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Effects of Oxygen Status on Endotoxemia Induced Inflammation and Hypoxia Inducible Factor-1α

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ClinicalTrials.gov Identifier: NCT01978158
Recruitment Status : Completed
First Posted : November 7, 2013
Last Update Posted : May 20, 2015
Sponsor:
Information provided by (Responsible Party):
Radboud University

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.

Condition or disease Intervention/treatment Phase
Hypoxia Normoxia Hyperoxia Drug: Lipopolysaccharide Phase 1 Phase 2

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.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 30 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Effects of Oxygen Status on Endotoxemia Induced Inflammation and Hypoxia Inducible Factor-1α. A Pilot Proof of Principle Study
Study Start Date : October 2013
Actual Primary Completion Date : December 2013
Actual Study Completion Date : December 2013

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Oxygen Therapy

Arm Intervention/treatment
Experimental: Hypoxia
Subjects will be breathing an individualized mix of nitrogen and room air titrated to an oxygen saturation of 80-85%.
Drug: Lipopolysaccharide
LPS is used to elicit an inflammatory response in all subjects
Other Name: Purified LPS from Escherischa coli (O:113)

Experimental: Hyperoxia
Subjects will be breathing 100% of oxygen
Drug: Lipopolysaccharide
LPS is used to elicit an inflammatory response in all subjects
Other Name: Purified LPS from Escherischa coli (O:113)

Active Comparator: Normoxia
Subjects wil be breathing room air (21%)
Drug: Lipopolysaccharide
LPS is used to elicit an inflammatory response in all subjects
Other Name: Purified LPS from Escherischa coli (O:113)




Primary Outcome Measures :
  1. Plasma TNF-alpha concentration following LPS administration [ Time Frame: 1 day ]
    Plasma TNF-α concentration after LPS administration (Area Under Curve); comparison of subjects treated with hypoxia compared to normoxia and hyperoxia compared to hypoxia


Secondary Outcome Measures :
  1. Hypoxia Inducible Factor 1 alpha in circulating leukocytes [ Time Frame: 1 day ]
    Hypoxia Inducible Factor 1 alpha in circulating neutrophils, lymfocytes and monocytes as measured with flow cytometry

  2. Hypoxia Inducible Factor mRNA and anti Hypoxia Inducible Factor mRNA in circulating leukocytes [ Time Frame: 24 hours ]
  3. Reactive Oxygen Species in circulating leukocytes [ Time Frame: 1 day ]
  4. Phagocytic function of circulating leukocytes [ Time Frame: 1 day ]
  5. cytokine production after ex vivo stimulation of leukocytes [ Time Frame: 1 day ]
  6. circulating cytokines (including but not limited to IL-6, IL-10, IL-1RA) [ Time Frame: 1 day ]
  7. Hemodynamic parameters [ Time Frame: 1 day ]
    Blood pressure, heart frequency, cardiac output measurement

  8. ventilatory response [ Time Frame: 1 day ]
    Measures of ventilation: respiratory rate, blood gas changes

  9. adenosine metabolism [ Time Frame: 1 day ]
    urine and plasma adenosine,adenosine receptor mRNA, purines

  10. alkaline phosphatase [ Time Frame: 1 day ]
  11. cognitive function [ Time Frame: 1 day ]
    neuropsychologic assessment of cognitive function

  12. Hepcidin and iron parameters [ Time Frame: 1 day ]
  13. catecholamines and cortisol [ Time Frame: 1 day ]
    adrenaline, noradrenaline, dopamine and cortisol

  14. Neutrophilic function [ Time Frame: 1 day ]
  15. body temperature [ Time Frame: 1 day ]
  16. oxygen saturation and arterial blood gas [ Time Frame: 1 ]
  17. subjective symptom scores [ Time Frame: 1 day ]
  18. high sensitive troponine [ Time Frame: 1 day ]
  19. iFABP [ Time Frame: 1 day ]
  20. brain specific proteins [ Time Frame: 1 day ]
  21. endocan [ Time Frame: 1 day ]
  22. downstream targets of HIF [ Time Frame: 1 day ]
    adrenomedullin, VEGF, EPO

  23. heart rate variability [ Time Frame: 1 day ]
  24. kidney injury markers in plasma and urine [ Time Frame: 2 days ]
  25. microbiome in feces [ Time Frame: -1 day untill 1 week ]
  26. markers of immunoparalysis [ Time Frame: 1 day ]
    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.

  27. measures of coagulation and plateletfunction [ Time Frame: 1 day ]
    platelet activation and platelet function, thrombin generation and other coagulation parameters, hematolocial infection profile using hematology analyser

  28. meausures of coagulation and fibrinolysis [ Time Frame: 1 day ]
    thrombin generation, thrombocyte function, ROTEM, plasmatic coagulation, fibrinolysis parameters



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Ages Eligible for Study:   18 Years to 35 Years   (Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   Yes
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01978158


Locations
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Netherlands
Intensive Care Medicine
Nijmegen, Gelderland, Netherlands, 6500HB
Sponsors and Collaborators
Radboud University
Investigators
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Principal Investigator: Peter Pickkers, MD, PhD Intensive Care Medicine, Radboud University Nijmegen Medical Centre

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Responsible Party: Radboud University
ClinicalTrials.gov Identifier: NCT01978158     History of Changes
Other Study ID Numbers: OX2
2013-002390-21 ( EudraCT Number )
NL44630.091.13 ( Other Identifier: CCMO )
2013/290 ( Other Identifier: CMO Arnhem-Nijmegen )
First Posted: November 7, 2013    Key Record Dates
Last Update Posted: May 20, 2015
Last Verified: May 2015

Keywords provided by Radboud University:
Oxygen
Hypoxia
Hyperoxia
Inflammation
Innate immunity

Additional relevant MeSH terms:
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Inflammation
Hypoxia
Endotoxemia
Hyperoxia
Pathologic Processes
Signs and Symptoms, Respiratory
Signs and Symptoms
Bacteremia
Sepsis
Infection
Toxemia
Systemic Inflammatory Response Syndrome