Iron Status and Hypoxic Pulmonary Vascular Responses

NCT01847352 | Completed

• 1 other identifier: 12/SC/0710
• Study Type: interventional
• Target: 31
• Locations: 1 country
• Sites: 1

Brief Summary

On exposure to hypoxia (low oxygen) the normal response is for pulmonary arterial systolic blood pressure (PASP, blood pressure through the lungs) to increase. We have previously shown that raising iron by giving an infusion of iron into a vein reduces this pressure rise and that lowering iron by giving a drug that binds iron, magnifies this response. This is potentially a clinically important observation since iron-deficient people may be at increased risk of pulmonary hypertension if exposed transiently or permanently to hypoxia due to lung disease or residence at high altitude; furthermore if this were true then intravenous iron could be an important treatment in this patient group in the event of hypoxic exposure. The observed effects of iron on PASP are likely to be because iron levels affect oxygen sensing. Low iron levels make the body behave as if exposed to low oxygen by inhibiting the breakdown of the family of oxygen-sensing transcription factors, 'hypoxia inducible factor' or HIF. This includes one of the body's normal responses to low oxygen levels - raising blood pressure through the lungs. This study will answer the question (1) do iron-deficient volunteers have a greater rise in PASP with hypoxia than those who are iron-replete, and (2) does giving intravenous iron cause a greater reduction in the rise in PASP in those who are iron-deficient than iron-replete? The purpose of this study is not to test the safety or clinical efficacy of iron which is already known.

Conditions

Lung Hypoxia; Pulmonary Arterial Hypertension; Iron Deficiency

Keywords

Hypoxia; Pulmonary hypertension; Iron deficiency; Hypoxic pulmonary vasoconstriction

Outcome Measures

Primary Outcomes (1)

• ∆PASP in iron-replete compared to iron-deficient volunteers

  Difference between the rise in pulmonary artery systolic pressure during a hypoxic challenge in iron-replete compared to iron-deficient volunteers

  During six hours of hypoxia without prior iron infusion

Secondary Outcomes (3)

• ∆PASP, with versus without prior iron infusion, in iron-replete compared to iron-deficient volunteers

  During two six-hour periods of hypoxia; assessments separated by at least a week

• Blood parameter changes, pre- versus post-intravenous iron, in iron-replete compared to iron-deficient volunteers

  After six hours of hypoxia, at both study assessments

• Ventilation parameter changes, pre- versus post-intravenous iron, in iron-replete compared to iron-deficient volunteers

  During six hours of hypoxia, at both study assessments

Other Outcomes (1)

• Fatigue scores in iron-replete versus iron-deficient volunteers

  Assessed at baseline visit

Study Arms (2)

Iron-deficient

OTHER

Healthy volunteers meeting iron-deficient entry criteria; Intravenous administration of ferric carboxymaltose; Subacute hypoxic exposures

Drug: Intravenous administration of ferric carboxymaltose; Other: Subacute hypoxic exposures

Iron-replete

OTHER

Healthy volunteers meeting iron-replete entry criteria; Intravenous administration of ferric carboxymaltose; Subacute hypoxic exposures

Drug: Intravenous administration of ferric carboxymaltose; Other: Subacute hypoxic exposures

Interventions

Intravenous administration of ferric carboxymaltose DRUG

Intravenous administration of ferric carboxymaltose 15mg/kg up to a maximum dose of 1000mg

Also known as: Ferinject

Iron-deficient; Iron-replete

Subacute hypoxic exposures OTHER

Exposure to six hours of isocapnic hypoxia with end-tidal partial pressure of oxygen clamped at 55 Torr, with and without prior iron infusion

Also known as: Hypoxia, Hypoxic challenge

Iron-deficient; Iron-replete

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Willing and able to give informed consent for participation in the study
• Men and women aged 18 years or older and generally in good health
• Detectable tricuspid regurgitation on echocardiography during both normoxia and hypoxia enabling measurement of pulmonary arterial pressure
• For iron-deficient volunteers: ferritin ≤15microg/L and transferrin saturation \<16%
• For iron-replete volunteers: ferritin ≥20microg/L and transferrin saturation ≥20%

You may not qualify if:

• Haemoglobin \<8.0g/dl
• Haemoglobinopathy
• Iron overload defined as ferritin \>300microg/L
• Hypoxia at rest or on walking (SaO2 \<94%) or significant comorbidity that may affect haematinics, pulmonary vascular or ventilatory responses, e.g. current infection, a chronic inflammatory condition, known cardiovalvular lesion or pulmonary hypertension, uncontrolled asthma or chronic obstructive pulmonary disease
• Exposure to high altitude (\>2,500m) within the previous six weeks or air travel \>4 hours within the previous week
• Iron supplementation or blood transfusion within the previous 6 weeks
• Pregnancy or breast feeding

Sponsors & Collaborators

• University of Oxford: lead
• National Institute for Health Research, United Kingdom: collaborator
• British Heart Foundation: collaborator

Study Sites (1)

University of Oxford Department of Physiology, Anatomy and Genetics

Oxford, Oxfordshire, OX1 3PT, United Kingdom

Location

Related Publications (5)

• Smith TG, Balanos GM, Croft QP, Talbot NP, Dorrington KL, Ratcliffe PJ, Robbins PA. The increase in pulmonary arterial pressure caused by hypoxia depends on iron status. J Physiol. 2008 Dec 15;586(24):5999-6005. doi: 10.1113/jphysiol.2008.160960. Epub 2008 Oct 27.

  PMID: 18955380 BACKGROUND

• Smith TG, Talbot NP, Privat C, Rivera-Ch M, Nickol AH, Ratcliffe PJ, Dorrington KL, Leon-Velarde F, Robbins PA. Effects of iron supplementation and depletion on hypoxic pulmonary hypertension: two randomized controlled trials. JAMA. 2009 Oct 7;302(13):1444-50. doi: 10.1001/jama.2009.1404.

  PMID: 19809026 BACKGROUND

• Talbot NP, Smith TG, Privat C, Nickol AH, Rivera-Ch M, Leon-Velarde F, Dorrington KL, Robbins PA. Intravenous iron supplementation may protect against acute mountain sickness: a randomized, double-blinded, placebo-controlled trial. High Alt Med Biol. 2011 Fall;12(3):265-9. doi: 10.1089/ham.2011.1005.

  PMID: 21962070 BACKGROUND

• Balanos GM, Dorrington KL, Robbins PA. Desferrioxamine elevates pulmonary vascular resistance in humans: potential for involvement of HIF-1. J Appl Physiol (1985). 2002 Jun;92(6):2501-7. doi: 10.1152/japplphysiol.00965.2001.

  PMID: 12015365 BACKGROUND

• Frise MC, Cheng HY, Nickol AH, Curtis MK, Pollard KA, Roberts DJ, Ratcliffe PJ, Dorrington KL, Robbins PA. Clinical iron deficiency disturbs normal human responses to hypoxia. J Clin Invest. 2016 Jun 1;126(6):2139-50. doi: 10.1172/JCI85715. Epub 2016 May 3.

  PMID: 27140401 RESULT

Related Links

• Research Group Website
• Funding Body Website

MeSH Terms

Conditions

Pulmonary Arterial Hypertension; Iron Deficiencies; Hypoxia; Hypertension, Pulmonary

Interventions

ferric carboxymaltose

Condition Hierarchy (Ancestors)

Lung Diseases; Respiratory Tract Diseases; Iron Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Signs and Symptoms, Respiratory; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Hypertension; Vascular Diseases; Cardiovascular Diseases

Study Officials

• Annabel H Nickol, MBBS PhD

  University of Oxford

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NON RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 1, 2013
• First Posted: May 6, 2013
• Study Start: February 1, 2013
• Primary Completion: April 1, 2014
• Study Completion: April 1, 2014
• Last Updated: May 6, 2016

Record last verified: 2016-05

Data Sharing

• IPD Sharing: Will not share

Locations

GB (1)