Oxygen is a widely available gas that is cheap, easy to get and extensively used in medicine. From animal studies it has become apparent that increasing or lowering the degree of oxygen in the blood, the inflammatory response can be altered. We will investigate of this is also true in humans by increasing, lowering or keeping oxygen levels normal while giving healthy subjects a short inflammatory stimulus.
The primary objective of the study is to determine the effects of hyperoxia and hypoxia compared to normoxia in the human endotoxemia model on the innate immune reponse in healthy volunteers. A parallel, randomized study in healthy male volunteers. The subjects will be randomized to hypoxia, hyperoxia, or normoxia, and will all undergo experimental human endotoxemia (administration of 2 ng/kg LPS iv). In the hypoxia group: the subjects will breathe an individualized mix of nitrogen and room air for 3.5 hours using an air-tight respiratory helmet. The gas mixture will be adjusted to achieve a saturation of 80-85%. In the hyperoxia group, subjects will breathe 100% oxygen for 3.5 hours using the same respiratory helmet. In the normoxia group, subjects will breathe room air (21% oxygen, 79% nitrogen) also wearing the respiratory helmet. 1 hour after oxygen status adjustment (t=0), all subject will be administered an intravenous bolus (2ng/kg) of LPS derived from E coli O:113. 2.5 hours after LPS administration, the helmets will be removed and all subjects will breathe ambient room air. The primary study endpoint is the difference in plasma cytokines between the hypoxia and normoxia group, and between the hyperoxia and normoxia group. Secondary objectives include HIF-1α protein and mRNA, aHIF mRNA expression in circulating leukocytes, measures of ROS, leukocyte phagocytosis, and cytokine production by leukocytes stimulated ex vivo with various inflammatory stimuli, and measurement of basic hemodynamic and ventilatory parameters and temperature.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
LPS is used to elicit an inflammatory response in all subjects
Intensive Care Medicine
Nijmegen, Gelderland, Netherlands
Plasma TNF-alpha concentration following LPS administration
Plasma TNF-α concentration after LPS administration (Area Under Curve); comparison of subjects treated with hypoxia compared to normoxia and hyperoxia compared to hypoxia
Time frame: 1 day
Hypoxia Inducible Factor 1 alpha in circulating leukocytes
Hypoxia Inducible Factor 1 alpha in circulating neutrophils, lymfocytes and monocytes as measured with flow cytometry
Time frame: 1 day
Hypoxia Inducible Factor mRNA and anti Hypoxia Inducible Factor mRNA in circulating leukocytes
Time frame: 24 hours
Reactive Oxygen Species in circulating leukocytes
Time frame: 1 day
Phagocytic function of circulating leukocytes
Time frame: 1 day
cytokine production after ex vivo stimulation of leukocytes
Time frame: 1 day
circulating cytokines (including but not limited to IL-6, IL-10, IL-1RA)
Time frame: 1 day
Hemodynamic parameters
Blood pressure, heart frequency, cardiac output measurement
Time frame: 1 day
ventilatory response
Measures of ventilation: respiratory rate, blood gas changes
Time frame: 1 day
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Enrollment
30
adenosine metabolism
urine and plasma adenosine,adenosine receptor mRNA, purines
Time frame: 1 day
alkaline phosphatase
Time frame: 1 day
cognitive function
neuropsychologic assessment of cognitive function
Time frame: 1 day
Hepcidin and iron parameters
Time frame: 1 day
catecholamines and cortisol
adrenaline, noradrenaline, dopamine and cortisol
Time frame: 1 day
Neutrophilic function
Time frame: 1 day
body temperature
Time frame: 1 day
oxygen saturation and arterial blood gas
Time frame: 1
subjective symptom scores
Time frame: 1 day
high sensitive troponine
Time frame: 1 day
iFABP
Time frame: 1 day
brain specific proteins
Time frame: 1 day
endocan
Time frame: 1 day
downstream targets of HIF
adrenomedullin, VEGF, EPO
Time frame: 1 day
heart rate variability
Time frame: 1 day
kidney injury markers in plasma and urine
Time frame: 2 days
microbiome in feces
Time frame: -1 day untill 1 week
markers of immunoparalysis
monocytic histone 3 lysine 4 trimethylation of the promotor region of pro-inflammatory genes, ex viv production of proinflammatory cytokines, HLA-DR expression on moncytes.
Time frame: 1 day
measures of coagulation and plateletfunction
platelet activation and platelet function, thrombin generation and other coagulation parameters, hematolocial infection profile using hematology analyser
Time frame: 1 day
meausures of coagulation and fibrinolysis
thrombin generation, thrombocyte function, ROTEM, plasmatic coagulation, fibrinolysis parameters
Time frame: 1 day