Neonatal blood banking and transfusion: Current questions and controversies

Use of hemoglobin for transfusion trigger

Hemoglobin and hematocrit levels are used as indications for transfusion across all patient populations and provide thresholds for RBC transfusion in clinical guidelines. Despite the intentions of these thresholds to provide a standard of treatment for patients, a single hemoglobin or hematocrit value may not be the best indicator for transfusion in all patients. Clinical guidelines are based on large randomized controlled trials in adults, children, and neonates but may not be generalizable to individuals of differing clinical status. In neonates there have been three large clinical trials attempting to answer the question of appropriate RBC thresholds for preterm infants using hemoglobin or hematocrit thresholds.

The TOP trial in the United States was a multicenter investigation of higher or lower transfusion thresholds for preterm infants and found no difference in survival, neurodevelopmental impairment, or other morbidities at 22 to 26 months of age for preterm infants in the lower threshold group (hemoglobin ~8 g/dL). The ETTNO trial in Europe achieved a difference in hematocrit values of 3% and similarly found no difference in morbidity or mortality between groups at 24 months of age. The Premature Infants in Need of Transfusion (PINT) trial reported a clinically (but not statistically) significant decrease in cognitive scores among infants in the lower threshold group at 18 to 21 months. There were more protocol violations in the lower threshold groups for the ETTNO and TOP trials possibly due to both trials being unmasked and providers choosing to transfuse during acute illness in the face of anemia. ^, Observational studies have suggested a relationship between RBC transfusion and necrotizing enterocolitis (NEC), but these findings remain inconsistent across different studies. In contrast, a prospective observational study supported the association of severe anemia (hemoglobin <8 g/dL) rather than transfusion with NEC. There was no difference in the rate of NEC between infants in the high or low threshold groups of the ETTNO, TOP, or PINT trials, but the studies were admittedly not powered to detect differences in many of the secondary outcomes. The trend toward more conservative transfusion practices to limit RBC exposure is likely to continue in the neonatal population, although there remains significant variation in transfusion thresholds and guidelines across US centers.

Near infrared spectroscopy (NIRS) is a noninvasive technology that provides information about regional tissue oxygenation and has been studied in term neonates undergoing cardiac and abdominal surgery, and may be an additional data point to help determine the need for transfusion. NIRS monitors are typically placed over the renal or cerebral tissue beds (back and forehead) and provide a weighted venous saturation value rather than the arterial saturation that pulse oximetry reflects. The NIRS value reflects the amount of oxygen extracted from the tissue with lower values indicating more oxygen extraction and increased metabolic demand. Studies have attempted to evaluate the relationship between anemia, NIRS, and transfusion. Mintzer et al. provided preterm neonates 500 to 1250 g with an empiric RBC transfusion of 15 mL/kg in the first week of life if their phlebotomy losses totaled at least 10 mL/kg. All infants demonstrated increases in cerebral, renal, and splanchnic NIRS readings, which was not observed in the control group. There were no changes in other markers of tissue perfusion, including pH, lactate, base deficit, and creatinine. While there is less evidence for the use of NIRS in premature infants, the data for term infants demonstrate that NIRS strongly correlates with invasive venous saturation monitoring and can detect hemodynamic changes compared to pulse oximetry. This technology may be useful in stratifying neonates to receive RBC transfusion based on indices of tissue perfusion rather than a single hemoglobin value.

Irradiation

Gamma irradiation of RBCs, with either x-rays or cesium, is the recommended strategy to prevent transfusion-associated graft vs. host disease (TA-GVHD). Irradiation targets nucleic acids within T lymphocytes contaminating the RBC component, preventing donor lymphocyte proliferation in the recipient. ^, TA-GVHD is rare but can be fatal when competent donor T lymphocytes from the blood donor recognize patient human leukocyte antigens (HLAs) on hematopoietic, skin, liver, spleen, and thymus cells in an immunocompromised or immune-incompetent host. Preterm infants are considered relatively immunocompromised due to an immature immune system, especially those weighing less than 1200 g, necessitating cellular product irradiation to prevent TA-GVHD. Irradiation to prevent TA-GVHD is also recommended for infants receiving directed blood donation from biologic relatives, in utero fetal transfusions, and rarely used granulocyte transfusions.

TA-GVHD has been reported as a complication of in utero transfusion for erythroblastosis fetalis, therefore irradiation is always recommended for this use. When ordering blood for exchange transfusion to treat hemolytic disease of the newborn, irradiation may not always be possible. If irradiation results in delay of care for the infant, it may not be clinically indicated. Unfortunately there are major effects to RBCs after irradiation, including lipid peroxidation, compromised integrity of the cell membrane leading to decreased deformability and elasticity, and leakage of potassium into the extracellular space. These effects result in increased hemolysis and decreased survivability of RBCs after transfusion. ^, Irradiation can also have minimal effects on platelets, fibrinolysis, and coagulation.

Irradiation has been shown to alter metabolic properties of RBCs and accelerate the aging process. Current US Food and Drug Administration (FDA) guidelines allow RBCs to be stored in CPDA-1 media up to 35 days following collection, but after the cells are irradiated, they must be used within 28 days, depending on the date the product was irradiated. Patel et al. used metabolomics to demonstrate that irradiated RBCs exhibited elements of the storage lesion after only 10 days.

There is variability in irradiation practice among US centers, including where the irradiation occurs (at the location of the supplier or in the hospital) and how long RBCs are considered safe following irradiation. ^, In the TOP trial, in which the appropriate threshold of hemoglobin for transfusion of premature infants was investigated, the 29 participating NICUs were surveyed for their irradiation practices. Ninety-three percent of centers reported irradiating blood with two-thirds performing irradiation on site. In the American Association of Blood Banks (AABB) survey of 35 pediatric centers’ blood banking practices, 88.6% of neonatal RBC transfusions were always irradiated and 11.4% were sometimes irradiated. Seventy-one percent were irradiated on site, 37% were irradiated at the time the order was received, and 31% were irradiated at the time the blood was issued. Irradiation is likely safest if performed immediately before transfusion so the effects of accelerated aging are not experienced by the recipient. ^{, ,}

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