This observational study evaluates the clinical impact of RBC unit length of storage in critically ill children. We report an independent association between more prolonged RBC unit length of storage and increased morbidity: patients who are transfused with at least one RBC unit stored for 14 days or longer had a significantly higher risk of new or progressive MODS and a longer PICU length of stay.
The relation between RBC unit length of storage and clinical outcome has been extensively debated recently. The results of many large observational studies in adults are conflicting. Some authors reported that transfusion of older RBC units (generally a storage time >14 days) is associated with adverse events that include diminished cerebral oxygenation [31
], increased rate of nosocomial infections [19
], increased deep vein thrombosis [9
], increased MODS [6
], and increased mortality [3
]. Others reported no significant clinical impact with transfusion of older RBC units [22
]. The only pediatric study evaluating the effect of RBC unit length of storage on outcome was a post-hoc
analysis by Kneyber and colleagues [26
]. They reported no differences in length of ventilation, PICU length of stay, or death rate in a small number of transfused patients (n = 67). Our data show that RBC units stored for 14 days or longer are independently associated with a worse clinical outcome, as reflected by the occurrence of new or progressive MODS and by the PICU length of stay.
Several possible mechanisms may explain the adverse clinical effects that are reported with transfusion of older RBC units. Various biochemical changes occur during the storage process, such as a decrease in 2,3-diphosphoglycerate and S-nitrosohemoglobin, which regulates the vasodilatory response to local hypoxemia [33
]. This could result in an increased mismatch that may compromise oxygen supply to certain tissues. This has been recently observed clinically by Kiraly and colleagues, who reported a decreased tissue oxygenation in patients receiving older blood transfusions [35
]. Older RBCs are less deformable [36
], contain more extracellular ubiquitin [37
] and advanced glycation end-products [38
], express more phosphatidylserine [39
], and induce more cytokine production [40
] and secretory phospholipase A2 [41
]. All these changes in stored RBCs are known to have immunologic or pro-coagulant properties, which could possibly increase the risk of poor outcomes, including multiple organ failure.
Our data also show an independent association between the number of RBC transfusions and the occurrence of new or progressive MODS, every additional transfusion increasing the odds of developing this outcome by 13%. Such a relation has also been described by others [4
]. A higher number of transfusions exposes the patient to more antigens and more inflammatory mediators, which may alter his immune status. In addition, patients with multiple transfusions have a higher mathematical probability of receiving at least one older RBC unit. A relation between severity of illness at baseline and multiple transfusions is also frequently reported. The data reported in the medical literature showed repeatedly a strong association between older RBC units, severity of illness, and/or more RBC transfusions, and worse outcome in critically ill patients, but it is almost impossible to determine if it is the length of storage, the number of transfusions, or the severity of illness that explained worse outcome. Our study shows that worse clinical outcome is associated with the number of transfusions independently of the longest length of storage; such an independent relation has only been reported recently in adult trauma patients [9
]. This implies that all studies assessing the association between length of storage and clinical outcome must take into account not only the age of the blood products, but also the total number of transfusions administered and the severity of illness.
There are several limitations in our study. The main limitation is that RBC unit length of storage was not available for one-third of the patients. Although it was not possible to recuperate the missing data, we do not anticipate that the cohort of patients with missing data would bias the results because missing data were not related to the severity of illness at admission. Furthermore, these missing data did not allow us to analyze the data according to other RBC length of storage cutoffs due to sample size issues. However, further support that our findings are valid comes from our analysis of the subgroup of patients who received only one transfusion whose length of storage was available and unequivocal. Although we did not attain sufficient statistical power, there was a trend for a higher adjusted odds ratio for developing new or progressive MODS (2.36, P = 0.09, n = 98) in those who received blood older than 14 days.
There are other limitations. It has been suggested that leukoreduction is associated with a better clinical outcome [44
]. Although it would have been ideal to include this covariable in our logistic regression, the database did not provide sufficient data on leukoreduction to allow for this adjustment. However, because most transfusions (86%) were leukoreduced, there is not sufficient power to analyze this variable. Infants got fresher blood than older children. This might be due to blood bank policies whereby fresher blood may have been provided for cardiac surgery patients, who are likely to be younger. However, our logistic models adjusted for patient age. In patients who received multiple transfusions, analysis was subject to confounding influences due to the mixture of storage times. Although it seems reasonable to adjudicate to the 'older blood' group those who had received at least one transfusion of old blood, one could argue that the groups should be allocated according to the freshest blood administered, or according to the mean or the median length of storage, or perhaps according to a weighted average of the length of storage all RBC units received. The best way to address length of storage issues in patients who received multiple transfusions remains to be determined. Despite the use of maximum RBC age to define old RBCs, which biases our results towards the null hypothesis, our analysis indicated a significant independent association between RBC unit length of storage and both the occurrence of new or progressive MODS and a more prolonged PICU length of stay. Caution is warranted in the interpretation of these results, which show an association between RBC length of storage and a more adverse clinical outcome in critically ill children. We must underline the fact that our study reported an independent association, not a cause-effect relation between more prolonged length of storage of RBC units and outcome in critically ill patients: only a randomized clinical trial on this question may prove that such cause-effect relation is real.