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Iron Metabolism: An Emerging Therapeutic Target in Critical Illness

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Annual Update in Intensive Care and Emergency Medicine 2019

Part of the book series: Annual Update in Intensive Care and Emergency Medicine ((AUICEM))

Abstract

Iron is required for erythropoiesis and is also essential for many other life-sustaining functions including deoxyribonucleic acid (DNA) and neurotransmitter synthesis, mitochondrial function and the innate immune response. Despite its importance in maintaining health, iron deficiency is the most common nutritional deficiency worldwide and many of the risk factors for iron deficiency are also risk factors for developing critical illness. The result is that iron deficiency is likely to be over-represented in critically ill patients, with an estimated incidence of up to 40% at the time of intensive care unit (ICU) admission [1].

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References

  1. Bellamy MC, Gedney JA. Unrecognised iron deficiency in critical illness. Lancet. 1998;352:1903.

    Article  CAS  Google Scholar 

  2. Tacke F, Nuraldeen R, Koch A, et al. Iron parameters determine the prognosis of critically ill patients. Crit Care Med. 2016;44:1049–58.

    Article  CAS  Google Scholar 

  3. Bazuave GN, Buser A, Gerull S, Tichelli A, Stern M. Prognostic impact of iron parameters in patients undergoing allo-SCT. Bone Marrow Transplant. 2011;47:60.

    Article  Google Scholar 

  4. Fernández-Ruiz M, López-Medrano F, Andrés A, et al. Serum iron parameters in the early post-transplant period and infection risk in kidney transplant recipients. Transpl Infect Dis. 2013;15:600–11.

    Article  Google Scholar 

  5. Mohus RM, Paulsen J, Gustad L, et al. Association of iron status with the risk of bloodstream infections: results from the prospective population-based HUNT Study in Norway. Intensive Care Med. 2018;44:1276–83.

    Article  CAS  Google Scholar 

  6. Litton E, Xiao J, Ho KM. Safety and efficacy of intravenous iron therapy in reducing requirement for allogeneic blood transfusion: systematic review and meta-analysis of randomised clinical trials. BMJ. 2013;347:f4822.

    Article  Google Scholar 

  7. Litton E, Baker S, Erber WN, et al. Intravenous iron or placebo for anaemia in intensive care: the IRONMAN multicentre randomized blinded trial: a randomized trial of IV iron in critical illness. Intensive Care Med. 2016;42:1715–22.

    Article  CAS  Google Scholar 

  8. Abbaspour N, Hurrell R, Kelishadi R. Review on iron and its importance for human health. J Res Med Sci. 2014;19:164–74.

    PubMed  PubMed Central  Google Scholar 

  9. Bruner AB, Joffe A, Duggan AK, Casella JF, Brandt J. Randomised study of cognitive effects of iron supplementation in non-anaemic iron-deficient adolescent girls. Lancet. 1996;348:992–6.

    Article  CAS  Google Scholar 

  10. Brutsaert TD, Hernandez-Cordero S, Rivera J, Viola T, Hughes G, Haas JD. Iron supplementation improves progressive fatigue resistance during dynamic knee extensor exercise in iron-depleted, nonanemic women. Am J Clin Nutr. 2003;77:441–8.

    Article  CAS  Google Scholar 

  11. Weiss G, Goodnough LT. Anemia of chronic disease. N Engl J Med. 2005;352:1011–23.

    Article  CAS  Google Scholar 

  12. Bobbio-Pallavicini F, Verde G, Spriano P, et al. Body iron status in critically ill patients: significance of serum ferritin. Intensive Care Med. 1989;15:171–8.

    Article  CAS  Google Scholar 

  13. Hobisch-Hagen P, Wiedermann F, Mayr A, et al. Blunted erythropoietic response to anemia in multiply traumatized patients. Crit Care Med. 2001;29:743–7.

    Article  CAS  Google Scholar 

  14. Ganz T. Hepcidin, a key regulator of iron metabolism and mediator of anemia of inflammation. Blood. 2003;102:783–8.

    Article  CAS  Google Scholar 

  15. Thomas DW, Hinchliffe RF, Briggs C, et al. Guideline for the laboratory diagnosis of functional iron deficiency. Br J Haematol. 2013;161:639–48.

    Article  CAS  Google Scholar 

  16. Litton E, Xiao J, Allen CT, Ho KM. Iron-restricted erythropoiesis and risk of red blood cell transfusion in the intensive care unit: a prospective observational study. Anaesth Intensive Care. 2015;43:612–6.

    Article  CAS  Google Scholar 

  17. Lasocki S, Baron G, Driss F, et al. Diagnostic accuracy of serum hepcidin for iron deficiency in critically ill patients with anemia. Intensive Care Med. 2010;36:1044–8.

    Article  CAS  Google Scholar 

  18. Litton E, Baker S, Erber WN, et al. Hepcidin predicts response to IV iron therapy in patients admitted to the Intensive Care Unit: a nested cohort study. J Intensive Care. 2018;6:60.

    Article  Google Scholar 

  19. Steensma DP, Sasu BJ, Sloan JA, Tomita DK, Loprinzi CL. Serum hepcidin levels predict response to intravenous iron and darbepoetin in chemotherapy-associated anemia. Blood. 2015;125:3669–71.

    Article  CAS  Google Scholar 

  20. Westbrook A, Pettila V, Nichol A, et al. Transfusion practice and guidelines in Australian and New Zealand ICUs. Intensive Care Med. 2010;36:1138–46.

    Article  CAS  Google Scholar 

  21. Lim J, Miles L, Litton E. Intravenous iron therapy in patients undergoing cardiovascular surgery: a narrative review. J Cardiothorac Vasc Anesth. 2018;32:1439–51.

    Article  Google Scholar 

  22. Klein AA, Collier T, Yeates J, et al. The ACTA PORT-score for predicting perioperative risk of blood transfusion for adult cardiac surgery. Br J Anaesth. 2017;119:394–401.

    Article  CAS  Google Scholar 

  23. Munoz M, Acheson AG, Auerbach M, et al. International consensus statement on the peri-operative management of anaemia and iron deficiency. Anaesthesia. 2017;72:233–47.

    Article  CAS  Google Scholar 

  24. Ng O, Keeler BD, Mishra A, Simpson A, Neal K, Brookes MJ, Acheson AG. Iron therapy for pre-operative anaemia. Cochrane Database Syst Rev. 2015:CD011588.

    Google Scholar 

  25. Shah A, Roy NB, McKechnie S, Doree C, Fisher SA, Stanworth SJ. Iron supplementation to treat anaemia in adult critical care patients: a systematic review and meta-analysis. Crit Care. 2016;20:306.

    Article  Google Scholar 

  26. Connor JR, Zhang X, Nixon AM, Webb B, Perno JR. Comparative evaluation of nephrotoxicity and management by macrophages of intravenous pharmaceutical iron formulations. PLoS One. 2015;10:e0125272.

    Article  Google Scholar 

  27. Pandharipande PP, Girard TD, Jackson JC, et al. Long-term cognitive impairment after critical illness. N Engl J Med. 2013;369:1306–16.

    Article  CAS  Google Scholar 

  28. Youdim MB, Yehuda S. The neurochemical basis of cognitive deficits induced by brain iron deficiency: involvement of dopamine-opiate system. Cell Mol Biol. 2000;46:491–500.

    CAS  PubMed  Google Scholar 

  29. Lozoff B. Early iron deficiency has brain and behavior effects consistent with dopaminergic dysfunction. J Nutr. 2011;141:740S–6S.

    Article  CAS  Google Scholar 

  30. Favrat B, Balck K, Breymann C, et al. Evaluation of a single dose of ferric carboxymaltose in fatigued, iron-deficient women—PREFER a randomized, placebo-controlled study. PLoS One. 2014;9:e94217.

    Article  Google Scholar 

  31. Guarneri B, Bertolini G, Latronico N. Long-term outcome in patients with critical illness myopathy or neuropathy: the Italian multicentre CRIMYNE study. J Neurol Neurosurg Psychiatry. 2008;79:838–41.

    Article  CAS  Google Scholar 

  32. Lasocki S, Chudeau N, Papet T, et al. Prevalence of iron deficiency on ICU discharge and its relation with fatigue: a multicenter prospective study. Crit Care. 2014;18:542.

    Article  Google Scholar 

  33. Jankowska EA, Kasztura M, Sokolski M, et al. Iron deficiency defined as depleted iron stores accompanied by unmet cellular iron requirements identifies patients at the highest risk of death after an episode of acute heart failure. Eur Heart J. 2014;35:2468–76.

    Article  CAS  Google Scholar 

  34. Jankowska EA, Tkaczyszyn M, Suchocki T, et al. Effects of intravenous iron therapy in iron-deficient patients with systolic heart failure: a meta-analysis of randomized controlled trials. Eur J Heart Fail. 2016;18:786–95.

    Article  CAS  Google Scholar 

  35. Maeder MT, Khammy O, dos Remedios C, Kaye DM. Myocardial and systemic iron depletion in heart failure: implications for anemia accompanying heart failure. J Am Coll Cardiol. 2011;58:474–80.

    Article  CAS  Google Scholar 

  36. Ramakrishnan L, Pedersen SL, Toe QK, Quinlan GJ, Wort SJ. Pulmonary arterial hypertension: iron matters. Front Physiol. 2018;9:641.

    Article  Google Scholar 

  37. Zochios V, Parhar K, Tunnicliffe W, Roscoe A, Gao F. The right ventricle in ARDS. Chest. 2017;152:181–93.

    Article  Google Scholar 

  38. Cassat JE, Skaar EP. Iron in infection and immunity. Cell Host Microbe. 2013;13:509–19.

    Article  CAS  Google Scholar 

  39. Ganz T. Iron and infection. Int J Hematol. 2018;107:7–15.

    Article  CAS  Google Scholar 

  40. Puntarulo S. Iron, oxidative stress and human health. Mol Asp Med. 2005;26:299–312.

    Article  CAS  Google Scholar 

  41. Neuberger A, Okebe J, Yahav D, Paul M. Oral iron supplements for children in malaria-endemic areas. Cochrane Database Syst Rev. 2016:CD006589.

    Google Scholar 

  42. Agarwal R, Kusek JW, Pappas MK. A randomized trial of intravenous and oral iron in chronic kidney disease. Kidney Int. 2015;88:905–14.

    Article  CAS  Google Scholar 

  43. Anker SD, Comin Colet J, Filippatos G, et al. Ferric carboxymaltose in patients with heart failure and iron deficiency. N Engl J Med. 2009;361:2436–48.

    Article  CAS  Google Scholar 

  44. Pammi M, Suresh G. Enteral lactoferrin supplementation for prevention of sepsis and necrotizing enterocolitis in preterm infants. Cochrane Database Syst Rev. 2017:CD007137.

    Google Scholar 

  45. Muscedere J, Maslove DM, Boyd JG, et al. Prevention of nosocomial infections in critically ill patients with lactoferrin: a randomized, double-blind, placebo-controlled study. Crit Care Med. 2018;46:1450–6.

    Article  CAS  Google Scholar 

  46. Sebastiani G, Wilkinson N, Pantopoulos K. Pharmacological targeting of the hepcidin/ferroportin axis. Front Pharmacol. 2016;7:160.

    Article  Google Scholar 

  47. Balhara M, Chaudhary R, Ruhil S, et al. Siderophores; iron scavengers: the novel & promising targets for pathogen specific antifungal therapy. Expert Opin Ther Targets. 2016;20:1477–89.

    Article  CAS  Google Scholar 

  48. Kim YW, Bae JM, Park YK, et al. Effect of intravenous ferric carboxymaltose on hemoglobin response among patients with acute isovolemic anemia following gastrectomy: the FAIRY randomized clinical trial. JAMA. 2017;317:2097–104.

    Article  CAS  Google Scholar 

  49. Johansson PI, Rasmussen AS, Thomsen LL. Intravenous iron isomaltoside 1000 (Monofer®) reduces postoperative anaemia in preoperatively non-anaemic patients undergoing elective or subacute coronary artery bypass graft, valve replacement or a combination thereof: a randomized double-blind placebo-controlled clinical trial (the PROTECT trial). Vox Sang. 2015;109:257–66.

    Article  CAS  Google Scholar 

  50. Bernabeu-Wittel M, Romero M, Ollero-Baturone M, et al. Ferric carboxymaltose with or without erythropoietin in anemic patients with hip fracture: a randomized clinical trial. Transfusion. 2016;56:2199–211.

    Article  CAS  Google Scholar 

  51. Froessler B, Palm P, Weber I, Hodyl NA, Singh R, Murphy EM. The important role for intravenous iron in perioperative patient blood management in major abdominal surgery: a randomized controlled trial. Ann Surg. 2016;264:41–6.

    Article  Google Scholar 

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Authors and Affiliations

  1. Intensive Care Unit, Fiona Stanley Hospital, Perth, WA, Australia

    E. Litton & J. Lim

  2. School of Medicine, University of Western Australia, Perth, WA, Australia

    E. Litton

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  1. E. Litton
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  2. J. Lim
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Correspondence to E. Litton .

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Editors and Affiliations

  1. Dept. of Intensive Care, Erasme Hospital, Université libre de Bruxelles, Brussels, Belgium

    Jean-Louis Vincent

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Litton, E., Lim, J. (2019). Iron Metabolism: An Emerging Therapeutic Target in Critical Illness. In: Vincent, JL. (eds) Annual Update in Intensive Care and Emergency Medicine 2019. Annual Update in Intensive Care and Emergency Medicine. Springer, Cham. https://doi.org/10.1007/978-3-030-06067-1_44

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  • DOI: https://doi.org/10.1007/978-3-030-06067-1_44

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