagus nerve in rats
greatly inhibits the innate immune response. Modulation of ANS activity could
therefore provide novel therapeutic options in limiting the inflammatory
response. In the present study we wish to investigate the effect of
concentration/meditation on the innate immune response in vivo. In addition we
wish to elucidate the mechanism via which this effect is mediated (e.g. the
autonomic nervous system). We aim to use the so called human endotoxemia model.
This model permits elucidation of key players in the immune response to a gram
negative stimulus in vivo, therefore serving as a useful tool to investigate
potential novel therapeutic strategies in a standardized setting. Since the
concentration/meditation technique can be taught to other individuals, it could
represent new treatment modalities for inflammatory conditions.

Primary objective: The primary objective of the study is to determine the
effect of concentration/meditation on the innate immune response induced by a
lipopolysaccharide (LPS) challenge.
Secondary Objective(s): There are two secondary objectives:
1. To determine the effects of concentration/meditation on ANS activity.
Electroencephalography (EEG), heart-rate variability (HRV), muscle sympathetic
nerve activity and plasma concentrations of catecholamines will be measured for
this purpose.
2. To determine if concentration/meditation can attenuate (subclinical) renal
damage known to occur during human endotoxemia, markers of proximal and distal
tubular damage will be measured at various time points.

Case-control study in a healthy male volunteer during experimental endotoxemia
using historical controls.

The day of the experiment, prehydration will be performed by infusion of 1.5 L
2.5% glucose/0.45% saline solution in 1 hour before LPS administration. LPS
derived from E coli O:113 will be injected (2 ng/kg i.v., infusion rate; 1
minute).

A medical interview and physical examination are part of this study. On the day
of the experiment, the volunteer will be monitored on the research unit of our
intensive care and receive an arterial line to facilitate blood pressure
monitoring, drug infusion during venous occlusion plethysmography and blood
sampling. The arterial line will be placed under local anaesthesia using 2%
lidocaine. Furthermore a venous cannula will be placed for the administration
of saline and glucose. Muscle sympathetic nerve activity (MSNA) will be
performed throughout the study using microneurography. A sterile microelectrode
will be inserted manually through the skin in the underlying peroneal nerve
below the fibular head. A second reference electrode will be placed
subcutaneously.
The administration of LPS induces flu-like symptoms for approximately 4 hrs.
This model of systemic inflammation has been applied for many years in various
research centres in the world. Endotoxin administration is considered safe and
no long-term effects have been observed.
At the Radboud University Nijmegen Medical Centre, over 150 volunteers have
received over 250 injections of lipopolysaccharide. Therefore, there is
sufficient experience with this model at this centre.
In total, approximately 350 ml blood will be drawn during the experiment and
urine will be collected.