Blood Component Therapy for the Neonate

Special Considerations for Transfusion Therapy in the Neonate

Neonates constitute one of the most heavily transfused patient groups in the hospital. In a Canadian study, over 50% of infants at less than 30 weeks’ gestation and more than 80% of infants with a birth weight of less than 1000 grams received at least one red blood cell (RBC) transfusion during their initial hospitalization. Neonatal transfusion practices differ substantially from adult and pediatric transfusion practices because of unique differences in neonatal physiology. Neonates have small blood volumes when compared with older children and adults but high blood volume per body weight. Their immature organ system function predisposes them to metabolic derangements from blood products and additive solutions and to the infectious and immunomodulatory hazards of transfusion such as transfusion-transmitted cytomegalovirus (TT-CMV) infection and transfusion-associated graft-versus-host disease (TA-GVHD). Neonates undergo rapid growth but have a limited capacity to expand their blood volume. In addition, passive transfer of maternal antibodies to the immunologically naïve newborn creates unique compatibility scenarios not commonly seen in children or adults. Their responses to stresses, including hypothermia, hypovolemia, hypoxia, and acidosis are dependent on gestational age, birth weight, and co-morbidities. These considerations necessitate special approaches to transfusion therapy in the neonate.

Risks of Transfusion Therapy

Advances in donor recruitment, blood screening, and processing have decreased the risks associated with blood transfusion. As part of patient blood management, current transfusion considerations and guidelines focus on reducing both transfusion number and donor exposures. Nevertheless, hematologic, immunologic, infectious, cardiovascular, and metabolic complications can occur. Many of these risks exist for transfusion recipients of any age, whereas others pose a greater threat to the neonatal recipient. These potential risks affect the choice and processing of blood products. Parents must be advised of the risks, benefits, and alternatives to transfusion, and informed consent should be documented in the medical record along with the indications for, and results of, the prescribed transfusion.

Metabolic Complications

Neonates, especially extremely premature infants, are more susceptible to metabolic alterations caused by the immaturity of many of their organ systems. Glucose imbalances, hyperkalemia, and hypocalcemia are the most common metabolic derangements related to transfusion, owing to the inability of the infant to efficiently metabolize and/or excrete elements intrinsic to blood and blood components, including anticoagulants, preservative solutions, and other solutes that accumulate during refrigerated storage.

Hypoglycemia

Hypoglycemia (see Chapter 86 ) can result from the combination of decreased glucose infusion rates during transfusion and impaired glycogenolysis and gluconeogenesis within the liver of the preterm neonate. Continuous glucose infusion rates of greater than 3-4 mg/kg per minute are often required in preterm infants; if maintenance fluids are suspended during transfusion, glucose infusion rates can decrease to approximately 0.2 mg/kg per minute for citrate-phosphate-dextrose-adenine (CPDA-1) preserved RBCs and 0.5 mg/kg per minute for the RBC additive Adsol® (AS-1) preserved RBCs. In neonatal intensive care units, holding feeds during blood transfusions, particularly for premature infants, has become a common practice to decrease the risk of neonatal enterocolitis (NEC). In a previous report of 31 fresh (<5 days old) small-volume RBC transfusions in 16 preterm infants (mean birth weight and gestational age: 863 grams and 26 weeks, respectively), 15% of infants receiving AS-1-preserved RBCs and 64% of infants receiving CPDA-1-preserved RBCs required supplemental dextrose infusions during the transfusion owing to hypoglycemia (blood glucose <40 mg/dL or symptoms of hypoglycemia). Subsequent analysis has shown similar frequency of transfusion-associated hypoglycemia when older (5-21 days old) AS-1-preserved units were used. Furthermore, reported incidences of hypoglycemia in neonates either during or after exchange transfusions range from 1.4%-3.6% with no difference in incidence when group O whole blood or reconstituted whole blood was used. Hypoglycemia occurring after exchange transfusion is believed to be caused by intraprocedural hyperglycemia, which causes rebound hypoglycemia from insulin secretion. Preventive measures for transfusion-associated hypoglycemia include recognizing those infants at risk for developing glucose homeostatic imbalances, continuing the infusion of maintenance fluids rich in dextrose (albeit at a slower rate) to maintain an adequate glucose infusion rate during simple transfusions and close monitoring of blood glucose during both small and large volume transfusions. To minimize the risk of RBC hemolysis and/or agglutination, dextrose-rich fluids should be infused in a separate intravenous line from the blood transfusion.

Hyperkalemia

The risk of transfusion-induced hyperkalemia is directly related to the magnitude of the K ⁺ load delivered with RBC transfusion, which depends on the age, plasma volume, and plasma concentration of K ⁺ of the unit, and the rate at which K ⁺ is delivered (potassium infusion rate). Potassium infusion rates greater than 0.01 mEq/kg per minute may pose a potential risk of transfusion-associated hyperkalemia and have been shown to result in cardiac arrhythmia/arrest in neonates. As stored red blood cells age, potassium leaks out into the plasma and raises the extracellular potassium level within the component. Units of RBCs in extended-storage media (AS-1, AS-3, AS-5) have a hematocrit (Hct) of approximately 60%, and RBCs stored in CPDA-1 have an Hct of approximately 70%. Furthermore, some pediatric transfusion centers centrifuge RBC aliquots before transfusions for neonates to further reduce the plasma component to 20% (e.g., RBC unit: Hct >80%). Such an approach helps reduce the content of potassium, mannitol, and RBC microvesicles in irradiated RBC aliquots stored up to 21 days. After 42 days of storage, K ⁺ levels in the plasma of an AS-1-preserved RBC unit approximate to 0.05 mEq/mL. Therefore, infusing 15 mL/kg over 3 hours would yield a potassium dose of 0.33 mEq/kg and a potassium infusion rate of 0.002 mEq/kg per minute (e.g., 1-kg infant receiving 15 mL RBC and 6 mL plasma). Conversely, after 35 days of storage of CPDA-1-preserved RBCs, potassium levels in the plasma approximate to 0.08 mEq/mL. Transfusing 15 mL/kg of the CPDA-1-stored product over 3 hours would yield a potassium dose of 0.36 mEq/kg (e.g., 1-kg infant receiving 15 mL RBC and 4.5 mL plasma) at a potassium infusion rate of 0.002 mEq/kg per minute. Given that daily potassium requirement is approximately 2-3 mEq/kg, simple RBC transfusions infused slowly over 2-4 hours (2-5 mL/kg per hour) do not pose a threat for hyperkalemia ( Table 80.1 ).

TABLE 80.1

Dose and Infusion Rate for Potassium in Small-Volume and Large-Volume Transfusion

Data from Fasano RM, Paul WM, Pisciotto P. Complications of neonatal transfusion. In: Popovsky MA, ed. Transfusion reactions . 4th ed. Bethesda, MD: AABB Press; 2012:471-518.

	CPDA-1 (35-Day)	Additive Solution * (42-Day)	Additive Solution * (20-Day)
Unit hematocrit	70%-75%	57%-60%	57%-60%
Plasma (K+)	0.080 mEq/mL	0.050 mEq/mL	0.030 mEq/mL
*15 mL/kg over 3 hours (0.08 mL/kg/min)*
K ⁺ dose K ⁺ infusion rate	0.36 mEq/kg 0.002 mEq/kg/min	0.33 mEq/kg 0.002 mEq/kg/min	0.20 mEq/kg 0.001 mEq/kg/min
*25 mL/kg over 3 hours (0.14 mL/kg/min)*
K ⁺ dose K ⁺ infusion rate	0.60 mEq/kg 0.003 mEq/kg/min	0.54 mEq/kg 0.003 mEq/kg/min	0.32 mEq/kg 0.002 mEq/kg/min
*25 mL/kg over 1 hour (0.42 mL/kg/min)*
K ⁺ dose K ⁺ infusion rate	0.60 mEq/kg 0.01 mEq/kg/min ^†	0.54 mEq/kg 0.009 mEq/kg/min	0.32 mEq/kg 0.005 mEq/kg/min
*25 mL/kg over 30 min (0.84 mL/kg/min)*
K ⁺ dose K ⁺ infusion rate ^†	0.60 mEq/kg 0.02 mEq/kg/min ^†	0.54 mEq/kg 0.018 mEq/kg/min ^†	0.32 mEq/kg 0.011 mEq/kg/min ^†

* AS-1, AS-3, or AS-5 RBC units.

† Potassium infusion rate may pose a potential risk of transfusion-associated hyperkalemia, which may result in cardiac arrhythmia/arrest, especially if given through a central line.

It has been shown in multiple studies that transfusing dedicated RBC units to their expiration dates does not cause hyperkalemia even in extremely preterm infants. Therefore, the routine practice of washing older RBCs is unnecessary for most small-volume RBC transfusions (10-20 mL/kg) in infants, including those with birth weights less than 1.5 kg. Irradiation of RBC components damages the erythrocyte membranes, causing K ⁺ leakage and a linear increase in plasma potassium concentration over time. Irradiation substantially increases plasma K ⁺ compared with nonirradiated RBC components, both within the first 24 hours after irradiation (twofold increase) and for the life of the RBC component. The difference was detectable as early as 2 hours after irradiation.

Large-volume RBC transfusions (>25 mL/kg), particularly if infused rapidly, may pose a significant risk to the neonate. There have been reports of hyperkalemia-induced electrocardiac abnormalities and cardiac arrest when RBC transfusions (fresh and old) have been administered via rapid infusion (10-20 mL/kg over 10-15 minutes) to neonates with concurrent low cardiac output states when the RBCs were irradiated more than 24 hours prior to infusion and/or when they were given via central line directly into the inferior vena cava. Whenever possible, fresh RBC units (<7-10 days) should be issued for large-volume RBC transfusions. When fresh RBC units are unavailable, they should be volume reduced or washed and transfused as soon as possible after washing to minimize K ⁺ re-accumulation. Previously irradiated and stored (≥24 hours) units may have plasma K ⁺ levels unsafe for large-volume transfusion to neonates, especially if administered rapidly. Therefore, they should be issued immediately postirradiation or volume-reduced or washed to remove extracellular K ⁺ that accumulates after processing. In emergent circumstances of unexpected massive bleeding, when neither fresh nor washed nor volume-reduced RBC units are available, infusion rate should not exceed 0.5 mL/kg per minute.

Special considerations should be taken when RBCs need to be transfused rapidly and should be coordinated with the transfusion center so that proper preparation can be performed to avoid hyperkalemia. Measures to reduce the risk of transfusion-associated hyperkalemia leading to cardiac arrest include anticipating and replacing blood loss before significant hemodynamic compromise occurs, using larger-bore (>23-gauge) peripheral intravenous catheters rather than central venous access, checking and correcting electrolyte abnormalities frequently, and using fresher RBCs for massive transfusion. For patients on extracorporeal membrane oxygenation, prebypass ultrafiltration helps normalize the electrolyte balance of the circuit prime and may reduce the risk of hyperkalemia-related cardiac arrest. In-line potassium adsorption filters have been shown to remove extracellular K ⁺ in stored AS-3 RBC units to minimal levels in vitro . A small randomized clinical trial in adults (>18 years of age) showed that the transfusion of one irradiated RBC unit with a potassium filter was as safe and efficacious as transfusion of one irradiated RBC unit with a standard blood infusion set. However, the use of potassium filters in neonatal RBC transfusions requires more extensive study.

Hypocalcemia

Infants, especially premature infants, are particularly susceptible to hypocalcemia (see Chapter 87 ) within the first week of life, owing to multiple factors. Because of the immaturity in neonatal liver and kidney function, and small skeletal muscle mass, transfusion of citrate-enriched blood can result in hypocalcemia from citrate toxicity. The amount of citrate infused into a neonate during a small-volume transfusion (10-15 mL/kg) is very unlikely to cause hypocalcemia; however, the citrate load during an exchange transfusion can reach very high levels and lead to symptomatic hypocalcemia. In a retrospective review of neonatal exchange transfusions, symptomatic hypocalcemia was one of the most common side effects along with bleeding associated with thrombocytopenia, catheter-related complications, apnea, bradycardia, and other metabolic disturbances. Adverse events were generally higher among ill neonates (i.e., presence of co-morbidities besides indication for exchange) when compared to healthy ones and complication frequency increased with decreasing birth weights. Because clinical manifestations of hypocalcemia are often subtle and/or variable in premature infants, many recommend monitoring ionized calcium levels and/or QT intervals throughout exchange transfusion procedures, in addition to minimizing potentiating factors such as hypomagnesemia, hyperkalemia, alkalosis, and hypothermia in high-risk (ill) patients. Insufficient evidence is currently available in the literature to support or reject the continual use of prophylactic intravenous calcium infusions in neonates receiving exchange transfusions.

Effect of Plasticizers (See Also Chapter 14 )

The toxicity associated with the use of the plasticizer di-(2-diethylhexyl) phthalate (DEHP) in blood storage bags has been debated in the transfusion medicine community for over 50 years. DEHP is added to polyvinylchloride plastic storage blood bags to increase bag flexibility, RBC survival, and oxygen permeability for platelet storage. DEHP also stabilizes RBC membranes, which prevents hemolysis and alteration during refrigerated storage. Because of its desirable structural properties, it is also widely used in medical plastics as well as in food storage and household products. Critically ill neonates exposed to endotracheal tubes, orogastric tubes, intravenous tubing, and blood products can have DEHP exposures that exceed safe levels by 3-5 orders of magnitude.

However, there is evidence that DEHP exerts detrimental effects on the endocrine system by acting as an androgen antagonist and an estrogen agonist. While DEHP is broken down in the gastrointestinal tract to some extent, transfusions bypass this protection. At particular risk for toxicity are neonates receiving high-volume transfusions, such as neonatal RBC exchange, during extracorporeal membrane oxygenation (ECMO), and during massive transfusion.

Manufacturers have attempted to find suitable alternatives to DEHP. For example, butyrul-n-trihexyl-citrate leaches from the plastic at a slower rate, exhibits lower toxicity, and provides similar antihemolytic effects. Other DEHP-free storage containers are at various stages of development throughout the world. However, a recent survey identified barriers to widespread implementation, including decreased quality of blood products stored in non-DEHP plastics, higher price, shorter shelf-life, and ongoing debate about the evidence of DEHP toxicity.

Immunologic Complications

Transfusion Reactions

Transfusion reactions are less common in neonates than in older children or adults. Nevertheless, whenever a patient is transfused, he/she should be closely monitored for symptoms and signs of a reaction. Often, potential reactions are noted by a change in vital signs or a rash early in the transfusion, but they may occur at any point. The Joint Commission recommends that vital signs be measured pretransfusion, within 15 minutes of initiation and within 1 hour of transfusion end. Hospital policies are based on these guidelines but may differ with respect to each other. In addition to vital signs, it is important to also assess the patient for cutaneous changes (e.g., rash, hives), respiratory distress, discomfort, or pain.

When an acute transfusion reaction occurs, it is crucial to discontinue the transfusion immediately, maintain intravenous access, and verify that the correct unit was transfused while treating the patient's symptoms. Notifying the transfusion service for further laboratory evaluation of the reaction is essential to properly classify the reaction so that the patient can be managed appropriately. Since a single blood donation often results in several different blood products, there may be untransfused co-components that must be quarantined until the investigation is complete.

Hemolytic Transfusion Reactions

Acute hemolytic transfusion reactions occur when RBCs are transfused to a recipient with preformed antibodies to antigens on the transfused RBCs. Almost all acute hemolytic transfusion reaction fatalities are the result of transfusion of ABO-incompatible blood because of clerical errors and misidentification; however, nonimmune causes of acute hemolysis may also occur. These include hemolysis from shear and/or heat stress imposed on erythrocytes by extracorporeal circuits, infusion devices, filters, blood warmers, or phototherapy light exposure. These reactions are characterized by fever, chills, diaphoresis, abdominal pain, hypotension, and hemoglobinuria with potential progression to disseminated intravascular coagulation (DIC) and acute renal failure. When a hemolytic transfusion reaction is suspected, the transfusion should be immediately stopped, blood cultures (from patient and blood component[s]) should be obtained, and the transfusion service should be notified. A clerical check of all labels, blood component inspection, post-transfusion hemolysis check, and direct antiglobulin test (DAT) should be completed by the transfusion service. The patient's hemoglobin/hematocrit, serum bilirubin, lactate dehydrogenase (LDH), and urobilinogen should be monitored, and intravenous fluids should be administered to offset hypotension and ensure adequate urine output. Mannitol may be administered to force diuresis, but osmotic diuresis in neonates is controversial because of concerns about alterations in cerebral microcirculation and risk of intraventricular hemorrhage. Although infants less than 4 months old have an absence of A and B hemagglutinins and other RBC alloantibodies, maternal IgG antibodies can cross the placenta, causing hemolysis of transfused RBCs and, therefore, should be considered when transfusing infants.

Delayed hemolytic transfusion reactions (DHTRs) occur 3-10 days following RBC transfusion and manifest as unexplained anemia, hyperbilirubinemia, and abdominal pain. As with acute hemolytic reactions, the diagnosis is confirmed by a positive DAT, identification of a new RBC antibody, hyperbilirubinemia, and a reduction in hemoglobin. DHTRs are extremely rare in neonates because of the immaturity of the immune system. Even though there have been case reports of anti-E and anti-Kell formation in infants as young as 18 days of life, the majority of reports have supported the infrequency of RBC alloimmunization and DHTRs in infants less than 4 months of age. A cohort study of 1641 neonates and children up to the age of 3 years found no alloimmunization cases within the first 6 months of life. The authors conclude that after initial testing, repeat antibody screening and cross-matching during the first 4 months of life can be safely omitted.

Febrile Nonhemolytic Transfusion Reactions

Febrile nonhemolytic transfusion reactions (FNHTRs) are characterized by fever, chills, and diaphoresis. These reactions are believed to result from the release of pyrogenic cytokines by leukocytes within the plasma during storage. The incidence of FNHTRs has decreased dramatically since the implementation of prestorage leukoreduction of RBCs and platelet products in 1999. Whereas FNHTRs occurred in approximately 10% of transfusions in the past, the incidence for all products since the introduction of leukoreduction is now 0.1% to 3% (approximately 0.2% for prestorage leukoreduction). When FNHTR is suspected, the transfusion should be stopped and more serious reactions ruled out. A sample of blood from the patient may be sent for DAT, plasma hemoglobin quantification, serum lactate dehydrogenase, and bilirubin level to ensure that the patient is not experiencing a hemolytic transfusion reaction. The transfusion service may repeat the crossmatch between the RBC unit and a post-transfusion patient sample to ensure there is no new unexpected incompatibility. Bacterial contamination should be assessed via cultures of the transfused product and the patient's blood; empiric antibiotic therapy may be warranted. Most FNHTRs respond to antipyretics, and meperidine may be used for rigors.

Allergic Transfusion Reactions

Allergic transfusion reactions (ATRs) are marked by urticaria and itching but can include flushing, bronchospasm, and anaphylaxis in severe cases. For mild or localized cases, transfusion can be continued once symptoms have subsided; however, severe allergic reactions (anaphylactoid or anaphylactic reactions) may require treatment with corticosteroids and/or epinephrine. The same blood unit should never be restarted in severe cases, even after symptoms have abated. Leukoreduction does not decrease the incidence of ATRs as it has for FNHTRs. Premedication with antihistamines with or without steroids is recommended for ATRs. Because these reactions are caused by an antibody response in a sensitized recipient to soluble plasma proteins within the blood product, washed RBCs and platelets may be used for severe or recurrent ATRs nonresponsive to medication. Severe ATRs leading to anaphylaxis can be caused by the development of anti-IgA antibodies in recipients who are IgA-deficient. In these instances, IgA-deficient plasma products may be obtained but require the use of rare donor registries. In patients of Asian descent, haptoglobin deficiency may also be associated with severe ATRs.

The use of platelets in additive solution (PAS) resulted in decreased incidence of ATRs and FNHTRs in one adult study, presumably because of decrease in donor plasma content in the blood products. Since neonates represented only 1.8% of the study population, the effect of PAS platelets in neonates requires further study.

Transfusion-Associated Graft-Versus-Host Disease

Transfusion-associated graft-versus-host disease (TA-GVHD) occurs when an immunosuppressed or immunodeficient patient receives cellular blood products, which contain immunologically competent lymphocytes. The transfused donor lymphocytes are able to proliferate and engraft within the immunologic incompetent recipient because the recipient is unable to detect and reject foreign cells. The degree of similarity between human leukocyte antigens (HLA) of donor and recipient also increases the likelihood of developing TA-GVHD. As an example, in the setting of directed donation from a first-degree relative, donor lymphocyte homozygosity for an HLA haplotype for which the recipient is haploidentical predisposes to recipient tolerance, donor lymphocyte engraftment, and alloreaction leading to TA-GVHD.

The clinical signs and symptoms of TA-GVHD include fever; generalized, erythematous rash that may progress to desquamation; watery diarrhea; mild hepatitis to fulminant liver failure; respiratory distress; and pancytopenia, which is unusually severe because hematopoietic progenitor cells are preferentially affected. Onset is from 3-30 days following transfusion of lymphocyte-replete cellular blood components in older children and adults; however, there may be a longer latency period before the onset of clinical manifestations of TA-GVHD and a longer course of disease before death in neonates. In a literature review of 27 cases of TA-GVHD in neonates in Japan, the median interval of clinical manifestations was 28 (fever), 30 (rash), and 43 (leukopenia) days, and death occurred in all affected patients at a median interval of 51 days. Prolonged latency of clinical manifestations and death is believed to result from thymic and/or extrathymic semi-tolerance for allogeneic cytotoxic T lymphocytes.

Neonates at “high risk” for TA-GVHD include those with impaired cellular immunity, such as severe combined immunodeficiency (SCID) or Wiskott-Aldrich syndrome, those receiving intrauterine transfusions and/or neonatal exchange transfusion, and those receiving cellular blood components from family members or those who are genetically similar to the recipient. Extremely premature neonates are also considered by many to be at significant risk for TA-GVHD.

No effective therapy is available to treat TA-GVHD except for hematopoietic stem cell transplantation, and owing to bone marrow hypoplasia, the mortality rate is 90% in the pediatric population. Fortunately, this complication can be prevented by pretransfusion gamma or X-ray irradiation of cellular blood components at a dose of 2.5 Gy, which effectively abolishes lymphocyte proliferation. The shelf life of irradiated red blood cells is 28 days; however, no data currently exist on the safety in the neonatal population of gamma-irradiated or X-ray-treated RBCs that are stored for this amount of time. Because potassium and free hemoglobin increase after irradiation and storage of RBCs, it is preferable to irradiate cellular blood products close to administration time for neonates, who may not be able to tolerate high potassium loads. Irradiation of RBCs also fosters the release of cell membrane microparticles, which may be associated with thrombotic risk. There exists no “standard of care” regarding irradiation of blood products for otherwise non-high-risk infants. Many transfusion services irradiate all cellular blood products given to preterm infants born weighing 1.0-1.2 kg or less, whereas some irradiate all cellular blood products for infants less than 4 months of age, citing the lack of clinical studies on the incidence of TA-GVHD in the neonatal population and the concern for failure to recognize an infant with an undiagnosed congenital immunodeficiency. When an infant requires irradiated blood components, all cellular blood components for that infant should be irradiated; however, it is not necessary to irradiate acellular blood components, such as fresh frozen plasma (FFP) and cryoprecipitate. The known and presumed indications for irradiation of blood components for neonates are listed in Box 80.1 .

Box 80.1

Modified from Wong ECC, Punzalan RC. Neonatal and pediatric transfusion practice. In: Fung, MK, ed. Technical manual of the American Association of Blood Banks . 19th ed. Bethesda, MD: American Association of Blood Banks; 2017;613-640; Savage WJ, Hod EA. Noninfectious complications of blood transfusion. In: Fung, MK, ed. Technical manual of the American Association of Blood Banks . 19th ed. Bethesda, MD: American Association of Blood Banks; 2017;569-597; and Roseff SD, Luban NL, Manno CS. Guidelines for assessing appropriateness of pediatric transfusion. Transfusion . 2002;42:1398-1413.

Indications for Administering Irradiated Blood Components to Neonates

Transfusion to a premature infant with birth weight <1200 g
Intrauterine transfusion
Known or suspected congenital cellular immunodeficiency
Hematologic malignancies or solid tumors
Significant immunosuppression related to chemotherapy, radiation, or immunosuppressive treatment
Transfusion of a cellular blood component obtained from a blood relative
Transfusion of an HLA-matched or platelet-cross-matched product
Granulocyte components

Transfusion-Related Acute Lung Injury

Transfusion-related acute lung injury (TRALI) is an uncommon, potentially fatal acute immune-related transfusion reaction, which typically occurs within 4-6 hours of transfusion and presents with respiratory distress caused by noncardiogenic pulmonary edema (normal central venous pressure and pulmonary capillary wedge pressure), hypotension, fever, and severe hypoxemia. Differentiation from transfusion-associated circulatory overload (TACO), an acute, nonimmune transfusion reaction that presents with respiratory distress, cardiogenic pulmonary edema, and hypertension caused by volume overload, is important because treatments differ. Furthermore, transient leukopenia, which is commonly seen with TRALI but is absent in TACO, can aid in differentiation of these reactions. Symptoms of TRALI usually improve within 48-96 hours; however, three-fourths of patients require aggressive respiratory support. Treatment is mainly supportive, including fluid and/or vasopressor support in the face of hypotension. Whereas aggressive diuresis is often required in TACO, this should be avoided in TRALI.

Although the exact mechanism of TRALI remains uncertain, it is generally believed to be caused by the passive transmission of HLA and/or neutrophil antibodies directed against recipient leukocyte antigens. These antibodies activate and sequester recipient neutrophils within the endothelium of the lungs, ultimately leading to the production of vasoactive mediators and capillary leak. Plasma products (such as FFP, plasma frozen within 24 hours of collection [FP24], and apheresis platelets) account for the majority of severe TRALI cases, and multiparous women are the most commonly implicated donors. Because of these findings, various preventative measures have been adopted in the United States and elsewhere. These include the use of male-only, high-volume plasma products (FFP, FP24, platelets), or the selection of donor products from donors who have a low likelihood of being alloimmunized via pregnancy or prior transfusions or who are negative on HLA antibody screen. Although there have been no definitive cases of TRALI documented in the neonatal population, TRALI has been well-documented in the pediatric population. A case has been reported of a 4-month-old girl who experienced respiratory distress, hypoxemia, hypotension, and fever within 2 hours of completion of an RBC transfusion from her mother. HLA antibodies were identified in the mother's serum, demonstrating the possible role of HLA antibodies in the pathogenesis of TRALI in the setting of a designated blood transfusion between mother and infant.

T-Antigen Activation

“T-activation” is a phenomenon that can cause immune-mediated hemolysis in neonates, ranging from minor to fulminant and fatal. Removal of N-acetyl neuraminic (sialic) acid residues from the O-linked oligosaccharides on glycophorins (A, B, and C) on RBC membranes by neuraminidase-producing bacteria, particularly Clostridium bacteroides and Streptococcus pneumoniae , results in exposure of the normally masked Thomsen-Friedenreich (T) cryptantigen on the RBC surface of the neonate. Transfusion of adult blood products containing plasma with naturally occurring anti-T antibodies into neonates with T-activation can produce intravascular hemolysis following transfusion or unexplained failure to achieve an expected post-transfusion hemoglobin increment. Alternatively, T-activation may be detected in the laboratory without any evidence of clinical hemolysis, making broad-based screening impractical. T-activation has been reported mainly in neonates with necrotizing enterocolitis, especially in those with severe disease requiring surgical intervention but also in septic infants with other surgical problems.

The incidence of T-activation has been reported in 5%-35% of infants with necrotizing enterocolitis (NEC). The rate of T-activation is higher in infants with more severe disease (e.g., multiple cultures positive for Clostridia , presence of intestinal perforation, need for surgical intervention). In a retrospective report, laboratory evidence of T-antigen activation was detected by lectin agglutination testing in 9% of 43 Taiwanese infants with stage II/III NEC but did not result in hemolysis regardless of whether washed or unwashed RBC units were administered or contribute to an increase in NEC-related mortality. A more recent publication reported that transfusion-associated hemolysis is often not seen in T-activated infants when transfused with donor anti-T-containing plasma. The authors concluded that the use of plasma-containing blood products is not contraindicated in NEC patients with coagulopathy or requiring hemostatic factors, even if T-activation is present. However, others have shown that infants with confirmed NEC and laboratory evidence of T-activation had more frequent and severe hemolysis, hyperkalemia, renal impairment, and hypotension than those without T-activation.

Routine cross-matching techniques may not detect the polyagglutination owing to T-activation when monoclonal ABO antiserum is used. Minor cross-matching of neonatal T-activated red blood cells with donor anti-T-containing serum may show agglutination, but this is not performed routinely. Infants with discrepancies in forward and reverse blood typing and those with evidence of hemolysis on smear should be suspected of T-activation. The diagnosis is confirmed by specific agglutination tests using peanut lectin Arachis hypogea and Glycine soja . Further hemolysis may be prevented by using washed RBCs and platelets and low-titer anti-T plasma if available. Exchange transfusion with plasma-reduced components may be necessary for infants with severe ongoing hemolysis. Alternatively, hemolysis associated with T-activation may occur independently of transfusion with anti-T-containing serum, and may be the result of sepsis or disseminated intravascular coagulation and cannot be prevented.

Transfusion-Associated Dyspnea (TAD)

TAD is defined as acute respiratory distress occurring within 24 hours of cessation of transfusion. Diagnosis requires ruling out other types of transfusion reactions associated with respiratory symptoms such as ATR, TACO, and TRALI. In some cases, TAD may represent allergic reactions without the full complement of cutaneous and hemodynamic manifestations.

Transfusion-Related Sepsis

Septic transfusion reactions generally present with fever, hypotension, shock, and acutely ill appearance. Platelets are most frequently implicated since their storage at room temperature can foster growth of bacterial contaminants. Based on the inoculum of the pathogen, the onset may be earlier or later in the transfusion. However, the diagnosis can be challenging since such symptoms may also present as part of other transfusion reactions or as a manifestation of the patient's underlying disease.

If a septic transfusion reaction is suspected, the transfusion should be stopped immediately. It is important to maintain venous access by running normal saline through the intravenous line. The remaining blood bag should be sent to the transfusion service for visual inspection, clerical check, possible culture, and placement of co-components into quarantine. If the clinical suspicion for sepsis is high, antibiotic therapy should be started immediately. Cultures of the patient and/or blood product may take some time to turn positive.

Transfusion-Related Necrotizing Enterocolitis (NEC)

NEC is a devastating gastrointestinal emergency that primarily afflicts premature infants but can occur in at-risk term gestation infants as well. Severity and treatment can range from full recovery with conservative medical management to intestinal perforation and bowel necrosis requiring surgical intervention. NEC-related morbidity and mortality remains quite high, with up to 30% of affected infants succumbing to the disease, many with an acute presentation followed by rapid deterioration and death. For full description of clinical presentations, pathophysiology, diagnosis, and treatment of NEC, refer to Chapter 85 .

Although the exact mechanism of NEC is not completely elucidated, ischemic insult to the gastrointestinal tract has been proposed as one major contributor to NEC. Some hypothesize that even subtle reductions in blood flow and subsequent reperfusion occurring in response to hypoxia may contribute to bowel injury. It has been demonstrated that high vascular resistance of the superior mesenteric artery determined by Doppler flow velocity on the first day of life in preterm infants is associated with an increased risk of NEC. Furthermore, the stressed newborn has been shown to exhibit abnormal regulation of intestinal vasomotor mediators (i.e., nitric oxide, endothelium, substance P, norepinephrine, and angiotensin), resulting in compromised intestinal flow. It has been proposed that anemia may impair blood flow to the intestine, with subsequent transfusion of RBCs leading to reperfusion injury. This phenomenon may be exacerbated by abnormalities associated with stored RBCs, including reduced erythrocyte deformability, increased erythrocyte adhesion/aggregation, and decreased nitric oxide stores. This last effect may predispose to vasoconstriction and further ischemic insult owing to transfused RBCs acting as a nitric oxide sink within the intestinal microvasculature. Similarly, stored platelets accumulate proinflammatory factors over time. One of these, neuropeptide Y, has splanchnic vasoconstrictor effects, enhances neutrophil adhesion to endothelial cells, induces histamine release, and stimulates macrophage phagocytosis. The use of near-infrared spectroscopy has gained popularity in recent years with its ability to measure regional tissue saturations. A prospective study to examine potential alterations in mesenteric tissue oxygenation demonstrated wide fluctuations and decreases in mesenteric oxygenation patterns in infants who developed transfusion-related NEC. Proposed, but unproven, pathologic mechanisms for transfusion-associated NEC include: a transfusion immunologic injury to the intestine similar to what is seen in transfusion-related acute lung injury (TRALI) and/or transfusion-related ischemia/reperfusion injury as described previously.

Several retrospective studies have demonstrated a temporal association between RBC transfusion and neonatal NEC. They report that 25%-38% of NEC cases occur within 48 hours of RBC transfusion and that the risk of transfusion-associated NEC increases with decreasing gestational age of the infant. Blau et al. found a convergence of transfusion-associated NEC at 31 weeks’ gestation, the age of presentation of O ₂ toxicity and other neovascularization syndromes. In another retrospective report, Singh et al. displayed a strong association of transfusion and NEC within 24 hours (OR = 7.60, p = .001), a significant albeit decreased association for transfusion within 48 hours (OR = 5.55, p = .001), and a statistically insignificant (absent) association for transfusion within 96 hours (OR = 2.13, p = .07) in their multivariate analysis. Although attempts were made to minimize the confounding effects of multiple variables, the effect of infants’ nadir hematocrit level on the risk of developing NEC remained statistically significant, making it impossible to separate the influence of hematocrit and RBC transfusion.

However, other studies suggest that RBC transfusions may be an epiphenomenon with respect to NEC rather than a contributor to the pathogenesis of disease. Bednarek et al. reported that there was no significant difference in the incidence of NEC between high versus low hematocrit threshold transfusion practices among six NICUs, and the Premature Infants in Need of Transfusion (PINT) (NCT00182390) trial did not show a difference in the incidence of NEC between the low versus high hematocrit transfusion threshold groups. In a meta-analysis of the published literature on transfusions and NEC, increased RBC transfusions were associated with lower rates of NEC; the direction of effect of RBC transfusions on NEC in randomized trials was opposite to that seen in observational studies. Keir and colleagues performed a separate systematic review and did not find an association between transfusions and NEC. One recent prospective study of 598 very low birth weight infants found that severe anemia (hemoglobin <8 g/dL), but not RBC transfusion, was associated with an increased risk of NEC. Thus, prevention of severe anemia may be more important than avoidance of RBC transfusion alone. The temporal relationship observed between RBC transfusion and neonatal NEC may represent reverse causation, whereby clinical instability from evolving NEC leads to RBC transfusion prior to the formal diagnosis of NEC.

A prospective, multicenter observational cohort study of infants with birth weight less than or equal to 1250 g is underway to investigate the associations between RBC transfusion, product irradiation, anemia, intestinal oxygenation, and injury that lead to NEC.

Transfusion-Related Intraventricular Hemorrhage (See Also Chapter 53 )

A newly postulated risk of transfusions among VLBW neonates has emerged based on an association between RBC transfusion and the development of, and progression to, severe intraventricular hemorrhage (IVH), which has been observed in retrospective case control reports. In a six-site prospective study, Bednarek et al. found a trend toward a higher incidence of severe IVH (adjusted for birth weight and illness severity) in NICUs administering RBC transfusions “liberally,” compared with other NICUs using transfusions in a more restricted fashion. Subsequently, a retrospective analysis of 155 VLBW neonates with normal head ultrasounds during the first week of life indicated an association between RBC transfusion and the risk of developing a severe IVH within the first month, independent of hemoglobin level, initial pH, sepsis, ventilation, coagulation studies, or severe thrombocytopenia. During the first 72 hours of life and when the head ultrasound was normal, 67% of those neonates who later developed severe IVH versus 31% who did not develop IVH received one or more RBC transfusions ( p < .001). Additionally, each subsequent RBC transfusion during the first week was determined to double the risk of a severe IVH (each transfusion increased relative risk 2.02; 95% CI 1.54-3.33). In another report by the same investigators, Baer et al. retrospectively compared 55 VLBW neonates in whom a grade I IVH evolved into a grade II or higher IVH to 362 VLBW neonates matched for demographic, level of illness, and coagulation parameters, who had a grade I IVH that resolved completely with no extension to a higher grade. On logistic (and Lasso-fit) regression analysis, an association was found between RBC transfusion up to and on the day of the grade I IVH and extension of the IVH (OR 2.92; 95% CI 2.19-3.90).

However, these associations do not necessarily indicate a cause-and-effect relationship because of inherent limitations in retrospective studies such as failure to recognize confounding variables and susceptibility to bias. Furthermore, no difference in risk of IVH (all grades, or ≥ grade III) was seen in those infants randomized to liberal versus restrictive transfusion practices in either the multi-institutional Canadian PINT study or the Bell study. A meta-analysis similarly did not identify increased rates of IVH in association with transfusions. Additional studies are needed to determine if early RBC transfusion plays any pathogenic role in IVH development or extension.

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