Does transfusion of stored red blood cells cause clinically important adverse effects? A critical question in search of an answer and a plan

This issue of TRANSFUSION features important additions to the growing literature on the adverse effects of blood storage and their possible implications for oxygen delivery by transfusion. Several months ago, I was an invited guest at the investigators' meeting for the grant recipients funded by the NHLBI research program titled “Immunomodulatory, Inflammatory, and Vasoregulatory Properties of Transfused Red Cells Units as a Function of Preparation and Storage.” This far-reaching program managed by Dr Simone Glynn was described in a comprehensive editorial in TRANSFUSION published in June 2010.1 I was struck, however, by the scientific value of the concepts behind these grants and felt that a minisymposium of the working hypotheses of these important studies would be extremely valuable to our readership. I also recalled my admiration and appreciation of the thoughtful Tibor Greenwalt scientific lecture delivered by Sunny Dzik at the Annual Meeting in Baltimore. Although the journal typically publishes the Greenwalt lecture in the September issue immediately preceding the next annual meeting along with a supplement of the upcoming meeting abstracts, I thought that coupling publication of the eight reviews from the grant program as a minisymposium together with the Dzik lecture “The Air We Breathe: Three Vital Respiratory Gases and the Red Blood Cell: Oxygen, Nitric Oxide, and Carbon Dioxide” would have symbiotic value to the reader. The Dzik lecture2 provides a thoughtful and well-illustrated view of our evolving concepts of how the red blood cell (RBC) works and the interplay of the RBC membrane constituents and hemoglobin (Hb) with the three vital respiratory gases. You will find it near the front of this edition, suggesting that it would provide a superb introduction to readers wanting to understand these issues of growing concern for oxygen delivery and blood storage. For those of you who are already highly knowledgeable about this field, I believe that you will admire the clarity with which complicated issues of RBC physiology are expressed and how they are coupled to other areas of medicine (pulmonary hypertension, oxygen delivery to the fetus, Hb based oxygen carriers, etc.) to clarify these complicated relationships that may have not been obvious to us in the past. The minisymposium features four papers on nitric oxide (NO) and its role in oxygen delivery. Although the evolving literature on NO certainly suggests its importance in the function of the RBC, platelet, and other physiologic activities, the specifics of how NO works remain controversial and subject to intense debate. The reviews that are featured include work from Gladwin's group suggesting that nitrate supplementation in blood storage would correct some of the purported deficits of stored blood and alleviate the effects of NO scavenging from hemolysis in stored units.3 Stamler's group offers a different concept, based on his studies of S-nitrosohemoglobin in stored blood,4 which have been previously reviewed in an editorial by the late Robert Winslow and Marcos Intaglietta in TRANSFUSION.5 Roback offers the concept that insufficient NO bioavailability, whatever the mechanism, affects oxygen delivery as a result of inadequate blood flow.6 Weinberg's studies will document the effects of NO depletion on trauma patients as well as looking at other proposed mechanisms of adverse storage effects: complement and neutrophil activation.7 The other four reviews outline studies of related issues but from other points of focus. Jy hypothesizes that the development of microparticles in stored blood has procoagulant and inflammatory effects for blood recipients.8 Norris and coworkers describe their concepts and planned studies to investigate the inflammatory and immune effects of stored blood.9 Blumberg's group describes its proposal that RBC-free Hb and lipid mediators in microparticles and plasma have potential adverse effects that could be mitigated by cell washing or rejuvenation.10 Hod and Spitalnik offer their concept that stored RBCs induce a proinflammatory cytokine response, in part due to the iron load from hemolyzed stored RBCs.11 Glynn's editorial1 provides an all-inclusive view of the NHLBI program, which I believe is an important proactive approach to our current state of equipoise about whether existing RBC preservation methods permitting storage for 42 days are harmful to some blood recipients. Important randomized controlled clinical trials are now under way in cardiac surgery12 and intensive care units.13 There are high expectations that these trials will provide the critical data we need to make informed policy decisions and will correct the deficiencies of previous retrospective cohort studies that have both supported and refuted the notion of an adverse clinical effect resulting from blood storage. Clearly, we cannot wait for the results of these trials, which will not be reported for several years. If older blood appears to be harmful to patients in these well-designed clinical trials, transfusion services and hospitals will need to meet the demand for fresher blood. In the event that reliable scientific evidence based on good methodology demonstrates that blood storage has adverse clinical effects, then our patients and their clinicians will not wait patiently for us to figure out methods to overcome such effects while continuing to offer prolonged storage-age blood; making our potential problem more acute, these demands are not likely to be limited to cardiac surgery or intensive care unit, even if the early supportive data are limited to these populations. On the other hand, if the studies show no benefit to fresher blood, we will still have learned a tremendous amount about the reality of oxygen delivery in patients that will yield future benefits. Knowing that clinical evidence is on the horizon that may require major changes in our practices, we can take advantage of the head start provided by the NHLBI grant program. We will likely learn what makes stored blood old, providing an early opportunity for our commercial support industry to develop improved methods of blood storage that will mitigate any important adverse effects of prolonged blood storage. I also believe that our blood centers must begin to plan for the possibility that clinical evidence will lead to a demand for fresher blood. The effects of a shorter storage period for RBCs can be mathematically modeled and plans for increased donations that would be required can be developed. This challenge is heightened by the increased demand for blood services that can be anticipated as the baby boomers move from being reliable blood donors to becoming patients requiring blood services. By thinking ahead, with the awareness that important debates on the quality, cost, and availability of blood may be generated, we can begin to balance the costs of providing fresher blood (both economic and the problems of a less reliable supply) versus the magnitude of any clinical benefit predicted by the clinical trials when completed.14 Our early publication of the Dzik lecture and the minisymposium from the NHLBI grant program are prompted by the belief that the question of whether or not older blood is less safe is the most critical issue facing transfusion medicine. Although we worry about other important issues such as emerging infectious risks, reducing the costs of our services, and transfusion reactions documented in biovigilance systems, there is nothing more important to our patients than making sure that the RBCs we provide are collected and stored by ways that do not impair their transport of vital respiratory gases. The author has no conflicts to disclose.