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Red Blood Cell Storage Outcomes

Currently red blood cells can be stored for up to 42 days, though most transfusions involve blood that is about 18 days old. During the storage of donated blood at 1–6 °C, red blood cells undergo physical and biochemical changes that may decrease their oxygen carrying capacity. The level of 2, 3-DPG is less than10% of the normal value in red blood cell units stored longer than 14 days. Other biochemical changes include decreased glucose, decreased ATP, increased lactic acid, decreased pH and increased plasma potassium. The oxygen dissociation curve becomes left-shifted, resulting in an increased hemoglobin-oxygen affinity and subsequently less oxygen carried to tissues. Potentially, these changes could lead to microvascular occlusion, inflammation, febrile transfusion reactions and immunomodulation.

More than 50 observational studies have been carried out during the past 30 years trying to determine if this so-called storage lesion affects clinical outcomes of transfusion recipients. Results of these studies have been mixed with approximately 50% showing that blood stored for more than 2 or 3 weeks was associated with worse outcomes while the other half did not detect any significant difference.

Recently, 4 large randomized clinical trials have been published that investigated clinical outcomes of fresher versus older RBC transfusions in 3 different patient populations. The Age of Red Blood Cells in Premature Infants (ARIPI) trial was a randomized controlled trial involving 377 very low birth weight infants in a neonatal intensive care unit (Fergusson DA, et al. JAMA 2012;308:1443-51). One hundred and eighty eight infants were transfused with fresh RBCs, having a median storage duration of 5.1 days and 189 were transfused with RBCs stored for a median duration of 14.9 days. The primary outcome was a composite measure of neonatal morbidities including necrotizing enterocolitis, retinopathy of prematurity, intraventricular hemorrhage, bronchopulmonary dysplasia and death. The primary outcome was met in 52.7% of neonates receiving fresher RBCs and 52.9% of neonates receiving older blood.

Secondary outcomes included infection rate and positive cultures. The rate of suspected infection in the fresher red cell group was 77.7% (n = 146) compared with 77.2% (n = 146) in the older red cell group. Positive cultures were present in 67.5% (n = 127) in the fresher red cell group compared with 64.0% (n = 121) in the older red cell group.

The ARIPI trial concluded that the use of fresher red cells did not improve outcomes in premature, very-low-birth-weight infants requiring a transfusion compared to those receiving standard of care. A benefit of using older blood was a reduction of total donor exposures to the neonates (3.7 ± 2.7 donors versus 2.1 ± 1.6 donors).

The Tissue Oxygenation by Transfusion in Severe Anemia with Lactic Acidosis (TOTAL) study compared the outcomes of longer storage versus shorter storage RBC units in children presenting with elevated blood lactate levels due to severe anemia. Reduction in blood lactate concentration was used as a surrogate marker for oxygen delivery to tissues. The study involved 290 severely anemic children, aged 6 months to 5 years who mostly had malaria (81%) or sickle cell disease (13%). Hemoglobin levels were 5 g/dL or less and blood lactate levels were 5 mmol/L of higher. These children were randomized to receive transfusions of RBCs that were stored for 10 days or less or units stored for 25 to 35 days.

The primary outcome measure was the proportion of patients with blood lactate levels of 3 mmol/L or less at 8 hours. Secondary outcomes included blood lactate levels at 2, 4, 6, 8, and 24 hours , cerebral tissue oxygen saturation, and survival. For the primary outcome, 87 of 143 children (61%) receiving older RBCs and 83 of 143 children (58%) receiving younger RBCs had a lactate level of 3 mmol/L or lower at 8 hours. There was no difference in any of the secondary measures between the two groups. This trial demonstrated that transfusion of very old RBC was just as effective as fresh RBCs in improving tissue oxygenation in severely anemic children.

The Red Cell Storage Duration Study (RECESS) study was a randomized controlled trial conducted at 33 medical centers in the United States that evaluated the effect of red blood cell storage time in 1481 patients aged 12 years or older undergoing complex cardiac surgery between 2010 and 2014(Steiner ME, et al. N Engl J Med.2015;doi:10.1056/NEJMoa 1414219).Patients were randomized to receive either fresher units of leukocyte reduced red blood cells stored for 10 days or less or older units stored for 21 days or more. The primary outcome was the change in the multi-organ dysfunction score (MODS) through day 7. Higher scores indicated more serious organ dysfunction. Secondary end points included changes in MODS through day 28, serious adverse events and mortality at 28 days post surgery.

Of the 1096 evaluable patients who received transfusions within 96 hours following surgery, 538 patients received blood with a median of 4 units of fresher RBCs with a median storage duration of 7 days and 560 patients received a median of 3 units of older RBCs with a median storage duration of 28 days. The mean change in MODS was an increase of 8.5 points in the shorter-term storage group and 8.7 points in the longer-term storage group (95% CI for the difference, –0.6 to 0.3; P = .44).  This difference was not statistically significant.

Seven-day mortality rates were 4.4% in the shorter-term storage group and 5.3% in the longer-term storage group (P = .57). There was no difference between the groups in adverse events except that the longer-term storage group was more likely to have hyperbilirubinemia.

This randomized trial did not detect differences in MODS, serious adverse events or mortality at day 28 in patients who were transfused with leukocyte-reduced red blood cells that were stored for shorter or longer periods.

The Age of Transfused Blood in Critically Ill Patients (ABLE) study randomized 2430 patients admitted to intensive care units at 64 medical centers in Canada and Europe to receive fresher blood that was stored for an average duration of 6 days or standard-issue blood that was stored for an average duration of 22 days (Lacroix J, et al. N Engl J Med 2015.doi.10.1056/NEJMoa1500704).

At 90 days, 37% of patients who received fresh blood had died, compared with 35% in the standard-issue blood group (time-to-death hazard ratio=1.1, p=0.38). Mortality rates were essentially the same. The groups exhibited no differences in secondary outcomes including major illnesses; duration of respiratory, hemodynamic or renal support; length of hospital stay; and transfusion reactions. The authors concluded that fresh RBcs did not appear to be superior to standard issue RBCs in critically ill patients.  

Four large randomized trials in neonates, cardiac surgery patients and ICU patients have concluded that freshly donated blood is not better than older blood when it is transfused into severely ill patients.These studies support continuation of the current inventory management practice of issuing the oldest units first before they outdate.

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