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ItemNon-anaemic iron deficiency: validity as a therapeutic target in the peri-operative settingMiles, Lachlan Fraser ( 2020)Given the known associations between iron deficiency anaemia (an advanced form of iron deficiency) and poor outcomes after major surgery, it is biologically plausible that early, or non-anaemic iron deficiency (NAID) may also be associated with worse outcomes. Accordingly, Australian guidelines recommend NAID be corrected routinely pre-operatively. However, evidence supporting independent associations between NAID and poor postoperative outcomes, and for postoperative outcomes to be improved if pre-operative NAID is treated, is limited. Additional evidence is required to answer the primary research question for this thesis: how should clinicians identify and manage NAID prior to major surgery? I have further divided this central question into four subsidiary research questions, which the various chapters in this thesis attempt to answer. Firstly, what are the associations between NAID and outcome following major surgery? In two retrospective observational studies presented in Chapters 2 and 3, I found a signal between iron deficient states and worse postoperative outcomes in non-anemic patients undergoing cardiac surgery and surgery for colorectal cancer. However, confounding associations were also found between NAID and other health conditions. The protocols for two currently running prospective observational studies in the same populations are presented which will provide more definitive evidence for these hypothesised associations. Secondly, are the current World Health Organization definitions of anaemia and non-anaemia an accurate reflection of peri-operative risk, especially when considering the inherent bias of biological sex? In Chapter 4, I present a study that examined the haemoglobin thresholds of anaemic (and by extension, non-anaemia) in women and men presenting for major abdominal surgery. My findings suggest that women with ‘borderline’ anaemia (a haemoglobin concentration of 120 – 129 g/L), despite being considered ‘normal’ under current guidelines have worse postoperative outcomes suggesting the threshold for pre-operative diagnosis of anaemia (and thus intervention) should be 130 g/L for women and men. Thirdly, what are the associations between the response of iron status to inflammation and outcomes after major surgery? This question is partially answered by a retrospective study presented in Chapter 5, where I explore a new, variant iron status termed inflammatory hyperferritinaemia and outline its associations between various negative biological markers and poor outcomes following major abdominal surgery. Finally, if one assumes that NAID is associated with poorer postoperative outcomes, the fourth logical question to be asked is whether administering iron intravenously to patients with pre-operative iron deficiency improves said outcomes? A Cochrane systematic review and meta-analysis examining intravenous iron for the treatment of adults with NAID is presented in Chapter 6, highlighting the paucity of evidence supporting this practice. Additionally, the results of a pilot and feasibility study in patients with NAID undergoing colorectal cancer surgery comparing intravenous iron with placebo are presented in Chapter 7. This latter study experienced considerable difficulty in recruitment; however, I discuss several important lessons for the design of subsequent clinical trials. Understanding how NAID influences postoperative outcomes and whether such outcomes can be modified is essential to guide clinicians in identifying and managing this common peri-operative condition. This thesis provides preliminary evidence that examines this problem and outlines a roadmap for future research.