Iron Status and Cardiopulmonary Physiology

NCT03707249 | Completed

• 1 other identifier: 663/MODREC/15
• Study Type: interventional
• Target: 18
• Locations: 0 countries
• Sites: N/A

Brief Summary

This study involved human volunteers undertaking a high-altitude expedition. It assessed changes in physiological parameters of relevance to high-altitude cardiopulmonary physiology. Participants included a subgroup of those taking part in an existing adventurous training expedition and were randomised in a 1:1 fashion to receive either intravenous iron or normal saline several weeks prior to departure. During the expedition, participants were investigated by means of transthoracic echocardiography, peripheral oxygen saturation measurement and heart rate monitoring and through the drawing of venous blood samples. Bloods were later analysed for markers of iron status.

Conditions

Iron-deficiency; Ventricular Function; Pulmonary Vascular Resistance Abnormality; Altitude Hypoxia

Outcome Measures

Primary Outcomes (8)

• Change in right ventricular systolic pressure (RVSP) with altitude

  Non-invasive measurement of Right ventricular systolic pressure (mmHg) estimated from the velocity of tricuspid regurgitation (TR) (m/s) measured during transthoracic echocardiographic (TTE) continuous wave (CW) Doppler assessment of the tricuspid valve regurgitant jet (RVSP = TR velocity\^2 \* 4)

  Measurement performed at baseline (2 weeks prior to commencing ascent to very high altitude) and at intervals during ascent to very high altitude (over a period of 2 weeks)

• Change in time from pulmonary valve opening to peak pulmonary flow velocity with altitude

  The time from pulmonary valve opening to peak velocity flow is inversely correlated with pulmonary artery pressure. This time is measured on a pulsed wave (PW) Doppler trace in the parasternal short axis view at the pulmonary valve level. The measurement is a time and the units are ms. Categories are: normal (\>130 ms), borderline elevated (100-130 ms), elevated (80-100 ms) and severely elevated (\<80 ms).

  Measurement performed at baseline (2 weeks prior to commencing ascent to very high altitude) and at intervals during ascent to very high altitude (over a period of 2 weeks)

• Change in left ventricular stroke volume (LV SV) with altitude

  The stroke volume of the left ventricle is calculated from 2-D parasternal echocardiographic measurement of the left ventricular outflow tract diameter (LVOT) and pulsed wave (PW) Doppler measurement of the flow through the LVOT during systole. PW of the LVOT allows measurement of the velocity.time integral of the LVOT flow (VTI). This value, when multiplied by the cross sectional area of the LVOT, allows an extimate of stroke volume. SV = (Pi\*(radius of LVOT\^2))\*VTI of LVOT

  Measurement performed at baseline (2 weeks prior to commencing ascent to very high altitude) and at intervals during ascent to very high altitude (over a period of 2 weeks)

• Change in left ventricular index of myocardial performance (LIMP) with altitude

  This is a non-invasive measurement of left ventricular function made by transthoracic echocardiography (TTE). Tissue Doppler imaging (TDI) is used to measure the behaviour of the left ventricle throughout the cardiac cycle (both systole and diastole). This allows the time (ms) of isovolumic contraction time (ICT), isovolumic relaxation time (IVRT) and ejection time (ET). The LIMP (also known as Tei index) = IVCT+IVRT/ET. It is a global measure of systolic and diastolic function of the heart.

  Measurement performed at baseline (2 weeks prior to commencing ascent to very high altitude) and at intervals during ascent to very high altitude (over a period of 2 weeks)

• Change in right ventricular index of myocardial performance (RIMP) with altitude

  This is a non-invasive measurement of right ventricular function made by transthoracic echocardiography (TTE). Tissue Doppler imaging (TDI) is used to measure the behaviour of the left ventricle throughout the cardiac cycle (both systole and diastole). This allows the time (ms) of isovolumic contraction time (ICT), isovolumic relaxation time (IVRT) and ejection time (ET). The RIMP = IVCT+IVRT/ET. It is a global measure of systolic and diastolic function of the heart.

  Measurement performed at baseline (2 weeks prior to commencing ascent to very high altitude) and at intervals during ascent to very high altitude (over a period of 2 weeks)

• Change in tissue Doppler velocity of the Right Ventricle (RV) and Left Ventricle (LV); units: cm/s, with altitude

  Tissue Doppler imaging (TDI) is performed on the ventricular myocardium 1cm apical to the atrioventricular valve annulus (either the tricuspid valve annulus, for the RV assessment, or the LV septum and LV lateral wall adjacent to the mitral valve for the LV assessment). The parameters are peak systolic velocity (s', cm/s), peak velocity during early diastole (e', cm/s) and peak velocity during atrial systole (a', cm/s).

  Measurement performed at baseline (2 weeks prior to commencing ascent to very high altitude) and at intervals during ascent to very high altitude (over a period of 2 weeks)

• Change in tricuspid annulus planar systolic excursion (TAPSE) with altitude

  This is a Doppler M-mode measurement of the full range of movement of the tricuspid annulus at the right ventricular (RV) free wall throughout the cardiac cycle. It is measured by placing an M-mode cursor through the connection of the tricuspid annulus to the RV free wall and measuring the basal-apical excursion of the annulus at this point, from end diastole until the most apical point that it reaches in systole. It is a measure of systolic RV function. Its units are cm.

  Measurement performed at baseline (2 weeks prior to commencing ascent to very high altitude) and at intervals during ascent to very high altitude (over a period of 2 weeks)

• Change in right and left ventricular strain with altitude

  Non-invasive tissue Doppler measurements are acquired on apical 4-chamber, apical 2-chamber and apical 3-chamber images throughout 3 cardiac cycles to allow later analysis to determine the longitudinal strain of the right and left ventricle

  Measurement performed at baseline (2 weeks prior to commencing ascent to very high altitude) and at intervals during ascent to very high altitude (over a period of 2 weeks)

Secondary Outcomes (7)

• Change in peripheral oxygen saturation with altitude

  Measurement performed at baseline (2 weeks prior to commencing ascent to very high altitude) and at intervals during ascent to very high altitude (over a period of 2 weeks)

• Change in heart rate with altitude

  Measurement performed at baseline (2 weeks prior to commencing ascent to very high altitude) and at intervals during ascent to very high altitude (over a period of 2 weeks)

• Change in blood ferritin level (ug/L) with altitude

  Measurement performed at baseline (2 weeks prior to commencing ascent to very high altitude) and at intervals during ascent to very high altitude (over a period of 2 weeks)

• Change in haemoglobin level (g/dL) with altitude

  Measurement performed at baseline (2 weeks prior to commencing ascent to very high altitude) and at intervals during ascent to very high altitude (over a period of 2 weeks)

• Change in transferrin saturation (%) with altitude

  Measurement performed at baseline (2 weeks prior to commencing ascent to very high altitude) and at intervals during ascent to very high altitude (over a period of 2 weeks)

Study Arms (2)

Iron

EXPERIMENTAL

Received a blinded single 15 mg/kg dose of iv ferric carboxymaltose (Ferinject) up to a maximum off 1g total dose 2 weeks prior to ascent to very high-altitude.

Drug: Ferric Carboxymaltose Injectable Product

Saline control

SHAM COMPARATOR

Received a blinded single dose of iv normal saline 2 weeks prior to ascent to very high-altitude.

Drug: Normal Saline 0.9% Infusion Solution Bag

Interventions

Ferric Carboxymaltose Injectable Product DRUG

iv iron infusion: 15 mg / kg up to a maximum 1g dose of Ferinject diluted in normal saline (0.9%) up to a total volume of 250 ml

Also known as: Ferinject

Iron

Normal Saline 0.9% Infusion Solution Bag DRUG

250 ml of normal (0.9%) saline given by intravenous infusion over 20 minutes. This constitutes the control for the iron infusion.

Saline control

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Healthy non-pregnant adults
• Age 18-55 years
• Serving in the UK Armed Forces
• Selected for a military mountaineering team intending to climb to very high altitude

You may not qualify if:

• Diabetes
• Any cardiovascular or respiratory illness
• Regular medication which would interfere with any outcome measures in the study
• Pregnancy
• Any condition which precludes the administration of Ferinject:
• (i) hypersensitivity to the active substance, to Ferinject® or any of its excipients (ii) known serious hypersensitivity to other parenteral iron products (iii) microcytic anaemia not attributable to iron deficiency (e.g. sickle cell anaemia) (iv) evidence of iron overload or disturbances in the utilisation of iron.

Sponsors & Collaborators

• Royal Centre for Defence Medicine: lead
• University of Oxford: collaborator

Related Publications (1)

• Holdsworth DA, Frise MC, Bakker-Dyos J, Boos C, Dorrington KL, Woods D, Mellor A, Robbins PA. Iron bioavailability and cardiopulmonary function during ascent to very high altitude. Eur Respir J. 2020 Sep 17;56(3):1902285. doi: 10.1183/13993003.02285-2019. Print 2020 Sep.

  PMID: 32430412 DERIVED

MeSH Terms

Conditions

Anemia, Iron-Deficiency; Altitude Sickness

Interventions

ferric carboxymaltose; Saline Solution

Condition Hierarchy (Ancestors)

Anemia, Hypochromic; Anemia; Hematologic Diseases; Hemic and Lymphatic Diseases; Iron Deficiencies; Iron Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Respiration Disorders; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Crystalloid Solutions; Isotonic Solutions; Solutions; Pharmaceutical Preparations

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Participants were blinded by the use of eye-masks during infusion and the physical covering of infusion bags and giving sets. Investigators were unaware of the allocation to iron or saline control. Outcomes assessors were also unaware of the allocation.
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER GOV
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Lecturer in Military Medicine, Consultant Cardiologist and General Physician

Model Details: 2 groups were randomised to receive a dose of intravenous iron or iv saline control to manipulate body iron stores. They were subsequently investigated non-invasively and with venous blood sampling during an ascent to very high altitude.

Study Record Dates

• First Submitted: October 1, 2018
• First Posted: October 16, 2018
• Study Start: January 19, 2016
• Primary Completion: May 1, 2016
• Study Completion: December 7, 2017
• Last Updated: October 18, 2018

Record last verified: 2018-10

Data Sharing

• IPD Sharing: Will not share