Background

Historically, hospitals often transfused preterm infants and very low birth weight (VLBW) neonates (infants weighing <1500 g) with red blood cells (RBCs) stored in CPD or CPDA-1. This practice was based on theperceived harmful effect of the additive solutions [e.g.Adsol (AS-1), Nutricel (AS-3), Optisol (AS-5)] that arenow routinely used for RBCs to allow a maximum shelflife of 42 days.

Neonates, particularly those who are premature, haveimmature immune and metabolic processes and arestill undergoing rapid neurodevelopment. The additivesolutions (AS) contain mannitol and/or adenine (seeTable 1). The perception is that these solutes maynot be metabolized by the neonate receiving multipletransfusions and could result in changes to intracerebral pressure or place the infant at risk for liver or kidney damage. Possible hyperkalemia from the storage duration of the AS units is another concern.

For premature infants, particularly VLBW neonates,anemia is common due to such factors as lowerhemoglobin at birth, blood losses from frequentphlebotomy and management of illnesses, and adecreased capacity to increase plasma erythropoietin.Consequently, most RBC transfusions to neonates are‘top-up’ transfusions (repeated small volumes of RBCs,up to 20 mL/kg). For these small volume transfusions,is there evidence to support the use of RBCs stored inadditive solution?

Evidence Supporting the Safety of RBCs in Additive Solution for Neonates

Since the introduction of AS, many years ofexperience as well as several studies have confirmedthat small volume transfusions (20 mL/kg)of unmodified RBCs stored in AS are safe andwell tolerated by the neonate.2-5 Estimates fromtheoretical calculations have demonstrated that thequantity of additives infused during a transfusion of15 mL/kg of either AS-1 or AS-3 RBC to a 1 kg neonateare far below that of toxic levels.1-3 (See Table 2)

Several subsequent in vivo studies have supportedthese calculations. Changes in pH, glucose, lactate,calcium, sodium, and potassium were minimal posttransfusion of AS RBCs. 3 In addition, use of RBCsstored in AS has resulted in reduced donor exposurefor the infant. In one study, mean donor exposure was1.6 for infants given AS-1 RBC transfusions comparedto mean of 3.7 donors when CPDA-1 RBCs weretransfused.

Another apprehension with the use of older AS RBCunits, especially those near expiration, is the loadof potassium that the infant may receive during thetransfusion. Surprisingly, a 10 mL/kg aliquot preparedfrom a 42-day old AS RBC unit is estimated to deliver0.1 mmol/L of potassium. This amount is less thanthe daily potassium requirement of 2-3 mmol/L for a1 kg neonate.⁶

Over time, most hospitals have become receptive tousing RBCs stored in AS for neonates. A 2008 surveyof 47 University Health System hospitals showedthat most centers (28 or 60%) were already usingor willing to accept unmodified RBCs stored in AS-1,AS-3, or AS-5 for small volume neonatal transfusions.7A subsequent survey in 2017 of 35 AABB-accreditedpediatric hospitals in the US found similar findingswith 57% of the institutions routinely using RBCs inadditive solution for low volume transfusions.8 Despitethe evidence supporting the safe use of AS RBCs forsmall volume transfusions, universal adoption of thispractice though appears to be lagging.

For large volume transfusions (≥20mL/kg) as withexchange transfusion or blood prime for cardiacbypass/extracorporeal membrane oxygenation, theevidence is less clear as to the actual risks. Over theyears, a majority of academic pediatric centers havetransitioned to use of AS-1 or AS-3 RBCs for largevolume transfusion, but provide fresh (e.g., <7-10days old) AS RBCs in these settings.^8,9 However, based on theoretical concerns cited above, some centers may continue with removal of the additive solutions by either centrifugation or washing before use of the unit for large volume transfusions. Recently, a single Midwest academic pediatric center retrospectively studied the safety of large volume (≥20 mL/kg) compared to small volume (<20 mL/kg) AS-1 RBC transfusions in patients less than 6 months of age undergoing cardiovascular surgery. A total of 201 transfusion events (large and small volume) in 129 patients were analyzed. Large volume AS-1 RBC transfusions had statistically significant greater change in post-transfusion Na+, K+, glucose, creatinine, arterial HCO3, hemoglobin, and arterial O2 saturation. However, these changes were not considered clinically significant when compared to small volume transfusions, and except for glucose, the values in both groups were within normal limits. In addition, there was no evidence of metabolic complications, nephrotoxicity or increase in intracerebral pressure after the large volume AS-1 RBC transfusions.¹⁰

This recent retrospective data and a growingnumber of anecdotal reports of no adverse effectssuggests that AS RBCs are safe for even largevolume transfusion in neonates. This is an importantconsideration for some centers who may find itincreasingly difficult to obtain RBC units withoutadditive solution and wish to simplify their neonataltransfusion protocols and eliminate the need for dualRBC inventory.

Recommendations:

RBC units stored in AS (e.g. AS-1 or AS-3) are an acceptable choice for small volume transfusion (20 mL/Kg) to preterm neonates and can safely be used for multiple small volume transfusions to a single neonate.

For large volume transfusions, such as for hearttransplant, cardiac surgery, or exchange transfusion,the safety of AS RBC units without removal of theAS (by centrifugation or washing) is less clear.Experience and limited retrospective data suggeststhat unmodified RBCs stored in AS could also beconsidered for large volume neonatal transfusions.Transfusion services, in collaboration with theirneonatologists, should establish guidelines forneonatal transfusions to optimize care and promoteeffective inventory management.

References:

1. Roseff SD, Wong ECC (eds). Pediatric Transfusion: A Handbook. 5th Ed. Bethesda MD: AABB; 2020, pages 11-12 , 250-251.
2. Luban NLC, Strauss RG, Hume HA. Commentary on the safety of red cells preserved in extended storage media for neonatal transfusions. Transfusion 1991;31:229-235.
3. Luban NLC. Neonatal red blood cell transfusions. Curr Opin Haematol 2002;9:533-536.
4. Strauss RG, Burmeister LF, Johnson K, et al. AS-1 red cells for neonatal transfusions: a randomized trial assessing donor exposure and safety. Transfusion 1996;36 (10):873-878.
5. Strauss RG, Burmeister LF, Johnson K: Feasibility and safety of AS-3 red blood cells for neonatal transfusion. J Pediatr 2000;136:215–219. https:// doi.org/10.1016/S0022-3476(00)70104-1
6. Wong ECC and Punzalan RC. Neonatal and pediatric transfusion practice. In: Cohn CS, Delaney M, Johnson ST, Katz LM, eds. Technical Manual, 20th ed. Bethesda MD, AABB, 2020:673- 703.
7. Fung MK, Roseff SD, Vermoch KL. Bloodcomponent preferences of transfusion servicessupporting infant transfusions: a UniversityHealth System Consortium benchmarking study.Transfusion. 2010;50:1921-1925.
8. Reeves HM, Goodhue Meyer E, Harm SK, et al.Neonatal and pediatric blood bank practicein the United States: Results from the AABBpediatric transfusion medicine subsection survey.Transfusion 2021;61:2265–2276.
9. Pyles RB, Lowery JT, Delaney M. The use of redcell units containing additives in large volumeneonatal transfusion in neonatology units in theUSA. ISBT Science Series 2017;12:322-323.
10. Phillips N. Comparison of small volume and largevolume transfusions of RBCs containing adsolin pediatric patients less than 6 months oldundergoing cardiopulmonary bypass surgery.2019 AABB Future Leader SBB ScholarshipRecipient Award.