Iron Metabolism: An Emerging Therapeutic Target in Critical Illness

  • E. LittonEmail author
  • J. Lim
Part of the Annual Update in Intensive Care and Emergency Medicine book series (AUICEM)


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].


  1. 1.
    Bellamy MC, Gedney JA. Unrecognised iron deficiency in critical illness. Lancet. 1998;352:1903.CrossRefGoogle Scholar
  2. 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.CrossRefGoogle Scholar
  3. 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.CrossRefGoogle Scholar
  4. 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.CrossRefGoogle Scholar
  5. 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.CrossRefGoogle Scholar
  6. 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.CrossRefGoogle Scholar
  7. 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.CrossRefGoogle Scholar
  8. 8.
    Abbaspour N, Hurrell R, Kelishadi R. Review on iron and its importance for human health. J Res Med Sci. 2014;19:164–74.PubMedPubMedCentralGoogle Scholar
  9. 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.CrossRefGoogle Scholar
  10. 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.CrossRefGoogle Scholar
  11. 11.
    Weiss G, Goodnough LT. Anemia of chronic disease. N Engl J Med. 2005;352:1011–23.CrossRefGoogle Scholar
  12. 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.CrossRefGoogle Scholar
  13. 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.CrossRefGoogle Scholar
  14. 14.
    Ganz T. Hepcidin, a key regulator of iron metabolism and mediator of anemia of inflammation. Blood. 2003;102:783–8.CrossRefGoogle Scholar
  15. 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.CrossRefGoogle Scholar
  16. 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.CrossRefGoogle Scholar
  17. 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.CrossRefGoogle Scholar
  18. 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.CrossRefGoogle Scholar
  19. 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.CrossRefGoogle Scholar
  20. 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.CrossRefGoogle Scholar
  21. 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.CrossRefGoogle Scholar
  22. 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.CrossRefGoogle Scholar
  23. 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.CrossRefGoogle Scholar
  24. 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. 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.CrossRefGoogle Scholar
  26. 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.CrossRefGoogle Scholar
  27. 27.
    Pandharipande PP, Girard TD, Jackson JC, et al. Long-term cognitive impairment after critical illness. N Engl J Med. 2013;369:1306–16.CrossRefGoogle Scholar
  28. 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.PubMedGoogle Scholar
  29. 29.
    Lozoff B. Early iron deficiency has brain and behavior effects consistent with dopaminergic dysfunction. J Nutr. 2011;141:740S–6S.CrossRefGoogle Scholar
  30. 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.CrossRefGoogle Scholar
  31. 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.CrossRefGoogle Scholar
  32. 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.CrossRefGoogle Scholar
  33. 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.CrossRefGoogle Scholar
  34. 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.CrossRefGoogle Scholar
  35. 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.CrossRefGoogle Scholar
  36. 36.
    Ramakrishnan L, Pedersen SL, Toe QK, Quinlan GJ, Wort SJ. Pulmonary arterial hypertension: iron matters. Front Physiol. 2018;9:641.CrossRefGoogle Scholar
  37. 37.
    Zochios V, Parhar K, Tunnicliffe W, Roscoe A, Gao F. The right ventricle in ARDS. Chest. 2017;152:181–93.CrossRefGoogle Scholar
  38. 38.
    Cassat JE, Skaar EP. Iron in infection and immunity. Cell Host Microbe. 2013;13:509–19.CrossRefGoogle Scholar
  39. 39.
    Ganz T. Iron and infection. Int J Hematol. 2018;107:7–15.CrossRefGoogle Scholar
  40. 40.
    Puntarulo S. Iron, oxidative stress and human health. Mol Asp Med. 2005;26:299–312.CrossRefGoogle Scholar
  41. 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. 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.CrossRefGoogle Scholar
  43. 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.CrossRefGoogle Scholar
  44. 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. 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.CrossRefGoogle Scholar
  46. 46.
    Sebastiani G, Wilkinson N, Pantopoulos K. Pharmacological targeting of the hepcidin/ferroportin axis. Front Pharmacol. 2016;7:160.CrossRefGoogle Scholar
  47. 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.CrossRefGoogle Scholar
  48. 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.CrossRefGoogle Scholar
  49. 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.CrossRefGoogle Scholar
  50. 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.CrossRefGoogle Scholar
  51. 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.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Intensive Care UnitFiona Stanley HospitalPerthAustralia
  2. 2.School of MedicineUniversity of Western AustraliaPerthAustralia

Personalised recommendations