Anemia in Critically Ill Patients E. Potolidis, E. Vakouti, and D. Georgopoulos z Introduction Anemia is a common problem in critically ill patients. Indeed it has been shown that at intensive care unit (ICU) admission the mean hemoglobin concentration (Hb) of critically ill patients is *11 g/dl, while in 60% and 30% of such patients, the mean Hb is less than 12 and 10 g/dl, respectively [1, 2]. It is of interest to note that in these patients the rate of hemoglobin decline is approximately 0.5 g/dl/day during the first days after ICU admission and continues to decline, particularly in pa- tients with severe illness [1]. Thus the majority of critically ill patients exhibit anemia on ICU admission, which persists throughout the duration of their ICU stay. z Causes of Anemia in Critically Ill Patients Several factors contribute to anemia in critically ill patients. The withdrawal of large amounts of blood for diagnostic reasons is an important but largely ignored factor for development of anemia in patients in ICUs [3]. Smoller and Kruskall showed that one half of patients who received blood transfusions had blood losses from phlebotomy that exceeded the equivalent of one unit of blood [4]. A recent European multicenter study (the ABC study) demonstrated that in critically ill pa- tients the blood loss through blood sampling for diagnostic purposes is consider- able, averaging 41 ml/day [1]. Nguyen and colleagues [5] also documented that the mean volume of blood drawn daily for laboratory studies was approximately 40 ml. Considering only septic patients this amount increased to 49 ml. In patients under- going renal replacement therapies the blood loss due to blood sampling may be in the range of 60 ml per day [6]. Obviously this type of blood loss has an impact on blood transfusion. Indeed, Corwin et al. showed a positive relationship between the number of phlebotomies performed for diagnostic purposes and the amount of red blood cell (RBC) transfusions [7]. Furthermore, in the ABC study [1] a positive correlation was observed between organ dysfunction and the number of blood draws and total volume drawn. We should note that in the process of blood sampling the ICU health care work- er has to discard a significant blood volume in order to obtain accurate results. This volume depends on medical practice and may vary from 2 to 10 ml [5]. It is recommended that the discard volume should not be greater than twice the catheter dead-space [8, 9]. Occult bleeding is another important factor that may contribute to anemia in critically ill patients [3]. Stress gastritis (stress ulcer) is a potential source for blood 492 E. Potolidis et al. loss. Surgical patients often have anemia in the postoperative period and should be monitored carefully. Blood loss into the retro-peritoneal space should be suspected and carefully investigated in patients with abdominal trauma who exhibit acute de- cline in hemoglobin. An important cause of anemia in critically ill patients is functional iron deficien- cy [10, 11]. Typically, critically ill patients have elevated serum ferritin concentra- tions, low transferrin saturation, and low serum iron concentration [11, 12]. There- fore, the low serum iron levels are not able to support the heme biosynthesis and the erythropoiesis. Systemic inflammatory response syndrome (SIRS) may be the pathogenic mechanism for this pattern. Cytokines that are released during the in- flammation process, like tumor necrosis factor (TNF)-a and interleukin (IL)-6, may induce the transcription and translation of ferritin and are able to down-regulate transferrin receptor messenger mRNA (iron uptake) [13]. In addition, it has been reported that nitric oxide (NO), which is increased in vasodilator shock, has the ability to reduce the ferrochelatase activity [14], thus contributing to the functional iron deficiency. Ineffective erythropoiesis in patients with critical illness could be the result of vitamin B12 or folic acid deficiency. Data in the literature indicate that these defi- ciencies do not play an important role in the pathogenesis of the anemia in these patients. Indeed, a recent study showed that 2% of critically ill patients were defi- cient in vitamin B12 and another 2% were deficient in folic acid [15]. Nevertheless, these deficiencies are rapidly correctable causes of ineffective erythropoiesis. It has been shown that IL-6 and TNF-a are both able to decrease the life span of RBCs [16, 17]. In addition to the reduced RBC life span due to proinflammatory cytokines, the erythrocytes of critically ill patients show decreased deformability [18]. Reactive oxygen species, increased concentrations of 2,3-DPG into the RBCs, and alterations in intracellular calcium content could be factors responsible for the decreased RBCs deformability [18]. The decrease in RBC deformability may play a role in disturbances in microcirculation, observed in critically ill patients. Inflammatory mediators released during SIRS may also influence the differentia- tion of erythroid progenitor cells. It is well known that cytokines are able to inhibit the differentiation of erythroid progenitor cells [19]. In addition, interferon (IFN)-c is able to induce apoptosis of the human erythroid colony forming cells via Fas ex- pression and caspase activation [19]. Papadaki et al. reported that patients with rheumatoid arthritis (anemia of chronic disease which shares similar characteristics to that of critical illness) exhibit reduced apoptosis of erythroid cells in the bone marrow after treatment with anti-TNF-a antibodies [20]. Histiocytic hyperplasia with hemophagocytosis (HHH), a syndrome observed during sepsis or malignancies, may contribute to anemia in critically ill patients. The syndrome is characterized by single cytopenia (anemia, neutropenia or throm- bocytopenia) or pancytopenia. Strauss et al. [21], in a postmortem clinico- pathologic study investigated 107 patients who were hospitalized and died in the ICU, showed that histiocytic hyperplasia with hemophagocytosis was present in 69 patients (64.5%). Predictors of histiocytic hyperplasia syndrome were treatment in- tensity and non-cardiovascular cause of death. This study demonstrated that sepsis and blood transfusion were triggering factors with a possible synergistic effect [21]. Peritubular interstitial cells in the renal cortex and parenchymal liver cells pro- duce a glycoprotein hormone named erythropoietin (EPO). This hormone binds to the EPO receptor on erythroid progenitor cells and promotes their maturity, while Anemia in Critically Ill Patients 493 on the other hand it decreases their apoptosis. Several studies have shown that EPO also has a neuroprotective effect [22, 23]. In patients with iron deficiency ane- mia, EPO concentration and Hb levels have a negative semilogarithmic correlation [24]. This is not the case in critically ill patients. It has been shown that in these patients for a given hematocrit (Hct) or hemoglobin, EPO plasma levels are signifi- cantly lower than those observed in patients with iron-deficiency anemia [25] (Fig. 1). von Ahsen et al. [12] calculated the erythropoietin response (Dlog/DHb) in ICU patients and noted that it was on average half of the response of patients with uncomplicated non-renal anemia. This phenomenon is referred to as blunted ery- thropoietic response. Studies have shown that the inappropriate low levels of ery- thropoietin significantly contribute to anemia in critically ill patients [26]. The blunted erythropoietic response is thought to result from decrease of erythropoietin gene expression by inflammatory mediators, such as TNF-a, IL-1 and IL-6 [3]. z RBC Transfusion Anemia in critically ill patients results in significant RBCs transfusions. Approxi- mately 40% of critically ill patients receive at least one unit of RBCs, relatively early after ICU admission [1, 2]. The mean number of RBC units transfused approaches five, while the pre-transfusion Hb is *8.5 g/dl, indicating that the large number of transfusions is not due to a very high Hb transfusion threshold [1, 2]. Corwin et al., investigated the transfusion practice of their tertiary care center and found that 85% of critically ill patients with an ICU length of stay greater than one week, re- ceived blood transfusions, with a mean of approximately 9.5 units per patient [7]. It follows that the rate of blood transfusions in these patients is very high [7, 25]. The amount of oxygen delivered to the whole blood (DO2) is given by the fol- lowing equation: DO2 CO Â CaO2 where CO is cardiac output (CO=SV´HR, SV is stroke volume and HR is heart rate) and CaO2 is the oxygen concentration of arterial blood (CaO2 = 1.36 Hb´SaO2+0.003´PaO2). It is apparent that Hb reduction decreases the amount of oxygen delivered to tissues and under certain circumstances may result in tissue hypoxia. It follows that the main goal of RBC transfusion in anemic patients is to prevent or reverse tissue hypoxia by increasing the oxygen-carrying capacity of the blood. We should note however, that in critically ill patients regional blood flow is an important determinant of oxygen supply to cells; severe tissue hypoxia may en- sue despite a normal value of Hb and global DO2 [28, 29]. RBC transfusion is associated with numerous adverse events (Table 1), including infection transmission [30], transfusion associated immunosuppression [27, 31±33], transfusion related acute lung injury (TRALI) [34], disturbances in microcircula- tion due to blood storage [35, 36], and allergic reactions [33]. The first reported cases of transfusion-associated human immunodeficiency virus (HIV) transmission occurred in 1982. Since then cases of HIV transmission have decreased due to development of antibody detection and p24 antigen detection [27, 37]. Hepatitis B virus (HBV) infection due to transfusion decreased after the introduction of screening tests for HbsAg in 1975 and the risk of transfusion trans- 494 E. Potolidis et al. Fig. 1. Log plasma concentration of erythropoietin (EPO) concentration as a function of hematocrit (Hct) in patients with uncomplicated iron deficiency anemia (control) and in various groups of critically ill pa- tients.