Understanding the role of intravenous iron to treat anaemia following critical care

The overarching aims of the work to be presented in this thesis are to investigate the role of intravenous iron for treating anaemia in survivors of critical illness and to improve our understanding of iron status and erythropoiesis in critical illness. I plan to achieve these aims by undertaking systematic reviews and meta-analyses, experimental work and a feasibility randomised controlled trial (RCT).
Intravenous iron is a biologically plausible treatment option for the anaemia of inflammation that accompanies critical illness. However, the evidence of efficacy for intravenous iron in this cohort is limited and there may be some associated harm, in particular the risk of causing or exacerbating infection. Guidelines do not recommend the routine use of iron therapy in critically ill patients, but clinician surveys have highlighted variation in practice. Expert panels have called for further research into the optimal timing, dose and route of administration of iron therapy in critically ill patients.
The objectives of this research are to determine:
1. The current evidence of the safety and efficacy of iron therapy in critically ill patients
2. The evaluate safety data for intravenous iron on the risk of infection across all patient groups
3. If newer markers of iron status, such as hepcidin, can better identify iron deficiency in the context of inflammation (or systemic iron requirement) than current routine tests
4. The variability in subpopulations of erythroid progenitors, as a marker of erythropoiesis, obtained from peripheral blood in a heterogenous cohort of critically ill patients at two distinct time points (acute illness and recovery)
5. If it is feasible to conduct a clinical trial of intravenous iron to treat anaemia in patients recovering from critical illness
I systematically evaluated the safety and efficacy of iron therapy, by any route, on treating anaemia in critically ill patients. I identified six RCTs comparing iron therapy with either no iron or placebo. Overall, there was no evidence of an effect of iron therapy on transfusion requirements (Risk Ratio (RR) 0.91; 95% Confidence Interval (CI): 0.80 to 1.04). There was no difference in infection (RR 0.95; 95% CI: 0.79 to 1.19). However, iron therapy did result in a modest increase in haemoglobin (Hb), particularly at longer follow-up time points (mean different 0.31 g/dl, 95% CI: 0.04 to 0.59). The clinical implications of this increase require further investigation. Trial sequential analysis suggested the current evidence is inadequate to detect or reject a clinically important benefit or harm from iron therapy. No trials evaluated participant health-related quality of life (HRQoL) or functional outcomes.
Many clinical practice guidelines, across a range of clinical conditions, advocate the use of intravenous iron to treat anaemia. Intravenous iron administration can lead to increased levels of free circulating iron which can promote pathogen growth and result in clinically important infection. As part of a comprehensive systematic review aiming to characterise the risk of infection across all clinical settings, I found an increased risk of infection with intravenous iron (RR 1.17; 95% CI: 1.04 to 1.31; 64 RCTs; 19,480 participants). I judged the certainty of evidence to be moderate (i.e. the true effect is probably close to the estimate effect). However, there was significant variation in the definitions and reporting of infection across included studies. Only fifteen RCTs attempted to define infection (guideline/consensus based (n = 8), investigator-defined (n = 7)). The increased risk of infection associated with intravenous iron must be considered alongside the potential benefits such as treatment of anaemia. There is a need for consistent and standardised reporting of this potential harm in ongoing and future RCTs.
In order to characterise iron status in patients recovering from critical illness, I analysed blood samples taken from a RCT evaluating the effect of a rehabilitation programme delivered to patients discharged from critical care. These samples were taken as close as possible to hospital discharge and were available for 117 participants. I measured hepcidin and soluble transferrin receptor using enzyme-linked immunoassay, along with other routine markers of iron status such as ferritin, serum iron and transferrin saturation. Using linear regression and area under the curve (AUC) receiver operator characteristic (ROC) analysis, I found that a hepcidin concentration of <19 ng/ml achieved the maximum AUCROC (0.72) and Youden index (0.47) with a sensitivity of 73% and specificity of 74%, for identifying true iron deficiency in the context of inflammation. Approximately one-third of patients (45/110) would be classified as being iron deficient based on this definition compared with only 10% using routine tests of iron status.
In a separate exploratory study, I aimed to determine the variability in subpopulations of erythroid progenitors, as a marker of erythropoiesis, obtained from peripheral blood in a heterogenous cohort of critically ill patients at two distinct time points (acute illness and recovery). This would enable a more precise investigation of the impaired erythropoiesis that accompanies the anaemia of critical illness. The study has been temporarily paused due to the restrictions placed by the COVID-19 pandemic. However, the important first phase of the study is complete. I have collected peripheral blood samples from 30 patients within 72 hours of an intensive care unit admission (ICU), with a follow-up sample available for 17 patients. CD34+ cells from all samples have been extracted and are currently stored in liquid nitrogen. The second phase will involve performing multi-colour flow cytometry to help establish the colony forming potential of the Megakaryocyte Erythroid Progenitor, with a particular focus on the erythroid output, as a marker of erythropoiesis. This work will form part of my post-doctoral training.
Building on the findings of my systematic reviews and the laboratory work, I hypothesised that the recovery phase of critical illness, when the iron and erythropoietic profiles are more favourable, may be a more suitable time point for evaluating the potential benefits (and harms) of intravenous iron. Patients recovering from critical illness experience a substantial burden of morbidity that is characterised by poor physical function, weakness and high levels of fatigue. These are also the cardinal symptoms of untreated anaemia. A large, multicentre RCT is required to answer this question but there are uncertainties regarding patient selection, recruitment and follow-up rates, variability in Hb and iron profiles in the post-ICU period, and choice of patient-centred outcome measures.
In order to address these uncertainties, I designed the INTACT (INtravenous iron to Treat Anaemia following CriTical care) feasibility RCT. Patients being discharged from critical care with moderate-severe anaemia (Hb ≤100 g/l) were randomly allocated to either intravenous iron (ferric carboxymaltose 1000mg) or usual medical care. Primary feasibility outcomes included recruitment rates, protocol adherence and completeness of follow-up. Secondary outcomes included clinical outcomes (nosocomial infection, in-hospital mortality, hospital length of stay), changes in haemoglobin, iron profiles and health-related quality of life (HRQoL), and safety data. Participants were followed up at 28 and 90-days post-randomisation. This study took place in four ICUs across three UK hospitals from September 2018 to December 2019 and 98 participants were randomised over 15 months, with 49 in each arm. The overall recruitment rate for the trial was 34% (95% CI: 28% to 40%) with 6.5 patients recruited per month. Forty-seven out of 49 participants (96%) received the intervention (95% CI: 86% to 100%). All HRQoL measures were collected for at least 79/93 (85%) (95% CI: 76% to 92%) survivors at the 90-day follow-up visit. Overall, INTACT satisfied the pre-defined criteria for demonstration of feasibility. Ferric carboxymaltose was well-tolerated during the study with no drug-related serious adverse events.
Intravenous iron resulted in a higher mean (SD) haemoglobin at 28 days (119.7 (13.3) vs. 106.7 (14.9) g/l) and 90 days (130.5 (15.1) vs. 122.7 (17.3), adjusted mean difference 11.0 (95% CI: 5.0 to 17.0) g/l, p <0.001). Ferritin, iron and transferrin saturation concentrations were higher in the intravenous iron group at 90 days. Median (IQR) hepcidin concentrations were lower in the usual care group at 90 days when compared with intravenous iron (13.9 (3.6-33.3) vs. 35.0 (7.6-60.1) ng/ml, p = 0.048). These data support the biological efficacy of intravenous iron in a cohort of patients with significant inflammation. Exploratory analyses suggested that baseline inflammation and iron status, as defined by C-reactive protein and hepcidin respectively, may be potential effect modifiers.
There were no differences in infection and in-hospital mortality in both groups. The median (IQR) post-ICU length of stay was shorter in the intravenous iron group when compared with usual care, but this did not reach statistical significance (5.0 days (3.0-13.0) vs. 9.0 days (5.0-16.0), p=0.15). Hospital readmissions in the first 90 days following discharge from the ICU were also lower in the intravenous iron group when compared with usual care (7/40 (17.5%) vs. 15/39 (38.4%), Odds Ratio 0.34 (95% CI: 0.12 to 0.96)). There were no statistically significant differences in HRQoL and fatigue scores between both groups, but INTACT was not powered to detect such differences.
The programme of work arising from this research has the potential to benefit the large number of patients that survive a critical care admission each year by improving their recovery. The findings of the INTACT trial are hypothesis-testing and an important step towards a larger definitive trial.

Keywords: IV iron
anaemia
critical care
Advisor: Stanworth, S
McKechnie, S
Robbins, P