Chapter 7 The modern blood transfusion era began with discovery of the ABO red cell antigen system in the early 1900s. It was soon found that adding citrate enabled the storage of anticoagulated blood. Blood banking in the United States began during the 1930s. Energetic pioneers, such as John Lundy of the Mayo Clinic, gained a wealth of clinical experience, prompting dissemination of expert-based advice, such as Lundy’s recommendation that blood transfusion was appropriate when a patient’s hemoglobin (Hgb) was less than 10 g/dL or when a patient lost more than 15% of circulating blood volume. These recommendations were not, however, based on rigorous controlled trials. Rapid expansion of blood banking occurred after World War II, and in subsequent decades, research focused on such critical issues as prolonging the storage life of blood products, component therapy, and reducing the risk of transfusion reactions and transfusion-related infections.1,2 More recently, at a time when more than 14 million units of packed red blood cells (PRBCs) are transfused yearly in the United States, research has increasingly focused on developing a more evidence-based approach to identification of appropriate transfusion triggers for all blood components, developing massive transfusion protocols, and reassessing the overall risks and benefits of transfusion.3–10 Although traditional allogenic donation methods still predominate, increasing use is being made of red cell apheresis technology (about 10% of all units donated), by which red cells are separated from the blood at the time of collection, with everything else returned to circulation. This allows collection of about two transfusable units during a single donation. Autologous blood collection, in which the donor is also the intended recipient, peaked in the early 1990s and continues to decline.11 Red blood cell (RBC) storage methods aim to ensure viability of at least 75% of the cells 24 hours after infusion.12 Blood collection bags contain an anticoagulant preservative of citrate, phosphate, dextrose, and adenine (CPDA-1), ensuring a shelf life of 35 days and hematocrit of 70 to 80% for PRBCs. Additive solutions (Adsol, Nutricel, Optisol) provide additional nutrients, extending maximum storage to 42 days and lowering viscosity, which makes infusion easier.13 Storage, however, impairs red cell function.14 Stored blood initially delivers oxygen to the tissues less efficiently. Although PRBCs are maintained at 1 to 6° C, cell metabolism continues, and changes occur. These changes are collectively referred to as the “storage lesion.”14 Documented alterations are numerous and include a decrease in both pH and the level of 2,3-diphosphoglycerate (2,3-DPG). In addition, the deformability of stored RBCs changes over time, making them more spherical and rigid, increasing resistance to capillary flow. After infusion, however, many of these changes are readily reversed. The decrease in 2,3-DPG, for example, results in a left shift in the Hgb-oxygen dissociation curve, but 2,3-DPG levels begin to recover within minutes and are fully restored within 24 hours.15 Further complicating the issue, the relationship between overall oxygen transport and oxygen delivery to tissues is complex. Depletion of S-nitrosohemoglobin during storage, for example, alters oxygen-dependent regulation of microcirculatory blood flow (“hypoxic vasodilation”).16 Research and debate are ongoing with regard to whether and when these and other changes are clinically significant, and how they might be addressed.17–20 Additional well-established changes in stored blood include cell leakage of potassium, although the amount (approximately 6 mEq/U) is readily tolerated by most otherwise healthy patients. PRBCs contain essentially no functional platelets or granulocytes.21 ABO grouping requires that the recipient’s red cells be tested with anti-A and anti-B serum and that his or her serum be tested with A and B red cells. At about 6 months of age, patients form antibodies against the A and B antigens they lack. Those with type AB blood form no ABO group antibodies. Patients with type O have antibodies against both. The major clinically significant Rh antigen is the D antigen. Rh typing is usually done by adding a commercial reagent (anti-D) to recipient RBCs.12 The antibody screen identifies unexpected antibodies in the patient’s serum. These result from prior exposure to foreign RBC antigens during allogenic transfusion or pregnancy. The antibody screen entails mixing commercial RBC reagents (mixtures of red cells expressing clinically significant antigens) with the patient’s serum. The incidence of these unexpected antibodies in the general population is low (<1-2%), but a positive screen prompts further compatibility testing, which can take hours to days. When transfusion is delayed by a positive antibody screen in a critically ill patient, clinicians should communicate directly with the blood bank to determine the best course of action. Although ABO compatibility is mandatory in all patients, non-ABO antigens are very unlikely to cause immediate intravascular hemolysis.15,21,22 Administering blood that is not completely crossmatched is therefore an option if the need is emergent. The traditional crossmatch requires mixing recipient serum with donor RBCs and observing for agglutination as a final compatibility test before transfusion. If the antibody screen is negative, an “immediate spin crossmatch” at room temperature serves as a final check for ABO incompatibility. A “complete crossmatch” is generally done before transfusion if the antibody screen is positive. This requires incubation to 37° C and the addition of antihuman globulin (Coombs’ reagent) to promote agglutination.13 Many blood banks also substitute a “computer crossmatch” for patients whose blood has been tested at least twice within their system. Decisions about which method is used, however, are generally made by the blood bank, not the clinician. Full compatibility testing takes time. An antibody screen and immediate spin crossmatch at a minimum take approximately 45 to 60 minutes. This assumes a negative antibody screen followed by an immediate spin crossmatch performed at room temperature. If the antibody screen is positive, the antibody is identified via more elaborate procedures, and a complete crossmatch (using a Coombs test with incubated serum) is required. This process can take up to several hours (or even days),21 an unacceptable delay in some emergent situations. Universal (group O) blood is used when RBCs are needed in hemorrhaging, unstable patients before any testing can be done.23,24 Female patients receive O-negative blood to prevent hemolytic disease of the newborn unless there is no chance of subsequent pregnancy. All others receive O-positive blood, because even if sensitization occurs, Rh antibodies generally do not fix complement and therefore would be unlikely to cause an acute intravascular hemolytic reaction in the unlikely event that an Rh-negative recipient twice received emergent transfusion of Rh-positive blood. Conversely, the “universal” type for fresh frozen plasma (FFP) is type AB, which contains no antibodies to either A or B antigens. Massive transfusion has no formal definition. Administration of at least 10 units of RBCs in 24 hours is a commonly used cutoff.25 Although patients receiving any amount of blood are susceptible to a variety of infectious, physiologic, and immunologic insults, this section will discuss those uniquely associated with massive transfusion. Some of these complications are well understood and easily managed. Hypothermia is common in these patients, and can reduce clotting factor activity.26 Warmed intravenous fluids, blood warmers, and warming lights and blankets are often needed. Frequent laboratory testing will identify electrolyte disturbances (low magnesium and calcium, and both high and low potassium), which are in general treated in a standard fashion by replenishing deficits, or administering calcium for hyperkalemia. Acidosis is a common finding with massive hemorrhage but can also be caused by hypoperfusion, and the contribution of transfused blood to acidosis is felt to be variable. Citrate from banked blood, for example, is metabolized in the liver to bicarbonate, which can sometimes result in metabolic alkalosis. With rapid infusion or reduced hepatic function, however, this pathway can be overwhelmed, and the net effect of infusing large amounts of citrate can be worsening metabolic acidosis. A rational response to metabolic acidosis is to optimize oxygen delivery and ventilation. Administering sodium bicarbonate may be considered in severe cases, but the benefits are less certain.27 Patients receiving massive transfusion are also prone to coagulopathy and thrombocytopenia. Consumption and dilution of clotting factors and platelets occur in these patients owing to ongoing hemorrhage, fluid boluses, and transfusion of PRBCs. This undoubtedly plays a role in the coagulopathy of trauma, but recent research asserts that coagulopathy often occurs in massive trauma even before these mechanisms have taken effect.28–30 A number of reports (none of them from randomized prospective trials) have stated that a more proactive approach to administering plasma and platelets in massive transfusion is associated with better outcomes.31–43 In response, many institutions have adopted massive transfusion protocols that call for plasma (and often platelets) to be given in a 1 : 1 ratio with RBCs.44 When set ratios are not used, clinical assessment and judgment often augment laboratory values such as international normalized ratio (INR), partial thromboplastin time (PTT), and fibrinogen and platelet counts because there is no direct evidence supporting any particular threshold for platelet or coagulation factor replacement in patients with severe hemorrhage.7 Commonly recommended goals in this setting would be to consider maintaining an INR below 1.5, a fibrinogen level greater than 1 to 2 g/L, and platelet count above 50,000 to 100,000/µL.7,45 A review of relevant literature supports the recent trend toward more conservative red cell transfusion triggers but also highlights the need for further investigation.46 The same can be said for FFP and other blood components.47,48 Benefits of transfusion have been difficult to prove,9 and the list of known and suspected associated risks is long and growing.49 Intriguing reports on the use of fresh whole blood in military field hospitals have been published,50,51 but in civilian practice in the United States, it is generally unavailable and rarely used. PRBCs are indicated only to improve oxygen delivery to tissues at the microvascular level and thus improve intracellular oxygen consumption. It bears repeating that demonstration of the efficacy of red cells for this purpose (or improved clinical outcomes) has proven elusive.52–54 A definitive randomized prospective study in which RBCs are withheld completely from one treatment group is unlikely to be done at this point. For decades, transfusion of RBCs was guided by the so-called “10/30 rule”: transfusion was indicated for an Hgb of less than 10 g/dL or a hematocrit of less than 30%. This practice is outdated. The largest published randomized trial in adult patients to date, the TRICC (Transfusion Requirements in Critical Care) trial, demonstrated that in the critical care setting, a transfusion threshold of 7 g/dL was as safe as a threshold of 10 g/dL.55 In this trial there was some concern that a higher trigger was more appropriate in patients with coronary artery disease (CAD).56 The FOCUS trial (Functional Outcomes in Cardiovascular Patients Undergoing Surgical Hip Fracture Repair) addresses this specific population, and results support a restrictive 8 g/dL trigger for red cell transfusion in these patients as well.57,58 Absent further research, the recommendations of the American Society of Anesthesiologists seem reasonable: transfusion is rarely needed with an Hgb concentration greater than 10 g/dL and is usually needed when the Hgb is less than 6 g/dL. Patients with an Hgb of 6 to 10 mg/dL require careful clinical judgment. Guidelines published in 2009 by the Eastern Association for the Surgery of Trauma and the American College of Critical Care Medicine and based on a thorough review of the available evidence likewise support this conservative strategy, advocating a cutoff of Hgb below 7 g/dL for most stable patients.3 Lastly, most emergency physicians would still transfuse any patient with ongoing severe hemorrhage and unstable vital signs despite adequate fluid resuscitation and would occasionally consider withholding transfusion for Hgb levels even lower than 6 g/dL in a young, healthy, asymptomatic patient at low risk for further bleeding. Another interesting area of investigation is the use physiologic transfusion triggers (such as lactate or mixed venous oxygen saturation), but further research is needed.10
Blood and Blood Components
Perspective
Pathophysiologic Principles
Blood Typing
Special Clinical Circumstances
Administering Blood before Completion of Compatibility Testing
Massive Transfusion
Management
Whole Blood
Packed Red Blood Cells
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