19 Anemia
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.
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
Etiology

Figure 19-1 Physiologic Classification of Anemia.
(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: http://www.accessmedicine.com. Copyright © The McGraw-Hill Companies, Inc. All rights reserved.)
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.
Laboratory Evaluation of Anemia in the Intensive Care Unit
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.
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 Increasing global travel has led to the emergence of infectious diseases not usually seen in the United States. Chagas disease, caused by Trypanosoma cruzi, is endemic in much of South and Central America. Immigrants from these endemic areas now form an increasing proportion of the blood donor pool. This issue is especially relevant in regions with high immigrant populations. In two such cities, Los Angeles and Miami, seropositive rates among donors were 1 in 7500 and 1 in 9000 and have been increasing.36 Once acquired, the parasitemia persists long after acquisition of the infection.37
Major ABO mismatching is estimated to occur in 1 of 138,673 PRBC units transfused and results in 1 death per 2 million units transfused.35 Incompatibility also may result from antigens not routinely detected by current antibody assays. As a consequence, fatal acute hemolytic reactions still occur in 1 of every 250,000 to 1 million transfusions, and 1 patient per 1000 demonstrates the clinical manifestations of a delayed hemolytic transfusion reaction.38
Transfusion-related acute lung injury (TRALI) is a potentially serious pulmonary complication of transfusion. In severe cases, its clinical presentation is similar to that of the acute respiratory distress syndrome (ARDS).39 Although initially described by Bernard in 195140 as noncardiogenic pulmonary edema related to transfusion, the term TRALI was coined by Papovsky et al.41 TRALI presents with dyspnea and bilateral pulmonary edema during or within up to 6 hours of a transfusion, with no other risk factors to explain its development. It must be distinguished from pulmonary insufficiency due to circulatory overload, where the central venous pressure and pulmonary artery wedge pressure would be elevated. Hypoxemia, fever, hypotension, tachycardia, and cyanosis also may occur. Most often, symptoms appear within 1 or 2 hours following transfusion, but a delayed form with dyspnea appearing as late as 48 hours after transfusion has been reported. The chest x-ray shows bilateral infiltrates, which may progress and cause whiteout of the entire lung field. The criteria for clinical diagnosis of TRALI42 include severe hypoxemia (with PaO2/FIO2 <300 or O2 saturation <90%), acute respiratory distress within 6 hours of a transfusion in the absence of evidence of circulatory overload, and x-ray evidence of bilateral pulmonary infiltrates. Differential diagnosis includes transfusion-associated circulatory overload, cardiac diseases, allergic and anaphylactic transfusion reactions, and bacterial contamination of the blood. Although the exact incidence is unknown, TRALI is estimated to occur in 1 of every 5000 transfusions43 and has a mortality rate of 5% to 10%. Current evidence suggests two forms of TRALI: immune and nonimmune. Potential mediators include antileukocytic antibodies, products of lipid peroxidation, and other as yet unrecognized agents. The neutrophil is the key effector cell. Transfusions from multiparous female donors, owing to exposure to paternal leukocytes, are associated with the highest risk for the development of TRALI in the recipient.44 Treatment is currently limited to supportive measures.
Transfusion-related immunomodulation (TRIM) results in an increased incidence of bacterial infections, cancer recurrence, and organ dysfunction.45,46 Opelz and colleagues first suggested clinical evidence of transfusion-associated immunomodulation in 1973, when improved renal allograft survival was observed in patients transfused prior to transplantation.47 Current evidence implicates transfusions in the development of nosocomial infections including wound infections, pneumonia, and sepsis. In a prospective observational study, Taylor et al. found a significant association between transfusion and development of nosocomial infections (14.3% versus 5.3%, P<0.0001). In addition, mortality and length of stay were increased in the transfused group. The risk of infection increases 9.7% for each unit of PRBC transfused.48 Development of these infectious complications results not only in increased length of stay but in increased in-hospital deaths and increased costs as well.49 These effects may be reduced by the use of prestorage leukocyte depletion.50
Other complications include transfusion-associated circulatory overload with the development of fluid overload and pulmonary edema, multisystem organ failure, systemic inflammatory response syndrome,51,52 hypothermia, coagulopathy, thrombocytopenia, hyperkalemia, and pulmonary hypertension with an increase in pulmonary vascular resistance and decreased right ventricular ejection fraction.53
Finally, the transfusion of PRBCs may not augment the oxygen-carrying capacity of blood. This results from development of the “storage lesion” due to changes in red blood cells that occur during ex vivo storage. These changes are both structural and functional54,55 and include reduced deformability impeding microvascular flow,56 altered adhesiveness and aggregation,57 reduced intracellular levels of 2,3-diphosphoglycerate (2,3-DPG, which shifts the oxyhemoglobin dissociation curve to the left and reduces oxygen delivery to the tissues), reduction in levels of nitric oxide and adenosine triphosphate,58 and accumulation of bioactive compounds with proinflammatory activity.59 The risk of complications increases with the duration of storage.60,61 Although the U.S. Food and Drug Administration (FDA) approves storage of red cells for up to 42 days, transfusion of blood older than 2 weeks appears to be associated with a significantly worse outcome. Koch and colleagues examined data from 6002 patients undergoing coronary artery bypass grafting, heart valve surgery, or both. “Newer blood” stored for less than 14 days was administered to 2872 patients, while the remaining 3130 received “older blood” stored for ≥14 days. Patients given older blood had higher rates of in-hospital mortality (2.8% versus 1.7%, P=0.004), need for longer duration of intubation (9.7% versus 5.6%, P<0.001), higher incidence of acute renal failure (2.7% versus 1.6%, P=0.003), and higher incidence of sepsis (4.0% versus 2.8%, P=0.001). The difference in mortality persisted even at 1 year after transfusion (7.4% versus 11.0%; P<0.001).62
Role of Erythropoietin
Many factors contribute to the development of anemia in the critically ill, but inappropriately low endogenous levels of erythropoietin in response to anemia represents a key pathophysiologic issue. Further, there is a failure of circulating erythropoietin to induce a response commensurate with the degree of anemia.63 Recognition of these considerations has prompted many clinicians to use pharmacologic doses of erythropoietin in an effort to reduce the need for and/or the amount of red cells transfused. While theoretically appealing, this approach has not been validated by scientific evidence. Corwin et al. conducted a prospective randomized, placebo-controlled trial (EPO3) that enrolled 1460 patients who were randomized to receive either 40,000 units of epoetin alfa or placebo weekly. Epoetin alfa therapy did not decrease the number of patients requiring a transfusion (46.0% versus 48.3%, relative risk 0.95, 95% CI 0.85–1.06, P=0.34), or the number of PRBC units transfused (mean 4.5 versus 4.3 units, P=0.42). No differences were seen in lengths of ICU or hospital stay, or time to weaning from mechanical ventilation. Although circulating Hb levels were significantly increased in the group receiving epoetin alfa, this effect did not translate into a survival benefit (adjusted hazard ratio 0.79, 95% CI 0.56–1.10). A significant increase in thrombotic events was noted (hazard ratio 1.41, 95% CI 1.06–1.86).64 Based upon these data, a large number of patients would need to be treated with erythropoietin in order to avoid one transfusion-related adverse event.65 As noted, treatment with erythropoietin also increases the risk for thrombotic complications. Accordingly, routine use of erythropoietin cannot be recommended. At our institutions, erythropoietin use is limited to patients with chronic renal failure and Jehovah’s Witnesses.
Current Recommendations
Transfusion of PRBCs should not be based on a transfusion trigger alone. The decision must be based instead on the patient’s intravascular volume status, evidence of shock, duration and extent of anemia, and cardiopulmonary physiologic parameters.1
Transfusion is indicated for patients with hemorrhagic shock. In this instance, the number of units transfused is based not on a particular Hb level but on the physiologic state of the patient. Transfusion is also indicated in the presence of evidence of acute hemorrhage with either hemodynamic instability or evidence of inadequate oxygen delivery as demonstrated by elevated blood lactate levels or base deficit. Serial assessment of these parameters can be used to determine the efficacy of resuscitation.66
For patients with cardiac disease undergoing coronary artery bypass graft surgery, increased mortality is observed in patients with admission Hb levels below 8 g/dL. Reduction in mortality can be achieved by transfusing to a hematocrit of 30% to 33%. No mortality benefit is seen with hematocrits above 33%, and increased mortality is observed when hematocrits above 36% are achieved.67–69
Use of transfusions to wean patients from mechanical ventilation is not indicated. No benefit in the weaning process or difference in duration of mechanical ventilation has been observed.70
Transfusions should not be employed as the absolute method to improve tissue oxygen delivery in critically ill patients. In septic patients, PRBC transfusion increases oxygen delivery but not consumption.71 Whereas increases in Hb levels are consistently seen following transfusion in septic patients, these increases do not translate to improvement in blood lactate levels or mixed venous oxygen saturation.72 Transfusion may be indicated for failure to achieve an adequate mixed venous saturation after adequate fluid resuscitation.73
The TRICC data fail to show any difference in outcome with a restrictive strategy in patients with traumatic brain injury, but the study was underpowered to detect differences in this subgroup of patients.74 Others have shown transfusion-related improvement in brain tissue partial pressure of oxygen independent of cerebral perfusion pressure, arterial oxygen saturation, and FIO2.75 Similar improvements have been observed in patients with subarachnoid hemorrhage who had higher initial and mean Hb values.76 In other studies, an increased amount of angiographically confirmed vasospasm has been seen in patients receiving postoperative blood transfusions. Salim et al. retrospectively evaluated the effect of transfusion on outcome in 1150 patients with traumatic brain injury. On logistic regression, when both anemia and transfusion were included in the model, transfusion resulted in an increased mortality while anemia did not. When transfusion was removed from the model, anemia was a significant risk factor for mortality and for complications.77 These confounding results preclude a definitive recommendation for patients with subarachnoid hemorrhage or brain trauma, and the decision to transfuse must be individualized. Recommendations are summarized in Table 19-3.
Novel Strategies
It is evident that hemodynamically stable patients can tolerate marked degrees of anemia. Inasmuch as the transfusion of PRBCs is clearly deleterious, preventing the development and/or progression of anemia is of paramount importance. Strategies to achieve this include retrieving and reusing blood shed during surgery,78 limiting transfusions, using low-volume adult or pediatric sampling tubes to reduce phlebotomy volumes, reducing the number of laboratory tests ordered, using point-of-care microanalysis for laboratory tests, and using closed blood conservation devices (Venous Arterial Blood Management Protection [VAMP], Edward Lifesciences, Irvine, California). Use of the blood conservation device is associated with reduced red cell transfusion requirements and a smaller decrease in Hb levels in the ICU.79
Other approaches include the development of newer methods of blood storage that retard the development of storage-related changes,80 use of advanced computing technologies to optimize the use of blood inventory,81 and the development of blood substitutes.
Blood substitutes are being developed largely in response to concerns regarding the potential transmission of infectious agents and the impending shortage of blood in the face of increasing demands.82 Blood substitutes offer the distinct advantages of better shelf life compared to banked blood, universal compatibility, clinically useful intravascular half-life (18–24 hours), and freedom from the risk of infectious disease transmission (possibly with the exception of prion-mediated diseases). Blood substitutes are also oncotically active and can increase blood volume by an amount in excess of the transfused volume.83 Furthermore, blood substitutes can improve microcirculatory flow by reducing blood viscosity.84 Most Hb-based oxygen carriers (HBOCs) scavenge nitric oxide and promote arteriolar vasoconstriction on this basis. Although nitric oxide scavenging was probably the cause of increased mortality in the trial of diaspirin cross-linked hemoglobin (DCLHb) for trauma victims,85 nitric oxide scavenging might prove beneficial in patients with sepsis. In septic patients, inducible nitric oxide synthase expression is increased, leading to overproduction of nitric oxide and hypotension on this basis. HBOCs might overcome this distributive shock and restore blood pressure.86
McKenzie and colleagues recently described the outcome in 54 patients with severe life-threatening anemia (median Hb 4 g/dL) treated with the blood substitute, HBOC-201; 23 (41.8%) of 54 patients survived to discharge. Survival was significantly more likely when the blood substitute was administered earlier (3.2 days in survivors versus 4.4 days in non-survivors, P=0.027).87
While results from small individual studies, such as the one by McKenzie et al.87 described earlier, have been promising, available data do not support the use of blood substitutes in their current form. In a meta-analysis of 16 trials involving 5 blood substitutes and over 3700 patients, Nathanson and colleagues88 found a significantly increased risk of myocardial infarction (relative risk 2.71, 95% CI 1.67–4.40) and death (relative risk 1.30, 95% CI 1.30–1.61) among HBOC-treated patients. Poorer outcome was not related to the type of blood substitute employed or the clinical indication for its use. In light of this evidence, future phase 3 trials of these products are not warranted.
Key Points
Weiskopf RB, Viele MK, Feiner J, et al. Human cardiovascular and metabolic response to acute, severe isovolemic anemia. JAMA. 1998;279(3):217-221.
Hébert PC, Wells G, Blajchman MA, et al. A multicenter randomized, controlled clinical trial of transfusion requirements in critical care. Transfusion Requirements in Critical Care Investigators, Canadian Critical Care Trials Group. N Engl J Med. 1999;340(6):409-417.
Corwin HL, Gettinger A, Pearl RG, et al. The CRIT study: anemia and blood transfusion in the critically ill—current clinical practice in the United States. Crit Care Med. 2004;32(1):39-52.
Koch CG, Li L, Duncan AI, et al. Morbidity and mortality risk associated with red cell and blood component transfusion in isolated coronary artery bypass grafting. Crit Care Med. 2006;34(6):1608-1616.
Corwin HL, Gettinger A, Fabian TC, et al. Efficacy and safety of epoetin alfa in critically ill patients. N Engl J Med. 2007;357(10):965-976.
Koch CG, Li L, Sessler DI, et al. Duration of red-cell storage and complications after cardiac surgery. N Engl J Med. 2008;358(12):1229-1239.
Natanson C, Kern SJ, Lurie P, Banks SM, Wolfe SM. Cell-free hemoglobin-based blood substitutes and risk of myocardial infarction and death: a meta-analysis. JAMA. 2008;299(19):2304-2312.
Napolitano LM, Kurek S, Luchette FA, et al. Clinical practice guideline: red cell transfusion in adult trauma and critical care. J Trauma. 2009;67(6):1439-1442.
1 Napolitano LM, Kurek S, Luchette FA, et al. Clinical practice guideline: red cell transfusion in adult trauma and critical care. J Trauma. 2009;67:1439-1442.
2 Nucci ML, Abuchowski A. The search for blood substitutes. Sci Am. 1998;278:72-79.
3 Cantor SB, Hudson DV, Lichtiger B, et al. Costs of blood transfusion: A process flow analysis. J Clin Oncol. 1998;16:2364-2370.
4 Napolitano LM. Scope of the problem: epidemiology of anemia and use of blood transfusions in critical care. Crit Care. 2004;8(Suppl 2):S1-S8.
5 Vincent JL, Baron LF, Reinhart K, et al. Anemia and blood transfusion in critically ill patients. JAMA. 2002;288:1499-1507.
6 Corwin HL, Gettinger A, Pearl RG, et al. The CRIT study: Anemia and blood transfusion in the critically ill: current clinical practice in the United States. Crit Care Med. 2004;32:39-52.
7 Whitaker B, Sullivan M. The 2005 Nationwide Blood Collection and Utilization Survey Report. Bethesda, MD: AABB; 2006.
8 Cardenas-Turanzas M, Cesta MA, Wakefield C, et al. Factors associated with anemia in patients with cancer admitted to an intensive care unit. J Crit Care. 2010;25:112-119.
9 Brandt MM, Rubinfeld I, Jordan J, et al. Transfusion insurgency: practice change through education and evidence-based recommendations. Am J Surg. 2009;197:279-283.
10 Vincent JL, Baron JF, Reinhart K, et al. Anemia and blood transfusion in critically ill patients. JAMA. 2002;288:1499-1507.
11 Corwin HL, Parsonnet KC, Gettinger A. RBC transfusion in the ICU: Is there a reason? Chest. 1995;108:767-771.
12 Fennerty MB. Pathophysiology of the upper gastrointestinal tract in the critically ill patient: Rationale for the therapeutic benefits of acid suppression. Crit Care Med. 2002;30(Suppl):351-355.
13 Cook DJ, Fuller HD, Guyatt GH, et al. Risk factors for gastrointestinal bleeding in critically ill patients: Canadian Critical Care Trials Group. N Engl J Med. 2004:377-381.
14 Rogiers P, Zhang H, Leeman M, et al. Erythropoietin response is blunted in critically ill patients. Intensive Care Med. 1997;23:159-162.
15 Weiss G, Goodnough LT. Anemia of chronic disease. N Engl J Med. 2005;352:1011-1023.
16 Fink MP. Pathophysiology of intensive care unit-acquired anemia. Crit Care. 2004;8(Suppl 2):S9-10.
17 Jelkman W. Proinflammatory cytokines lowering erythropoietin production. J Interferon Cytokine Res. 1998;18:555-559.
18 Sihler KC, Napolitano LM. Anemia of inflammation in critically ill patients. J Intensive Care Med. 2008;23:295-302.
19 Adamson JW. Iron deficiency and other hypoproliferative anemias. In: Harrison’s Principles of Internal Medicine. New York: McGraw Hill; 2001.
20 Ponka P, Nam Lok C. the transferrin receptor: The role in health and disease. Int J Biochem Cell Biol. 1999;31:1111-1137.
21 National Blood Data Resource Center FAQ’s. National Blood Resource Center web site http//www.nbdrc.org/faq.htm accessed May 16,2010
22 Walsh TS, Carrioch M, Maciver C, et al. Red cell requirements for intensive car units adhering to evidence-based transfusion guidelines. Transfusion. 2004;44:1405-1411.
23 Palmeri TL, Caruso DM, Foster KN, et al. Effect of blood transfusion on outcome after major burn injury a multicenter study. Crit Care Med. 2006;34:1602-1607.
24 Rao MP, Boralessa H, Morgan C, et al. Blood component use in critically ill patients. Anaesthesia. 2002;57:530-534.
25 Viele MK, Weiskopf RB. What can we learn about the need for transfusion from patients who effuse blood. Transfusion. 1994;34:396-401.
26 Weiskopf RB, Viele MK, Feiner J, et al. Human cardiovascular and metabolic response to acute, severe isovolemic anemia. JAMA. 1998;279:217-221.
27 Marik PE, Corwin HL. Efficacy of red blood cell transfusion in the critically ill: A systematic review of the literature. Crit Care Med. 2008;36:2667-2674.
28 Valsef SN, Knudsen NW, Neligan PJ, Sebastian MW. Massive transfusion exceeding 50 units of blood products in trauma patients. J Trauma. 2002;53:291-295.
29 Weiskopf RB, Toy P, Hopf HW, et al. Acute isovolemic anemia impairs central processing as determined by P300 latency. Clin Neurophysiol. 2005;116:1028-1032.
30 Hebert PC, Wells G, Blajchman MA, et al. A multicenter randomized, controlled clinical trial of transfusion requirements in critical care. Transfusion Requirements in Critical Care investigators, Canadian Critical Care Trials Group. N Engl J Med. 1999;340:409-417.
31 Wu WC, Rathore SS, Wang Y, et al. Blood transfusion in elderly patients with acute myocardial infarction. N Engl J Med. 2001;345:1230-1236.
32 Koch CG, Li L, Duncan AI, et al. Morbidity and mortality risk associated with red cell and blood component transfusion in isolated coronary artery bypass grafting. Crit Care Med. 2006;34:1608-1616.
33 Koch CG, Li L, Duncal AI, et al. Transfusion in coronary artery bypass grafting is associated with reduced long-term survival. Ann Thorac Surg. 2006;81:1650-1657.
34 Goodnough LT, Shander A, Bresher ME. Transfusion medicine: Looking into the future. Lancet. 2003;361:161-169.
35 Andreu G, Morel P, Forestier F, et al. Hemovigilance network in France: Organization and analysis of immediate transfusion incident reports from 1994-1998. Transfusion. 2002;42:1356-1364.
36 Lelby DA, Herron RM, Read EJ, et al. Trypanosoma cruzi in Los Angeles and Miami blood donors: impact of evolving demographics on seroprevalence and implications for transfusion transmission. Transfusion. 2002;42:549-555.
37 Lelby DA, Herron RM, Garratty G, Herwaldt BL. Trypanosoma cruzi parasitemia in US blood donors with serologic evidence of infection. J Infect Dis. 2008;198:609-613.
38 Goodnough LT, Brecher ME, Kanter MH, Aubuchon JM. Transfusion medicine. N Engl J Med. 1999;340:438-447.
39 Silliman CC, Boshkov LK, Mehdizadehkashi Z, et al. Transfusion-related acute lung injury; Epidemiology and a prospective analysis of etiologic factors. Blood. 2003;101:454-462.
40 Barnard RD. Indiscriminate transfusion: a critique of case reports illustrating hypersensitivity reactions. NY State J Med. 1951:2399-2402.
41 Papovsky MA, Moore SB. Diagnostic and pathogenetic considerations in transfusion-related acute lung injury. Transfusion. 1985;25:573-577.
42 Bux J. Transfusion-related acute lung injury (TRALI): a serious adverse event of blood transfusion. Vox Sang. 2005;89:1-10.
43 Triulzi DJ. Transfusion-related acute lung injury: An update. Hematology Am Soc Hematol Educ Program. 2006:497-501.
44 Chapman CE, Stainsby D, Jones H, et al. Ten years of hemovigilance reports of transfusion-related acute lung injury in the United kingdom and the impact of preferential use of male donor plasma. Transfusion. 2009;49:440-452.
45 Vamvakas EC, Blajchman MA. Deleterious clinical effects of transfusion-associated immunomodulation: Fact or fiction? Blood. 2001;97:1180-1195.
46 Hill GE, Frawley WH, Griffith KE, et al. Allogeneic blood transfusion increases the risk of postoperative bacterial infection: a meta-analysis. J Trauma. 2003;54:908-914.
47 Oplez G, Sengar DP, Mickey MR, Terasaki PI. Effects of blood transfusion on subsequent kidney transplants. Transplant Proc. 1973;51:253-259.
48 Taylor RW, O’Brien J, Trottier SJ, et al. Red blood cell transfusions and nosocomial infections in critically ill patients. Crit Care Med. 2006;34:2302-2308.
49 Zilberberg MD, Stern LS, Wiederkehr DP, et al. Anemia, transfusions and hospital outcomes among critically ill patients on prolonged mechanical ventilation: a retrospective cohort study. Crit Care. 2008;12:R60.
50 Taylor RW, Mangannaro L, O’Brien J, et al. Impact of allogenic packed red blood cell transfusion on nosocomial infection rates in the critically ill patient. Crit Care Med. 2002;30:2249-2254.
51 Aboshi J, Moore EE, Ciesla DJ, Silliman CC. Blood transfusion and the two-insult model of post-injury multiple organ failure. Shock. 2001;15:302-306.
52 Sauaia A, Moore FA, Moore EE, Haenel JB, et al. Early predictors of multiple organ failure. Arch Surg. 1994;129:39-45.
53 Fernandes CJ, Akamine N, De Marco FV, et al. Red blood cell transfusion does not increase oxygen consumption in critically ill septic patients. Crit Care. 2001;5:362-367.
54 Tinmouth A, Fergusson D, Yee IC, et al. Clinical consequences of red cell storage in the critically ill. Transfusion. 2006;46:2014-2027.
55 Wolfe LC. Oxidative injuries to the red cell membrane during conventional blood preservation. Semin Hematol. 1989;26:307-312.
56 Berezina TL, Zaets SB, Morgan C, et al. Influence of storage on red blood cell rheological properties. J Surg Res. 2002;102:6-12.
57 Valeri CR, Collins FB. The physiologic effect of transfusing preserved red cells with low 2,3-diphosphoglycerate and high affinity for oxygen. Vox Sang. 1971;21:97-108.
58 Jia L, Bonaventura C, Bonaventura J, Stamler JS. S-nitrosohemaglobin: a dynamic activity of blood involved in vascular control. Nature. 1996;380:221-226.
59 Ho J, Sibbald WJ, Chin-Yee IH. Effects of storage on efficacy of red cell transfusion: when is it not sate? Crit Care Med. 2003;31(12 Suppl):S687-S697.
60 Tinmouth A, Fergusson D, Yee IC, Hebert PC. Clinical consequences of red cell storage in the critically ill. Transfusion. 2006;46:2014-2027.
61 Zallen G, Offner PJ, Moore EE, et al. Age of transfused blood is an independent risk factor for postinjury multiple organ failure. Am J Surg. 1999;178:570-572.
62 Koch GC, Li L, Sessler DI, et al. Duration of red-cell storage and complications after cardiac surgery. N Engl J Med. 2008;358:1229-1239.
63 Rogiers P, Shang H, Leeman M, et al. Erythropoietin response is blunted in critically ill patients. Intensive Care Med. 1997;23:159-162.
64 Corwin HL, Gettinger A, Fabian TC, et al. Efficacy and safety of epoetin alfa in critically ill patients. N Engl J Med. 2007;357:965-976.
65 Shermock KM, Lipsett PA, Provonost PJ, Dorman T. Number needed to treat and cost of recombinant human erythropoietin to avoid one transfusion-related adverse event in critically ill patients. Crit Care Med. 2005;33:497-503.
66 Spahn DR, Cerny V, Coats TJ, et al. Management of bleeding following major trauma: A European Guideline. Crit Care. 2007;11(1):R17.
67 Wu WC, Rathore SS, Wang Y, et al. Blood transfusion in elderly patients with acute myocardial infarction. N Engl J Med. 2001;345:1230-1236.
68 Carson JL, Duff A, Psoes RM, et al. Effect of anaemia and cardiovascular disease on surgical mortality and morbidity. Lancet. 1996;348:1055-1060.
69 Hebert PC, Wells G, Tweeddale M, et al. Does transfusion practice affect mortality in critically ill patients? Transfusion Requirements in Critical care (TRICC) Investigators and the Canadian Critical Care Trials Group. Am J Respir Crit Care Med. 1997;155:1618-1623.
70 Hebert PC, Blajchman MA, Cook DJ, et al. Do blood outcomes improve outcomes related to mechanical ventilation? Chest. 2001;119:1850-1857.
71 Zimmerman JL. Use of blood products in sepsis: an evidence-based review. Crit Care Med. 2004;32(11 Suppl):S542-S547.
72 Mazza BF, Machado FR, Mazza DD, et al. Evaluation of blood transfusion effects on mixed venous oxygen saturation and lactate levels in patients with SIRS/sepsis. Clinics (Sao Paulo). 2005;60:311-316.
73 Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med. 2001;345:1368-1377.
74 Carlson AP, Schermer CR, LU SW. Retrospective evaluation of anemia and transfusion in traumatic brain injury. J Trauma. 2006;61:567-571.
75 Smith MJ, Stiefel MF, Magge S, et al. Packed red blood cell transfusion increases local cerebral oxygenation. Crit Care Med. 2005;33:1104-1108.
76 Chang H, Hail GA, Greets WH, et al. Allogeneic red blood cell transfusion is an independent risk factor for the development of postoperative bacterial infection. Vox Sang. 2000;78:13-18.
77 Salim A, Hadjizacharia P, DuBose J, et al. Role of anemia in traumatic brain injury. J Am Coll Surg. 2008;207:398-406.
78 Murphy GJ, Allen SM, Unsworth-White J, et al. Safety and efficacy of perioperative cell salvage and autotransfusion after coronary artery bypass grafting: a randomized trial. Ann Thorac Surg. 2004;77:1553-1559.
79 Mukhopadhyay A, Yip HS, Prabhuswamy D, et al. The use of a blood conservation device to reduce red blood cell transfusion requirements: a before and after study. Crit Care. 2010;14:R7.
80 Yoshida T, AuBuchon JP, Tryzelaar L, et al. Extended storage of red cells under anaerobic conditions. Vox Sang. 2007;92:22-31.
81 Chapman JF, Hyam C, Hick R. Blood inventory management. Vox Sang. 2004;87(Suppl 2):143-145.
82 Winslow RM. Blood substitutes: refocusing an elusive goal. Br J Hematol. 2000;111:387-396.
83 Migita R, Gonzales A, Gonzales ML, et al. Blood volume and cardiac index in rates after exchange transfusion with hemoglobin based oxygen carriers. J Appl Physiol. 1997;82:1995-2002.
84 Intaglietta M, Johnason PC, Winslow RM, et al. Microvascular and tissue oxygen distribution. Cardiovasc Res. 1996;32:632-643.
85 Gould SA, Moore EE, Hoyt DB, et al. the first randomized trail of human polymerized hemoglobin as a blood substitute in acute trauma and emergent surgery. J Am Coll Surg. 1998;187:113-120.
86 Gomez-Jimenez J, Salgado A, Mourelle A, et al. L-arginine: nitric oxide pathway in endotoxemia and human septic shock. Crit Care Med. 1995;23:253-258.
87 MacKenzie CF, Moon-Massat PF, Shander A, et al. When blood is not an option: factors affecting survival after the use of hemoglobin-based oxygen carrier in 54 patients with life-threatening anemia. Anesth Analg. 2010:685-693.
88 Natanson C, Kern SJ, Lurie P, et al. Cell-free hemoglobin-based blood substitutes and risk of myocardial infarction and death. JAMA. 2008;299:2304-2312.
89 Chant C, Wilson G, Friedrich JO. Anemia, transfusion, and phlebotomy practices in critically ill patients with prolonged ICU length of stay: a cohort study. Crit Care. 2006:R140.
90 Hendrickson JE, Hillyer CD. Noninfectious serious hazards of transfusion. Anesth Analg. 2009;108:759-769.
91 American College of Surgeons. Shock. In: Advanced Trauma Life Support Manual. Eight Edition, ATLS Manual, 2008. Chicago: American College of Surgeons; 2008:••-••.
92 Hebert PC, Wells G, Blajchman MA, et al. A multicenter randomized, controlled clinical trial of transfusion requirements in critical care. Transfusion Requirements in Critical Care investigators, Canadian Critical Care Trials Group. N Engl J Med. 1999;340:409-417.
93 McIntyre L, Hebert PC, Wells G, et al. Is a restrictive transfusion strategy safe for resuscitated and critically ill trauma patients? J Trauma. 2004;57:563-568. discussion.568
94 Wu WC, Rathore SS, Wang Y, et al. Blood transfusion in elderly patients with acute myocardial infarction. N Engl J Med. 2001;345:1230-1236.
95 Tsai AG, Cabrales P, Intaglietta M. Microvascular perfusion upon exchange transfusion with stored RBC’s in normovolemic anemic conditions. Transfusion. 2004;44:1626-1634.
96 Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med. 2001;345:1368-1377.
97 Haidech AM, Drescher J, Ault ML, et al. Higher hemoglobin is associated with less cerebral infarction, poor outcome, and death after subarachnoid hemorrhage. Neurosurgery. 2006;59:775-779. discussion 779-80
98 McIntyre AL, Fergusson DA, Hutchison JS, et al. Effect of a liberal versus restrictive transfusion strategy on mortality in patients with moderate to severe head injury. Neurocrit Care. 2006;5:4-9.