Critical Care Medicine (C) 2000 Lippincott Williams & Wilkins, Inc. Volume 28(8), August 2000, pp 3098-3099 Anemia of the critically ill: "Acute" anemia of chronic disease [Editorials] Corwin, Howard L. MD, FCCM; Krantz, Sanford B. MD Dartmouth Medical School Dartmouth-Hitchcock Medical Center Lebanon, NH Vanderbilt University School of Medicine VA Medical Center Nashville, TN Supported, in part, by Ortho Biotech Inc. Address requests for reprints to: Howard L. Corwin, MD, Dartmouth-Hitchcock Medical Center, One Medical Center Drive, Lebanon, NH 03756-0001. ---------------------------------------------- Outline REFERENCES Anemia is common in the critically ill. By intensive care unit (ICU) day 3, ~95% of patients have hemoglobin concentrations below normal (1). Phlebotomy and gastrointestinal blood loss contribute significantly to the development of this anemia (2, 3). However, it is becoming increasingly apparent that red cell production of critically ill patients is not normal and is also involved in the development and maintenance of the anemia observed in the critically ill. In this current issue of Critical Care Medicine, Dr. van Iperen and colleagues (4) demonstrate a blunted endogenous erythropoietin (EPO) response to anemia as well as iron studies consistent with inflammation (low serum iron, low transferrin and transferrin saturation, and high serum ferritin concentrations), and these patients exhibit a bone marrow response to exogenous EPO. This study adds to a growing literature suggesting that the anemia observed in the critically ill is an underproduction anemia consistent with what is commonly referred to as the anemia of chronic inflammatory disease. More than 90% of ICU patients have low serum iron, total iron binding capacity, and serum iron/total iron binding capacity ratio but do have a normal or, more usually, an elevated serum ferritin concentration (1). Similarly, Gabriel et al. (5) noted low iron variables and elevated ferritin concentrations in patients with multiple organ dysfunction. At a time when iron studies are abnormal, serum EPO concentrations are only mildly elevated, with little evidence of reticulocyte response to endogenous EPO (1). Rogiers et al. (6) compared EPO concentrations in critically ill patients with those in patients with iron-deficiency anemia. Although EPO concentrations were somewhat elevated compared with adults without anemia, they were significantly lower as compared with patients with iron-deficiency anemia, despite similar hematocrits. A comparably blunted EPO response to physiologic stimuli also has been reported in critically ill children (7). This blunted EPO response observed in the critically ill appears to result from inhibition of the EPO gene by inflammatory mediators (8, 9). It has been shown that these same inflammatory cytokines directly inhibit red cell production by the bone marrow and may produce the distinct abnormalities of iron metabolism (10, 11). Concentrations of interleukin-1 are elevated in patients with rheumatoid arthritis and are proportional to the degree of anemia. Interleukin-1 activates T lymphocytes, which increase the production of interferon-[gamma], which in turn, directly inhibits red cell production in vitro. Likewise, concentrations of tumor necrosis factor are elevated in patients with inflammatory and infectious diseases and cancer. Tumor necrosis factor also inhibits erythropoiesis both in vitro and when administered to human beings (12). Thus, the anemia of chronic disease is an anemia of immune activation in reaction to new foreign antigens (bacteria, parasites, viruses, neoplasms), with the production of cytokines that inhibit the action of EPO on bone marrow cells and the production of EPO by the kidney, thereby producing an underproduction anemia. As reported by van Iperen and colleagues (4), the bone marrow of critically ill patients is able to respond to the administration of exogenous EPO. A similar response to exogenous EPO has also been reported in patients with multiple organ failure (5). This suggests a possible role for pharmacologic doses of EPO in the treatment of critically ill patients to reduce blood transfusions and to raise hemoglobin concentrations. In a recently reported randomized, controlled trial (13), the administration of EPO to critically ill patients resulted in an ~50% reduction in blood transfusions. Despite the reduced number of blood transfusions, hemoglobin concentrations were significantly higher in those patients receiving EPO. Avoidance of blood transfusion is becoming increasingly important as more data linking blood transfusion to adverse clinical outcomes in critically ill patients accumulates. Blood transfusion clearly has effects on the immune system, which may persist long after transfusion (14, 15). There is also concern that transfusion of "old" blood may be associated with significant adverse effects in critically ill patients (16, 17). Recently, Hebert et al. (18) demonstrated that a more liberal transfusion strategy is associated with increased morbidity and mortality in some critically ill patients. Although the optimal hemoglobin in critically ill patients remains to be determined, EPO may help to answer this question by allowing patients to achieve higher hemoglobin concentrations without exposure to the negative effects of transfused blood. It is now clear that the view that anemia in the critically ill is simply the result of excess phlebotomy by "medical vampires" is inaccurate (19). Rather, the anemia of critical illness is a distinct clinical entity characterized by a blunted EPO production and abnormalities in iron metabolism identical to what is commonly referred to as the anemia of chronic disease. As such, the bone marrow in many of these patients responds to the administration of exogenous EPO, despite their critical illness. This may present a thera- peutic option for the treatment of the anemia of critical illness. REFERENCES 1. Corwin HL, Rodriguez RM, Pearl RG, et al: Erythropoietin response in critically ill patients. Crit Care Med 1997; 25 (Suppl 1): A82 2. Corwin HL, Parsonnet K, Gettinger A: Blood transfusion in the ICU: Is there a reason? Chest 1995; 108: 767-771 Bibliographic Links 3. Brown RB, Klar J, Teres D, et al: Prospective study of clinical bleeding in intensive care unit patients. Crit Care Med 1988; 16: 1171-1176 Ovid Full Text 4. Gabriel A, Kozek S, Chiari A, et al: High-dose recombinant human erythropoietin stimulates reticulocyte production in patients with multiple organ dysfuction syndrome. J Trauma 1998; 44: 361-367 Ovid Full Text Bibliographic Links 5. van Iperen CE, Gaillard CAJM, Kraaijenhagen RJ, et al: Response of erythropoiesis and iron metabolism to recombinant human erythropoietin in intensive care unit patients. Crit Care Med 2000; 28: 2773-2778 Ovid Full Text 6. Rogiers P, Zhang H, Leeman M, et al: Erythropoietin response is blunted in critically ill patients. Intensive Care Med 1997; 23: 159-162 7. Krafte-Jacobs B, Levetown ML, Bray GL, et al: Erythropoietin response to critical illness. Crit Care Med 1994; 22: 821-826 Ovid Full Text Bibliographic Links 8. Frede S, Fandrey J, Pagel H, et al: Erythropoieitn gene expression is suppressed after lipopolysaccharide or interluekin-1B injections in rats. Am J Physiol 1997; 272: R1067-R1071 9. Jelkmann W: Proinflammatory cytikines lowering erythropoieitn production. J Interferon Cytokine Res 1998; 18: 555-559 Bibliographic Links 10. Means RT, Krantz SB: Progress in understanding the pathogenesis of the anemia of chronic disease. Blood 1992; 80: 1639-1647 Bibliographic Links 11. Krantz SB: Pathogenesis and treatment of the anemia of chronic disease. Am J Med Sci 1994; 307: 353-359 Ovid Full Text Bibliographic Links 12. Blick M, Sherwin SA, Rosenblum M, et al: Phase I study of recombinant tumor necrosis factor in cancer patients. Cancer Res 1987; 47: 2986-2989 13. Corwin HL, Gettinger A, Rodriguez RM, et al: Efficacy of recombinant human erythropoietin in the critically ill patient: A randomized double blind placebo controlled trial. Crit Care Med 1999; 27: 2346-2350 Ovid Full Text 14. Blumberg N, Heal JM: Blood transfusion: The silent epidemic. Arch Pathol Lab Med 1998; 122: 117-118 15. Mickler TA, Longnecker DE: The immunosuppressive aspects of blood transfusion. J Intensive Care Med 1992; 7: 176-188 16. Marik PE, Sibbaid WJ: Effect of stored-blood transfusion on oxygen delivery in patients with sepsis. JAMA 1993; 269: 3024-3029 Bibliographic Links 17. Fitzgerald RD, Martin CM, Dietz GE, et al: Transfusing red blood cells stored in citrate phosphate dextrose adenine-1 for 28 days fails to improve tissue oxygenation in rats. Crit Care Med 1997; 25: 726-732 Ovid Full Text Bibliographic Links 18. Hebert P, Wells G, Blajchman MA, et al: A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. N Engl J Med 1999; 340: 409-417 19. Burnum JF: Medical vampires. N Engl J Med 1986; 314: 1250-1251 Key Words: blood transfusion; erythropoietin; anemia of chronic diseaseAccession Number: 00003246-200008000-00079