Anemia—preexisting or new onset—is common in the critical care units (ICUs), and blood transfusions are routinely employed to “correct” anemia in this setting. In a surgical ICU, about 19% of the patients had Hb less than 7 g/dL and 30% had Hb levels between 7 and 9 g/dL,12 indicating that a significant number of ICU patients were anemic (many, moderately or severely anemic) according to the WHO definition of anemia.10 The reported incidence and prevalence were 46.6% and 68%, respectively among cancer patients admitted to another ICU.13 Another prospective study reported that almost all consecutive patients admitted to a general ICU were anemic, and patients' Hb level continued to drop during their ICU stay.11 The etiology of anemia in the ICU is varied and often multifactorial, and can include iron deficiency, inflammatory responses, blunt response to endogenous erythropoietin, bleeding and aggressive diagnostic blood draws.14,15 A large and evergrowing body of evidence supports the independent link between anemia and unfavorable clinical outcomes in various patient populations including the critically ill.10
Although transfusion of blood components in ICU is common, the clinical evidence to guide the use of these products is limited. It has been estimated that greater than 40% of patients receive one or more RBC transfusions while in the ICU, and about 90% of transfusions are provided in the context of stable anemia without evidence of need or benefit of the transfused blood.25 In a matched-cohort study of nonbleeding critically ill patients with moderate anemia (Hb between 7 and 9.5 g/dL), RBC transfusions were associated with increased mortality and nosocomial infections.26 Several other studies have indicated that transfusions are associated with worsening of clinical outcomes, and they are often ineffective in improving oxygen consumption, questioning the main reason they are given to the patients in the first place.10,27
In a single-center study it was reported that about 50% of patients received blood products during their ICU stay: 48.3% received packed red blood cells; 18.3% received FFP, and 8.4% of patients received platelet transfusion. Interestingly, approximately one-fourth to one-half of these transfusions were not medically indicated.28 According to a study performed in 29 ICUs in the United Kingdom, 9% of the patients received platelet transfusion in ICU, one-third of which occurred in patients with platelet counts above 50 × 109/L and in absence of clinically significant bleeding.29 In a prospective cohort study of septic shock patients, 57% of the patients received FFP transfusion during ICU stay; one-third of the plasma transfusions were given without any evidence of bleeding or any planned invasive procedures.30 A survey has also shown substantial variations in transfusion practices and uncertainties toward indications of plasma transfusions in ICU among clinicians.31
On the other hand, one study in 47 ICUs in Australia and New Zealand indicated (although somewhat broadly interpreted) that 98% of RBC transfusions were performed according to the national transfusion guidelines, while only 47% of platelet, 71% of FFP, and 12% of cryoprecipitate transfusions were done according to the guidelines.32 Of note, in this study 40.2% of the RBC transfusions were given to improve oxygen delivery (DO2) and 43.6% of the RBC transfusions were given for bleeding (nearly half of which were considered to be “minor”).32 As will be discussed later, these numbers may not be necessarily consistent with current evidence or guidelines for use of RBC transfusions in critically ill patients.
Somewhat similar results were observed in a single-center study in Spain where RBC transfusion seem to be more restrictive than any of the other blood components.33 These findings are also consistent with the high frequency of blood product transfusion and high variability in transfusion practices reported in many other studies and reviews.34
Evidence-based general recommendations for transfusion of RBCs, plasma, and platelets were discussed in previous sections. Here we take a closer look at these blood components and their usage in ICU.
RBC is a heterogeneous group of products that includes packed red blood cells (PRBCs), gamma-irradiated blood, washed RBCs, and whole blood. PRBC is the preparation used in most clinical situations. One unit PRBC has an average volume of 300 mL, of which two-thirds is consisted of RBCs, and the remaining is mostly the preservative solution. Each unit has a hematocrit of approximately 55% to 60% and approximately 200 mg of iron.35 PRBCs undergo leukoreduction (removal of leukocytes) and hence are known as leukoreduced PRBCs. Universal leukoreduction of allogeneic blood as part of blood banking process has been implemented in an increasing number of nations. Leukoreduction has been suggested to improve the safety profile of allogeneic blood by reducing the risk of febrile transfusion reactions, alloimmunization and transmission of some pathogens (cytomegalovirus [CMV] and possibly prions), but the overall impact on patient outcomes and its cost-benefits are still a matter of debate.36 Although leukoreduced PRBC units are gaining universal acceptance, these units are more costly, and in some instances may be preferred for chronically transfused patients, potential transplant recipients, patients with previous transfusion reactions, patients undergoing cardiopulmonary bypass, and CMV seronegative patients at risk for CMV infection.
Gamma-irradiated RBC units are produced by subjecting the units of blood to external-beam radiation. This process results in destruction of donor T-lymphocytes in the blood and is effective for prevention of graft-versus-host disease (GVHD) in the transfused patients, particularly the transplant patients and severely immunocompromised patients. However, irradiation is associated with several changes in the RBCs which could result in reduced life span of these units.37
As the name suggests, washed RBCs are produced by “washing” the donor cells with normal saline solution to remove as much of the proteins and macromolecules of the donor plasma as possible. These units are preferred for patients with immunoglobulin A deficiency and those at high risk for anaphylactic reaction.38 Lastly, whole blood is rarely indicated and seldom available and it is most often considered in the context of massive blood transfusion. The rationale is to avoid dilutional deficiencies that can be caused with transfusion of other components.39
For many decades, transfusion of RBCs was used to maintain a blood hemoglobin level above 10 g/dL or a hematocrit above 30% (the 10/30 rule), even though these thresholds were arbitrary numbers with no proven physiologic or clinical significance. Emergence of a large body of work and clinical evidence, especially within the last 25 years, has changed transfusion practice to balance the benefit of treating anemia with the desire to avoid unnecessary transfusion and its associated risks and complications in various medical settings including in the ICU.40 However, there is evidence to suggest that considerable variation in RBC transfusion practices in critical care still exists. A Canadian scenario-based national survey sent to critical care practitioners demonstrated that transfusion thresholds differed significantly (P < 0.0001) when faced with different medical scenarios.41 A study by Herbert and colleagues examined blood use in 5298 consecutive patients admitted to 6 tertiary level ICUs.42 The overall number of transfusions per patient day ranged from 0.82 ± 1.69 to 1.08 ± 1.27 between institutions (P < 0.001).
The multicenter Transfusion Requirements in Critical Care (TRICC) trial showed that a restrictive strategy, that is, a threshold for transfusion for hemoglobin less than 7 g/dL in critically ill patients is safe.43 Furthermore, there is a trend toward decreased hospital morbidity and mortality when compared to patients with a more liberal (transfusion for a hemoglobin < 10 g/dL) transfusion strategy. An exception to this strategy is patients with acute myocardial ischemia. The optimal transfusion threshold for these patients has not been determined because such patients were excluded from most clinical trials. Similarly, the Transfusion Requirements in Pediatric ICU (TRIPICU) study showed that in stable, critically ill children, using a Hb threshold of 7 g/dL for transfusion can reduce the transfusions compared with a Hb threshold of 9.5 g/dL without negatively affecting the outcomes.44 Subsequent subgroup analyses of this trial further supported the restrictive transfusion strategy in patients with higher severity of illness, postsurgical patients and those with respiratory dysfunction, sepsis, neurologic disorders, and severe trauma.45
The joint taskforce of Eastern Association for Surgery of Trauma (EAST) and the American College of Critical Care Medicine (ACCM) of the Society of Critical Care Medicine (SCCM) have developed clinical practice guidelines for RBC transfusion in the critically ill patients.36 Based on these guidelines, RBC transfusion is indicated for patients with evidence of hemorrhagic shock, and it may also be indicated for those with evidence of acute hemorrhage and hemodynamic instability or inadequate DO2. According to these guidelines, in hemodynamically stable critically ill patients, transfusion of RBC at hemoglobin level of less than 7 g/dL is as effective as using a more liberal trigger of Hb less than 10 g/dL, with the possible exception of patients with acute myocardial infarction or unstable myocardial ischemia, given the paucity of data on these patients. However, the guidelines emphasize that use of hemoglobin as the only “trigger” for RBC transfusion should be avoided, and transfusion decisions should be made based on other parameters such as patient's volume status, evidence of shock, duration and severity of anemia, and cardiopulmonary status of the patient.36 Based on these guidelines, RBC transfusion should be considered in critically ill patients with Hb less than 7 g/dL in following conditions: patients who require mechanical ventilation (despite lack of conclusive evidence), resuscitated trauma patients, and patients with stable cardiac disease. Despite lack of supportive evidence, the guidelines recommend that RBC transfusion may be considered in critically ill patients with acute coronary syndrome with Hb less than or equal to 8 g/dL. The guidelines recommend against RBC transfusion as an absolute method to improve tissue oxygen consumption (VO2). When indicated and with exception of acute hemorrhage, RBC transfusion should be given 1 unit at a time, with reevaluation of the patient prior to giving the next unit.36 The guidelines call for individual assessment of transfusion needs in each septic patient given that optimal transfusion threshold and the impact of transfusion on oxygen consumption in these patients are not well established.36
In critically ill patients with or at risk of acute respiratory distress or lung injury, the guidelines call for making all efforts to avoid RBC transfusions after completion of resuscitation, and to appropriately diagnose transfusion-related acute lung injury (TRALI) given its prominence as a leading cause of morbidity and mortality in transfused patients. The guidelines proscribe against use of RBC transfusion with the goal of facilitating weaning patients from mechanical ventilation.36
The guidelines indicate no benefit for liberal transfusion (at Hb > 10 g/dL) in patients with moderate-to-severe traumatic brain injury (TBI). In patients with subarachnoid hemorrhage (SAH), transfusion decisions must be made on case-by-case basis since the optimal transfusion threshold and the impact of transfusion on outcomes in these patients are undetermined.36 The guidelines provide an overview of various blood management strategies that can be used in critically ill patients to reduce the avoidable allogeneic transfusions and improve the outcomes of the patients.36 Of note, the guidelines emphasize the insufficiency of the available evidence in many of the discussed topics,36 underscoring the importance of further research in the field.
Similar to general critically ill patient populations, evidence regarding transfusion in critically ill children is very limited. Anemia and transfusion are both common in these patients, and in addition to proper management of anemia, transfusion decisions should be made based on the individual patient's factors and characteristics, rather than using general transfusion triggers, and appropriate blood management strategies should be utilized.46
Another set of transfusion guidelines for the critically ill adult patients has recently been developed by the British Committee for Standards in Haematology (BCSH).24 These guidelines share many similarities with the ACCM/SCCM transfusion guidelines discussed above.36 They recommend a Hb level of less than or equal to 7 g/dL (with a target Hb range of 7-9 g/dL) as the default transfusion threshold in critically ill patients in general. Again, despite lack of evidence, a target Hb level of 7 to 9 g/dL has been recommended in patients with TBI as well as during later stages of severe sepsis (vs a Hb target of 9-10 g/dL during early resuscitation of severe sepsis with evidence of inadequate DO2). Similarly, despite lack of supporting data, the guidelines recommend that Hb level of patients with stable angina should be maintained above 7 g/dL. In addition, a target Hb level of 8 to 10 g/dL is recommended in patients with SAH and the Hb should be kept greater than 8 to 9 g/dL in patients with acute coronary syndrome. Finally, a target Hb level of greater than 9 g/dL is recommended in TBI patients with evidence of cerebral ischemia and patients with acute ischemic stroke.24 Similar to the ACCM/SCCM guidelines, the BCSH guidelines recommend against use of RBC transfusion to facilitate weaning patients from mechanical ventilation if Hb greater than 7 g/dL.24
Most recently and as part of its evidence-based “Choosing Wisely” recommendations, the Critical Care Societies Collaborative (CCSC)—a multidisciplinary group composed of the American Association of Critical-Care Nurses (AACN), American College of Chest Physicians (ACCP), American Thoracic Society (ATS), and SCCM—have identified transfusion of RBCs as one of routine practices in the ICUs that should be questioned, given its doubtful benefits and certain harms. The group has made the recommendation to not transfuse RBCs in hemodynamically stable, nonbleeding critically ill patients with Hb greater than 7 mg/dL.ii The AACN—as part of the CCSC—has identified 5 routine critical care practices that should be questioned because they may not always be necessary and could, in fact, be harmful.
Plasma is the portion of whole blood that remains after white cells, red cells, and platelets are removed by centrifugation. Plasma contains various macromolecules namely procoagulation and anticoagulation factors, albumin, and immunoglobulins. It is indicated when inadequate hemostasis is present and the benefits of correction outweighs risks of transfusion. However, the benefit of plasma administration remains controversial, and with the advent of more specific factor concentrates, its indications are on the decline.
Plasma products come in a number of forms. FFP is separated from freshly drawn blood by removing the cellular components. It is frozen for storage and thawed when needed for transfusion. Once thawed, FFP needs to be transfused within 24 hours as factors V and VIII decline with time. Also, FFP must be cross-matched to confirm ABO compatibility. Thawed plasma is a plasma not transfused within 24 hours of thawing. It can be transfused for up to 5 days if it is kept refrigerated at 1°C to 6°C. Other plasma products include jumbo apheresis plasma, single-donor, liquid plasma, and solvent/detergent-treated (SD) plasma (Octaplas). Cryoprecipitate is a by-product of FFP and it is obtained by thawing FFP at 4°C and collecting the white precipitate. It is rich in von Willebrand factor (vWF), factors VIII and XIII, and fibrinogen. It allows replacement of these factors using much smaller volumes compared with plasma volumes needed to achieve the same level of factors.
A prospective, observational study of an adult ICU determined that the incidence of laboratory evidence of coagulopathy was 67% of patients and 14% of patients received transfusion of FFP.47 Approximately one-third of FFP usage is for correction of elevated international normalized ratio (INR) prior to invasive and surgical procedures48; however, there is a paucity of evidence to support this practice. Furthermore, plasma should not be used to reverse supratherapeutic warfarin effects, unless in the presence of active bleeding or need for invasive or surgical procedures because plasma products are only partially effective,49 its action is of short duration and it could increase the risk of hypervolemia (transfusion-associated circulatory overload [TACO]) and other complications such as TRALI).50
The response to plasma transfusion is directly proportional to the difference between the patient level of coagulation factors and that of the infused plasma. Thus, patients with severe deficiencies are more likely to see a more significant change in their INR than patients with mild deficiencies. It is worth noting that the INR of a unit of plasma is usually elevated itself and tends to be around 1.3.51 The dose of FFP transfused to patients is also commonly erroneous and often inadequate to achieve the desire impact on coagulation. The response to cryoprecipitate transfusion is even more difficult to predict; 10 bags of cryoprecipitate is expected to increase fibrinogen level by approximately 70 mg/dL. With availability of prothrombin complex concentrates (PCC)—particularly the 4-factor products—there is less need to plasma for reversing the effects of warfarin.52 Use of plasma in conjunction with other blood components to create a “balanced” transfusion strategy in trauma resuscitation has been gaining more interest. The Prospective, Observational, Multicenter, Major Trauma Transfusion (PROMMTT) study has indicated that higher plasma (and platelet) to RBC ratios during early resuscitation of trauma patients were associated with better survival in patients who received at least 3 units of RBC during the first 24 hours.53 Another phase III trial in massively transfused trauma patients, Pragmatic, Randomized Optimal Platelets and Plasma Ratios (PROPPR) study compared the effectiveness of transfusing patients with severe trauma and major bleeding using plasma, platelets and red blood cells in a 1:1:1 ratio compared with a 1:1:2 ratio. No significant differences in mortality were detected at 24 hours or at 30 days. However, exsanguination, which was the prominent cause of death within the first 24 hours, was significantly decreased in the 1:1;1 group (9.2% vs 14.6% in the 1:1:2 group, P = 0.03) and more patients achieved hemostasis in the 1:1:1 group (86% vs 78%, P = 0.006).54 Of note, rapid anatomic control of bleeding (e.g., primary surgical hemostasis) was not reported and might have influenced the hemostasis results. Furthermore, ratio-based transfusion is not intended to replace transfusion based on coagulation testing but rather to supplement it with the goal of more effective control of acute trauma coagulopathy and hemorrhagic shock.55
Platelet concentrates are prepared from whole blood by centrifugation at low speeds to separate the erythrocytes. The supernatant, “platelet-rich plasma” is then centrifuged at high speeds to separate the platelets. This results in “pooled concentrates.” It is less expensive to produce, but more donors are required because the yield is lower; 6 to 10 donors are required per platelet transfusion. Single-donor apheresis platelet concentrates are obtained by apheresis; that is, whole blood from a donor passes through a device that separates the platelets while returning the remainder to the donor. This process is more expensive, but it has a higher yield, fewer donors are necessary (one donor per platelets transfusion), and hence the risk of transmission of infection is lower compared with pooled platelets. Platelet concentrates can be stored for up to 7 days, but platelets start losing their efficacy (viability) after 3 days.56
The generally expected response to transfusion of 1 unit of platelets is a rise in platelet count by 5 to 10,000; presence of platelet destruction or consumption at the bleeding site can blunt this response. Efficacy is reduced by the presence of antibodies to ABO antigens on platelets or to leukocyte antigens. This can be ameliorated with transfusions of ABO-compatible platelets or using single-donor concentrates.
Current indications for platelet transfusions in thrombocytopenic patients can be therapeutic or prophylactic.56 These include the following:
Platelet count less than 10,000, to reduce the risk of spontaneous bleeding
Platelet count less than 50,000, in patients who are actively bleeding, or are scheduled for invasive procedures, or have a qualitative platelet defect
Platelet count between 70,000 and 100,000, with a central nervous system (CNS) injury, or undergoing neurosurgery or intrathecal catheter insertion
Normal platelet count, with active bleeding due to platelet dysfunction (although platelet transfusion is not consistently effective in these patients)
As discussed earlier, the most efficient use of platelets (alongside plasma) as part of “balanced” transfusion protocols to supplement RBCs during trauma resuscitation is still under investigation.
A number of complications can result from transfusions of blood products. Often, the greater the volume of transfusion, the greater is the risk or severity of the complication. These complications can be infectious (human immunodeficiency virus [HIV], hepatitis B virus [HBV], hepatitis C virus [HCV], hepatitis A virus [HAV], human T-cell leukemia/lymphoma virus [HTLV], parvovirus B19, bacterial) or noninfectious which include acute hemolytic reactions, delayed hemolytic reactions, febrile reactions, allergic reactions, posttransfusion purpura (rare), acute lung injury (TRALI), immunomodulation, that is, the immunosuppressive activity of allogeneic blood transfusion, and transfusion-related GVHD.57 Other complications include volume overload (TACO) with consequent pulmonary edema due to expansion of the intravascular volume especially in patients with compromised cardiac or renal function or due to fluids shift due to increased oncotic pressure particularly with FFP; hypothermia if large volumes are transfused rapidly (blood products are stored at cold temperatures); coagulopathy presumably as a result of hemodilution from resuscitative fluids and acidosis secondary to tissue hypoxia; and life-threatening hyperkalemia (especially in pediatric population with relatively large transfusion volume). Citrate is present in stored blood products and can lead to metabolic alkalosis and hypocalcemia.57
With significant advances in the screening and testing of donors for transmittable diseases, the infectious risks are very rare with an incidence ranging from 1 for every 7,800,000 units of RBC units transfused for HIV to 1 in 50,000 units transfused for bacterial contamination. However, the incidence of bacterial contamination is much more common with platelet transfusion with a reported incidence of 1 infection per 1000 units of platelets transfused,57 and septic transfusion reactions remain a concern with platelet transfusions, making the case for additional testing. The American Association of Blood Banks (now referred to as AABB) standards call for the use of enhanced bacteria detection methods and require blood banks or transfusion services to employ methods to detect bacteria in all platelet components.iii The nature of allogeneic blood and reliance on donors and screening tests means that the risk of transmitting infections through blood can never be fully eliminated and some residual risk of undetected and/or emerging pathogens remains.57
Acute hemolytic reactions occur due to antibodies, usually IgM in the recipient's serum against major antigens present on the donor's RBCs. These are almost always due to ABO incompatibility. The frequency has been described to range from 1 in 40,000 to 1 in a 1,000,000. These occur within the first several minutes of transfusion and manifest acutely with fever, tachycardia, hypotension, dyspnea, and back and chest pain.57
Delayed hemolytic reactions usually occur more than 24 to 48 hours, and up to 7 to 10 days after the transfusion. They result from antibodies in the recipient's serum directed toward minor antigens on the donor's RBCs. These reactions occur with a frequency of 1 in 7000 with a sudden decrease in hemoglobin. They are often mild and frequently undetected and require no specific therapy.57
Febrile nonhemolytic reactions result from the presence of antileukocyte antibodies induced by previous transfusions acting against leukocytes in the donor's product or secondary to accumulated cytokines in stored blood components. It is relatively frequent, ranging from 1 in 20 (with platelets transfusion) to 1 in 300. These reactions are manifested acutely by an increase in body temperature. These are usually self-limited, but can be treated with antipyretics and the transfusion allowed to be completed. Leukoreduction of stored blood can reduce the incidence of febrile nonhemolytic reactions.57
Allergic reactions occur because of presence of allergens in the donor's blood component to which the patient has preexisting antibodies; they do not require previous blood exposure. These reactions can vary from urticaria and/or bronchospasm with a frequency of 1 in 100 to anaphylaxis, with a frequency of 1 in 40,000. Patients with IgA deficiency are especially at risk for severe anaphylactic reactions. These reactions are best prevented with washed RBCs, but can be treated with high-dose corticosteroids, antihistamines, and airway protection.57
TRALI is related to presence of alloreactive plasma antibodies within red blood cell products or FFP which can lead to agglutination and diffuse activation of leukocytes with subsequent diffuse capillary damage of the pulmonary vasculature and rapid onset of acute pulmonary injury and development of inflammatory pulmonary edema. The pulmonary dysfunction may not manifest for hours to, less frequently, days after the transfusion was administered. The incidence of TRALI varies from 1 in 700, especially with FFP to 1 in 5000; however, this incidence may be underestimated as the reaction may go unrecognized.57
The adverse events discussed here are often recognized as known immediate complications of allogeneic blood transfusion, and most of the time, a causal link can be established and recognized. In critically ill patients, it is difficult at time to recognize these events because of the underlying acuity of the illness. Hypotension, sepsis, and shock can accompany some of the complications stated earlier or can occur independent of transfusion and due to the underlying disease. What complicates this picture is the delayed adverse outcomes that are associated with allogeneic transfusions. Several studies have shown that blood transfusions are independently associated with increased risk of wound infection, pneumonia, sepsis, and other nosocomial infections, multiorgan failure, systemic inflammatory response syndrome (SIRS), and other morbidities and mortality.10,36