CHAPTER 140 PRESERVATION AND CLINICAL USE OF ERYTHROCYTES AND WHOLE BLOOD
CHAPTER 140 PRESERVATION AND CLINICAL USE OF ERYTHROCYTES AND WHOLE BLOOD
Principles of Storage and Preservation of Blood
Liquid Preservation of Erythrocytes
Frozen Storage of Erythrocytes
Whole Blood Preparations
ACD (Acid-Citrate-Dextrose), CPD (Citrate-Phosphate-Dextrose), and CPDA-1 (CPD with Adenine) Whole Blood
Packed Red Blood Cells
Leukocyte-Reduced Red Blood Cells
Washed Red Blood Cells
Frozen Red Blood Cells
Artificial Blood Substitutes
Indications for Transfusion Therapy
Mode of Administration
Hazards of Transfusion Therapy
Immediate Transfusion Reactions
Delayed Adverse Effects of Blood Transfusion
Transfusion of whole blood or of red cell concentrates is important in the treatment of acute blood loss and of anemia. Red cells can be stored at 4°C for 5 weeks in media that are specially designed to maintain the physical and biochemical integrity of the erythrocytes and that maintain their viability after reinfusion. Citrate-phosphate dextrose with adenine (CPDA) is commonly used for the collection of blood. The use of whole blood as a therapeutic agent has been almost entirely replaced by the use of blood fractions. Red cells can be stored in residual plasma or in additive solutions such as AS-1, a solution containing glucose, adenine, and mannitol. Erythrocytes can also be frozen after addition of a cryoprotective agent such as glycerol, and such cells can be stored for years. A variety of “blood substitutes” based either on hemoglobin or perfluorocarbons have been designed, but all have a short intravascular half-life and have not yet been found to be clinically useful.
Transfusion of red cells can cause febrile reactions, usually due to residual leukocytes, and the transmission of infectious diseases such as HIV and hepatitis. Other adverse effects include pulmonary hypersensitivity reactions, incompatible transfusions either because of unsuspected antigens or human error, and, in immuncompromised recipients, graft-versus-host disease.
Acronyms and abbreviations that appear in this chapter include: ACD, acid-citrate-dextrose; AIHA, autoimmune hemolytic anemia; ATP, adenosine 5′-triphosphate; 2,3-BPG, 2,3-bisphosphoglycerate; CPD, citrate-phosphate-dextrose; CPDA-1, CPD with adenine; DIC, disseminated intravascular coagulation; IgA, immunoglobulin A; IMP, inosine monophosphate; PIP, phosphate, inosine, and pyruvate.
Although the association of blood with life and vitality was recognized by primitive man, the transfusion of blood was not undertaken until after Harvey had described the circulation of the blood in 1628. During the following 40 years, animal blood was transfused directly into animals and humans, sometimes with unfortunate results.1 Interest in blood transfusion waned, and it was not until 1828 that Blundell2 successfully treated postpartum hemorrhage by direct transfusion of human blood. However, the mortality associated with transfusion was approximately 33 percent,3 a figure surprisingly lower than the calculated frequency of ABO incompatibility.
Safe and effective transfusion therapy had to await the discovery of red cell blood group antigens by Landsteiner4 and the development of nontoxic anticoagulants so that blood could be stored and used for indirect transfusions.5,6 and 7 In 1937 Fantus8 described the establishment at Cook County Hospital in Chicago of a blood bank for the collection, storage, and compatibility testing of blood for transfusion therapy.
Extensive experience with transfusion therapy accumulated during World War II (see, for example, reference 9). Subsequently, major technical developments included the introduction of closed plastic equipment consisting of tubing and bags that minimize the risk of bacterial contamination, the availability of a practical refrigerated centrifuge that facilitates separation of components, and the introduction of automated equipment for continuous-flow cell separations.10,11
PRINCIPLES OF STORAGE AND PRESERVATION OF BLOOD
Erythrocytes are preserved either by liquid storage at 4°C or frozen storage with various cryoprotective agents, at either –80 or –150°C. During liquid storage, red blood cells undergo changes that lead to a loss in viability and a diminished capacity to off-load oxygen. When stored red blood cells are reinfused into the circulation, some perish within a few hours, but the remainder appear to return to an entirely normal state. The survival of those cells not removed within the first 24 h is normal.12
Many attempts have been made to devise a means of predicting the proportion of transfused erythrocytes that remain viable. The ATP level of the erythrocytes enjoys a reputation as a predictor of viability of red blood cells after reinfusion that is poorly deserved.13,14 The osmotic fragility and plasma hemoglobin levels are also of little value in predicting the viability of stored red blood cells. Indeed, the increase in osmotic fragility of stored erythrocytes is almost entirely due to their becoming loaded with lactate. Not freely diffusable, this exerts an unbalanced osmotic effect when osmotic fragility is tested in saline solutions.15
Stored red blood cells develop multiple and complex changes in membrane structure.16 Although it has been suggested that the exposure of phosphatidyl serine on the outer membrane, which has increasingly been implicated as a signal of red cell aging (see Chap. 29), may play a role in the loss of viability of stored erythrocytes,17 this does not seem to be the case.18,19 and 20 The critical changes associated with loss of viability have not been identified, so that of necessity preservative solutions are evaluated by red cell survival studies in volunteers. Licensure of preservative solutions in the United States requires that more than 70 percent of the transfused red blood cells remain in the circulation 24 h after administration.
After reinfusion, stored red blood cells need to function properly in delivering oxygen to the tissues. The loss of 2,3-bisphosphoglycerate (2,3-BPG, 2,3-DPG) (see Chap. 26) during storage results in an increase in oxygen affinity that may compromise the ability of the stored erythrocytes to deliver oxygen to the tissues.21,22 After reinfusion the red cell 2,3-BPG level returns to half-normal in 4 h and to normal in 24 h.23,24 Although the clinical significance of 2,3-DPG loss in stored blood is difficult to assess,25 there is general agreement that blood with nearly normal oxygen affinity should be used for massive transfusions, particularly in infants, older patients, and patients with cardiovascular and pulmonary disease.
Ideally, preservative solutions for erythrocytes should ensure maximum viability for the longest possible storage time and should allow optimal oxygen delivery. Unfortunately, with commonly used preservative solutions optimal storage conditions for either of the two critical components, ATP and 2,3-BPG, usually produce adverse effects on the other. The effect of various preservative solutions on maintenance of ATP and 2,3-BPG levels during liquid storage is summarized in Table 140-1.
TABLE 140-1 PRESERVATION OF ATP AND 2,3-BPG RED CELL CONCENTRATIONS DURING STORAGE IN DIFFERENT PRESERVATIVE SOLUTIONS
LIQUID PRESERVATION OF ERYTHROCYTES
The preservative solutions used in the past for the storage of whole blood or red blood cells contain glucose and a citrate buffer at an acid pH. The citrate ion chelates calcium and thus prevents coagulation of the blood, glucose sustains the metabolism of red blood cells during storage, and the acid pH counteracts the marked rise of pH that occurs when blood is cooled to 4°C.26 The two preservative solutions of this type in use until CPD-adenine was introduced in 1978 were acid-citrate-dextrose (ACD) and citrate-phosphate-dextrose (CPD) (see “ACD and CPD Whole Blood”).
When whole blood or packed red blood cells are stored in either ACD or CPD, a series of well-defined biochemical changes, designated collectively as the storage lesion, takes place in the erythrocytes (Table 140-2). The concentration of red cell ATP falls gradually during storage.24,26 As ATP is dephosphorylated, the levels of ADP and AMP rise at first but diminish with time as AMP is irreversibly deaminated to IMP, which is ultimately broken down to hypoxanthine.27 When the ATP level declines to 0.4 mM or less, the capacity of red blood cells to phosphorylate glucose is impaired, and their viability is lost. The level of 2,3-BPG and consequently the hemoglobin oxygen affinity changes rapidly in ACD blood. Some 40 percent of the 2,3-BPG is lost in the first week of storage, resulting in a significant increase in oxygen affinity. After 2 weeks’ storage, nearly all the 2,3-BPG has disappeared from blood stored in ACD solution. The loss of 2,3-BPG occurs more slowly in blood stored in CPD solution, because of its higher pH.28 The oxygen affinity and 2,3-BPG levels remain nearly normal during the first week of storage, and then fall rapidly. Potassium rapidly leaks from the stored blood cells, and sodium seeps in29 because the sodium-potassium ATPase is exquisitely sensitive to changes in temperature. The osmotic fragility of the red blood cells gradually increases, but this change is largely an artifact produced by the intracellular accumulation of lactate.15 Some erythrocytes undergo spontaneous lysis, causing a rise of plasma hemoglobin levels. Di-(2-ethylhexyl) phthalate plasticizer leached from the polyvinyl chloride plastic in which whole blood and red cell preparations are stored retards hemolysis and improves the viability of the cells when they are reinfused.30 Microvesicles filled with hemoglobin begin to form.31 Erythrocytes stored at 4°C also show a progressive increase in rigidity as measured by their rate of flow through filters. Their loss of deformability correlates to some extent with the loss of ATP.32 Because some residual leukocytes are invariably present, various cytokines are also found in stored blood,33 and these may play a role in some transfusion reactions. This seems particularly to be the case when certain types of apparatus are used for intraoperative salvage of erythrocytes.34 Blood stored in ACD or CPD will yield a 70 percent 24-h survival of transfused red blood cells for up to 21 days of storage.
TABLE 140-2 EFFECT OF STORAGE IN ACD ON ERYTHROCYTE PROPERTIES
Major efforts have been directed toward development of preservative solutions that will maintain adequate erythrocyte levels of ATP and 2,3-BPG. Adenine and inosine are two additives that have been extensively studied. Addition of adenine to give a final concentration of 0.25 to 0.75 mM at the beginning of storage helps to prevent the loss of ATP,35 since it can serve as a substrate for synthesis of adenine nucleotides (see Chap. 26). The addition of adenine does not prevent the loss of 2,3-BPG and may slightly hasten its depletion.
The addition of adenine alone at the end of storage is not helpful if red blood cells have lost a substantial portion of their ATP. Under these circumstances, they are unable to phosphorylate glucose and thus are unable to synthesize adenine nucleotides, or to phosphorylate ADP and AMP to ATP. If inosine is supplied, ATP formation can occur even when red cell ATP levels are very low. The phosphorolysis of inosine yields ribose-1-phosphate, which can be metabolized to yield high-energy phosphates and maintain 2,3-BPG levels (see Chap. 26). The addition of inosine either at the beginning of storage or before infusion of ATP-depleted blood markedly improves the storage viability of red blood cells,35 but a concentration of inosine of about 10 mM is required. Infusion of inosine or of the hypoxanthine formed by its catabolism may result in dangerous hyperuricemia.
The reported capacity of ascorbic acid to maintain 2,3-BPG levels36 is due to contaminating oxalate,37,38 which seems to exert its function largely by inhibiting pyruvate kinase.38 Certain xanthone derivatives exert a direct effect on the oxygen dissociation curve of hemoglobin and, in addition, elevate red cell 2,3-BPG levels39 because of their inhibitory effect on 2,3-BPG phosphatase.40 Dihydroxyacetone is metabolized by erythrocytes and helps to maintain 2,3-BPG levels during storage.41,42 and 43 Periodic agitation of blood during storage improves the maintenance of 2,3-BPG levels in some preservatives, probably by preventing a localized decrease in pH in the gravity-sedimented red blood cells44 but has little effect on red blood cells in blood collected in CPD solution.45 Several other additives have been used experimentally to maintain or restore 2,3-BPG levels of stored red blood cells. The 2,3-BPG content of stored blood can be restored to normal or supranormal levels46 by incubating the erythrocytes with phosphate, inosine, and pyruvate (PIP). Both 2,3-BPG and ATP levels in outdated blood can be restored by incubation with PIP and adenine. Phospho(enol)pyruvate can enter red blood cells when they are suspended in a slightly acidic solution, and it has also been proposed that this source of metabolic energy may be useful in red cell preservation.47 The rejuvenated erythrocytes can be recovered by centrifugation and washing and either used for transfusion or frozen for future use.48
Preservative solutions that contain high concentrations of inorganic phosphate, are hypotonic, and contain ammonium have been found to maintain 2,3 BPG and ATP levels for a prolonged time.49,50 The effects of such solutions are primarily a function of the ammonium, which relieves phosphofructokinase inhibition by ATP, and of phosphate.51,52
The conversion of whole blood into components requires the removal of a significant fraction of both plasma and red cell preservative solution from the red blood cells. Red cell preservation, however, can be optimized if a nutrient solution is added to the isolated red blood cells.53 The initial blood collection can be into CPD solution or half-strength CPD (0.5 CPD).54 The nutrient solutions that have been developed generally contain glucose as a source of energy, adenine to help support ATP levels, and mannitol to prevent hemolysis. The mechanism by which mannitol exerts this effect is unknown. Originally added to such solutions for osmotic support,55 it has been shown that its osmotic effect is not the mechanism of action.56 Several different additive solutions are now available in the United States (AS-3, Nutricell, Cutter Labs, Berkeley, CA; and AS-1, Adsol, Fenwall Labs, Morton Grove, IL) and in Sweden.57 ATP levels are well maintained, and good survival is obtained after 42 days’ storage with the use of additive solutions, but the 2,3-BPG level is reduced by 90 percent at 42 days.58,59 The loss of 2,3-BPG can be prevented by incorporating bicarbonate and a CO2 trap into the system.60
FROZEN STORAGE OF ERYTHROCYTES
Uncontrolled freezing and thawing of erythrocytes results in hemolysis. Freeze-thaw injury is dependent on the rate of freezing, the physical structure of ice, and the properties of water, cell membranes, and solutions at various temperatures. A current theory of freeze-thaw hemolysis suggests that slowly cooled red blood cells are damaged by osmotic dehydration as they are exposed to increasing extracellular electrolyte concentration and osmolality as water is removed by freezing.61 Irreversible biochemical changes in the membrane may result from the prolonged exposure of the dehydrated, hypertonic red cell to temperatures insufficiently low to prevent biochemical alterations.62 If such changes are prevented, then lysis of the red blood cells may occur on return to isotonicity, because of the excess solute content acquired during the hypertonic phase of freezing.63 Although the precise biochemical and biophysical changes leading to hemolysis are not fully understood, empirical methods have been developed for the practical freeze-preservation of red blood cells. Preservation of erythrocytes by freezing retards or arrests the deleterious biochemical changes that occur during liquid storage.64 Frozen cells have maintained satisfactory viability for as long as 21 years.65 Under some conditions it is possible to preserve the metabolic activity and physical integrity of erythrocytes after lyophilization,66,67 but the usefulness of such cells for transfusion purposes has not been documented.
Glycerol is the most commonly used cryoprotective agent for freeze-preservation of erythrocytes. Hydroxyethyl startch68 and dextran69 also appear to have desirable cryoprotective properties. The most commonly utilized technique currently is a slow freezing method in which the red blood cells are equilibrated with 40 to 50% glycerol and cooled to –80 to –120°C using mechanical refrigeration.70 All methods of freeze-preservation of erythrocytes involving the use of cryoprotective agents require the technical capability for introducing and removing high concentrations of the cyoprotective agent (glycerol) under sterile conditions. Frozen red blood cells must be thawed and the glycerol removed gradually by washing in glycerol solutions of decreasing concentration to prevent osmotic hemolysis. Under optimum conditions of processing, storage, and cell washing, over 80 percent of the freeze-preserved red blood cells from a unit of blood will survive and function normally after transfusion. Such thawed and washed red blood cells must be used within 24 h because processing breaks the closed system and introduces the possibility of bacterial contamination.
WHOLE BLOOD PREPARATIONS
Most clinical situations require the use of specific blood components, and the use of whole blood is limited to correction or prevention of hypovolemia in patients with severe acute blood loss.
ACD (ACID-CITRATE-DEXTROSE), CPD (CITRATE-PHOSPHATE-DEXTROSE), AND CPDA-1 (CPD WITH ADENINE) WHOLE BLOOD
ACD and CPD are the two preservative-anticoagulant solutions used exclusively in the past in the United States. They have been largely superseded by adenine-containing solutions. Blood is currently collected and stored in bags manufactured from plastic films.
For each 100 ml of whole blood there should be 15 ml of ACD solution or 14 ml of CPD or CPDA-1. The ACD solution (formula A) contains 8.0 g of citric acid (C6H8O7·2O), 22 g of sodium citrate (Na3C6H5O7·2O), and 24.5 g of glucose (C6H12O6·2O) per liter. CPD is a modified ACD solution which is slightly less acid and therefore improves the preservation of 2,3-BPG (Table 140-1). It contains 3.27 g of citric acid, 23.6 g of sodium citrate, 25.5 g of glucose, and 2.22 g of NaH2PO4·2O per liter.
Adenine is incorporated into CPD or ACD preservatives in amounts sufficient to provide a concentration of 0.25 mM to 0.75 mM to increase the shelf life of the stored red blood cells.71 CPD with adenine (CPDA-1) contains CPD, modified to contain 125 percent of the usual concentration of glucose, and adenine to provide a final concentration of 0.25 mM. Although still suboptimal, the higher glucose concentration provides an additional supply for cells packed immediately after collection so that the blood may be fractionated into components.72,73
A unit of whole blood may contain from 405 to 495 ml of blood.70 The volume of each anticoagulant solution used for 450 ml of whole blood is 67.5 ml of ACD or 63 ml of CPD or CPDA-1 solution. The total fluid volume actually administered in transfusing 450 ml of whole blood is 517.5 ml of ACD and 513 ml for CPD collected blood. If the volume collected is between 300 and 405 ml, the red blood cells can be used for transfusion if they are labeled “Low Volume Unit __ ml. Red Blood Cells.”70
With proper collection and storage at 2 to 6°C, ACD whole blood and CPD whole blood can be used within 21 days after collection. The 21-day storage limit has been established based on survival of 70 percent of the transfused erythrocytes at 24 h after transfusion (see “Transfusion Therapy”). Blood collected in CPDA-1 is licensed for 35 days’ storage.
Requests for “fresh” blood are usually justified by the recognition that there is a relatively rapid loss of platelets, leukocytes, and some coagulation factors with liquid storage as well as a progressive increase in the levels of undesirable products such as potassium, ammonium, and hydrogen ions.74,75 Blood stored at 4°C over 48 h using ACD, CPD, or their adenine-containing derivatives is depleted of viable platelets.76 Factor V remains at adequate levels (greater than 80 percent) for at least 5 days,77 factor VIII remains above 80 percent of its original level for 1 to 2 days,77 and factor XI activity rapidly falls to about 20 percent of its original level within the first week of storage.78 All other clotting factors appear to be stable during liquid storage.79,80 and 81
Blood “freshness” cannot be precisely defined, since it depends upon the storage stability of the particular component in blood that is needed. The loss of platelets and coagulation factors in stored whole blood may be a consideration in massive transfusions following trauma or surgery. Thrombocytopenia and decreased levels of labile coagulation factors with oozing of blood may occur when more than the patient’s blood volume11 (12 to 14 units) is replaced by banked blood within a 24-h period.82 In such cases, packed red blood cells, fresh-frozen plasma, and platelet concentrates are superior to “fresh” whole blood.
Whole blood less than 5 to 7 days old may be indicated when changes in stored blood such as increased plasma potassium and ammonium and a decreased pH must be avoided, as in patients with advanced renal or liver disease or newborn infants who are given exchange transfusions.
In a seriously ill patient massively transfused with 2- or 3-week-old banked blood, the low levels of 2,3-BPG may compromise tissue oxygenation. Although the 2,3-BPG levels are regenerated within a day or so,23,24 it is probably prudent to administer a significant proportion of CPD blood less than 5 days old or ACD blood less than 2 days old.21 It is also appropriate to provide patients with refractory anemias red blood cells that are less than 10 days old to avoid the infusion of nonviable cells that add unnecessarily to the patient’s iron burden.
Four types of erythrocyte preparations are in common use: packed red blood cells, washed red blood cells, leukocyte-reduced red blood cells, and frozen red blood cells. Washed red blood cells can be obtained from liquid-stored blood by saline washing using a continuous-flow cell separator or from frozen erythrocytes that have been extensively washed to remove the cryoprotective agent.
PACKED RED BLOOD CELLS
At any time before the expiration date of the blood, erythrocytes can be separated and recovered from ACD, CPD, or CPDA-1 whole blood by centrifugation and removal of plasma to give a hematocrit of 60 to 90 percent. Red blood cells packed to a hematocrit of less than 80 percent, or sedimented red blood cells stored at 1 to 6°C are suitable for transfusion for the full shelf life of the preservative-anticoagulant solution (21 or 35 days). Red blood cells packed to a higher hematocrit do not survive as well, chiefly because they exhaust available glucose.72,73,83 If the blood is exposed to the external environment during preparation, the packed or sedimented red blood cells must be transfused within 24 h.84
Red blood cells rather than whole blood should be used for the treatment of all patients who require transfusion because of a red cell mass deficit. Packed red blood cells and balanced salt solutions appear to be as effective as whole blood in correcting the blood loss that occurs at surgery.85
Red blood cells are administered in the same fashion as is whole blood. The rate of administration may be slower with packed red blood cells but approaches that of whole blood if a 17-gauge or larger needle is used or if a diluting solution such as saline is used86 or if the red blood cells have been stored in an additive solution.87
LEUKOCYTE-REDUCED RED BLOOD CELLS
There are three major reasons for the use of leukocyte-reduced red blood cells: (1) to prevent or avoid nonhemolytic febrile reactions due to antibodies to white cells and platelets in the recipient exposed to previous transfusions or pregnancies (see below); (2) To prevent sensitization of patients with aplastic anemia who may be candidates for marrow transplantation; and (3) to minimize transmission of viral disease such as HIV or cytomegalovirus. To prevent febrile reactions, a unit of red blood cells should contain no more than 5 × 108 leukocytes; for the prevention of alloimmunization and to minimize transmission of viral diseases it has been recommended that no more than 5 × 106 leukocytes remain.70
Leukocyte-reduced blood is best prepared by passing the whole blood or packed cells through specially designed filters.88,89,90 and 91 Such filters can be used either in the blood bank or at the bedside as the red blood cells are being transfused. Other methods that have been used include sedimentation, inverted centrifugation, filtration through nylon or cotton, and saline batch washing using a cell processor, frozen-thawed red blood cells, or blood filtration through a microaggregate filter.92
WASHED RED BLOOD CELLS
Washed red blood cells are usually obtained from whole blood. Packed red blood cells collected by centrifugation can be washed with saline using either manual batch centrifugation or continuous-flow cell separators.93 Washed red blood cells must be used within 24 h after processing because of the risk of bacterial contamination during preparation. Frozen red blood cells are an excellent albeit expensive source of washed red blood cells.
Washed red blood cells are indicated in the rare patient who is hypersensitive to plasma. Such patients develop an allergic or febrile reaction following whole blood transfusion that can be reproduced with the injection of even a small quantity of plasma.4 Some of these patients have a deficiency of IgA and have formed antibodies to IgA from a previous transfusion or pregnancy.95 Saline washed red blood cells may be indicated in neonatal transfusions96 to reduce the quantity of anticoagulant, metabolic breakdown products, extracellular potassium, and risk of cytomegalovirus infection (see “Hazards of Transfusion Therapy”).
FROZEN RED BLOOD CELLS
Frozen red blood cells have a shelf life measured in years65 rather than weeks, which simplifies the efficient management of blood inventories. These cells are somewhat leukocyte-poor and relatively free of plasma. The potential advantages of frozen red blood cells have stimulated intensive efforts to develop more practical and less costly procedures for preserving erythrocytes and other cellular blood components by freezing.
Frozen red blood cells are admirably suited for autotransfusion (see “Autologous Transfusions”). Other advantages include availability of an inventory of rare blood97,98; reduction in sensitization to histocompatibility antigens for potential transplant recipients as compared to unfiltered red blood cells; and more efficient inventory control. However, a unit of frozen blood costs two to three times as much as a unit stored in the liquid state.
ARTIFICIAL BLOOD SUBSTITUTES
Some functions of blood such as maintaining circulating volume and osmotic pressure can be replaced with various crystalloid and colloid macromolecules such as dextran and hydroxyethyl starch (Chap. 59). These blood substitutes, however, do not provide for oxygen transport.
Materials with the potential of supporting oxygen transport such as stroma-free hemoglobin solutions, liposome-encapsulated hemoglobin, and perfluorocarbons have been under active investigation.99 Interest in such preparations has largely been driven by fear of transmitting microbial diseases through blood transfusion.
Perfluorochemicals are organic compounds in which all the hydrogen atoms are replaced by fluorine. Per-unit volume solutions bind almost three times the oxygen carried by blood. They are chemically inert and are not metabolized but require emulsification with surfactants to be miscible with blood. Rats survived up to 8 h following complete replacement of their blood with liquid fluorocarbon. A perfluorocarbon-hydroxyethyl starch preparation developed in Japan and marketed as Fluosol-DA (Green Corp., Osaka, Japan) that requires concurrent administration of 60 to 100 percent oxygen has been used experimentally in human volunteers and in a few patients, but no evidence of therapeutic value has been found.100 Moreover, its use has been associated with pulmonary reactions, cytotoxicity, complement activation, retention of the fluorocarbon in the liver and spleen, and vulnerability to oxygen toxicity.
Stroma-free hemoglobin solutions have been investigated as oxygen-carrying blood substitutes.101 Their usefulness is limited because of toxicity,102,103 high affinity for oxygen, and a very short intravascular half-life (2 to 4 h). Hemoglobin complexes and recombinant mutant hemoglobin molecules have been prepared that will increase the intravascular life span to 10 to 12 h, and some of these have a more favorable oxygen affinity.99 Numerous clinical studies of hemoglobin solutions have been conducted.104 With some preparations significant hypertension occurs after infusion, and although this has been thought to be due to the binding and depletion of NO giving rise to vasospasm, the actual mechanism is not entirely clear.105
Hemoglobin has also been encapsulated in artificially prepared liposomes enabling the addition of 2,3 BPG to achieve near-normal oxygen-hemoglobin dissociation properties.106,107 The relatively short life span of liposomes, problems in scaling-up the process, nonuniformity of liposome size, complement activation,108 and difficulties in ensuring sterility make it unlikely that such encapsulated hemoglobin preparations will ever have any clinical utility.
A patient should be transfused only when specific, well-established indications are present and in practically all cases with blood components rather than whole blood. Informed consent should be obtained from patients except in life-threatening emergencies. Patients who are candidates for transfusion should be provided with specific information regarding the risks and benefits of the proposed transfusion therapy, and the discussion should be documented by an entry in the patient’s medical record.109
INDICATIONS FOR TRANSFUSION THERAPY
A major clinical indication for transfusion therapy is the need to restore and maintain the volume of circulating blood to prevent or treat shock, as in hemorrhage or trauma. Probably more than 50 percent of the blood transfused is in the support of surgery.110 Another indication is the need for specific cellular or protein components such as erythrocytes, specific coagulation factors, or platelets. Exchange transfusions may be required to remove deleterious materials from the blood, in the past primarily in infants for hemolytic disease of the newborn. Blood is also used to maintain the circulation as in extracorporeal or cardiac bypass shunts.111,112
HEMORRHAGE AND SHOCK
A major indication for transfusion of blood or components is existing or anticipated hemorrhage (Chap. 59). Treatment of acute blood loss should be devoted to volume support and only secondarily be concerned with loss of red cell mass. A loss of approximately 1 liter of blood in a patient without cardiovascular disease can be treated with electrolyte solutions. Colloids for volume support and possibly red blood cells may be needed with losses of 1 to 2 liters. Acute blood losses in excess of 2 to 3 liters require correction of both volume deficiency and red cell mass loss.113
If the history and the clinical picture suggest that the patient has sustained a significant loss of blood, replacement therapy with whole blood or red blood cells is indicated. Clinical114 and experimental85 observations in hypovolemic (hemorrhagic) shock suggest that the combination of packed red blood cells with crystalloids or albumin is as effective as whole blood in correcting a volume deficit. Blood of any age within the usual storage limits is suitable. Many patients who have sustained blood loss do not need a whole blood transfusion and should not be exposed to the associated risks (see “Hazards of Transfusion Therapy”).
The loss of 500 ml of blood during a surgical procedure is well tolerated by the average patient. Maintaining normovolemia with crystalloid solutions appeared to be a significant factor in preventing morbidity and mortality. One hundred patients undergoing major surgery with blood losses greater than 1000 ml were treated with Hartmann’s solution (lactated Ringer’s solution: NaCl, 102 meq per liter; KCl, 4 meq per liter; CaCl2, 3.5 meq per liter; and sodium lactate, 27 meq per liter), using two to three times the estimated volume of blood lost. Postoperative mortality and morbidity were not affected by the use of crystalloid rather than blood, and there were no unexpected complications.115 Even patients undergoing open heart surgery have been managed successfully without transfusions116 despite a severe, acute decrease in red blood cell mass.
Initially volume resuscitation is required in patients with severe burns because of the marked increase in permeability of the microcirculation in burned tissue.117 Patients with a burn injury of more than 25 percent surface area require large volumes of balanced salt solutions during the initial 24 h.118,119 Plasma loss, which ensues during the next 5 days, can be corrected with plasma and colloids. The progressive development of anemia during the early postburn period is best treated with packed red blood cells.
Blood transfusion of patients with chronic stable anemia is probably unjustifiable if the hemoglobin level is above 7 g per 100 ml unless the patient is elderly or severe cardiac or pulmonary disease is present. There is probably significant misuse of blood transfusions in patients with chronic anemia. Data from 300 hospitals over a 1-year period (1974) revealed that 401 nonoperated patients with anemia were transfused, even though they had a hemoglobin concentration greater than 10 g per 100 ml.120 Audit criteria for the evaluation of transfusion practice have been established.121
Multiple, repeated transfusions of whole blood or packed red blood cells have been used to suppress erythropoiesis in patients with thalassemia and sickle cell diseases (Chap. 46 and Chap. 47). However, transfusional hemochromatosis (see Chap. 42) may limit the usefulness of this therapy of managing the hemoglobinopathies. One approach to the control of iron accumulation in transfusion-dependent patients with thalassemia is the use of red blood cells enriched in their content of young red blood cells, “neocytes.” Young red blood cells are obtained based on size and density using a continuous-flow cell separator.122,123 and 124 The administration of neocytes has been associated with a decreased transfusion requirement.122,125 However, despite the fact that with modern equipment neocyte preparations can be prepared without too much difficulty,125 they are costly and their routine use has been limited. Furthermore, the effectiveness of transfused neocytes may be less than predicted by in vitro and in vivo studies.126
The clinical uses of other types of blood components are presented in Chap. 141 (leukocytes, dendritic cells, and stem cells), Chap. 142 (platelets), and Chap. 143 (plasma and plasma fractions).
MODE OF ADMINISTRATION
The most important action the physician or nurse can take before administering blood or a blood product is to read the label to verify that the unit to be used is the one selected by the laboratory for that particular patient (see “Hazards of Transfusion Therapy”).
Blood need not be warmed before its use unless unusually large amounts must be given (more than 3 liters) at a rapid rate (greater than 100 ml per min).127 At the usual rate of administration (500 ml in 1 to 2 h), the agglutinates that may occur in patients with high-titer cold agglutinins are usually dispersed as the transfused blood reaches body temperature.
Blood should be administered slowly during the first 30 min to minimize the amount given if an untoward reaction occurs. It is safe to transfuse 1000 ml of citrated blood within a period of 2 to 3 h to the average patient without cardiovascular disease.127
Drugs or medications should not be added to blood or components. Several intravenous solutions are incompatible with banked blood and should not be administered through the blood lines. Aqueous dextrose solutions cause agglomeration (clumping) and hemolysis of red blood cells, and calcium-containing solutions such as Ringer’s lactate may exceed the calcium-binding capacity of the citrate in the anticoagulated blood with formation of clots.128,129 Physiological saline is compatible with all blood components.
Most transfusion therapy is administered intravenously. A vein in the forearm or antecubital fossa is ordinarily used, although any accessible vein or a central line may be employed. Infrequently used routes for the administration of blood and components are intraarterial and intraperitoneal. Because of the hazards, transfusion into an artery should be reserved for patients who have failed to respond to rapid, large-volume intravenous transfusion. Intraperitoneal transfusions may be indicated for children in whom suitable veins are difficult to find and occasionally for the fetus in utero.130,131
Single-unit transfusions have sometimes been condemned as an unwarranted use of blood.132 However, single-unit transfusions are often justifiable. Examples include elderly surgical patients with coronary disease, patients who have sustained an acute loss of two or three units who achieve circulatory stability with one unit, and patients whose bleeding during surgery or from the gastrointestinal tract is controlled after transfusion of the first unit. Single-unit transfusion in such cases represents good judgment and therapeutic skill.133,134
In autologous transfusions (autotransfusion) blood removed from a patient is returned to the patient’s circulation after storage, or blood lost at or immediately after surgery is reinfused. Transfusion of autologous blood averts some problems associated with the use of homologous donor blood, such as febrile and allergic reactions, immunologic incompatibilities that may lead to hemolysis, alloimmunization, and the transmission of disease.
Three variations of autotransfusion have been used: preoperative blood collection, with storage for a variable time and retransfusion during surgery; immediate preoperative phlebotomy and hemodilution with postoperative return of the phlebotomized blood135; and intraoperative collection of shed blood with reinfusion during surgery.136 Equipment designed for intraoperative autotransfusion is commercially available.137,138 and 139
In many elective surgical procedures the recipient can predeposit autologous blood.140 In some patients the amount of predeposited autologous blood may be increased through the use of recombinant human erythropoietin therapy.141 Predeposited autologous blood also may be frozen and represents the ideal product for patients with rare blood types (e.g., Rh-null) or for patients with antibodies in numbers and combinations that make it nearly impossible to find compatible units of blood.
DIRECTED OR DESIGNATED DONATIONS
Donors recruited from among family members or friends (donor-specific) contrary to expectation are no safer than volunteer blood donors. Fatal graft-versus-host reactions have been reported involving unusual HLA similarities between close relatives (see “Graft-Versus-Host Disease”).
BLOOD FOR EXCHANGE TRANSFUSIONS
Exchange transfusions are used to treat the newborn who has severe hemolytic disease due to a feto-maternal blood group incompatibility, G6PD deficiency, or an unknown cause (Chap. 7, Chap. 45, and Chap. 58).
Exchange transfusions have been simplified by the introduction of equipment that automatically harvests blood components from an individual (Chap. 144).
BLOOD FOR PATIENTS WITH AUTOIMMUNE HEMOLYTIC DISEASE
The provision of compatible red blood cells for patients with AIHA is one of the most difficult and challenging problems in transfusion medicine.142 Compatibility usually cannot be assured because of the effect of autoantibodies on routine serological tests. Transfusion management of the patient with AIHA involves a risk-benefit judgment; namely: Does the need for increased oxygen-carrying capacity justify the risks of a possible hemolytic reaction? Transfusion should be avoided in these patients whenever possible.143,144
Ideally donor blood should be selected so that it lacks those antigens corresponding to the antibodies in the recipient, whether autoimmune or alloimmune. Patients with red cell autoantibodies are serologically incompatible with their own red blood cells and with those of most if not all donors. Such patients if previously transfused or pregnant may also have clinically significant alloantibodies difficult to detect in the presence of the autoantibody.
Usually no autoantibody specificity can be established, and it may be impossible to find serologically compatible blood. However, it may be possible to find units that react more weakly than others. A variety of time-consuming serological procedures are available to detect alloantibodies in the presence of autoantibodies, but it may require 51Cr survival studies to establish compatibility. Many of these patients will tolerate hemoglobin levels of 5 to 7 g per 100 ml and should not be transfused. If life-threatening anemia is present, a transfusion may be required even in the face of serological incompatibility. In such cases blood should be selected that is at least as compatible as the patient’s cells in their own serum. Packed red blood cells rather than whole blood should be used, and sometimes packed red blood cells less than 10 days old may be indicated to minimize the number and frequency of transfusions required.
BLOOD FOR EMERGENCIES
Emergencies in which no time is available to type, select, and cross-match compatible blood should be a rare occurrence, except for trauma, unexpected intraoperative hemorrhage, massive gastrointestinal bleeding, or ruptured aneurysm.145
If the urgency of the patient’s need justifies the administration of uncross-matched blood, type O, Rh-negative blood with low plasma anti-A and anti-B titers can be used. Unfortunately, tests for donor anti-A and anti-B levels are not done routinely. The use of packed red blood cells will reduce the quantity of anti-A or -B administered. It is preferable, however, to use ABO group and Rh-type-specific blood, which is usually available within 15 min if the patient’s blood is available for testing. Administration of uncross-matched group-specific blood will prevent hemolysis that may occur if a high-titered anti-A or anti-B group O blood is given to a non-O recipient. If 15 to 30 min are available, an abbreviated antibody screen can be carried out using low ionic strength conditions.146 Group- and type-specific uncross-matched blood with a negative antibody screen provides compatibility for the recipient equivalent to that of cross-matched blood in essentially all cases.147 The routine cross-match should be carried out retrospectively to identify any incompatibility when uncross-matched or partially cross-matched blood is administered.
BLOOD FOR TRANSPLANT RECIPIENTS
Kidney Grafts Random donor blood transfusions can result in allogeneic immunization,148,149 and in the early days of transplantation they were avoided in order to prevent the possibility of inducing anti-HLA antibodies in potential transplant recipients. However, a series of reports from 1973 to 1978150,151 and 152 surprisingly demonstrated that kidney transplant patients who had received multiple blood transfusions before transplantation actually had better graft survival. This was particularly true for black and hispanic patients,153 two groups that often demonstrate lower kidney graft survival rates than age- and gender-matched caucasian patients. While the mechanism of this apparent paradox is still not clear, the purposeful administration of random donor blood transfusions became common practice. In kidney transplant patients with living related donors, the blood transfusions were given from the related donor, a practice called “donor-specific transfusion.”154 The beneficial effect appears mediated by the HLA antigens expressed on donor leukocytes, probably monocytes but possibly also B cells.155,156 In patients receiving donor-specific transfusions, the coadministration of low-dose azathioprine (Imuran) reduced the risk of sensitization to the donor HLA antigens from 30 percent to less than 10 percent.157 That an immunosuppressive drug with antiproliferative effects on B cells could reduce the risk of antibody-mediated sensitization without altering the beneficial effect on graft survival supported the hypothesis that blood transfusions could generate some form of suppressor cell phenomenon presumably mediated by memory T cells. An alternative theory is that blood transfusions represent a selection process for patients prone to be “responders” to certain donor HLA antigens. In other words, if a patient is sensitized by a specific HLA antigen after a transfusion, then that antigen is avoided when matching that patient for the kidney transplant, and better graft survival results.
The current practice of blood transfusion in kidney transplantation has been changed dramatically by three developments: the introduction of cyclosporine and erythropoietin and the increasing concern over the danger of exposure to random donor transfusions. Cyclosporine is so potent an immunosuppressive drug that its use has challenged any additional beneficial effect of blood transfusions,158,159 and the blood transfusion effect is no longer demonstrable in kidney transplantation,153 even in black and hispanic patients. The only possible exception is that patients transplanted under the age of 15 years still demonstrate a small transfusion effect. The widespread use of erythropoietin has ended the routine practice of blood transfusions to treat the anemia of end-stage renal disease.
Marrow Grafts Previous blood transfusions, especially from the intended donor, are associated with a high rate of marrow graft rejection in patients with aplastic anemia but are not a serious problem in marrow transplantation of leukemic patients.160 ABO incompatibility in otherwise histocompatible donors does not appear to affect the marrow transplant outcome.161 There is a need to avoid an immediate transfusion reaction caused by the red blood cells in the marrow inoculum when an ABO-incompatible engraftment is carried out. Such a complication may be averted by removing anti-A or -B from the recipient by plasma exchange, by neutralization in vivo, or by removing mature red blood cells from the inoculum.161 Indications for blood component therapy in marrow transplantation have been reviewed.162
Liver Grafts Unusually large volumes of blood and the ability to recognize and correct complex hemostatic deficiencies are required for liver transplantation.163 The demand for blood is influenced by the underlying liver disease, the nature of the preoperative coagulation defect,164 and the intraoperative blood loss associated with handling a large vascular organ. An additional problem is that the large number of donors increases the risk of disease transmission (see “Hazards of Transfusion Therapy”). In a 1987 study the mean number of donor exposures per patient receiving a liver transplant ranged from 170 to 200 units.163
Blood requirements for liver transplants can be significantly reduced with intraoperative cell salvage and expansion of the blood bank erythrocyte inventory using AS-l preservative. In 100 transplants the median intraoperative erythrocyte use was 12.6 units per transplant recipient.165
HAZARDS OF TRANSFUSION THERAPY
Transfusion therapy, even under ideal conditions, carries a significant risk of an adverse reaction. Such reactions are associated with significant morbidity and in some cases with a fatal outcome. Most of the reported fatalities involve human error. In one study of 70 fatalities, 56 percent were due to acute hemolytic reactions. Half of these were preventable, since they involved an ABO mismatch due to human error. Seventy-five percent of the fatalities were due to administration of correctly cross-matched blood to the wrong patient.166 Two subsequent reviews of FDA fatality reports from 1976 to 1978167 and from 1976 through 1985168 continue to confirm these findings, i.e., a majority of transfusion fatalities are managerial-clerical and not technical failures.
Up to 20 percent of all transfusions may lead to some type of adverse reaction.169 The precise risk is difficult to estimate, since many reactions may be clinically occult, accuracy of reporting is poor, the risk is influenced by the nature of the recipient population and the source of donor blood and by the diligence and expertise of the blood bank laboratory staff.
An additional problem is that about one-half of transfusions are given to anesthetized patients.110,170 If a reaction is suspected, the transfusion should be immediately discontinued and appropriate laboratory tests and clinical studies undertaken to establish the diagnosis and institute appropriate therapy (see “Immediate Transfusion Reactions”).
Transfusion reactions may be categorized as either immediate or delayed.
IMMEDIATE TRANSFUSION REACTIONS
Symptoms of an immediate reaction begin within minutes to hours and are nonspecific with respect to etiology. They may include chills, fever, urticaria, tachycardia, dyspnea, nausea and vomiting, tightness in the chest, chest and back pain, hypotension, bronchospasm, angioneurotic edema, anaphylaxis, shock, pulmonary edema, and congestive failure. In the anesthetized patient undergoing surgery, an immediate transfusion reaction may manifest itself as generalized oozing of blood from the operative site and by shock that is not corrected by the administration of blood.
Immediate transfusion reactions may be hemolytic, febrile, or may be due to contaminated blood. The symptoms may not reflect the severity of the reaction. An etiologic diagnosis usually requires additional laboratory studies.
ACUTE HEMOLYTIC TRANSFUSION REACTIONS
Hemolytic transfusion reactions may be associated with a variety of signs and symptoms such as fever, low-back pain, sensations of chest compression, hypotension, nausea, and vomiting. Two mechanisms may account for hemolysis of transfused red blood cells: (1) intravascular breakdown, most commonly due to an incompatibility in the ABO system, or (2) destruction occurring in the extravascular space, i.e., the macrophage system of the spleen, liver, and bone marrow.
Important pathogenetic mechanisms in intravascular hemolysis are DIC and a series of hemodynamic alterations leading to ischemic necrosis of tissues, notably the kidneys.171,172 Abnormal bleeding due to a consumptive coagulopathy may develop in one-half to one-third of patients who develop major intravascular hemolysis following an incompatible transfusion.173,174
Infrequently an asymptomatic hemolytic transfusion reaction occurs without demonstrable antibody.175 Such patients do not show the expected hemoglobin increment following transfusion and have hemoglobinuria and hemoglobinemia. Such reactions are rare, and the absence of demonstrable antibody requires postulating a direct cell-mediated destruction of the incompatible red blood cells.
The clinical management of a hemolytic transfusion reaction should include immediate termination of the transfusion and institution of measures to correct shock, maintain renal circulation, and correct the bleeding diathesis. The risk of serious sequelae is proportional to the volume of incompatible blood transfused. Severe complications rarely follow the transfusion of under 200 ml of red blood cells.171 If a hemolytic reaction is suspected, therapy designed to correct bleeding and to protect the kidneys (see below) should be begun promptly without waiting for the laboratory studies to confirm its presence.
The laboratory diagnosis of an acute hemolytic reaction is based on evidence of hemolysis (hemoglobinemia and/or hemoglobinuria) and of a blood group incompatibility (antibodies in the recipient reacting with blood group antigens on transfused red blood cells). A sample of blood carefully drawn to avoid artifactual hemolysis is centrifuged for cell separation. The plasma is examined for hemoglobin (pink) or methemalbumin (brown) and is compared with the pretransfusion specimen. The urine should be examined for hemoglobin and urinary output monitored. The entire typing and cross-match procedure should be repeated to identify the blood group incompatibility. The patient and the blood transfused should be retyped, the cross-match reconfirmed, the patient’s red blood cells examined for the presence of bound immunoglobulins and/or complement (antiglobulin or Coombs’ test), and the patient’s serum tested for the presence of blood group alloantibodies. The donor’s plasma should be examined for the presence of antibodies that may react with the patient’s red blood cells.
The major effort in a hemolytic reaction should be directed toward control of bleeding, if it is present, and prevention of acute tubular necrosis. If bleeding is due to DIC (Chap. 126), heparin may be helpful, particularly in pregnant women.174,176 Heparin therapy is not without potential risk, and its use should be restricted to cases in which a severe reaction has been confirmed. To be effective, heparin should be used early in the course of DIC.174 When intravascular coagulation is controlled, the depleted coagulation factors can be restored by transfusing fibrinogen-rich cryoprecipitate, platelet concentrates, and fresh-frozen plasma.177
The prevention of renal complications relies on maintaining renal blood flow. Systolic blood pressure should be maintained above 100 torr, if necessary by administration of intravenous fluids and transfusion. Mannitol has been used by some to protect against renal failure,178,179 but others rely solely on diuretics.127,180 If mannitol is used, it should be given in quantities sufficient to maintain a urine flow of 100 ml per hour. Initially, 100 ml of a 20% solution are infused intravenously in 5 min. This dose can be repeated if diuresis does not occur, but not more than 100 g of mannitol should be given in a 24-h period. Diuretics such as furosemide (40–80 mg IV) or ethacrynic (50–100 mg IV) acid may be more effective in maintaining renal blood flow.
If anuria ensues, standard measures for management of the anuric patient should be instituted.
A febrile response associated with the administration of blood may be due to a hemolytic reaction, sensitivity to leukocytes or platelets, bacterial pyrogens, or to unidentifiable causes. Febrile reactions due to bacterial pyrogens have become uncommon with the introduction of commercially manufactured disposable transfusion equipment.
The decision to stop the administration of blood in a febrile reaction is a difficult one. Many but not all febrile reactions can be tolerated by the patient with supportive care, e.g., antipyretics, antihistamines. A chill, however, may herald a more serious reaction such as a hemolytic reaction or may be due to grossly contaminated blood. Unfortunately, reliable guidelines are not available to help with this decision. The clinician should exercise his or her best judgement but should not hesitate to stop the transfusion if there is any doubt about the underlying cause of the reaction.
SENSITIVITY TO LEUKOCYTES AND PLATELETS
A frequent cause of a nonhemolytic febrile reaction is sensitization to white cell or platelet antigens.148,181,182,183 and 184 Febrile reactions to buffy coat are predominantly due to leukocyte antigens.184 Clinically there is a temperature rise during the administration of blood or shortly thereafter. The temperature continues to rise for 2 to 6 h after cessation of transfusion, and the fever may persist for 12 h. Occasionally there may be more severe manifestations and, rarely, a drop in blood pressure with nausea, vomiting, accompanied by chest and back pains. Reactions due to leukocyte antigens have a good prognosis but may be confused with a hemolytic transfusion reaction. Nonhemolytic febrile reactions account for up to 30 percent of all recognized reactions. Usually at least seven transfusions are required to induce sensitization to leukocyte antigens in men, nonparous women, or children. In gravid or parous women, reactions may occur with the first or second transfusion. Diagnosis depends on laboratory demonstration of HLA or non-HLA antibodies to white cell antigens, usually leukoagglutinins or lymphocytotoxins. Most reactions of this type are associated with sensitivity to granulocytes, but sensitivity to lymphocytes or to platelets can also cause the reaction. Treatment is supportive. Most of these reactions can be prevented if the blood or red blood cells are passed through a leukocyte filter.
PULMONARY HYPERSENSITIVITY REACTION (NONCARDIOGENIC PULMONARY EDEMA)
Occasionally, incompatibility to leukocyte antigens may also produce pulmonary edema of noncardiac origin with acute respiratory distress, chills, fever, and tachycardia usually occurring within 4 h of transfusion. Chest x-rays show bilateral diffuse, patchy pulmonary densities without cardiac enlargement.185 Leukocyte incompatibility can be demonstrated in most cases. Sometimes recipient antibodies react with donor leukocytes,186,187 and in other cases188 passively transferred donor antibodies react with the recipient leukocytes or with recently transfused (interdonor) leukocytes. It is unclear why only a relatively few individuals respond to leukocyte incompatibility by the pulmonary hypersensitivity reaction instead of the usual febrile response. The reaction can also occur with platelet concentrates, fresh-frozen plasma, whole blood, and packed red blood cells. Almost 25 percent of multiparous women donors have leukoagglutinins and lymphocytotoxins that can cause these reactions. Therapy is supportive. In a healthy recipient the symptoms subside in less than 24 h, with pulmonary infiltrates clearing within 4 days. The reaction in a compromised recipient, however, can be fatal.186 The frequency of this reaction has been estimated as 1 in 5000 transfusions.189
Severe pulmonary toxicity characterized by respiratory deterioration and alveolar hemorrhage has been reported in neutropenic patients receiving granulocyte transfusions and amphotericin B simultaneously. A retrospective study, however, shows that usually causes other than the concomitant administration of granulocytes and amphotericin B could account for the fatal pulmonary toxicity.190 Moreover, it may be prudent to separate infusions of granulocytes and of amphotericin by as many hours as is practical.
A catastrophic reaction to reinfusion of blood collected with the Cell-Saver apparatus has been documented.34 Termed “disseminated intravascular inflammation,” this disorder is characterized by massive fluid accumulation, rapidly developing anemia, thrombocytopenia, and bleeding. The outcome is frequently fatal. This syndrome is believed to be due to the release of cytokines by leukocytes directly contacting the polycarbonate surface of the separating bowl used in the apparatus, and it has been suggested that it can be avoided by exercising care in the aspiration of material from the operative field, avoiding aspiration of cellular debris, irrigating fluid, and blood that has been greatly diluted into the salvage apparatus.
Transfusions of blood or blood products in some patients may result in generalized pruritus and urticaria. Occasionally there may be bronchospasm, angioneurotic edema, or anaphylaxis. The cause of allergic reactions is poorly understood. It has been suggested that they are due to sensitivity to plasma proteins or other agents passively transferred from the donor to the recipient. Subsequent exposure of the recipient to the antigen through medication or possibly allergens in food precipitates the reaction. Antibodies to leukocyte or platelets do not seem causally related to urticarial reactions.191 These reactions are usually mild and respond readily to parenteral antihistamines. Serious reactions require the prompt parenteral administration of epinephrine.
ANTI-IgA IN IgA-DEFICIENT RECIPIENT
Severe anaphylactoid transfusion reactions can occur in IgA-deficient patients who have formed anti-IgA.95 Such patients either lack or have a marked deficiency of IgA and have developed an IgG or occasionally IgM anti-IgA that may be either class-specific (IgA) or allotype-specific (Am).192 Deficiency or absence of IgA occurs infrequently; about 1 in 650 persons lack IgA by immunodiffusion and about 1 in 886 have no demonstrable IgA.193 The IgA present in the plasma of the transfused blood probably reacts with the anti-IgA to produce the anaphylactoid reaction. Small amounts of plasma (less than 10 ml) can produce the reaction. The reaction usually is not associated with fever but may produce dyspnea, nausea, chills, abdominal cramps, emesis, diarrhea, and profound hypotension. A fatal reaction due to anti-IgA occurring 45 min after administration of about 50 ml of blood has been reported.194 Diagnosis requires laboratory demonstration of the absence of IgA and the presence of anti-IgA in the recipient’s circulation. Reactions can usually be prevented by using washed or frozen red blood cells, since these components are prepared by procedures effective in removing donor plasma. Plasma protein components, such as albumin or plasma protein fraction, may contain sufficient IgA to produce a reaction. If platelet or granulocyte transfusions are required for IgA-deficient patients, they should be obtained from donors who lack IgA (Rare Donor File, American Association of Blood Banks).
Blood may be contaminated by cold-growing organisms (Pseudomonas or colon-aerogenes group). These microorganisms can utilize citrate as the primary source of carbon, and growth of blood by these microorganisms may deplete its citrate concentration sufficiently to result in clotting. Visual inspection of the blood unit may reveal clots and suggest the presence of contamination. The infusion of large numbers of gram-negative microorganisms results in a serious reaction, endotoxin shock, characterized by fever, marked hypotension, abdominal pain, vomiting, diarrhea, and the development of profound shock.195 The reaction may start with shaking chills following a latent period of 30 min or more. As little as 10 ml of blood may contain sufficient microorganisms to produce the reaction. Rapid diagnosis is essential and can be made by drawing a small sample of residual donor blood from the container or administration tubing. The plasma obtained by slow centrifugation is smeared on a slide, fixed by heating, and Gram-stained. If the blood is heavily contaminated, several organisms can be clearly identified in most oil-immersion fields.
Septic shock is a complex disorder, and comprehensive supportive therapy is essential once the diagnosis is made. Treatment is often ineffective. The fatality rate with this type of overwhelming shock is estimated to be from 50 to 80 percent.
Bacterial contamination of blood is an uncommon complication since the introduction of disposable plastic blood bags. This transfusion hazard, however, is significant with platelet concentrates stored at room temperature (see Chap. 142).
Hypervolemia produced by administration of excess blood in patients with a compromised cardiovascular system may provoke the development of congestive heart failure and pulmonary edema. Treatment of this reaction includes administration of diuretics and in some cases rapid digitalization. Repeated phlebotomies with reinfusion of the erythrocytes as packed red blood cells may sometimes be helpful.
Patients with severe chronic anemia (hemoglobin less than 4 gm per 100 ml), such as those with pernicious anemia, who are rapidly transfused with whole blood or packed red blood cells may develop congestive failure and pulmonary edema. The slow administration of packed red blood cells appears to be well tolerated by the patient in a semiupright position. Venous pressure should be monitored in such patients, diuretics administered, and the transfusion given at a rate of 2 ml per kg of body weight per hour. It is unlikely that a transfusion will precipitate congestive heart failure if the venous pressure is normal before transfusion.196
Air embolism is now a rare complication of transfusion therapy following the introduction of plastic equipment that provides a closed system. Only large volumes of air and not the entry of a few bubbles results in clinically significant air embolism. Symptoms associated with air embolism include pain, cough, and sudden onset of dyspnea. Treatment consists of clamping off administration tubing; placing the patient on the left side in the head-down position with closed chest compression, so that air in the right ventricle flows away from the pulmonary outflow tract; and if possible air aspiration through a right atrial or Swan-Ganz catheter.197
MICROAGGREGATES IN BLOOD
Particles consisting largely of platelets and fibrin198 form in blood stored in ACD, CPD, or CPDA-1 solutions. Such debris, consisting of particles 13 to 100 µm in size and collectively designated microaggregates, is not removed by the ordinary blood filter that has a pore size of about 170 µm. Microaggregates have been shown to produce pulmonary insufficiency in clinical situations involving massive transfusions of banked blood. Pulmonary complications and histologic changes in the lungs have been observed in patients receiving massive transfusions.199,200 Infusion of nonfiltered blood resulted in a consistent increase in the pulmonary vascular resistance in experimental animals.201 Patients transfused over 20 percent of their blood volume have increased pulmonary arteriovenous shunting when the blood is filtered with standard blood filters, but this can be prevented if microaggregate filters are used.202
The clinical importance of microaggregates in routine transfusions is questionable.203 Several investigators, however, believe that microaggregate filters should be used in cardiac surgery and in critically ill patients with pulmonary insufficiency who will receive more than 3 to 5 units of banked blood in less than 12 h.204
REACTIONS ASSOCIATED WITH MASSIVE TRANSFUSIONS
The use of large quantities of banked blood for massive transfusions may lead to a number of complications. Among these are circulatory overload (see above), air embolism (see above), citrate intoxication, and a bleeding syndrome. Blood transfused into adults at a rate greater than a liter in 10 min will produce significant reduction in ionized calcium with myocardial depression and ECG changes. Citrate intoxication can be prevented by giving 10 ml of 10% calcium gluconate for every liter of citrated blood.
Bleeding may be a complication of transfusion either because an antigen-antibody reaction involving a red cell antigen initiates DIC or because coagulation factors and platelets are diluted following large-volume compatible transfusions of banked blood.173 It should always be kept in mind that the most common cause of bleeding in surgical patients is a severed vessel.
Unexplained bleeding may be the first sign of incompatibility in the anesthetized patient and may follow the administration of 200 to 500 ml of incompatible blood. Local bleeding at the surgical site or epistaxis, bruising, or purpura due to DIC may occur following an acute hemolytic transfusion reaction. The diagnosis and management of this complication are outlined above under “Acute Hemolytic Transfusion Reactions.”
Bleeding associated with transfusion of large amounts of compatible stored blood is largely due to the dilution of the intravascular volume with blood lacking in both cellular and plasma coagulation components. Since platelets do not survive in stored blood, transfusion of a volume of blood equal to that to the recipient will produce thrombocytopenia through a dilutional effect. Stored blood is deficient in platelets and in factors V, VIII, and XI. These clotting components may be depleted when a large volume transfusion is given.
DELAYED ADVERSE EFFECTS OF BLOOD TRANSFUSION
DELAYED HEMOLYTIC REACTION
In the delayed hemolytic reaction, development of previously undetected alloantibodies occurs some 4 to 14 days after transfusion of apparently compatible blood. In such cases the patient usually has been alloimmunized by a previous pregnancy or transfusion, and the concentration of antibody was below the level of serologic detection at the time of transfusion. If the transfused blood contains the corresponding antigen, an anamnestic response ensues with formation of detectable antibody that coats the transfused red blood cells and leads to their hemolysis. The principal clinical signs are onset of jaundice and absence of the expected increment in red cell mass. These reactions are associated with the development of a positive direct antiglobulin reaction (Coombs’ test),205,206 which in such patients may be confused with autoimmune hemolytic anemia,207 or in one report with sickle-cell crisis.208 Generally, these reactions are clinically less severe than the acute hemolytic reaction and frequently are not detected until more blood is ordered for a transfusion-unresponsive anemia. The frequency of delayed hemolytic anemia was 1 in 4000 in one report,205 with no deaths in the 37 cases studied. Delayed hemolytic reactions, as a result, are frequently undetected.206
A rare complication of transfusion therapy is posttransfusion purpura, which occurs approximately 1 week after transfusion and is associated with the development of an antibody to the platelet-specific antigen in a Pla1-negative recipient (see Chap. 117).
TRANSMISSION OF DISEASE
The greatest risk to which the transfused patient is exposed is that of infection with viral agents, such as those that cause acquired immunodeficiency syndrome, lymphomas, or hepatitis, or protozoal organisms, particularly malaria. The prevention of disease transmission is discussed in Chap. 139.
Graft-versus-host disease is an uncommon complication of transfusion therapy,209 preventable by blood irradiation.
OTHER TYPES OF DELAYED REACTIONS
Other complications of transfusion therapy are iron overload with hemochromatosis (see Chap. 42), which occurs in patients who receive many transfusions, and alloimmunizations to red cell and histocompatibility antigens.
Alloimmunization as a transfusion complication may occur in immunocompetent transfusion-dependent recipients. Blood is matched routinely only with respect to ABO antigens and the major Rh antigen, Rho(D). There is a high probability that the donor will have red cell antigens not present in the recipient which will result in alloimmunization. The incidence of alloimmunization is influenced by the number of units transfused, the immune status of the recipient, and probably other undefined factors. The prevalence of alloantibodies in multiply transfused patients with various hematological disorders was 11.8 percent210; in multiply transfused sickle cell anemia patients the prevalence has been variously reported as 36 percent,211 23 percent,212 and in one series only 7.75 percent.213 The incidence of alloimmunization in thalassemia major patients214 is lower (5.2 percent).
More extensive pretransfusion typing including the matching for additional antigens of recipients who will require frequent transfusions appears to reduce the risk of alloimmunization. Pretransfusion matching for the major antigens (Rh, Kell, Kidd and Duffy) in patients with sickle cell anemia reduced the incidence of alloimmunization tenfold.215 This measure alone may not be cost-effective, since not all individuals are capable of mounting an immune response to blood group antigens. A few Rho(D)-negative individuals fail to produce anti-Rho(D) in spite of intentional immunization with the antigen.216,217 However, 95 percent of Rh-negative individuals receiving large quantities (average 19.4 units) of Rh-positive blood during open heart surgery formed anti-D.218 More extensive pretransfusion matching would be justifiable if a marker could be found that unequivocally identifies the responder population of recipients.
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