Iron Status and Cardiopulmonary Physiology

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.

Aim

The aim of the study was to investigate the effects of iron status on human cardiopulmonary physiology during ascent to very high altitude. Differences in iron status were brought about using intravenous iron, and outcomes were assessed using echocardiography and self-reported functional performance scores.

Objectives

Principal objective: To compare echocardiographic parameters in individuals of differing iron status during the expedition.

Secondary objectives: To compare physiological variables (oxygen saturation, pulse) and self-reported functional measures, in individuals of differing iron status during the expedition.

Hypotheses

The primary hypothesis was that iron status, manipulated using intravenous iron, would influence the echocardiographic indices of cardiopulmonary physiological function over the course of the ascent.

A secondary hypothesis was that iron status would influence cardiopulmonary responses in terms of pulse and oxygen saturation, and additionally the perceived exertion involved in ascent to very high altitude.

Design of the Study

The study randomised 18 individuals to iron or normal saline in a 1:1 ratio giving two groups of 9 people. The randomised infusion (control or iron) was undertaken at a pre-expedition meeting approximately 2 weeks prior to the flight to Nepal. The profile of ascent to high altitude will followed internationally accepted acclimatisation guidelines.

Preliminary Testing

To exclude elevated iron stores prior to enrollment, participants underwent an initial blood test. At the pre-exercise mounting station, prior to the flight to Nepal, baseline echocardiography was performed, and blood samples were collected immediately prior to randomisation and infusion. All blood samples in the study were analysed for full blood count, ferritin, iron, transferrin and C-reactive protein (CRP).

Expedition-based tests

Waking peripheral oxygen saturation (%) of haemoglobin (SpO2) and pulse were recorded daily. Venous blood samples were taken for later analysis of variables relevant to iron homeostasis including full blood count, erythropoietin, soluble transferrin receptor and hepcidin. These samples were taken in Kathmandu on the morning following arrival, at the intermediate staging camp (\~3,200m) and then at the Dhaulagiri base camp on arrival and after descents from 6,000m and 7,000m.

Measures of both left and right heart function were performed and included: pulmonary artery systolic pressure, pulmonary acceleration time, pulmonary regurgitation end diastolic velocity and tricuspid annular plane systolic excursion (distance of systolic excursion of the right ventricular annular plane towards the apex - TAPSE). Echo parameters were acquired and processed by an appropriately experienced researcher. Measures were taken during exercise on arrival at each test altitude and at rest the following morning. Measurements taken from climbers returning from either 6,000 m or 7,000 m were taken as soon as possible after their return to base camp.

Subjective ratings scales include those for breathlessness (Borg 1-10) and perceived exertion (Borg 6-20).

Blood sample storage and analysis

Once drawn, venous blood was placed on ice. Following centrifugation (3,500 rpm for 10 minutes at 4OC), aliquots of plasma were stored in cryogenic vials at -20°C. Samples drawn at high altitude were transported on dry ice or in liquid nitrogen 'dry-shippers' (safe liquid nitrogen containers that cannot leak nitrogen as liquid) back to the UK (United Kingdom). Subsequent analysis was performed at the University of Oxford.

Statistical analysis

Data were analysed using statistical tests with International Business Machines (IBM) 'statistical package for social sciences' (SPSS) version 22 software.

Eligibility Criteria:
Inclusion Criteria:

* 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

Exclusion Criteria:

* 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.