Red Cell Storage and Clinical Outcomes
The association between the transfusion of relatively older blood and morbidity and mortality has been demonstrated in multiple retrospective studies utilizing various study designs (Table
2). In 1997, Purdy et al. reported the association between blood storage age and survival among 31 septic ICU patients[
18]. No differences were observed between survivors and nonsurvivors concerning age, gender, ICU length of stay, APACHE II score, or total number of red cell units transfused. However, the median age of red cell units transfused to survivors during sepsis was 17 days (range 5-35) versus 25 days (range 9-36) for nonsurvivors (P < 0.0001).
Table 2
Clinical outcome studies reviewing the effects of red cell storage age, in order of publication
| Septic ICU patients | 31 | Patients who died received older RBC |
| CABG patients | 416 | Transfusion of RBC with longer storage time associated with pneumonia |
| Trauma patients who received 6-20 RBC in the first 12 hours post-injury | 63 | Patients who developed MOF received older blood (30 vs. 24 days) |
| CABG patients | 268 | Transfusion of old RBC was not associated with increased morbidity or mortality |
| Trauma patients who received 6-20 RBC in the first 12 hours post-injury | 62 | Transfusion of old blood was associated with increase risk of infection |
| Trauma patients who received ≥1 RBC within 48 hours of admission | 86 | Older RBC were associated with longer hospital length of stay |
| Trauma patients who received ≥1 RBC | 275 | Patients who received older RBC had longer length of ICU stay but no increased in-hospital mortality |
| CABG patients who received exclusively young or old blood | 6,002 | Patients receiving old RBC had higher mortality (short and long term) |
| Trauma patients who received ≥1 RBC within the first 24 hours post-injury | 1,813 | Blood storage age potentiated the increased odd of mortality seen with larger volumes of transfusion |
| Less severely injured trauma patients who received no RBC in the first 48 hours post-injury | 1,624 | Transfusion of old blood was associated with increased mortality, renal failure, and pneumonia |
In 1999, Zallen et al. examined the association between red cell storage age and multiple organ failure (MOF) in a matched case-control study concerning trauma patients that received between 6 and 20 units of red cells in the first 12 hours following injury[
19]. No difference in ISS or transfusion requirement was observed between MOF positive (n = 23) and MOF negative (n = 40) groups. The authors identified that the mean age of transfused blood was significantly greater in the MOF positive patients (30.5+/-1.6 days versus 24+/-0.5 days). Multivariate analysis identified mean age of blood, number of units older than 14 days, and number of units older than 21 days as independent risk factors for MOF.
From the same institution, Offner et al. evaluated the association between transfusion of relatively older blood and post-injury infection in a similar patient cohort[
20]. In this study of 61 patients who each received between 6 and 20 units of red cells in the first 12 hours after injury, patients who developed infections were found to have received 11.7 +/- 1.0 and 9.9 +/- 1.0 units of red cells older than 14 and 21 days, respectively, compared with 8.7 +/- 0.8 and 6.7 +/- 0.08 units in patients who did not develop infections (both p < 0.05). Multivariate analysis demonstrated age of blood to be an independent risk factor for post-injury infection.
Keller et al. examined the influence of blood storage age on hospital length of stay in a trauma patient cohort of 86 patients[
21]. Univariate analysis demonstrated that the number of units of transfused blood older than 14 days correlated significantly with hospital length of stay. They also evaluated the total number of units transfused, mean age of blood, age of the oldest unit, and average of the two oldest units for associations with length of stay; none correlated significantly with length of stay. Multivariate analysis was then performed and indicated that the number of units of blood older than 14 days remained significantly associated with increased length of stay.
As evident in the studies described above, the evaluation of the independent role of storage age on outcomes in patient populations that received a heterogeneous distribution of relatively old and young blood is far from straightforward. Utilization of measures of central tendency, such as the mean or median age of all units transfused to a given patient, may simplify the analysis from a statistical standpoint, but is flawed in that it makes an assumption of mechanism, whereby the transfusion of relatively younger units engenders a protective (or a watering down) effect, offsetting the proposed deleterious effect of older blood. Given the present understanding of the storage lesion, there is no evident rationale for the assumption of such. Alternatively, analyses that focus on the volume of old blood transfused, while avoiding this assumption of mechanism, are hindered by the confounding of total transfusion volume. The observed associations between the transfusion of relatively older blood and morbidity or mortality may actually be more reflective of the residual effect of total transfusion volume rather than blood storage age, as transfusion volume and transfusion storage age are necessarily linked variables. The more units of blood a patient receives the greater likelihood that the mean age of those units will be older. Further, given that receipt of larger units of blood likely reflects more serious injuries, and therefore a greater likelihood of morbidity and mortality, any adverse association with older mean age may simply reflect higher injury severity. It is therefore important to consider not only the age of the blood transfused but also the volume and these measures should not be treated in an independent manner. If the associations between older blood and outcomes as outlined above were actually secondary to the residual confounding of transfusion volume, the associations between outcome and the volume of young blood transfused would be expected to be similar.
With this in mind, we recently evaluated the association between mortality and the transfusion of both older and younger blood, respectively[
22]. Among 1,813 severely injured patients (mean ISS 26) admitted to the trauma service of the University of Alabama at Birmingham University Hospital, who received one or more units of blood within the initial 24 hours of hospitalization, we determined that while larger volumes of blood, irrespective of storage age, were associated with an increased odds of mortality, the transfusion of blood stored beyond 14 days appeared to significantly potentiate this association, suggesting the existence of a veritable association between storage age and outcome.
In a second study, we evaluated the relationship between blood storage age and adverse outcomes in a relatively less injured population[
23]. This cohort of 1,624 trauma patients comprised those with blunt mechanism of injury, ISS < 25, and no blood transfusions administered within the first 48 hours of hospital admission. Similar to our previous work, we determined the effect of both young and old blood on outcome, respectively. We observed that the receipt of old blood was significantly associated with mortality, acute renal dysfunction, and pneumonia, whereas the receipt of young blood was not, further suggesting that transfusion of older blood is independently associated with outcome, even in relatively less severely injured patients.
Nonetheless, the methodological difficulties presented by patients receiving a heterogeneous distribution of old and young blood remain; analyses limited to those patients that received exclusively old versus exclusively young blood may simplify things considerably. In our study concerning 1,813 trauma patients, we performed a subgroup analysis concerning only those patients who received exclusively young or old blood, and found that among those patients receiving a total of 3 or more red cell units, receipt of old blood was associated with an over 2-fold increased odds of death[
22]. Koch et al. performed a similar analysis concerning 6,002 cardiac surgery patients, and observed that patients in the older blood group had significantly higher incidences of in-hospital mortality, intubation beyond 72 hours, renal failure, and sepsis[
24]. Again, however, the coupling of storage age and volume of transfusion must be acknowledged. Although the distribution of transfusion volume in both the young and old groups in this study (and in our subgroup analysis) as represented by the mean was similar between groups, it remains plausible that transfusion volume remains a relevant residual confounder. In fact, the report by Koch et al. has been vocally criticized for failure to adequately account for multiple potential confounders including differences concerning total transfusion volume, underlying comorbidities, and ABO blood groups between groups[
25,
26].
It is notable that in our reported experience described above, all patients were transfused with blood that had undergone prestorage leukoreduction[
22,
23]. Although leukoreduction has well documented efficacy related to specific clinical circumstances, a generalized benefit remains unproven[
27]. Indeed, Nathens et al. performed a randomized trial comparing prestorage leukoreduced versus standard nonleukoreduced transfusions to evaluate whether or not leukoreduction might improve outcomes among trauma patients, and found no difference in mortality or infectious morbidity among the 268 patients eligible for analysis[
28]. Our clinical experience as described above demonstrates associations concerning both morbidity and mortality with older blood despite universal leukoreduction, further suggesting that the existence of a clinically relevant benefit of leukoreduction in the trauma setting remains doubtful.
Summary
Although the growing body of literature demonstrating the deleterious effects of relatively old blood is compelling, we must be mindful that all of these reports have been retrospective, and most of these studies have evaluated patients who received a mixture of red cell units of varying storage age. As highlighted above, the difficulty in distinguishing the effect of storage age from the effect of transfusion volume in these studies is not insignificant. In our own work, we have employed statistical analysis that we feel best attenuates the potential residual confounding of transfusion volume. It remains quite possible, however, that prospective evaluation of the effect of storage age on outcome might yield contradictory results.
Certainly, prospective confirmation of the effect of blood storage on morbidity and mortality is now warranted. Schulman et al. attempted such a trial in the setting of a single-center Level 1 trauma center, randomizing patients to receive exclusively young (<11 days) versus old (>20 days) blood during the first 24 hours of hospitalization[
29]. Unfortunately, in 1 year they were only able to enroll a small number of patients secondary to limitations of the blood bank. It is reasonable to expect that other institutions would face a similar challenge given the tight supply of blood. It is clear that only inter-institutional cooperation in the form of a multi-institutional trial will be successful in the recruitment of enough patients for a robust analysis. Hebert et al. performed a multi-center feasibility study in Canada, and reported that a large scale study would be feasible, but challenged by the maintenance of a sufficient blood supply to allow for randomization between old and young groups with a limited number of subsequent group crossovers[
30]. Until such prospective studies have been completed and produce confirmative results, it would be premature to recommend any modification of current transfusion practice regarding storage age. Nonetheless, the implication that the transfusion of blood of relatively longer storage age may have negative consequences demands attention and, most importantly, further rigorous evaluation.
Competing interests
The authors declare that they have no competing interests.
Authors' contributions
MV and JW drafted the manuscript and performed critical revision. GM performed critical revision. All authors have read and approved the final manuscript.