Anaemia in Surgical Sepsis and Stress: The Roles of Erythropoietin, Iron and Steroids

Michael Smits¹, Colby Hart², Gausihi Sivarajah³, Matija Radojcic^1, and Saleh Abbas⁴

¹Department of Surgery, Austin Health, Heidelberg, Victoria, Australia

²Department of Surgery, Alfred Health, Melbourne, Victoria, Australia

³Department of Surgery, St Vincent’s Hospital, Fitzroy, Melbourne, Australia

⁴Department of Surgery, University Hospital Geelong, Geelong, Australia

Cite this paper:
Michael Smits, Colby Hart, Gausihi Sivarajah, Matija Radojcic and Saleh Abbas. Anaemia in Surgical Sepsis and Stress: The Roles of Erythropoietin, Iron and Steroids. Global Journal of Surgery. 2019; 7(1):12-18. doi: 10.12691/js-7-1-3

Abstract

Background: Inflammation in surgical sepsis and stress frequently causes anaemia, leading to increased rates of blood transfusions. Recent evidence shows that blood transfusions carry a greater risk for short- and long-term complications than previously thought. Objective: To review the role of erythropoietin (EPO), iron and/or steroids as an alternative treatment to blood transfusions in critically ill patients. Methodology: A systematic review was prepared from recent literature on inflammation-induced anaemia, anaemia in the critically ill and/or septic patient and the roles of EPO, iron and corticosteroids in these patients. A meta-analysis was completed for EPO. Results: Inflammatory cytokines alter haematopoietic and biochemical pathways, leading to anaemia. Inflammation decreases circulating EPO and upregulates hepcidin, resulting in decreased free iron. Twelve randomised-controlled trials demonstrate that EPO administration in critically ill patients reduces the need for blood transfusions by 31% (p=0.005) however does not significantly decrease mortality (p=0.15). Intravenous iron also reduces the need for blood transfusions but has not been utilised in sepsis-associated anaemia. No trials focusing on the effects of steroids on sepsis-associated anaemia were identified. Conclusion: Due to the lack of data specific to sepsis-associated anaemia in post-operative patients, the roles of EPO, iron and steroids remain under investigation. More research specific to surgical patients is needed.

Keywords:
anaemia sepsis erythropoietin iron steroids

This work is licensed under a Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

References:

[1]	Moore LJ, Moore FA, Todd SR, Jones SL, Turner KL, Bass BL. Sepsis in General Surgery. Arch Surg [Internet]. American Medical Association; 2010 Jul 1; 145(7): 695-700.
[2]	Piagnerelli M, Boudjeltia K, BOUDJELTIA KZ, GULBIS B, Gulbis B, et al. Anemia in sepsis: the importance of red blood cell membrane changes. Transfus Alternat Transfus Med [Internet]. 2007 Sep; 9(3): 143-9.
[3]	Vamvakas EC, Blajchman MA. Transfusion-related mortality: the ongoing risks of allogeneic blood transfusion and the available strategies for their prevention. Blood [Internet]. American Society of Hematology; 2009 Apr 9; 113(15): 3406-17.
[4]	Roback JD. Non-Infectious complications of blood transfusion. 17 ed. Bethesda: AABB; 2011.
[5]	Karim F, Moiz B, Shamsuddin N, Naz S, Khurshid M. Root cause analysis of non-infectious transfusion complications and the lessons learnt. Transfusion and Apheresis Science [Internet]. Elsevier; 2014 Feb; 50(1): 111-7.
[6]	Bernard AC, Davenport DL, Chang PK, Vaughan TB, Zwischenberger JB. Intraoperative Transfusion of 1 U to 2 U Packed Red Blood Cells Is Associated with Increased 30-Day Mortality, Surgical-Site Infection, Pneumonia, and Sepsis in General Surgery Patients. Journal of the American College of Surgeons [Internet]. Elsevier; 2009 May; 208(5): 931-2.
[7]	Weber EWG, Slappendel R, Prins MH, van der Schaaf DB, Durieux ME, Str mper D, et al. Perioperative Blood Transfusions and Delayed Wound Healing After Hip Replacement Surgery: Effects on Duration of Hospitalization. Anesthesia & Analgesia [Internet]. 2005 May; 100(5): 1416-21.
[8]	Surgenor SD, Kramer RS, Olmstead EM, Ross CS, Sellke FW, Likosky DS, et al. The Association of Perioperative Red Blood Cell Transfusions and Decreased Long-Term Survival After Cardiac Surgery. Anesthesia & Analgesia [Internet]. 2009 Jun; 108(6): 1741-6.
[9]	Taylor RW, Manganaro L, O'Brien J, Trottier SJ, Parkar N, Veremakis C. Impact of allogenic packed red blood cell transfusion on nosocomial infection rates in the critically ill patient. Critical Care Medicine [Internet]. 2002 Oct; 30(10): 2249-54.
[10]	Raghavan M, Marik PE. Anemia, Allogenic Blood Transfusion, and Immunomodulation in the Critically Ill. Chest [Internet]. American College of Chest Physicians; 2005 Jan; 127(1): 295-307.
[11]	Toy P, Popovsky MA, Abraham E, Ambruso DR, Holness LG, Kopko PM, et al. Transfusion-related acute lung injury: definition and review. Critical Care Medicine [Internet]. 2005 Apr; 33(4): 721-6.
[12]	Heiss MM, Mempel W, Delanoff C, Jauch KW, Gabka C, Mempel M, et al. Blood transfusion-modulated tumor recurrence: first results of a randomized study of autologous versus allogeneic blood transfusion in colorectal cancer surgery. Journal of clinical oncology: official journal of the American Society of Clinical Oncology [Internet]. 1994 Sep; 12(9): 1859-67.
[13]	Shiba H, Ishida Y, Wakiyama S, Iida T, Matsumoto M, Sakamoto T, et al. Negative Impact of Blood Transfusion on Recurrence and Prognosis of Hepatocellular Carcinoma After Hepatic Resection. J Gastrointest Surg [Internet]. Springer-Verlag; 2009 Jul 7; 13(9): 1636-42.
[14]	Cata JP, Wang H, Gottumukkala V, Reuben J, Sessler DI. Inflammatory response, immunosuppression, and cancer recurrence after perioperative blood transfusions. British Journal of Anaesthesia [Internet]. 2013 Apr 18; 110(5): 690-701.
[15]	Holst LB, Haase N, Wetterslev J, Wernerman J, Guttormsen AB, Karlsson S, et al. Lower versus Higher Hemoglobin Threshold for Transfusion in Septic Shock. N Engl J Med [Internet]. 2014 Oct 9; 371(15): 1381-91.
[16]	Corwin HL, Gettinger A, Pearl RG, Fink MP, Levy MM, Abraham E, et al. The CRIT Study: Anemia and blood transfusion in the critically ill—Current clinical practice in the United States*. Critical Care Medicine [Internet]. 2004 Jan; 32(1):39-52.
[17]	Juffermans NP, Prins DJ, Vlaar APJ, Nieuwland R, Binnekade JM. Transfusion-Related Risk of Secondary Bacterial Infections in Sepsis Patients. Shock [Internet]. 2011 Apr; 35(4): 355-9.
[18]	Vincent J, Baron J-F, Reinhart K, Gattinoni L, Thijs L, Webb A, et al. Anemia and blood transfusion in critically ill patients. JAMA: the journal of the American Medical Association [Internet]. 2002 Sep 25; 288(12): 1499-507.
[19]	Hayden SJ, Albert TJ, Watkins TR, Swenson ER. Anemia in Critical Illness. Am J Respir Crit Care Med [Internet]. 2012 May 15; 185(10): 1049-57.
[20]	Rogiers P, Zhang H, Leeman M, Nagler J, Neels H, Mélot C, et al. Erythropoietin response is blunted in critically ill patients. Intensive Care Med [Internet]. 1997 Feb; 23(2): 159-62.
[21]	Piagnerelli M, Cotton F, Herpain A, Rapotec A, Chatti R, Gulbis B, et al. Time course of iron metabolism in critically ill patients. Acta clinica Belgica [Internet]. 2013 Jan; 68(1): 22-7.
[22]	Walsh TS, Wyncoll DL, Stanworth SJ. Managing anaemia in critically ill adults. BMJ [Internet]. 2010 Sep 3;341 (sep03 1): c4408-8.
[23]	Jacober MLV, Mamoni RL, Lima CSP, Anjos Dos BL, Grotto HZW. Anaemia in patients with cancer: role of inflammatory activity on iron metabolism and severity of anaemia. Medical oncology (Northwood, London, England) [Internet]. 2007; 24(3): 323-9.
[24]	Shinoda N, Sullivan KM, Tripp K, Erhardt JG, Haynes BM, Temple VJ, et al. Relationship between markers of inflammation and anaemia in children of Papua New Guinea. Public Health Nutr [Internet]. 2012 May 21; 16(02): 289-95.
[25]	Faquin WC, Schneider TJ, Goldberg MA. Effect of inflammatory cytokines on hypoxia-induced erythropoietin production. Blood [Internet]. 1992 Apr 15; 79(8): 1987-94.
[26]	Jelkmann W. Proinflammatory Cytokines Lowering Erythropoietin Production. Journal of Interferon & Cytokine Research [Internet]. 1998 Aug; 18(8): 555-9.
[27]	Okonko DO, Marley SB, Anker SD, Poole-Wilson PA, Gordon MY. Suppression of erythropoiesis in patients with chronic heart failure and anaemia of unknown origin: evidence of an immune basis. International Journal of Cardiology [Internet]. Elsevier Ireland Ltd; 2013 Jul; 166(3): 664-71.
[28]	Lang KS, Duranton C, Poehlmann H, Myssina S, Bauer C, Lang F, et al. Cation channels trigger apoptotic death of erythrocytes. Cell Death Differ [Internet]. 2003 Feb; 10(2): 249-56.
[29]	Fleming RE, Sly WS. Hepcidin: A putative iron-regulatory hormone relevant to hereditary hemochromatosis and the anemia of chronic disease. Proceedings of the National Academy of Sciences [Internet]. National Acad Sciences; 2001 Jul 17; 98(15): 8160-2.
[30]	Nemeth E, Tuttle MS, Powelson J, Vaughn MB, Donovan A, et al. Hepcidin Regulates Cellular Iron Efflux by Binding to Ferroportin and Inducing Its Internalization. Science [Internet]. 2004 Dec 17; 306(5704): 2090-3.
[31]	McKie AT, Marciani P, Rolfs A, Brennan K, Wehr K, Barrow D, et al. A novel duodenal iron-regulated transporter, IREG1, implicated in the basolateral transfer of iron to the circulation. Molecular cell [Internet]. 2000 Feb; 5(2): 299-309.
[32]	Sonnweber T, Nachbaur D, Schroll A, Nairz M, Seifert M, Demetz E, et al. Hypoxia induced downregulation of hepcidin is mediated by platelet derived growth factor BB. Gut [Internet]. BMJ Publishing Group Ltd and British Society of Gastroenterology; 2014 Oct 31; 63(12): 1951-9.
[33]	Kemna E, Kemna E, Pickkers P, Nemeth E, van der Hoeven H, Swinkels D. Time-course analysis of hepcidin, serum iron, and plasma cytokine levels in humans injected with LPS. Blood [Internet]. 2005 Sep 1; 106(5): 1864-6.
[34]	van Eijk LT, Kroot JJ, Kroot JJC, Tromp M, van der Hoeven JG, Swinkels DW, et al. Inflammation-induced hepcidin-25 is associated with the development of anemia in septic patients: an observational study. Crit Care [Internet]. BioMed Central Ltd; 2011; 15(1): R9.
[35]	Broudy VC, Lin NL, Priestley GV, Nocka K, Wolf NS. Interaction of stem cell factor and its receptor c-kit mediates lodgment and acute expansion of hematopoietic cells in the murine spleen. Blood [Internet]. 1996 Jul 1; 88(1): 75-81.
[36]	Bauer A, Tronche F, Wessely O, Kellendonk C, Reichardt HM, Steinlein P, et al. The glucocorticoid receptor is required for stress erythropoiesis. Genes & development [Internet]. 1999 Nov 15; 13(22): 2996-3002.
[37]	Maxime V, Lesur O, Annane D. Adrenal Insufficiency in Septic Shock. Clinics in Chest Medicine [Internet]. 2009 Mar; 30(1): 17-27.
[38]	Beishuizen A, Thijs LG, Vermes I. Patterns of corticosteroid-binding globulin and the free cortisol index during septic shock and multitrauma. Intensive Care Med [Internet]. 2014 Apr 21; 27(10): 1584-91.
[39]	Huang ZH, Gao H, Xu RB. Study on glucocorticoid receptors during intestinal ischemia shock and septic shock. Circulatory shock [Internet]. 1987; 23(1): 27-36.
[40]	Still JM, Belcher K, Law EJ, Thompson W, Jordan M, Lewis M, et al. A double-blinded prospective evaluation of recombinant human erythropoietin in acutely burned patients. J Trauma [Internet]. 1995 Feb; 38(2): 233-6.
[41]	van Iperen CE, Gaillard CA, Kraaijenhagen RJ, Braam BG, Marx JJ, van de Wiel A. Response of erythropoiesis and iron metabolism to recombinant human erythropoietin in intensive care unit patients. Critical Care Medicine [Internet]. 2000 Aug; 28(8): 2773-8.
[42]	Georgopoulos D, Matamis D, Routsi C, Michalopoulos A, Maggina N, Dimopoulos G, et al. Recombinant human erythropoietin therapy in critically ill patients: a dose-response study [ISRCTN48523317]. Crit Care [Internet]. BioMed Central Ltd; 2005; 9(5): R508-15.
[43]	Silver M, Corwin MJ, Bazan A, Gettinger A, Enny C, Corwin HL. Efficacy of recombinant human erythropoietin in critically ill patients admitted to a long-term acute care facility: A randomized, double-blind, placebo-controlled trial*. Critical Care Medicine [Internet]. 2006 Sep; 34(9): 2310-6.
[44]	Corwin HL, Gettinger A, Fabian TC, May A, Pearl RG, Heard S, et al. Efficacy and Safety of Epoetin Alfa in Critically Ill Patients. N Engl J Med [Internet]. 2007 Sep 6; 357(10): 965-76.
[45]	Corwin HL, Gettinger A, Rodriguez RM, Pearl RG, Gubler KD, Enny C, et al. Efficacy of recombinant human erythropoietin in the critically ill patient: a randomized, double-blind, placebo-controlled trial. Critical Care Medicine [Internet]. 1999 Nov; 27(11): 2346-50.
[46]	Corwin HL, Gettinger A, Pearl RG, Fink MP, Levy MM, Shapiro MJ, et al. Efficacy of recombinant human erythropoietin in critically ill patients: a randomized controlled trial. JAMA: the journal of the American Medical Association [Internet]. 2002 Dec 11; 288(22): 2827-35.
[47]	Gabriel A, Kozek S, Chiari A, Fitzgerald R, Grabner C, Geissler K, et al. High-dose recombinant human erythropoietin stimulates reticulocyte production in patients with multiple organ dysfunction syndrome. J Trauma [Internet]. 1998 Feb; 44(2): 361-7.
[48]	Luchette FA, Pasquale MD, Fabian TC, Langholff WK, Wolfson M. A randomized, double-blind, placebo-controlled study to assess the effect of recombinant human erythropoietin on functional outcomes in anemic, critically ill, trauma subjects: the Long Term Trauma Outcomes Study. The American Journal of Surgery [Internet]. Elsevier; 2012 Apr; 203(4): 508-16.
[49]	Madi-Jebara SN, Sleilaty GS, Achouh PE, Yazigi AG, Haddad FA, Hayek GM, et al. Postoperative intravenous iron used alone or in combination with low-dose erythropoietin is not effective for correction of anemia after cardiac surgery. Journal of Cardiothoracic and Vascular Anesthesia [Internet]. 2004 Feb; 18(1): 59-63.
[50]	de Seigneux S, Ponte B, Weiss L, Pugin J, Romand JA, Martin P-Y, et al. Epoetin administrated after cardiac surgery: effects on renal function and inflammation in a randomized controlled study. BMC Nephrol [Internet]. BioMed Central Ltd; 2012 Oct 3; 13(1): 14.
[51]	VINCENT J-L, Vincent J, Spapen HDMH, Creteur J, Piagnerelli M, PIAGNERELLI M, et al. Pharmacokinetics and pharmacodynamics of once-weekly subcutaneous epoetin alfa in critically ill patients: Results of a randomized, double-blind, placebo-controlled trial*. Critical Care Medicine [Internet]. 2006 Jun; 34(6): 1661-7.
[52]	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 [Internet]. 2013; 347: f4822.
[53]	Pieracci FM, Barie PS. Iron and the Risk of Infection. Surgical Infections [Internet]. 2005 Jun;6(s1): s41-6.
[54]	Ashby DR, Gale DP, Busbridge M, Murphy KG, Duncan ND, Cairns TD, et al. Plasma hepcidin levels are elevated but responsive to erythropoietin therapy in renal disease. Kidney International [Internet]. 2009 May; 75(9): 976-81.
[55]	Cooke KS, Cooke KS, Hinkle B, Hinkle B, Salimi-Moosavi H, Salimi-Moosavi H, et al. A fully human anti-hepcidin antibody modulates iron metabolism in both mice and nonhuman primates. Blood [Internet]. 2013 Oct 24; 122(17): 3054-61.
[56]	Annane D, Bellissant E, Bollaert P-E, Briegel J, Confalonieri M, De Gaudio R, et al. Corticosteroids in the Treatment of Severe Sepsis and Septic Shock in Adults. JAMA [Internet]. 2009 Jun 10; 301(22): 2362-75.
[57]	Annane D, Sébille V, Charpentier C, Bollaert P-E, François B, Korach J-M, et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA: the journal of the American Medical Association [Internet]. 2002 Aug 21; 288(7): 862-71.
[58]	The Surviving Sepsis Campaign Guidelines Committee including The Pediatric Subgroup*, Dellinger RP, Levy MM, Rhodes A, Gerlach H, Annane D, et al. Surviving Sepsis Campaign: International Guidelines for Management of Severe Sepsis and Septic Shock, 2012. Intensive Care Med [Internet]. Springer-Verlag; 2013 Jan 30; 39(2): 165-228.
[59]	Retter A, Wyncoll D, Pearse R, Carson D, McKechnie S, Stanworth S, et al. Guidelines on the management of anaemia and red cell transfusion in adult critically ill patients. Br J Haematol [Internet]. 2012 Dec 27; 160(4): 445-64.
[60]	Hoen B, Paul-Dauphin A, Kessler M. Intravenous iron administration does not significantly increase the risk of bacteremia in chronic hemodialysis patients. Clinical nephrology [Internet]. 2002 Jun; 57(6): 457-61.
[61]	Heming N, Lettéron P, Driss F, Millot S, Benna El J, Tourret J, et al. Efficacy and toxicity of intravenous iron in a mouse model of critical care anemia*. Critical Care Medicine [Internet]. 2012 Jul; 40(7): 2141-8.