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Effects of Oxygen Status on Hypoxia Inducible Factor 1-α and Inflammation. A Pilot Proof of Principle Study.

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ClinicalTrials.gov Identifier: NCT01889823
Recruitment Status : Completed
First Posted : June 28, 2013
Last Update Posted : March 25, 2015
Sponsor:
Information provided by (Responsible Party):
Peter Pickkers, Radboud University

Brief Summary:
It has been shown in in vitro and animal models that hypoxia can have pro-inflammatory effects and hyperoxia can have anti-inflammatory effects. The pro-inflammatory effect could be the result of activation of Hypoxia Inducible Factor, a transcription factor that is known to activate many cell systems aimed at cell survival, including the inflammatory response. The anti-inflammatory effects of hyperoxia could be the annihilation of Hypoxia Inducible Factor, but also a decrease in inflammation due to oxygen toxicity resulting in a decrease in clearance of pathogens. These effects have been sparsely studied in humans. Therefore, we hypothesize that hypoxia results in an increase in Hypoxia Inducible Factor in circulating leukocytes and increases inflammatory reactions, whereas hyperoxia decreases these reactions.

Condition or disease Intervention/treatment Phase
Hypoxia Hyperoxia Other: Hypoxia Other: Hyperoxia Phase 1

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 20 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Study Start Date : June 2013
Actual Primary Completion Date : August 2013
Actual Study Completion Date : December 2014

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%.
Other: Hypoxia
Subjects will be breathing an individualized mix of nitrogen and room air titrated to an oxygen saturation of 80-85%.

Experimental: Hyperoxia
Subjects will be breathing 100% of oxygen
Other: Hyperoxia
Subjects will be breathing 100% oxygen




Primary Outcome Measures :
  1. Hypoxia Inducible Factor 1 alpha in circulating leukocytes [ Time Frame: 24 hours ]
    Hypoxia Inducible Factor 1 alpha in circulating neutrophils, lymphocytes and monocytes as measured with flow cytometry


Secondary Outcome Measures :
  1. Hypoxia Inducible Factor mRNA and anti Hypoxia Inducible Factor mRNA in circulating leukocytes [ Time Frame: 24 hours ]
  2. Reactive Oxygen Species in circulating leukocytes [ Time Frame: 24 hours ]
    ROS in circulating leukocytes, subclassified in neutrophils and monocytes

  3. Phagocytic function of circulating leukocytes [ Time Frame: 24 hours ]
  4. cytokine production after ex vivo stimulation of leukocytes [ Time Frame: 24 hours ]
  5. circulating cytokines (including but not limited to IL-6, IL-10, IL-1RA) [ Time Frame: 24 hours ]
  6. Hemodynamic parameters [ Time Frame: 24 hours ]
    Blood pressure, heart frequency, cardiac output measurement

  7. ventilatory response [ Time Frame: 24 hours ]
    Measures of ventilation: respiratory rate, blood gas changes

  8. adenosine metabolism [ Time Frame: 24 hours ]
    urine and plasma adenosine,adenosine receptor mRNA, purines

  9. alkaline phosphatase [ Time Frame: 24 hours ]
  10. cognitive function [ Time Frame: 24 hours ]
    neuropsychologic assessment of cognitive function

  11. Hepcidin and iron parameters [ Time Frame: 24 hours ]
  12. catecholamines [ Time Frame: 24 hours ]
    adrenaline, noradrenaline and dopamine

  13. Neutrophil function [ Time Frame: 24 hours ]
  14. body temperature [ Time Frame: 24 hours ]
  15. oxygen saturation and PaO2 [ Time Frame: 24 hours ]
  16. subjective symptoms [ Time Frame: 24 hours ]
  17. high sensitive troponin [ Time Frame: 24 hours ]
  18. iFABP [ Time Frame: 24 hours ]
  19. Brain specific proteins [ Time Frame: 24 hours ]
  20. endocan [ Time Frame: 24 hours ]
  21. adrenomedullin [ Time Frame: 24 hours ]
  22. EPO [ Time Frame: 24 hours ]
  23. VEGF [ Time Frame: 24 hours ]
  24. Heart rate variability [ Time Frame: 24 hours ]


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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:

  • Age ≥18 and ≤35 yrs
  • Male
  • Healthy

Exclusion Criteria:

  • Use of any medication
  • Smoking
  • History, signs or symptoms of cardiovascular disease
  • History of atrial or ventricular arrhythmia
  • (Family) history of myocardial infarction or stroke under the age of 65 years
  • Cardiac conduction abnormalities on the ECG consisting of a 2nd degree atrioventricular block or a complex bundle branch block
  • Hypertension (defined as RR systolic > 160 or RR diastolic > 90 mmHg)
  • Hypotension (defined as RR systolic < 100 or RR diastolic < 50 mmHg)
  • Renal impairment (defined as plasma creatinine >120 μmol/l)
  • Liver enzyme abnormalities alkaline phosphatase>230 U/L and/or ALT>90 U/L
  • Medical history of any obvious disease associated with immune deficiency
  • CRP > 20 mg/L, WBC > 12x109/L, or clinically significant acute illness, including infections, within 4 weeks before endotoxemia day
  • Participation in a drug trial or donation of blood 3 months prior to the experiment
  • Pre-existent lung disease or asthma
  • Use of recreational drugs within 21 days prior to experiment day
  • Visit to altitude >1500m within 4 weeks prior to the experiment
  • Air travel with flight time over 3 hours within 4 weeks prior to the experiment
  • History of acute mountain sickness
  • Recent hospital admission or surgery with general anaesthesia (<3 months)
  • Claustrophobia
  • Feelings of discomfort during a 10 minute test wearing the transparent respiratory helmet at the screening visit

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): NCT01889823


Locations
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Netherlands
Intensive Care Medicine, Radboud University Nijmegen Medical Centre
Nijmegen, Nijmegen, Gelderland, Netherlands, 6500 HB
Sponsors and Collaborators
Radboud University
Investigators
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Principal Investigator: Dorien Kiers, MD Intensive Care Medicine, Radboud University Nijmegen Medical Centre
Study Director: Peter Pickkers, MD,PhD Intensive Care Medicine, Radboud University Nijmegen Medical Centre
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Responsible Party: Peter Pickkers, Prof. dr. P. Pickkers, Radboud University
ClinicalTrials.gov Identifier: NCT01889823    
Other Study ID Numbers: OX1
First Posted: June 28, 2013    Key Record Dates
Last Update Posted: March 25, 2015
Last Verified: March 2015
Keywords provided by Peter Pickkers, Radboud University:
Oxygen
Hypoxia
Hyperoxia
Inflammation
Innate immunity
Additional relevant MeSH terms:
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Hypoxia
Hyperoxia
Signs and Symptoms, Respiratory