Anemia

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19 Anemia

Anemia is a common clinical problem in critically ill patients. A large proportion of these patients are anemic on admission, and the majority of the remainder become anemic during their intensive care unit (ICU) stay. The likelihood of becoming anemic increases with the duration of stay in the ICU.

The traditional approach for the management of anemia in the ICU has been the administration of packed red blood cell (PRBC) transfusions. On average, about 40% of ICU patients are transfused (a mean of 5 units of PRBCs) in response to a mean pretransfusion hemoglobin (Hb) concentration of 8.5 g/dL.1 Over the last decade, several studies have shown that PRBC transfusion is independently associated with worse clinical outcomes, independent of the degree of anemia or the severity of illness. Myriad complications resulting from PRBC transfusion are increasingly being recognized, and the scarcity of blood (expected annual shortfall of 4 million units by the year 20302) and economic impact of PRBC transfusion (approximately $270 per unit transfused3) have prompted a paradigm change for managing anemia in the ICU.

Current approaches include recognition of absolute indications for PRBC transfusion, avoidance of transfusions based on “transfusion triggers” alone, prevention of anemia in critically ill patients, use of PRBCs that have been stored in the blood bank for shorter periods, and increasing acceptance of anemia. Many of these changes in approach are now evidence based.

Future directions focus on prevention of anemia, blood conservation, and the evaluation of blood substitutes.

image Epidemiology

Anemia is defined as Hb level less than 13 g/dL for adult males and less than 12 g/dL for adult nonpregnant females.4 Using this definition, more than 60% of all patients are anemic at admission, and the majority of those with normal Hb levels at admission become anemic while in the ICU.5,6 Given enough time, virtually all patients will become anemic during their ICU stay. In the anemia and blood transfusion in critically ill patients study (the ABC trial), 63% of patients had Hb levels below 12 g/dL, and 29% had Hb levels below 10 g/dL.5 Similarly, in the CRIT study, mean Hb level at baseline was 11 g/dL.6

The most frequent strategy for treatment of anemia is the transfusion of PRBC. As a consequence, more than 14 million units are transfused annually in the United States.7 In patients with malignancy as their admission diagnosis, the prevalence and incidence of anemia are 68% and 47%, respectively.8 Each day in the ICU increases the chance of being transfused by about 7%.9

image Etiology

The etiology of anemia in the ICU is most often multifactorial, belonging to one or more of three major classes:

image

Figure 19-1 Physiologic Classification of Anemia.

CBC, complete blood count.

(Adapted from Fauci AS, Kasper DL, Braunwald E, et al, editors. The physiologic classification of anemia. In: Harrison’s Principles of Internal Medicine, 17th ed., online: www.accessmedicine.com. Copyright © The McGraw-Hill Companies, Inc. All rights reserved.)

The most common causes of anemia include phlebotomy for diagnostic laboratory testing; acute hemorrhage due to trauma, gastrointestinal (GI) bleeding, or surgery—often exacerbated by the presence of coagulation abnormalities; treatment with chemotherapeutic agents; underlying chronic diseases such as renal and hepatic failure; reduced erythropoiesis; and shortened red cell survival.

Blood loss due to phlebotomy is an often unrecognized yet significant cause of anemia in the ICU, where patients are phlebotomized on average 4.6 times a day, with removal of 40 to 60 mL of blood daily.5,6,10,11 The volume of blood removed varies with the test being ordered, but average volumes typically drawn are presented in Table 19-1. The presence of an arterial line further increases the phlebotomized blood volume.11 Approximately half of all patients are transfused as a direct result of phlebotomy.11

TABLE 19-1 Average Volumes of Blood Drawn for Diagnostic Testing89

Arterial blood gas 2 mL
Chemistry 5 mL
Coagulation studies 4.5 mL
Complete blood counts 5 mL
Blood culture 10 mL
Drug levels 5 mL
Standard discard amount 2 mL

Although rare since the advent of effective GI prophylaxis, GI bleeding can be a serious problem in the ICU. The overwhelming majority of critically ill patients demonstrate evidence of mucosal damage within the first 24 hours of admission. Overt anemia occurs in 5% of patients with stress-related GI bleeding, and clinically important bleeding necessitating transfusion is observed in 1% to 4% of critically ill patients.12 Bleeding secondary to erosive gastritis is predominantly seen in patients on mechanical ventilation, patients with coagulopathy, patients with head injury, and/or patients receiving corticosteroids.13

Reduced erythropoietin production is a key feature of anemia of critical illness, a distinct clinical entity similar to anemia of chronic disease. This blunted erythropoietic response to low Hb concentration in the face of apparently adequate iron stores is due to a failure to produce appropriate levels of erythropoietin.14,15 Blunted erythropoietin production in critically ill patients is probably mediated by proinflammatory cytokines such as tumor necrosis factor (TNF), interleukin (IL)-1, and IL-6, which down-regulate expression of the gene encoding erythropoietin.16 IL-6 inhibits renal erythropoietin production.17 Additional contributory effects of these proinflammatory cytokines include induction of a state of relative iron deficiency, vitamin deficiency, and altered iron metabolism in the bone marrow.6,18 Anemia, therefore, is a result of both a blunted response to erythropoietin and abnormalities in iron metabolism.

image Laboratory Evaluation of Anemia in the Intensive Care Unit

A comprehensive treatise on the evaluation of anemia is beyond the scope of this chapter. Discussion here is limited to pertinent iron studies that aid in the diagnosis of anemia of critical illness. A brief review of iron metabolism is essential to understanding the rationale behind the laboratory tests ordered.

Iron absorbed from food or released from stores circulates in plasma bound to transferrin, the iron transport protein. This iron-transferrin complex interacts with a specific transferrin receptor protein on the surface of early erythroid cells. This complex is then internalized and the iron released intracellularly. Within the erythroid cells, iron in excess of that needed for Hb synthesis binds to the storage protein, apoferritin, forming ferritin. Iron in the ferritin pool can be released and reused in the iron metabolism pathway. The levels of ferritin in serum correlate with total body iron stores and are therefore a suitable laboratory estimate of iron stores.19 During maturation of reticulocytes to erythrocytes, the cells lose all activities of the Hb-synthesizing system, including surface expression of the transferrin receptors, which are released into the circulation.20 Levels of transferrin receptor protein in the circulation provide a quantitative measure of total erythropoiesis and can be used to measure the expansion of the erythroid marrow in response to recombinant erythropoietin therapy. Serum iron levels represent the amount of circulating iron bound to transferrin. The total iron-binding capacity is an indirect measure of the circulating transferrin concentration.

Key tests necessary for establishing a diagnosis of anemia of critical illness include serum iron concentration, serum transferrin, transferrin receptor protein concentration, total iron-binding capacity, and serum ferritin concentration.

Anemia of critical illness is caused by impaired iron release, reduced production of erythropoietin, and a blunted response to erythropoietin, so this syndrome is characterized by a low serum iron concentration, low total iron-binding capacity, low transferrin saturation, normal transferrin-receptor protein levels, and a normal to high ferritin level. In contrast, iron-deficiency states are associated with transferrin saturation less than 18%. Consequently, critically ill patients may develop iron-deficiency anemia, anemia of chronic disease, or a combination of both.

image Management

Red Cell Transfusion

Transfusion of PRBCs remains the standard approach for the management of anemia in critically ill patients. Most transfusions are administered in response to a particular Hb level, the “transfusion trigger.” Historically, transfusion was indicated for Hb concentrations below 10 g/dL. However, several considerations suggest a need to critically reevaluate this approach. First, scientific evidence suggests that most critically ill patients can safely tolerate lower Hb levels. Second, PRBC transfusions are associated with numerous potential complications. Third, blood is a scarce and costly resource that may not always be available,21 hence its use must be limited to those most likely to benefit. Finally, transfusions are associated with worse clinical outcomes. Transfusion of PRBCs must therefore be used for a physiologic indication and not in response to a transfusion trigger. The goals of these transfusions are to treat hemorrhage not responsive to fluid resuscitation and to correct hypoperfusion (as evidenced by blood lactate concentrations or base deficit measurements) not responsive to fluid resuscitation.

In recent years, evidence has begun to accumulate against the traditional liberal strategy of transfusion to achieve Hb concentration ≥10 g/dL. In the ABC trial, a prospective observational study of 3534 patients from 146 western European ICUs, 37% of all patients were transfused while in the ICU. The majority of transfusions were administered during the first week of ICU stay. Transfusion was more common in the elderly and in those with ICU stays longer than 1 week. Mortality, both in the ICU and overall, was significantly higher in the transfused group than for the group which avoided transfusion (18.5% versus 10.1%, P<0.001 for ICU death and 29.0% versus 14.9%, P<0.001 for overall mortality). The differences persisted even after the patients were matched for the degree of organ dysfunction.5 In addition, transfused patients had longer lengths of stay and more severe degrees of organ failure. The CRIT study was a prospective, multicenter, observational study of 284 ICUs in 213 hospitals in the United States. Overall, 44% of patients were transfused, most often within the first week of ICU admission; transfusion was independently associated with longer ICU and hospital stays and increased mortality.6 Walsh and colleagues prospectively collected data on 1023 sequential admissions in 10 ICUs over 100 days in Scotland. Approximately 40% of patients were transfused, even with the application of evidence-based transfusion guidelines.22 The multicenter trials group of the American Burn Association studied patients with ≥20% total body surface burns at 21 burn centers in the United States and Canada. Overall, they found that nearly 75% of patients were transfused during their hospital stay, receiving a mean of 14 units. The number of units transfused correlated significantly with the number of infections and mortality.23 In a prospective observational study by the North Thames Blood Interest Group, 53% of patients were transfused for a mean pretransfusion Hb level of 8.5 g/dL. About two-thirds were transfused for low Hb levels and only 25% for hemorrhage. ICU mortality in the transfused patients was significantly higher than in the nontransfused patients (24.8% versus 17.7%, respectively).24

There is increasing recognition that anemia is well tolerated in critically ill patients. Much of clinical evidence in support of this approach comes from studies in Jehovah’s Witness patients, who refuse to accept PRBC transfusions on religious grounds. Mortality increases significantly at Hb values below 5 g/dL, more so in individuals older than 50 years of age.25 In conscious health volunteers, isovolemic dilution was performed to reduce the Hb concentration from 13.1 g/dL to 5 g/dL. Critical oxygen delivery was assessed by oxygen consumption, blood lactate concentration, and changes in the ST segment on the electrocardiogram. Oxygen consumption increased, but no increase in lactate concentration was found, suggesting that resting healthy humans can tolerate acute reductions in Hb to levels of 5 g/dL without the development of inadequate tissue perfusion.26

Clearly the risks of anemia must be balanced against the potentially deleterious effects of transfusion, especially since the efficacy of PRBC transfusions to augment oxygen delivery and the impact of this increase on tissue metabolism and clinical outcome remain unproven. In a recent meta-analysis, Marik and Corwin performed a systematic review of the literature and analyzed outcomes in 272,596 patients as reported in 45 studies. Blood transfusion was associated with an increased risk of death (pooled odds ratio 1.69, 95% confidence interval [CI] 1.46–1.92), increased risk of infectious complications (pooled odds ratio 2.5, 95% CI 1.52–2.44), and an increased risk of the development of acute respiratory distress syndrome (ARDS) (pooled odds ratio 1.88, 95% CI 1.66–3.34).27

The only absolute indication for PRBC transfusion is in the therapy of hemorrhagic shock.28 However, only 20% of transfusions are used for this indication.

Most transfusions in the ICU are administered for the treatment of anemia. In the CRIT trial, over 90% of transfusions were given for this reason.6 Perceived benefits of transfusion include increase in oxygen delivery to the tissues; increase in the cell mass and blood volume; alleviation of symptoms of anemia, including dyspnea, fatigue, and diminished exercise tolerance; and relief of cardiac effects. The optimal Hb concentration remains unknown and is likely influenced by the premorbid health status, disease process, and other unknown factors. Based on studies involving acute isovolemic reductions of blood Hb concentration, it has been demonstrated that reduction of the Hb concentration to levels of 5 g/dL does not produce evidence of inadequate systemic critical oxygen delivery as evidenced by blood lactate concentration26; significant cognitive changes were noted, however.29 These effects were not seen when isovolemic dilution was performed to Hb levels of 7 g/dL. Clinical evidence of the validity of these findings is seen in the seminal Transfusion Requirements in Critical Care (TRICC) trial and has been instrumental in changing transfusion practices over the last decade.30 In this study, 838 euvolemic critically ill patients with Hb levels less than 9 g/dL were enrolled. Of these, 418 patients were randomly assigned to a restrictive transfusion strategy, where transfusion was provided if the Hb level fell below 7 g/dL, with a goal of maintaining circulating Hb concentration between 7 and 9 g/dL; and 420 patients were assigned to the liberal transfusion group and received transfusions for Hb levels of less than 10 g/dL, with transfusions provided to keep the Hb between 10 and 12 g/dL. Overall the 30-day mortality was similar between the two groups (18.7% versus 23.3%, P=0.11). However, a significantly lower mortality was seen with a restrictive transfusion strategy in those less severely ill who had APACHE II scores of ≤20 (8.7% versus 16.1%, P=0.03) and in those younger than 55 years of age (5.7% versus 13.0%, P=0.02). No difference in mortality was observed in those with stable, clinically significant cardiac disease (20.5% versus 22.9%, P=0.69). This strategy resulted in a 54% decrease in average number of units transfused and avoidance of transfusion in 33% of patients. Lowering of the transfusion threshold, therefore, is a simple and inexpensive strategy for improving outcome for critically ill patients. Caution must be used in applying this restrictive transfusion strategy to those patients with acute myocardial ischemia and unstable angina, as this group was excluded from the TRICC trial. Compensatory cardiac mechanisms in anemic patients include increases in blood flow during rest and a redistribution of blood away from the endocardium. In the presence of significant coronary artery disease, these adaptive changes are poorly tolerated, and anemic patients with myocardial infarction may have increased mortality.31

Adverse Effects of Transfusion

A large proportion of ICU patients continue to receive PRBC transfusions for anemia, exposing them to serious risks, including transmission of infectious diseases, immune-mediated reactions (acute or delayed hemolytic reactions, febrile allergic reactions, anaphylaxis, and graft-versus-host disease), and non–immune related complications (fluid overload, hypothermia, electrolyte toxicity, and iron overload). Transfusion-related complications are encountered in approximately 4% of PRBC transfusions.6 The risk of adverse outcomes increases incrementally with each unit of PRBCs transfused.32,33 In an observational cohort study of 5814 patients undergoing coronary artery bypass grafting, each unit of PRBC transfused resulted in more than 100% odds of renal dysfunction, 79% odds for the need for mechanical ventilation for over 72 hours, 76% increase in odds for developing a serious postoperative infection, a 55% increase in odds for postoperative cardiac morbidity, and a 37% increase in odds for postoperative neurologic morbidity. Overall, there was a 73% increase in the odds of a major morbidity for each unit transfused (Table 19-2).32

TABLE 19-2 Potential Adverse Consequences Associated with Red Cell Transfusion90

Infectious Complications
Human immunodeficiency virus infection
Human T-lymphotropic virus infection
Hepatitis C virus infection
Hepatitis B virus infection
Parvovirus B19 virus infection
Bacterial infections (Staphylococcus, streptococci, Yersinia enterocolitica, etc.)
Parasitic infections (Chagas disease)
1 in 2.3 million
1 in 2 million
1 in 1.8 million
1 in 350,000
1 in 10,000
1 in 250,000
1 in 29,000 donors seropositive
Noninfectious Complications
Hemolytic transfusion reactions
Delayed hemolytic transfusion reaction
Febrile nonhemolytic transfusion reactions
Major allergic reactions
ABO mismatching
Transfusion-related acute lung injury (TRALI)
Transfusion-related immunomodulation (TRIM)
Transfusion-associated circulatory overload (TACO)
Coagulopathy
Iron overload
Hypothermia
Hyperkalemia
Thrombocytopenia
Pulmonary hypertension
1 in 10,000 to 1 in 50,000
1 in 1500
1 in 100 to 35 in 100
1 in 20,000 to 1 in 50,000
1 in 14,000 to 1 in 38,000
1 in 5000
1 in 100
Observed once 2 blood volumes replaced
Observed after transfusion of 10 to 15 units

With advances in screening and improvements in blood banking technology, transmission of infectious agents is less common. Current estimates of the risk of infection per unit of blood are approximately 1 in 2 million for human immunodeficiency virus (HIV), 1 in 1 million for hepatitis C virus, and 1 in 100,000 for hepatitis B virus.34 The most common transfusion-related infections are secondary to bacterial contamination, which has an incidence of 12.6 events per 1 million units of allogeneic blood components transfused.35 The risk of bacterial contamination is higher for PRBCs than for whole blood. Transfusion-related bacterial infections are most often caused by gram-positive organisms (e.g., staphylococcal spp., streptococcal spp., 58%) but also may be caused by gram-negative organisms (e.g., Yersinia enterocolitica, 32%). About 10% of these infections will result in a fatal outcome.35

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