Pathophysiology of intensive care unit-acquired anemia.

The formation of red blood cells (RBCs) in the bone marrow is regulated by erythropoietin in response to a cascade of events. Anemia in the intensive care unit can be caused by a host of factors. Patients in the intensive care unit may have decreased RBC production and a blunted response to erythropoietin. Administration of recombinant human erythropoietin may stimulate erythropoiesis, increase hematocrit levels and hemoglobin concentration, and reduce the need for RBC transfusions.

Anemia is a common problem in intensive care unit (ICU) patients. Included among the numerous factors that may contribute to the development of anemia in critically ill patients are the following.

• Frequent blood sampling for measurements of arterial blood gases and other laboratory parameters.

• Clinically apparent and/or occult blood loss from the gastrointestinal tract due to erosive gastrointestinal mucosal disease or tissue trauma caused by suctioning of gastric contents.

• Blood loss at the time of surgical procedures preceding admission to the ICU.

• Blood loss due to trauma preceding admission to the ICU.

• Inappropriately low circulating concentrations of erythropoietin (EPO) [1-6], the main humoral regulator of red blood cell (RBC) production.

• Diminished responsiveness of bone marrow precursor cells to EPO, for example due to decreased availability of iron.

Erythropoietin is a glycoprotein that regulates RBC production by modulating the survival and proliferation of erythroid colony-forming units in the bone marrow. Diminished tissue oxygen tension is the primary stimulus for EPO release, and in humans, the kidney is the main organ responsible for EPO production. Tissue oxygen tension is thought to regulate EPO production via an oxygen-responsive transcription factor called hypoxia-inducible factor (HIF)-1 [7]. First identified by Semenza and Wang [8], HIF-1 is a heterodimeric transcription factor composed of a hypoxia-inducible HIF-1α chain and a constitutively expressed HIF-1β chain. Although mRNA for HIF-1α is expressed at relatively high levels in normoxic cells, HIF-1α protein is present at extremely low levels under these conditions. In normoxic cells, newly synthesized HIF-1α is subjected to polyubiquitination and targeted for degradation in proteosomes. Thus, the half-life for this protein is very short, and its concentration under normoxic conditions is low. However, when cells become hypoxic, polyubiquitinization of nascent HIF-1α decreases, and cytosolic levels of this protein increase. HIF-1α combines with HIF-1β to form the fully functional transcription factor, which is capable of binding to cis-acting regulatory elements in a number of hypoxia-responsive genes, including the gene for EPO. A phosphorylation event also may be important in the regulation of HIF-1 activity.

Numerous clinical studies support the notion that the EPO response to anemia is blunted in critical illness. Rogiers and coworkers [4] took serial measurements of serum EPO levels in 36 critically ill adults. Eighteen ambulatory patients with iron-deficiency anemia served as a control group. As expected, a significant inverse correlation between hematocrit values and EPO levels was observed in the control individuals (r = -0.81; P < 0.001). However, no such correlation was apparent for the critically ill patients (r = -0.09; P = NS).

Krafte-Jacobs and coworkers [5] conducted a similar study, but they evaluated EPO levels in critically ill pediatric patients instead of adults. In 21 acutely anemic critically ill patients, the mean hemoglobin concentration was 7.8 ± 1.5 g/dl and the mean EPO level was 39 ± 62 mU/ml. In comparison, the mean hemoglobin concentration in 21 chronically anemic patients was 7.3 ± 1.3 g/dl and the mean EPO level was 861 ± 758 mU/ml. Similar findings were obtained in a third study conducted by Von Ahsen and coworkers [6]. Studying patients in a medical ICU, those investigators also found that EPO levels were inappropriately low for the degree of anemia in critically ill adults. In addition, they found that iron deficiency (plasma transferrin saturated < 20%) is also common in critically ill patients. Inappropriately low EPO levels persist for the duration of critical illness [3].

Although endogenous EPO levels tend to be low in ICU patients, these patients appear to retain their responsiveness to the hormone. Three randomized prospective trials [9-11] documented that administration of recombinant human erythropoietin (rHuEPO) can stimulate reticulocytosis and increase circulating hemoglobin concentration in critically ill adults. Those studies demonstrated that the cumulative number of units of packed RBCs transfused was significantly less in the rHuEPO group than in the placebo group [9-11]. The third study found that patients receiving rHuEPO were less likely to undergo transfusion [11].

Functional iron deficiency is a major cause for anemia in critically ill patients and in patients with anemia of chronic disease [4]. In both groups, laboratory studies typically reveal low serum iron concentration, low transferrin level, low transferrin saturation, and elevated serum ferritin concentration; these findings are consistent with an acute-phase response and inflammation [1,9,12]. Despite evidence of increased iron storage, circulating iron concentrations are low, and thus less free iron is available to support erythropoiesis [13]. Similar observations have been reported from studies of patients with multiple organ failure [14], victims of multiple trauma [2], and patients recovering from major surgery [15].

Low concentrations of vitamin B12 and folic acid, which are essential for normal RBC development, also might contribute to ineffective erythropoiesis in critically ill patients. Von Ahsen and coworkers [6] observed normal vitamin B12 levels but abnormally low folic acid concentrations in some anemic ICU patients. RBC size was not increased, and therefore the significance of folic acid deficiency as a factor contributing to ICU-acquired anemia remains uncertain. Recently, Rodriguez and colleagues reported iron deficiency in 9% of ICU patients [1]; 2% of the patients were deficient in vitamin B12, and another 2% suffered from folic acid deficiency.

Competing interests

MPF has received funding from Ortho Biotech Products, L.P. (Johnson & Johnson).

Abbreviations

EPO = erythropoietin; HIF = hypoxia-inducible factor; ICU = intensive care unit; RBC = red blood cell; rHuEPO = recombinant human erythropoietin.