Award Title: Understanding the role of intravenous iron to treat anaemia in survivors of critical illness
Funder: Department of Health and Social Care

Abstract: Background Approximately 30-50% of intensive care unit (ICU) survivors leave hospital with a haemoglobin (Hb) of 100 g.L-1 which equates to 'moderate / severe anaemia'. Patients surviving ICU often experience poor health-related quality of life, high levels of fatigue and weakness. Anaemia could be causing some of these symptoms, but the precise contribution it makes, over and above other causes such as deconditioning, muscle wasting and nerve damage, remains unclear.Iron restriction is a major factor underlying anaemia in ICU either because of absolute iron deficiency, iron sequestration (impaired iron trafficking) or functional iron deficiency (imbalance between iron requirements of the bone marrow and availability. Standard biochemistry tests are unable to identify specific causes because of inflammation - which is present in nearly all ICU patients. The discovery of the iron hormone hepcidin has improved our understanding of iron metabolism. Hepcidin is elevated in inflammation where it blocks the duodenal absorption of iron (thereby limiting the efficacy of oral iron) and release from macrophages. Conversely, low hepcidin levels facilitate the absorption of iron and release of iron from body stores. Evidence from other patient groups has shown it can identify absolute iron deficiency in spite of inflammation and it can also predict responsiveness (increase in haemoglobin) to iron (i.e. lower the hepcidin the more likely a response).Available evidence so far has not demonstrated any benefit in using iron to treat anaemia in ICU. This can partly be explained by study limitations but also becuase patients may have simply been too sick to utilise the iron. No trials have attempted to treat anaemia after critical illness where it is plausible that iron utilisation will be greater as inflammation regresses.Aims The overall aim of this fellowship is to undertake a feasibility study to determine whether or not a large multicentre trial of intravenous iron versus placebo in ICU survivors with anaemia can be carried out. Research obejctives to be address in this fellowship 1) To estimate important feasibility and clinical outcomes, such as number of eligible participants, recruitment rates, follow-up rates, metrics of changes in haemoglobin concentration and quality of life scores, which would be required for the larger study.2) To identify the patient characteristics and biological profiles of patients who respond to intravenous iron and whether or not biomarkers such as hepcidin predict response to iron.Research methods To answer these objectives I will use the following methods.1) A feasibility open-label randomised trial of intravenous iron versus no iron (control) in ICU survivors with anaemia. Participants will receive a one-off dose of 1000mg of ferric carboxymaltose within 72 hours of leaving ICU. This contains the equivalent of 2-3 months of oral iron. Intravenous iron is also more efficacious than oral iron as it bypasses the hepcidin-block created by inflammation. Participants will be followed up at 4 weeks, 3 month and 6 months post-randomisation. 2) For all participants, I will analyse their biological (biochemistry, iron, inflammatory and bone marrow) profiles. Novel techniques developed in our institution are now able to provide a functional quantitative result of bone marrow function from a blood test, thereby avoiding the need for a bone marrow aspirate which is invasive and painful. In the group that received iron, I will explore if hepcidin can predict a rise in haemoglobin. Analysis of the control group will help determine which biological factors, if any, are associated with a spontaneous improvement (or lack of) in haemoglobin.Potential impact This research has the potential to treat a common and potentially easily reversible condition, which could alleviate symptoms and improve quality of life in ICU survivors.

Lay Abstract: Background of the research Anaemia is also known as low red blood cell count or low haemoglobin. Haemoglobin carries oxygen and therefore anaemia reduces the amount of oxygen that is available to the body. Anaemia is very common in intensive care unit (ICU) patients and also in those who leave ICU alive. 164,000 patients are admitted to ICU per year in the United Kingdom. Nearly half of these who survive ICU will leave with a haemoglobin of less than 100 grams per liter (g/L), which is termed 'moderate-severe' anaemia.The body reacts to infection or injury by producing inflammation (an attempt to heal or mend the body). Inflammation is present in nearly all ICU patients. However, whilst doing this, the body is unable to use available iron to make haemoglobin resulting in anaemia because iron is essential to make haemoglobin. Current blood tests are not able to reliably tell us how much iron is available because of inflammation. A new blood test of the main hormone that controls iron in body - hepcidin, has become recently available and may be a better test.Patients who survive ICU often experience high levels of tiredness and weakness resulting in a poor quality of life. These could be symptoms of anaemia, but may also relate to other complications the patient may have experienced during their illness such as muscle wasting and nerve damage. Given that so many patients leave ICU with anaemia, it is important to see whether treating this aspect of their ill health improves their symptoms. To our knowledge, there is no research that has investigated treating anaemia with iron after the patient has left ICU.Aims The aim of this research is to understand the role of intravenous ('through a drip') iron in treating anaemia in patients who are recovering from intensive care.Study design Currently, patients do not routinely receive intravenous iron to treat anaemia after intensive care. I will compare a group of patients who have survived ICU to receive intravenous iron (treatment group) to a group that will not recieve iron (control or 'usual care' group). My objective is to see if this study is feasible. If so, the results would be used to facilitate a larger study involving other hospitals where we would investigate whether treating anaemia with intravenous iron after intensive care improves quality of the life after hospital by treating the symptoms mentioned above. I am using intravenous iron because it works more effectively than oral iron. A one-off injection, lasting 15 minutes, contains the equivalent of 2-3 months of oral iron. Oral iron also has unpleasant side effects such as constipation and nausea. Furthermore, the body is not able to use oral iron because of inflammation whereas it can use intravenous iron. In patients with cancer or kidney problems, who also have inflammation, intravenous iron has been shown to work very well. In this study, a computer will decide randomly (based on chance) which group a patient will be allocated to (randomisation). The control group will not receive any treatment from us. The treatment group will receive the intravenous iron within 72 hours of leaving ICU. I will collect information on how many patients are eligible for the study, how many agree to participate and how many I am able to follow-up after ICU. I will take blood tests, which will include hepciidn, prior to and 4 weeks, 3 months and 6 months after randomisation. These will be looking at the levels of inflammation and iron stores in the body which will further develop our understanding of anaemia after ICU. Patients in both groups will also be asked about symptoms of faitgue and their quality of life using validated questionnaires.Patient and public involvement I have spoken to ICU survivors from our hosptial's ICU support group. Many of them felt weak and tired for a long time after leaving ICU. They were not aware of how common anaemia is after intensive care, the negative impact it could have and what little research into treatment exists for it. They understood why undertaking this research to treat a potentially easily treatable condition has the potential to improve quality of life after ICU.Dissemination of findings of this research The findings of this research will be shared with regional research groups, the local and international academic community through forums and conferences, and to our local and national patient groups. The findings will also be published in highly read intensive care medical journals.

Research Activity Codes: 6.1 PHARMACEUTICALS
Health Categories: BLOOD