Red Blood Cell Transfusions and Erythropoietin Therapy

Chapter 464 Red Blood Cell Transfusions and Erythropoietin Therapy

Red blood cells (RBCs) are transfused to increase the oxygen-carrying capacity of the blood and, in turn, to maintain satisfactory tissue oxygenation. Guidelines for RBC transfusions in children and adolescents are similar to those for adults (see Table 464-1 on the Nelson Textbook of Pediatrics website at www.expertconsult.com). However, transfusions may be given more stringently to children, because normal hemoglobin levels are lower in healthy children than in adults and, often, children do not have the underlying multiorgan, cardiorespiratory, and vascular diseases that develop with aging in adults. Thus, children often compensate better for RBC loss and, as is true for patients of all ages, there is increasing enthusiasm for conservative practices (i.e., low pre-transfusion hematocrit values).

In the perioperative period, it is unnecessary for most children to maintain hemoglobin levels of 8 g/dL or greater, a level frequently desired for adults. There should be a compelling reason to prescribe any postoperative RBC transfusion, such as continued bleeding with hemodynamic instability, because most children (without continued bleeding) can, over time, restore their RBC mass with iron therapy. The most important measures in the treatments of acute hemorrhage are to control the hemorrhage and to restore the circulating blood volume and tissue perfusion with crystalloid and/or colloid solutions. If the estimated blood loss is > 25% of the circulating blood volume (>17 mL/kg) and the patient’s condition remains unstable, RBC transfusions may be indicated along with plasma transfusions at a 1 : 1 ratio of RBC : plasma volumes. In acutely ill children with severe pulmonary disease requiring assisted ventilation, it is common practice to maintain the hemoglobin level close to the normal range, although the efficacy of this practice has not been documented by controlled scientific studies.

The pre-transfusion blood hemoglobin level or hematocrit that should prompt a RBC transfusion is controversial (i.e., restricted or a low pre-transfusion level vs liberal or a high pre-transfusion level) despite a substantial amount of published information, including randomized clinical trials. Some physicians in critical care settings prefer to transfuse RBCs quite conservatively (i.e., restricted guidelines) and to permit modest anemia, because patients with levels close to the normal range (i.e., liberal guidelines) have poorer outcomes. Studies in critically ill adults demonstrated better outcomes when the hemoglobin level was maintained at 7-9 g/dL than at 10-12 g/dL. However, anemic adults with significant cardiac disease did better with hemoglobin levels maintained at 13 g/dL than at 10 g/dL. Similar studies in children admitted to intensive care units found no inferiority when RBC transfusions were given by restricted guidelines (transfusion threshold of 7 g/dL), although the patients were in stable clinical status and needed few transfusions. In contrast, unstable critically ill children may need more liberal RBC transfusions.

With chronic anemia, the decision to transfuse RBCs should not be based solely on blood hemoglobin levels, because children compensate well and may be asymptomatic despite low hemoglobin levels. Patients with iron deficiency anemia are often treated successfully with oral iron alone, even at hemoglobin levels < 5 g/dL. Factors other than hemoglobin concentration to be considered in the decision to transfuse RBCs include: (1) the patient’s symptoms, signs, and compensatory capacities; (2) the presence of cardiorespiratory, vascular, and central nervous system disease; (3) the cause and anticipated course of the anemia; and (4) alternative therapies, such as recombinant human erythropoietin (EPO) therapy, which is known to reduce the need for RBC transfusions and to improve the overall condition of children with chronic renal insufficiency (Chapter 529.2). In anemias that are likely to be permanent, it is also important to balance the detrimental effects of anemia on growth and development against the potential toxicity associated with repeated transfusions. RBC transfusions for disorders such as sickle cell anemia and thalassemia are discussed in Chapters 456.1 and 456.9.

For neonates, nearly all aspects of RBC transfusions remain controversial (i.e., the accepted indications for RBC transfusions, restricted vs liberal pre-transfusion hemoglobin/hematocrit levels, optimal RBC product to be transfused) despite data from several controlled scientific studies. Generally, RBCs are given to maintain a hemoglobin value believed to be the most desirable for each neonate’s clinical status (see Table 464-1). More restricted guidelines (i.e., lower pre-transfusion hemoglobin/hematocrit levels) have been studied, but results are controversial, and conventional guidelines are recommended until more definitive data are published (see Table 464-1). This clinical approach is imprecise, but more physiologic indications, such as measurement of RBC mass, available calculations of oxygen delivery and tissue extraction, and imaging of tissue perfusion, are too cumbersome for clinical practice. Because definitive data are limited, it is important for pediatricians to critically evaluate the need for neonatal RBC transfusions in light of the pathophysiologic need, as discussed later.

During the first few weeks of life, all neonates experience a decline in circulating RBC mass caused both by physiologic factors and, in sick premature infants, by phlebotomy blood losses. In healthy term infants, the nadir hemoglobin value rarely falls to < 11 g/dL at an age of 10-12 wk. This “physiologic” drop in RBCs does not require transfusions. In contrast, the decline occurs earlier and is more pronounced in premature infants, even in those without complicating illnesses, in whom the mean hemoglobin concentration falls to approximately 8 g/dL in infants of 1.0-1.5 kg birthweight and to 7 g/dL in infants weighing < 1.0 kg at birth. Most infants with birthweight <1.0 kg experience significant “anemia of prematurity” and need RBC transfusions. A key reason that the nadir hemoglobin values of premature infants are lower than those of term infants is the former group’s relatively diminished plasma EPO level in response to anemia (Chapters 97.1 and 440). The mechanisms responsible for low plasma EPO levels are only partially defined. One factor is the reliance of preterm infants on the liver as the primary site of EPO production during the first few weeks of life. The liver is less responsive than the kidneys to anemia and tissue hypoxia. Thus, preterm infants exhibit a sluggish EPO response to falling hematocrit values. The second factor is that EPO disappears more rapidly from the plasma in infants than in adults (i.e., rapid clearance or metabolism).

Low plasma EPO levels provide a rationale for the use of recombinant EPO in the treatment of anemia of prematurity. Proper doses of EPO and iron effectively stimulate neonatal erythropoiesis. However, the efficacy of EPO therapy to substantially diminish the need for RBC transfusions has not been convincingly demonstrated, particularly for sick, extremely premature neonates, and recombinant EPO has not been widely accepted as a treatment for anemia of prematurity (Chapter 97.1). In rare cases, some preparations of EPO have been associated with the development of anti-EPO antibodies in adults that have produced severe anemia.

Because of the controversies over recombinant EPO therapy, many low birthweight preterm infants need RBC transfusions (see Table 464-1). In neonatal patients with severe respiratory disease, defined as requiring relatively large quantities of oxygen and ventilator support, it has been customary to maintain blood hemoglobin at > 13 g/dL (hematocrit > 40%). Proponents believe that transfused RBCs containing adult hemoglobin, with their superior interaction with 2,3-diphosphoglycerate and leading to better oxygen offloading than that of fetal hemoglobin, are likely to provide optimal oxygen delivery throughout the period of diminished pulmonary function. Although this practice is widely recommended, little evidence is available to firmly establish its efficacy or to define its optimal use (the best hemoglobin level for each degree of pulmonary dysfunction), and as mentioned earlier, more restricted guidelines have been suggested. Infants with less severe cardiopulmonary disease may require less vigorous support; hence, a lower hemoglobin level is suggested for those with only moderate disease. Consistent with the rationale for oxygen delivery in neonates with severe respiratory disease, it seems appropriate to keep the hemoglobin value > 13 g/dL (hematocrit > 40%) in neonates with severe cardiac disease leading to either cyanosis or congestive heart failure.

The optimal hemoglobin level for neonates facing major surgery has not been established by definitive studies. However, it seems reasonable to maintain the hemoglobin level at > 10 g/dL (hematocrit > 30%) because of the limited ability of a neonate’s heart, lungs, and vasculature to compensate for anemia; the inferior off-loading of oxygen because of the diminished interaction between fetal hemoglobin and 2,3-diphosphoglycerate; and the developmental impairment of neonatal renal, hepatic, and neurologic function. This transfusion guideline must be applied with flexibility to individual infants facing different kinds of surgery.

Stable neonates do not require RBC transfusion, regardless of their blood hemoglobin levels, unless they exhibit clinical problems attributable to anemia. Proponents of RBC transfusions for symptomatic anemia believe that the low RBC mass contributes to tachypnea, dyspnea, tachycardia, apnea and bradycardia, feeding difficulties, and lethargy, which can be alleviated by transfusion of RBCs. However, anemia is only one of several possible causes of these problems, and RBC transfusions should only be given when clinical problems are attributable to the anemia.

The RBC product of choice for children and adolescents is the standard suspension of RBCs separated from whole blood by centrifugation and resuspended in an anticoagulant/preservative storage solution at a hematocrit value of approximately 60% for storage up to 42 days, per U.S. Food and Drug Administration (FDA) approval. The usual dose is 10-15 mL/kg, but transfusion volumes vary greatly, depending on clinical circumstances (continued vs arrested bleeding, hemolysis). For neonates, many centers transfuse the same RBC product as selected for older children, whereas others prefer a packed RBC concentrate (hematocrit 70-90%). Either is infused slowly (over 2-4 hr) at a dose of approximately 15 mL/kg. Because of the small quantity of extracellular fluid given at these relatively high hematocrit values and the slow rate of transfusion, the type of RBC anticoagulant/preservative solution used does not pose risks for premature infants. Packing RBCs by centrifugation at the time the aliquot is issued for transfusion ensures that a consistent RBC dose is infused with each transfusion but is not mandatory and is impractical for some blood banks.

The traditional use of relatively fresh RBCs (<7 days of storage) has been halted in many centers in favor of diminishing donor exposure by using a single unit of RBCs to obtain aliquots for transfusing each infant throughout its permitted duration of storage (currently 42 days). Neonatologists who insist on transfusing only fresh RBCs generally are fearful of the rise in the plasma potassium (K⁺) level that occurs in RBC units during extended storage. After 42 days of storage, plasma K⁺ levels are approximately 50 mEq/L (0.05 mEq/mL), a value that, at 1st glance, seems alarmingly high. However, the actual dose of K⁺ transfused in the extracellular fluid is tiny. An infant weighing 1.0 kg, given a 15 mL/kg transfusion of packed RBCs (hematocrit 80%), receives 3 mL of extracellular fluid that contains only 0.15 mEq of K⁺, and it will be transfused slowly. However, the safety of stored RBCs may not apply to large-volume (>25 mL/kg) transfusions infused rapidly, in which greater doses of K⁺ may be harmful.

For children weighing >30-40 kg who are to undergo surgery, autologous RBC transfusions may be another alternative to donor allogeneic RBCs. Preoperative autologous blood collections from the patient occur up to 6 wk before the surgery and require careful considerations for the volume to be drawn, vascular access, use of EPO and iron to help restore the donated RBCs, and so on. Acute normovolemic hemodilution occurs in the preoperative period, in which blood is withdrawn from the patient and replaced with saline, a task often difficult in centers without experience in the process. Salvaged autologous blood is collected from blood loss during the operation but is impractical unless the volume of blood salvaged is fairly large to permit washing and transfusion of a significant number of RBCs.

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