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Transfusion medicine
The year 1492 is often recalled as the year in which “Columbus sailed the ocean blue.” In that same year the first recorded attempt at therapeutic transfusion occurred in Rome. After having an apoplectic stroke, Pope Innocent VIII lapsed into a coma. His physician ordered that the blood of three of the pope’s young sons be transfused in an attempt to revive him. Unsurprisingly, the attempt failed (the route of transfusion was per os) leading to the death of the pope and his sons. More than 300 years later, the first successful human transfusion was performed in Philadelphia, credited to the University of Edinburgh–trained “Father of American Surgery,” Philip Syng Physick. He did not publish his accomplishment, and few details exist of the circumstances or outcome ( ).
The deaths of the pope’s children are a reminder that blood is a precious resource and should be conserved whenever possible. This chapter describes the techniques available for conserving the blood of pediatric patients and provides insight into hemoglobin function, anemia, blood banking, and transfusion medicine practices.
Hemoglobin structure and function in the neonate, infant, and child
Hemoglobin, the primary oxygen-carrying blood constituent, is a complex tetrameric protein consisting of iron-containing heme groups and the globin protein moiety ( Fig. 22.1 ). The paired arrangement of polypeptide globin chains each interacting with an attached heme group provides the complex with reversible interactions with oxygen, thereby allowing it to be bound and unbound in a compartment-specific manner. Because each heme moiety has the capacity to bind a single oxygen molecule, a molecule of hemoglobin can transport as many as four oxygen molecules.
In the healthy child and adult, hemoglobin is a heterotetramer consisting of two polypeptide alpha (α) chains and two beta (β) chains that are designated hemoglobin A. The chains differ in the number and sequence of amino acids and their chromosomal location. The gene for the α chain is located on chromosome 16, whereas the genes for the β chain and for the embryonic and fetal chains (gamma [γ], epsilon [ε], and zeta [ζ]) are closely linked on chromosome 11.
Hemoglobin structure during the embryologic period is characterized by three hemoglobin species, including Gower-1 (ζ 2 ε 2 ), Gower-2 (α 2 ε 2 ), and Portland (ζ 2 γ 2 ) ( Fig. 22.2 ). By the 10th week of gestation, these embryonic hemoglobin species are nearly completely replaced by fetal hemoglobin (α 2 γ 2 ), commonly referred to as hemoglobin F. At 10 to 12 weeks of gestation, the distribution of hemoglobin is about 80% to 90% fetal hemoglobin and 10% hemoglobin A. Synthesis of fetal hemoglobin ceases at approximately 38 weeks of gestation; at birth, the percentage of fetal hemoglobin has decreased to about 70% to 80% and, under normal circumstances, continues to decrease thereafter. By 6 months of age, fetal hemoglobin levels typically have decreased to less than 5% and by 1 year, to 2%, a level similar to that in adults.
The primary physiologic function of hemoglobin is to bind oxygen in the capillary beds of the pulmonary alveoli (or, in fetal life, the chorionic villi of the maternal placenta) and release it in the reduced oxygen environment of the tissues. Hemoglobin also is important as a biological buffer and in the transport of both carbon dioxide (the Bohr effect; Fig. 22.3 ) and nitric oxide. In its primary role as an oxygen carrier, hemoglobin alters its affinity for oxygen through changes in the quaternary structure of the protein heterotetramer. This relationship can be usefully illustrated by examining the appearance of the oxyhemoglobin dissociation curve ( Fig. 22.4 ), which describes hemoglobin saturation at various oxygen tensions. Its shape is sigmoidal because the four globin chains directly interact with oxygen to affect the affinity of the other chains for oxygen. This sigmoidal affinity curve demonstrates hemoglobin’s low affinity (flat, leftward portion of the sigmoid) for oxygen in hypoxic environments, a rapidly increasing affinity (steep portion) as oxygenation of each heme group occurs until the molecule becomes saturated (flat, rightward portion of the sigmoid). The classic shape of the curve is described for hemoglobin A and reflects the physiologic requirement to load and unload oxygen within a narrow range of oxygen tensions. Other hemoglobin species and mixtures of species have different affinities for oxygen and therefore produce different dissociation curves.
The dissociation curve for fetal hemoglobin reflects its need to bind oxygen from maternal hemoglobin A; fetal hemoglobin has a greater affinity for oxygen than maternal hemoglobin A, allowing hemoglobin F to accept oxygen carried to the uterine villi. The increased affinity of fetal hemoglobin for oxygen can be traced to its lower capacity to interact with 2,3-diphosphoglycerate (2,3-DPG) because the binding site for 2,3-DPG is on the β chain, a chain absent in fetal hemoglobin ( ). Although one would expect that the increased affinity for oxygen of fetal hemoglobin would be essential for adequate oxygen delivery in the fetus, that appears not to be the case as illustrated by the lack of deleterious effects on the fetus when hemoglobin A is transfused in utero ( ). Furthermore, infants born to mothers with hemoglobinopathies characterized by an increased affinity for oxygen show no apparent effects ( ). By extension, it can be presumed that in the neonate, transfusion with blood containing hemoglobin A is not harmful and may in fact have clear advantages, especially in critical illness ( ).
As previously discussed, the sigmoidal shape of the oxyhemoglobin dissociation curve of hemoglobin A is a reflection of its structure, whereas its position with respect to oxygen saturation and oxygen tension is a function of various factors. Under normal circumstances, the oxygen tension at which hemoglobin A is 50% saturated (P 50 ) is 27 mm Hg. Temperature, pH, Pco 2 , and 2,3-DPG levels all affect oxygen affinity (and therefore P 50 ), resulting in a leftward or rightward displacement of the curve. Because the oxyhemoglobin dissociation curve for the neonate is identical to that of the adult at a pH of 7.6, environmental differences are potentially more important to hemoglobin functional affinity than are fundamental differences in the hemoglobin molecule itself ( ). Under normal development, the P 50 increases from about 19 mm Hg at age 1 day to the adult level of 27 mm Hg at age 4 to 6 months. At the end of the first year, the P50 actually exceeds that of the adult at a level of slightly greater than 30 mm Hg ( ).
The red blood cell (RBC) is of great importance to the function of hemoglobin. Loss of its nucleus during erythropoiesis imposes on the RBC a finite existence in the circulation. The absence of a nucleus allows it to function more effectively in oxygen transport but limits its ability to repair defects in the cell membrane because it lacks the ability to synthesize the necessary proteins. The mature RBC maintains approximately 40 enzymes for various functions, including electrolyte homeostasis, anaerobic glycolysis, maintenance of cell membrane shape and integrity, maintenance of heme iron in the ferrous state, and maintenance of appropriate levels of 2,3-DPG. Free hemoglobin is rapidly removed from the circulation, whereas hemoglobin maintained within the RBC membrane has a life span of up to 120 days; fetal RBCs have a decreased life span of 60 to 90 days. With prematurity, RBC life span is progressively shorter, contributing to the frequency of transfusions among the most premature neonates. RBC senescence results from the loss of enzyme function necessary for maintenance of the membrane integrity. Ultimately, progressive loss of membrane results in the loss of the characteristic biconcave shape of the RBC, decreased deformability, and increased fragility that culminates in sequestration and destruction in the spleen.
Physiologic anemia and the anemia of prematurity
At term, the neonate has a hemoglobin concentration of approximately 17 g/dL. As hemoglobin F is replaced with hemoglobin A over the ensuing months, the hemoglobin level decreases to a nadir of 10 g/dL, and the oxyhemoglobin dissociation curve shifts rightward. This shift is the result of the combination of increasing levels of hemoglobin A and increased levels of 2,3-DPG or, as described by , an increased 2,3-DPG fraction indicating that the decreased affinity of hemoglobin for oxygen is the result of the interaction of 2,3-DPG with hemoglobin A. An increase in the levels of either one alone is insufficient. The importance of this is apparent in infants who have respiratory distress syndrome with abnormally low levels of 2,3-DPG and who show improved oxygen unloading at the tissue level after transfusion with fresh adult blood. The transition from a P 50 of 19 mm Hg in the term neonate to 27 mm Hg (as in the adult) typically occurs over 4 to 6 months. However, in the premature infant this transition may be delayed to as late as age 12 months.
The conversion from hemoglobin F to hemoglobin A results in the physiologic anemia of infancy , and the hemoglobin concentration decreases from 17 to 18 g/dL at birth to a nadir of 10 to 11 g/dL at age 8 to 12 weeks. The anemia in the healthy neonate is asymptomatic and is therefore not a true anemia; thus physiologic is used to differentiate the normal decrease in hemoglobin in the term neonate from that in the premature. In the premature infant, this anemia occurs earlier, persists longer, and is symptomatic, with hemoglobin levels frequently decreasing to as low as 8.0 g/dL as early as the fourth week after birth.
The origin of physiologic anemia (and to a lesser extent, the anemia of prematurity) can be traced to a dramatic decrease in levels of erythropoietin (EPO). EPO is initially synthesized in the fetal liver and thereafter in the kidney and is the primary growth factor for erythropoiesis. Its activity is primarily regulated by oxygen tension: as oxygen tension decreases, expression of the EPO gene increases. In the fetus, EPO gene expression is high because oxygen tensions are low. The leftward position of the oxyhemoglobin dissociation curve necessitates that hemoglobin concentration be maintained at levels that will deliver sufficient oxygen to fetal tissues despite the high oxygen affinity of fetal hemoglobin.
At birth, oxygen tensions increase quickly, effectively halting EPO synthesis and, consequently, erythropoiesis. In the term neonate, EPO and consequently hemoglobin levels begin increasing around the age of 4 months, resulting in the correction of physiologic anemia, which is often called the physiologic nadir to emphasize the physiologic or nonpathologic nature of the decrease in hemoglobin in term infants. In premature infants, the phenomenon is more complex and is complicated by the need for frequent blood sampling in hospitalized premature infants. Often the blood-sampling requirements equal or exceed half of the total blood volume in infants weighing less than 1 kg, increasing the need for transfusion of adult banked blood ( ). The resulting increase in tissue oxygen tension further decreases EPO synthesis and prolongs the duration of anemia. Factors that influence the duration of the anemia include weight, gestational age, and the underlying reasons for continued transfusions.
The anemia of prematurity is a true anemia that produces clinical signs and symptoms such as tachycardia, bradycardia, apnea, delayed growth, and poor weight gain. Treatment is directed at these consequences and consists of either transfusion or the use of recombinant erythropoietin. Studies examining the potential benefit of booster transfusions on premature infants targeted to keep hemoglobin levels greater than 10 g/dL have been mixed: some have shown improvements in weight gain and others have failed to demonstrate benefit ( ; ; ).
The use of recombinant EPO in premature infants has also been studied extensively. A 2014 Cochrane Review described the results of 34 studies involving 3643 infants ( Fig. 22.5 ). They concluded that early administration of EPO decreased the need for transfusions. In addition, early administration of EPO was not associated with an increased risk of retinopathy of prematurity and significantly decreased the risk of intraventricular hemorrhage, periventricular leukomalacia, and necrotizing enterocolitis. Neurodevelopmental outcomes at 18 to 22 months of age were evaluated but were inconclusive. Despite this encouraging evidence, prophylactic administration of EPO was not advised by the authors because of high heterogeneity in the analysis, and they suggested awaiting the results of ongoing trials. Transfusion practices and indications in this group are discussed later in this chapter.
Preoperative anemia
Anemia is common in neonates, infants, and children. The incidence of anemia from birth to 4 years of age is 20% in industrialized countries ( ). There are several etiologies for anemia in the pediatric population, and iron deficiency is the most common. Regardless of the etiology, the presence of preoperative anemia increases perioperative complications and mortality for adult and pediatric patients, alike. Specifically, preoperative anemia is associated with increased length of stay, transfusion requirements, and 30-day in-hospital mortality ( ; ; ). This has been demonstrated in both neonates and children. It is not clear whether transfusion therapy will reduce or enhance this association because RBC transfusions themselves are associated with increased in-hospital mortality. Patient blood management programs may be beneficial and would serve to identify patients at risk for preoperative anemia, optimize anemic patients through alternative therapies (e.g., iron therapy rather than transfusion therapy), and maximize perioperative blood conservation strategies. These programs in adults have been shown to reduce morbidity and mortality ( ).
Erythrocyte antigens and compatibility testing
Red blood cells contain antigens that determine the blood type of every individual. Although over 300 discrete erythrocyte antigens have been defined that vary in terms of structure, function, and immunogenicity, the most important erythrocyte antigens for transfusion medicine are the ABO and Rh group antigens ( ). Together, these systems have the primary role of determining both the blood type of the patient and the safety of any blood product to be transfused.
The ABO antigen system
With the exception of an extremely rare blood type termed Bombay phenotype, which lacks the ability to synthesize H-antigen, all red blood cells in all persons express H-antigen on their external surface ( ). H-antigen is a precursor carbohydrate that is attached to surface proteins or lipids during erythropoiesis. This carbohydrate may undergo further modification with the aid of genes encoded by the ABO locus on chromosome 9. This locus has three functional types—type A, type B, and type O—that encode proteins that add simple sugars to H-antigen and thereby determine the ABO blood type of the individual. Persons with an “A-type” locus modify H-antigen into “A antigen” and are therefore said to have “type A” blood; persons with a “B-type” locus convert H-antigen into “B antigen” and are said to have “type B” blood. Every individual possesses two ABO loci, one inherited from each parent. ABO inheritance is codominant, such that persons with both an “A” and a “B” locus convert H-antigen into both A- and B-antigens, thereby having “type AB” blood. Many individuals possess “O-type” loci that do not express the genes necessary to modify H-antigen. These individuals have erythrocytes that contain unmodified H-antigen and have blood termed “type O.” As inheritance is codominant, individuals with one functional copy of an ABO locus (such as type A) and one nonfunctional copy (type O) have a phenotype of that of the functional locus. As an example, a person with both a type A and type O locus would have the same phenotype as an individual with two copies of the type A locus—both persons would have “type A” blood.
One function of the immune system is to produce antibodies to foreign (nonself) antigens. As such, the plasma of persons with specific ABO blood types contains antibodies to opposing AB-group antigens; persons with type A blood have antibodies targeted to type B antigen, persons with type B blood have antibodies targeted to type A antigen, and persons with type O blood have antibodies targeted to both A and B antigens. In contrast, persons with type AB blood produce neither anti-A nor anti-B antibodies. These erythrocyte antigens, and their corresponding plasma antibody profile, have important ramifications on transfusion medicine. Patients with blood type O, Rh D negative (discussed in the next section), are considered the universal donor for erythrocytes, as these cells lack the major antigens to which recipients typically have preformed antibodies. In contrast, persons with blood type AB, Rh D positive, are considered the universal donor of plasma, as their plasma is devoid of antibodies targeted to major red cell antigens.
The RH antigen system
The Rh antigen system, so named as it was thought to be that which prevented the safe transfusion of blood from Rhesus monkeys into other nonhuman species, is one of the most intricate erythrocyte antigen systems ( ). Although there are nearly 50 known discrete Rh antigens, the most important is the D antigen. D antigen is a complex transmembrane protein located on red blood cells, and persons who express the Rh D antigen are said to be “Rh positive.” Persons who do not express Rh D antigen are termed “Rh negative.” In common parlance, the Rh D and ABO antigen systems together define the basic blood type of every patient. As an example, a person who expresses type A and Rh D antigen would be referred to having the blood type “A positive.” A person who expresses neither type A, nor type B, nor Rh D antigen has blood type “O negative.”
Inheritance of the D-antigen gene is autosomal dominant, such that persons with either one or two functional copies of the D-antigen gene are phenotypically identical and said to be “Rh positive”; one must possess two nonfunctional copies of the D-antigen gene in order to be “Rh negative.” Unlike the ABO system where persons of a single blood type have detectable antibodies targeted to opposing blood group antigens within the first few months of life, persons who are Rh negative typically do not have antibodies targeted to D antigen. D antigen, however, is highly immunogenic—Rh negative persons transfused with Rh positive blood (a process termed alloimmunization) will produce IgG antibodies against D antigen. If a sufficient amount of time has elapsed between transfusions to allow antibody production to occur, these anti-Rh D antibodies will bind to and induce hemolysis of transfused Rh positive erythrocytes in Rh negative recipients. Such alloimmunization can also occur with seemingly trivial amounts of blood. One classic example is the small amount of fetal blood that can gain access to the maternal circulation during pregnancy and parturition; if the fetus is Rh positive and the mother Rh negative, alloimmunization of the mother may occur ( ). Though the first child is typically not at risk as insufficient time has elapsed for sufficient antibody production, in subsequent pregnancies these maternal antibodies can cross the placenta and induce hemolysis of fetal erythrocytes in utero. These antibodies are responsible for hemolytic disease of the newborn, once a common cause of fetal mortality. For these and other reasons, Rh factor type is determined in every donor, recipient, and expectant mother. Of note, despite the presence of preformed antibodies, ABO blood type incompatibility between the mother and fetus does not typically cause severe hemolytic disease of the newborn as anti-A and anti-B antibodies from blood type B/A (respectively) mothers are typically of IgM subtype, which do not cross the placenta. Parturients with blood type O, however, produce IgG subtype antibodies to both A- and B-group antigens that can cross the placenta and cause hemolytic disease of the newborn; this disease, however, is much less severe than that from D-antigen incompatibility, and clinically significant hemolysis is uncommon.
In addition to the numerous other antigens in the Rh system, other minor antigen systems (such as the Kell, Duffy, and Kidd antigen systems) exist and affect transfusion decision-making. Like the Rh D system, individuals that have never been transfused do not commonly possess preformed antibody to these minor blood group antigens. However, patients who have received transfusions in the past may be alloimmunized against these and other minor blood group antigens. The production of alloantibodies in these patients may restrict the availability of appropriate blood donors, a relatively common problem in children who have received multiple transfusions such as those patients with sickle cell disease ( ).
Compatibility testing
All candidates for transfusion are subject to testing in order to prolong the transfused erythrocyte lifespan and avoid harmful transfusion reactions. In addition to positive identification of the donor and recipient, compatibility testing commonly refers to three laboratory tests: ABO and Rh D antigen typing, antibody screening, and crossmatching ( ). In ABO and Rh D antigen typing, the laboratory determines the ABO and D-antigen status of all donor and recipient blood samples, typically by both forward and reverse group testing. In forward testing, the sample’s erythrocytes are incubated with anti-A and B-group antibodies to determine their ABO blood type directly. In reverse testing, the plasma of the sample is tested for antibodies against type A and B antigens, from which the erythrocyte ABO status may be inferred. The results from forward and reverse testing are combined to determine the ABO type. In the case of neonates, who have not had sufficient time to make antibodies against ABO antigens, reverse group testing is omitted.
Antibody screening consists of reacting a potential transfusion recipient’s serum with a panel of erythrocytes with defined antigens commonly implicated in hemolytic transfusion reactions. Should the recipient possess antibodies against one of these antigens, a hemolytic reaction may be detected in vitro; the specific antigen can then be determined and erythrocytes lacking this antigen used for transfusions. In a crossmatch, a similar process is undertaken, except that a pilot transfusion is undertaken in vitro by reacting donor erythrocytes with recipient serum. In addition to determining the potential compatibility of a recipient with a specific blood sample, a crossmatch also checks against errors in ABO and Rh typing that may have occurred during sample acquisition and processing.
For infants less than 4 months of age, maternal IgG is invariably present in infant serum, which may be targeted to erythrocyte antigens of a potential donor or of the infant his/herself (see previous discussion). In order to perform transfusions in these patients, two general approaches are used ( ). The first involves transfusion of type O Rh D negative erythrocytes for all newborns. Even though this strategy simplifies blood banking procedures, trace amounts of alloantibodies contained in the transfusate may react with erythrocytes of the recipient and require washing for removal. An alternative transfusion strategy is to use ABO and Rh D type–compatible blood. In this scenario, the infant’s serum is first tested for maternal anti-A or anti-B alloantibodies so that such donor cells can be avoided.
Perioperative strategies for blood conservation
This section discusses the following techniques and drugs that have been studied to limit allogenic blood transfusion in the pediatric population: erythropoietin, iron supplementation, hemostatic drugs, preoperative autologous blood donation, preoperative hemodilution, and deliberate hypotension. Not all these methods of blood conservation are ideal for every patient or surgical procedure, but each method has a place in the perioperative management of blood conservation in the pediatric patient.
Erythropoietin
As discussed in the previous section, EPO is an inducible peptide hormone produced in the kidneys and extrarenal tissues in response to tissue hypoxia. Acute anemia is associated with large increases in plasma EPO. However, in the critically ill, EPO induction is blunted, as has also been observed in numerous chronic illnesses in childhood. The exact mechanism of inhibition is unclear ( ). Regardless of the mechanism, both situations frequently lead to the need for blood transfusion. The use of recombinant EPO has been investigated as a means of reducing the need for transfusion or the frequency of transfusion in chronic or critical illness.
Adult studies have shown mixed results in the efficacy of recombinant human EPO to avoid or limit blood transfusion. Several randomized controlled studies have shown that at least 1 unit of blood was saved in adult intensive care unit patients ( ; ). However, Corwin and colleagues reported that in a large, prospective, randomized controlled trial involving more than 1400 adult patients, the group receiving EPO had a 10% decrease in the need for transfusion compared with the control group ( ). Unfortunately, that study and others found an increase in the frequency of thrombotic events among patients receiving erythropoietin.
A benefit, albeit small, was found in studies that examined the use of perioperative EPO for reducing the need for transfusion during and after procedures in which transfusion is frequently required. Performing a meta-analysis involving adults undergoing either orthopedic or cardiac surgery, Laupacis and Fergusson ( ) found a significant reduction in allogeneic RBC transfusion in both groups of patients. A 2013 meta-analysis also found evidence of efficacy for EPO in avoiding transfusions in adult patients undergoing a variety of orthopedic, cardiac, oncologic, gastrointestinal, and gynecologic surgical procedures; however, evidence of increased thromboembolism was continued to be found ( ). In a study by of 32 randomized controlled trials involving over 2400 adult patients, erythropoietin was associated with reduced red cell transfusions and no added risk of thromboembolism ( Fig. 22.6 A and B)
![Fig. 22.6, A, The weighted (pooled) estimate for the effect of preoperative erythropoietin (EPO) administration on incidence of whole hospitalization allogeneic transfusions (risk ratio [RR], 0.59; 95% CI, 0.47–0.73; p < 0.001) compared with placebo administration (Cho et al. 2019). B, The weighted (pooled) estimate for the effect of preoperative erythropoietin (EPO) administration on incidence of thromboembolic events (risk ratio [RR], 1.02; 95% CI, 0.78–1.33; p = 0.68) compared with placebo administration (Cho et al. 2019).](https://storage.googleapis.com/dl.dentistrykey.com/clinical/Transfusionmedicine/5_3s20B978032369825200031X.jpg "Fig. 22.6, A, The weighted (pooled) estimate for the effect of preoperative erythropoietin (EPO) administration on incidence of whole hospitalization allogeneic transfusions (risk ratio [RR], 0.59; 95% CI, 0.47–0.73; p < 0.001) compared with placebo administration (Cho et al. 2019). B, The weighted (pooled) estimate for the effect of preoperative erythropoietin (EPO) administration on incidence of thromboembolic events (risk ratio [RR], 1.02; 95% CI, 0.78–1.33; p = 0.68) compared with placebo administration (Cho et al. 2019).")
Two studies of children undergoing craniofacial repair found that children receiving preoperative EPO required transfusions significantly less often than controls ( ; ). A retrospective study that included over 300 infants having craniofacial surgery did not find an increased incidence of thromboembolic events in this pediatric population ( ). Other small studies and case reports have reported efficacy for EPO in reducing the need for RBC transfusion in children, but in the absence of data from large, well-designed prospective trials, its routine use has not been recommended. Both the FDA and the European Union have restricted erythropoietic stimulating agents use for specific types of adult patients in elective surgical settings. In selected patient populations, the risk may be significantly outweighed by the benefit, such as in Jehovah’s Witness patients ( ).
Iron supplementation
The main cause of iron deficiency anemia in the developed world is blood loss, primarily from gastrointestinal tract bleeding, menstruation, frequent blood draws, or surgical hemorrhage. The development of iron deficiency is dependent on the individual’s iron reserve, which in turn is dependent on the age, sex, rate of growth, and rate of absorption of iron.
The frequency of iron deficiency anemia is approximately 9% among children 1 to 2 years old in the United States ( ). For adult patients with normal iron storage, there is conflicting evidence as to whether iron supplementation perioperatively improves the hemoglobin level. Several randomized control trials have failed to show that oral iron supplementation increases hemoglobin levels perioperatively ( ; ; ; ; ). However, two clinical trials (one randomized and one nonrandomized) with colorectal surgical patients have shown that treatment with iron oral supplementation for 2 weeks significantly increased hemoglobin levels and decreased blood transfusion rates ( ; ). The conclusion of a 2008 review by Beris and colleagues for the Network for Advancement of Transfusion Alternatives was that there is insufficient evidence to recommend the use of intravenous iron as a means of reducing the need for perioperative transfusion in adults ( ). As with the use of erythropoietin, few data from children are available.
Hemostatic drugs
Three currently available hemostatic drugs have been well investigated and extensively used to limit blood loss perioperatively. Two of the drugs, aminocaproic acid (EACA) and tranexamic acid (TA), are lysine amino acid derivatives; the third, aprotinin, is a naturally occurring antifibrinolytic and proteinase inhibitor. These drugs have been extensively used in adults and, more recently, in children.
Fibrinolysis, the lysis of formed fibrin clot, results from the enzymatic conversion of the proenzyme plasminogen to plasmin, a process that is mediated by tissue plasminogen activator, urokinase, factors XIa and XIIa, and kallikrein. Fibrinolysis results in the cleavage of polymerized fibrin strands at multiple sites and releases fibrin degradation products such as D-dimer ( ). EACA and TA exert their antifibrinolytic activity by reversibly blocking the lysine binding site on plasminogen, preventing binding to fibrin and conversion to active plasmin ( Fig. 22.7 ). As an inhibitor of fibrinolysis, TA is 10 times more potent than EACA. TA may also improve hemostasis by preventing plasmin-induced platelet activation. Although both EACA and TA have antiinflammatory properties, they are less than those of aprotinin ( ).
Antifibrinolytics have been used in children primarily for spine surgery, cardiac surgery, and craniofacial reconstruction, although they have been used for other procedures, including repair of congenital diaphragmatic hernia during extracorporeal membrane oxygenation (ECMO). In two well-designed prospective studies, tranexamic acid clearly demonstrated a benefit in reducing exposure to allogeneic blood in infants and children having craniofacial surgery ( ; ). Several studies have evaluated the use of TA and EACA in reducing blood loss and transfusion in pediatric spine surgery. A systemic review evaluated these data and reported that although both EACA and TA reduce blood loss and transfusion requirements in pediatric spine surgery, the data originate from small, single-center, and primarily retrospective trials ( ); however, a randomized controlled trial reported a 27% decrease in blood loss and exposure to allogeneic blood with TA in adolescents having scoliosis surgery ( ) ( Fig. 22.8 ).
For adult cardiac surgery, the use of antifibrinolytics is well established. For children, although the efficacy data are less available and of lower quality, they support the use of TA and EACA primarily in children undergoing repair of cyanotic congenital heart disease. , in a series of studies involving 750 cyanotic patients, found that both TA and EACA were beneficial in reducing transfusion requirements by up to 50%, reducing blood loss by 44%, and significantly reducing times for sternal closure and rate of reexploration. A 2012 metaanalysis of 8 studies containing 848 children reported mildly decreased rates of RBC, platelet, and plasma transfusions in pediatric cardiac surgery patients when TA was used relative to placebo; the effect of TA on various postoperative complications (thrombosis, renal insufficiency, and chest reexploration due to bleeding, mortality) was not possible as these data were not included in the majority of the original manuscripts ( ). In adult trauma patients, a metaanalysis concluded that provision of TA within 3 hours of injury reduced mortality without adverse events ( ).
Few complications have been associated with the use of TA and EACA, although concerns have been related to thrombosis in patients, such as those undergoing ECMO or a Fontan procedure requiring the use of a baffle fenestration. Although case reports suggest the potential for concern, studies involving 71 patients undergoing a Fontan procedure and 431 patients undergoing ECMO have failed to demonstrate an increased risk of thrombosis ( ; ; ). Generally accepted contraindications include drug hypersensitivity, thromboembolic disease, and fibrinolytic conditions with consumptive coagulopathy ( ). Dose recommendations are found in Table 22.1 . A retrospective review from a craniofacial database did not demonstrate an increase in complications (seizures or thromboembolic events) when exposed to either TA or EACA ( ). However, in two studies of pediatric trauma patients, the rates of thromboembolism were similar to controls, but there was an increased association with seizures in those exposed to TA ( ; ).
TABLE 22.1
Dosing Recommendations for Antifibrinolytic Agents
| Drug | Dose |
|---|---|
| TXA * | Load 10–30 mg/kg Continuous infusion 5–10 mg/kg/hr |
| EA † | Load 100 mg/kg Continuous infusion 40 mg/kg/hr |
* Goobie, S. M., & Faraoni, D. (2019). Tranexamic acid and perioperative bleeding in children: What do we still need to know? Current Opinion in Anaesthesiology, 32 (3), 343–352.
† Stricker, P. A., Zuppa, A. F., Fiadjoe, J. E., et al. (2013). Population pharmacokinetics of epsilon-aminocaproic acid in infants undergoing craniofacial reconstruction surgery. Br J Anaesth, 110 , 788–99.
Aprotinin is a nonspecific serine protease inhibitor derived from bovine lung that inhibits proteases with active serine residues, especially plasmin. The resulting effects are an attenuation of inflammatory responses and antifibrinolysis. Aprotinin and the lysine analogs have very different modes and scopes of action, but ultimately both function by inhibiting fibrinolysis through the inhibition of plasmin. Additionally, aprotinin is thought to restore the adhesive properties of platelets, independently of its effect on the inhibition of fibrinolysis ( ). The efficacy of aprotinin is somewhat less clear than that of either EACA or TA.
The use of aprotinin has raised concerns about the potential for complications, including thrombosis, anaphylaxis, and, most importantly, renal failure. In 2006 the Multicenter Study of Perioperative Ischemia Research Group reported on the largest observational prospective study of antifibrinolytic therapy ( ). The study tracked 4374 patients undergoing coronary artery bypass grafting and compared the use of aprotinin (1295 patients), EACA (883), and TA (822) with placebo (1374 patients). Aprotinin was associated with higher risk of death, cardiovascular event, cerebrovascular event, and renal failure. EACA and TA were not associated with increases in renal, cardiac, or neurologic complications. All three agents decreased blood loss to essentially the same degree.
In 1993, the Food and Drug Administration (FDA) approved aprotinin for patients at high risk of bleeding who were undergoing coronary artery bypass grafting with cardiopulmonary bypass ( ). After the publication of the Blood Conservation Using Antifibrinolytics in a Randomized Trial (BART) study ( ) in May 2008, Bayer Pharmaceuticals notified the FDA of its intent to withdraw aprotinin from the market. In that study of 2331 high-risk adult cardiac surgery patients, the investigators sought to determine whether aprotinin was superior to either TA or EACA in decreasing significant postoperative bleeding. The trial was terminated early because of an excess of deaths in the aprotinin group (6%) compared with the TA group (3.9%) and the EACA group (4.0%). A Belgium-Netherland retrospective study of aprotinin use during 2002 to 2007 was compared with tranexamic acid in 2008 to 2015 in a tertiary children’s hospital. They found that the aprotinin group had higher blood exposure rate (78% vs 60%) and higher mortality and/or severe morbidity (33% vs 28%) than TA ( ). It is unclear whether aprotinin will be remarketed in the future.
Preoperative autologous blood donation
Preoperative autologous donation (PAD) of blood 2 to 3 weeks before the operation has been used since the 1980s for adult surgical procedures in which blood loss and the need for blood transfusion are expected. The primary goal is to decrease the amount of allogeneic blood transfused ( ; ; ).
Numerous studies have documented the safety and benefit of this practice for adults in various settings. The main benefit is that it decreases the exposure to allogeneic blood. A concern, though, is the amount of blood transfused (both allogeneic and autologous) in patients who undergo PAD ( ). The increased rate of transfusion is thought to lead to an increased risk of administrative errors, with the increased number of units transfused ( ). reported statistically higher complication rates among patients who had PAD compared with controls who did not preoperatively donate their own blood.
Published studies of children and PAD are limited mostly to patients undergoing orthopedic or cardiac surgery; furthermore, although reports of PAD exist in infants as young as 6 months of age, most studies enroll children with a minimum weight of 20 kg ( ; ). No large pediatric randomized controlled trials of this technique have been performed. Many of the case series involved a combination of PAD and other techniques, such as acute normovolemic hemodilution, erythropoietin, and controlled hypotension, making the evaluation of PAD alone somewhat difficult.
studied children weighing less than 20 kg. The children were not given erythropoietin, and each child predonated a mean (SD) of 48 (17) mL/kg over a mean (SD) period of 50 (16) days. No child in the study group received allogeneic blood transfusion, but 80% in the control group did. pretreated children in a PAD group with subcutaneous EPO three times a week for 3 weeks preceding cardiac surgery and once intravenously on the day of the operation. The controls were 39 consecutive age-matched patients from the previous year. Children predonated 9 mL/kg on two separate occasions if the hematocrit was greater than 33%. Three of the 39 children in the study group required transfusion with allogeneic blood compared with 24 of the 39 in the control group.
Most orthopedic studies of PAD involve scoliosis surgery. studied 243 consecutive pediatric patients undergoing spinal fusion and found that 90% of the children who predonated did not require allogeneic blood during surgery. reported similar results in their study of children undergoing spinal fusion. In that study, the proportion of patients who needed allogeneic blood (11%) was nearly identical to that found by Murray and colleagues. In both studies, at least 70% of the children were able to complete the donation process. Concern about the ability of children, especially young children, to complete the donation program is often cited as an obstacle to PAD. However, in both of these studies, children younger than 10 years successfully completed the donation process. Clearly the ability of infants, toddlers, and young school-aged children to tolerate the donation process is uncertain at best. The use of sedation to facilitate this process would seem to be questionable, albeit reported ( ).
Compared with acute normovolemic hemodilution (ANH), PAD has important disadvantages. The risk of transfusion errors (e.g., wrong unit or wrong patient) is not less with PAD than with the use of allogeneic blood; the cost of obtaining, storing, and processing the predonated blood is not less with PAD; and the likelihood of contamination of the unit is not less with PAD. Each of the problems is eliminated or nearly eliminated with ANH. ANH also has the advantage of returning fresh whole blood to the patient in contrast to PAD, which provides only the RBC component. Furthermore, potassium levels rise in donated blood with increased storage time and have been reported to be over 70 mM ( ; ). Therefore, PAD should be reserved for older children, and the indications for the use of the predonated blood should be identical to those for allogeneic units.
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