More data on red blood cell storage could clarify confusing clinical outcomes

For more than two decades clinical studies, mostly observational, have been published investigating possible detrimental effects of prolonged storage of red blood cells (RBCs).1, 2 Most of the studies were performed in North America (United States and Canada) but these results differed from most of the studies performed in Europe (Denmark, Spain, Finland, Norway, the Netherlands, the United Kingdom).2-10 These differences can be explained in part by the different patient populations being studied, with most studies on trauma being performed in North America5, 11-16 reporting significant associations and the studies in colorectal cancer patients all being performed in Europe17-19 reporting no associations or even more beneficial outcomes with older RBCs. Cardiac surgery patients, however, were studied on both sides of the Atlantic. In North America nearly all studies reported adverse outcomes to be associated with prolonged RBC storage. Vamvakas and Carven20 reported 1% more infections for every additional day of mean storage of the RBC (p < 0.005), Eikelboom and colleagues3 reported a hazard ratio of 1.013 on in-hospital mortality for every additional day of storage (p = 0.026), and Koch and colleagues4 reported besides higher rates of in-hospital mortality (2.8% vs. 1.7%, p = 0.004), sepsis (4.0% vs. 2.8%, p = 0.01), and renal failure (2.7% vs. 1.6%, p = 0.003) also a higher percentage of patients in need of prolonged mechanical ventilation (9.7% vs. 5.6%, p < 0.001). On the other side, most European studies in cardiac surgery patients did not find the above-mentioned associations between prolonged RBC storage and adverse outcomes.6, 8, 21, 22 An increase in infectious complications was sometimes reported, but only in a post hoc sub-subgroup analysis or in comparison with nontransfused controls.6, 22 This “continental divide,” the conflicting results reported from both sides of the Atlantic, can only partly be explained by errors in study designs, which were made on both sides of the Atlantic.23 More and more, it has become obvious that there must be additional factors. In a presentation at the 2012 ISBT in Cancun preliminary data were shown suggesting a remarkable change in RBC storage quality after a change in the RBC production process in Canada. Differences in the RBC production processes like centrifugation protocol, buffy coat depletion, additive solutions (ASs), leukoreduction (type of filters), and bag systems are all candidate factors that may play a key role in explaining the different study results and the change in Canada.24 Sadly, information on variables in component preparation is lacking from most of the studies in literature.25 Future clinical studies would be more useful (and progress could be faster) when this type of information as described13 is made available, for instance, as a supportive data file. To investigate the effects of RBC ASs on storage, it is insufficient to only test for how long the RBCs can still meet or exceed the current quality specifications. Protocols have been published years ago to extend the maximum storage period well beyond 10 weeks, although today clinicians request RBCs stored less than 2 weeks.26 It clearly is insufficient to only study RBCs that are at the end of their possible storage as most RBCs are transfused weeks before their final outdate. The gold standard would be to perform clinical studies looking at quality-adjusted life-years after RBC transfusions. However, to perform this type of studies for all (new) ASs in all possible protocols is impossible. The number of strata to analyze would be too large and the number of patients to include immense. Studies examining in vitro variables investigating one AS in different protocols, or different ASs using one protocol would be more manageable. In this issue of TRANSFUSION, Sparrow and coworkers27 report their study on the different effects of two commonly used RBC ASs, SAGM and AS-1, on the RBC membrane during storage. As earlier studies have shown, the seemingly small differences in composition of these ASs may result in significant differences in RBC quality tests.24 One should realize that most RBC ASs are optimized for specific production protocols. So where one AS may produce better results in one study, results may be different if another production protocol is used. Thus far it has not been possible to create one AS that performs “best” in all situations. To determine which AS is best in your specific situation (centrifugation protocol, leukoreduction, bag system, etc.) studies using a direct comparison, like the study by Sparrow and coworkers, are the best first step to collect reliable information. The value of these in vitro studies will ultimately depend on the chosen tests or as the authors stated: “The effect of these differences on the function and survival of RBCs after transfusion remains to be determined.” Finding which in vitro tests reliably predict posttransfusion RBC function would be another big step in optimizing transfusion medicine and helping to resolve the differences in clinical trials with variable practices. None.