Clinical trial NCT01978158: Effects of Oxygen Status on Endotoxemia Induced Inflammation and Hypoxia Inducible Factor-1α
Official title: Effects of Oxygen Status on Endotoxemia Induced Inflammation and Hypoxia Inducible Factor-1α. A Pilot Proof of Principle Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Hypoxia
Normoxia
Hyperoxia
Keywords: Oxygen
Hypoxia
Hyperoxia
Inflammation
Innate immunity
Lead sponsor: Radboud University Medical Center
Sponsor class: OTHER
First posted: 2013-11-07
Enrollment: 30
Sex: MALE
Minimum age (years): 18
Maximum age (years): 35
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

* Written informed consent to participate in this trial
* Male subjects aged 18 to 35 years inclusive
* Healthy as determined by medical history, physical examination, vital signs, 12-lead electrocardiogram, and clinical laboratory parameters

Exclusion Criteria:

* Use of any medication(including herbal remedies and vitamin/mineral supplements) or recreational drugs within 7 days prior to profiling day
* Smoking
* Use of caffeine, or alcohol or within 1 day prior to profiling day
* Previous participation in a trial where LPS was administered
* Surgery or trauma with significant blood loss or blood donation within 3 months prior to profiling day
* Participation in another clinical trial within 3 months prior to profiling day.
* History, signs or symptoms of cardiovascular disease
* An implant that in the opinion of the investigator may make invasive procedures risky for the subject due to the increased risks associated with a possible infection.
* Subject has an implanted active cardiac device (ICD, IPG and/or CRT) Implanted active neurostimulation device
* Subject has internal jugular vein that cannot be accessed
* History of vaso-vagal collapse or of orthostatic hypotension
* History of atrial or ventricular arrhythmia
* Resting pulse rate ≤45 or ≥100 beats / min
* 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
* Subject is diagnosed with epilepsy or history of seizures
* Renal impairment: plasma creatinine \>120 μmol/L
* Liver function abnormality: alkaline phosphatase\>230 U/L and/or ALT\>90 U/L
* Coagulation abnormalities: APTT or PT \> 1.5 times the reference range
* History of asthma
* Immuno-deficiency CRP \> 20 mg/L, WBC \> 12x109/L, or clinically significant acute illness, including infections, within 2 weeks before profiling day
* Known or suspected of not being able to comply with the trial protocol - Inability to personally provide written informed consent (e.g. for linguistic or mental reasons) and/or take part in the study.

Primary outcomes:
measure: Plasma TNF-alpha concentration following LPS administration
timeFrame: 1 day
Secondary outcomes:
measure: Hypoxia Inducible Factor 1 alpha in circulating leukocytes
timeFrame: 1 day
measure: Hypoxia Inducible Factor mRNA and anti Hypoxia Inducible Factor mRNA in circulating leukocytes
timeFrame: 24 hours
measure: Reactive Oxygen Species in circulating leukocytes
timeFrame: 1 day
measure: Phagocytic function of circulating leukocytes
timeFrame: 1 day
measure: cytokine production after ex vivo stimulation of leukocytes
timeFrame: 1 day
measure: circulating cytokines (including but not limited to IL-6, IL-10, IL-1RA)
timeFrame: 1 day
measure: Hemodynamic parameters
timeFrame: 1 day
measure: ventilatory response
timeFrame: 1 day
measure: adenosine metabolism
timeFrame: 1 day
measure: alkaline phosphatase
timeFrame: 1 day
measure: cognitive function
timeFrame: 1 day
measure: Hepcidin and iron parameters
timeFrame: 1 day
measure: catecholamines and cortisol
timeFrame: 1 day
measure: Neutrophilic function
timeFrame: 1 day
measure: body temperature
timeFrame: 1 day
measure: oxygen saturation and arterial blood gas
timeFrame: 1
measure: subjective symptom scores
timeFrame: 1 day
measure: high sensitive troponine
timeFrame: 1 day
measure: iFABP
timeFrame: 1 day
measure: brain specific proteins
timeFrame: 1 day
measure: endocan
timeFrame: 1 day
measure: downstream targets of HIF
timeFrame: 1 day
measure: heart rate variability
timeFrame: 1 day
measure: kidney injury markers in plasma and urine
timeFrame: 2 days
measure: microbiome in feces
timeFrame: -1 day untill 1 week
measure: markers of immunoparalysis
timeFrame: 1 day
measure: measures of coagulation and plateletfunction
timeFrame: 1 day
measure: meausures of coagulation and fibrinolysis
timeFrame: 1 day
Other outcomes:
Locations:
city: Nijmegen
country: Netherlands
facility: Intensive Care Medicine
state: Gelderland
Study officials:
affiliation: Intensive Care Medicine, Radboud University Nijmegen Medical Centre
name: Peter Pickkers, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: