Trials show no benefit from fresher red cells

Anne Paxton

September 2015—Whether transfusion recipients are better off receiving fresher red blood cells has probably been the most pressing and controversial question in blood banking in the past several years. So much so that enormous randomized, prospective trials involving patients in the U.S., Canada, Europe, Australia, and Africa have been comparing outcomes from RBC units of different duration in a variety of patient subpopulations. One of the goals of these trials was to test findings of a Cleveland Clinic retrospective study, published in 2008, that older blood did seem to produce worse outcomes.

The results of two trials were announced this spring, and the findings have taken at least a few blood bankers aback. Shattering preconceptions on the part of some, results published in the April 9 New England Journal of Medicine from pivotal studies in the U.S. and Canada indicate that whether patients requiring transfusion receive fresh red blood cells or standard-issue cells that may be up to 42 days old, there is no difference in clinical outcome in the populations studied.

The RECESS study looked at the duration of red cell storage and cardiac surgery patients’ changes in the Multiple Organ Dysfunction Score, or MODS, and found duration was not associated with significant differences in MODS (Steiner ME, et al. 2015;372[15]:1419–1429). The Canadian ABLE study assigned critically ill adults to receive either red cells stored for less than eight days or standard-issue red cells, and found that fresh red cells did not decrease the 90-day mortality of critically ill adults (Lacroix J, et al. 2015;372[15]:1410–1418).

“These were really large and well-done studies that didn’t even give a hint that storing blood cells for a longer time period would be detrimental,” says James AuBuchon, MD, president and CEO of Bloodworks Northwest in Seattle. “The prospective, objective data speak very loudly, and those data do not indicate that the storage period of red cells is a concern, at least in most circumstances.”

With such apparently definitive results, there is wide agreement that storage duration of red blood cells is no longer the front-burner blood banking issue. Yet, as blood researchers interviewed by CAP TODAY suggest, many burning questions remain open, key differences in blood centers’ policies on RBC storage duration are likely to persist, and intriguing and unexpected discoveries during the trials will ensure that debate continues to simmer over several issues.

RECESS and ABLE were well carried-out studies, but they have not answered every question about possible risks created by older RBCs, says Harvey G. Klein, MD, chief of the National Institutes of Health Clinical Center’s Department of Transfusion Medicine.

“RECESS and ABLE did precisely what they were designed to do, and their conclusions were very closely based on the data they have,” Dr. Klein says. “But I think what the studies say—which is sometimes misinterpreted—is that there is no advantage to transfusing blood that’s fresher than the standard-issue blood that is transfused. These studies were not designed to look, nor did they look, at the issue of whether there’s any toxicity in the ‘old’ blood that has been 36 to 42 days in storage.” Nor did the studies address every clinical situation, he adds—only cardiac surgery and critical care patients.

“First in, first out” is the strategy of blood banks for inventory control. “So ordinarily, you use the oldest blood that you have. Having said that, in most large metropolitan centers, blood is turned over so quickly that the national mean average of blood that’s transfused is about 17 to 18 days on the shelf.”

That may partly explain why the retrospective studies had different findings than the most recent randomized prospective trials. In fairness, Dr. Klein notes, the retrospective studies looked at blood that was older than the blood in the randomized, controlled trials. “Retrospective studies really are only generators of hypotheses,” he says. “The Cleveland Clinic published data from two groups, one of which they noted as being fresher and one older, and older was not in the last week of storage; the median storage age was 20 days. That doesn’t mean their conclusion is necessarily correct, but they are looking at something a little different than the randomized trials are looking at.”

“The issue that has been resolved, at least to my satisfaction, is when someone in the civilian sector requests fresher blood than is the standard for transfusion, there is no evidence that it brings benefits—at least to cardiac surgery patients and to patients in critical care. Whether it does in other settings hasn’t been specifically studied, but I think it’s unlikely that fresher blood in most circumstances is going to be better.”

What hasn’t been settled is whether blood that has been stored for 36 to 42 days (the maximum storage duration under Food and Drug Administration rules) is riskier in terms of mortality or morbidity than is standard or fresher blood, Dr. Klein says. NIH studies using animal models suggest patients who have established infections might be at risk from the oldest blood. “We’re continuing to study the pathophysiology of what happens when we give animals the oldest blood, but even large animals’ red cells are not exactly like humans’ red cells. So our studies don’t tell you exactly what happens in the human setting, but I think they certainly suggest we need to be concerned about this.”

The United Kingdom and the Netherlands, and several other countries, Dr. Klein notes, do not use blood older than 35 days. “They don’t have supply issues at all, so they’ve already taken the position that they don’t need to use the oldest blood and they simply don’t.”

In the U.S., for the past five years, supply has not been a problem either and many blood centers have cut back on their recruiting, so he does not think shortages would result from adopting the U.K. policy here. “That doesn’t mean if you changed a storage date, you wouldn’t have to do something about increasing recruiting and probably the cost of blood.” Although hard national figures are not available, Dr. Klein estimates that between eight and 20 percent of blood transfused in the U.S. is in the last week of storage.

That’s not the case at NIH, however. “For more than a year, we have not used blood in that last week of storage. We’ve not discarded it; we’ve put it on a shelf called ‘36-Plus,’ and if a unit on there is unusual and is needed, then it becomes a risk-benefit calculation whether to use it. Obviously, if you need a rare unit, it’s better to have a 36-Plus than no unit at all. So it’s important to realize all blood units are not the same.”

As far as he knows, NIH is the only hospital in the U.S. that has adopted this policy.

“We made the determination based first of all on our own pre-clinical studies. It’s a strategy we feel is safe and can be done without a big impact on patient care since we collect our own blood.”

Dr. Klein does not consider the RBC storage question to be resolved. “We know that during storage, dramatic changes take place in the red cell. The cells ‘run down,’ but we don’t know to what extent and what the timelines are. The question is: Are the changes clinically important?” Although fresh versus standard-
issue blood appears to have been addressed, he notes, “For ethical reasons the clinical studies have not been powered to specifically compare the oldest blood and the freshest blood, and in animal models we’ve found a dramatic difference.”

What is known with certainty is that blood donors are different. “Your cells store differently than my cells. Our red cells store differently because of our genetics. So it’s been known for 40 years that some donors are actually better for the blood supply.” The degree to which this occurs is of increasing interest, Dr. Klein says.

In the future, he predicts, with the information systems now available, “you can see a time when red cells will have a molecular profile for their antigenicity so that we can tell you all about the compatibility at the molecular level and perhaps their storage capability, and our computer would be able to tell us what the best cell is for the individual patient and their disease condition. We might be able to personalize red cell transfusion to a much greater degree than we do today.”

One of the best examples of precision medicine since the beginning of the 20th century, he notes, has been transfusion where blood is selected based on antigens. “Today we can do that based on the molecular profile, and tomorrow perhaps we’ll base it on the storage characteristics of the red cells as well. It will be much more precise than it is today.”

A study comparing the very oldest blood with blood in the first week of storage could find a difference, Dr. AuBuchon agrees. But he questions the wisdom of undertaking such a study. For one thing, “We know that transfusing all units within the first week of storage is not feasible, and it’s rare for someone to be transfused only with the oldest chunk of blood.”

Mounting such a prospective study would also have ethical and logistic hurdles. “Ethically, one would be challenged because researchers would be positing that the oldest blood was detrimental to recipients, and anyone already transfused is already in a difficult situation, and you would potentially risk giving them the ‘worst’ blood possible. It would also be challenging to have the inventory for such a study.”

When RECESS and ABLE were funded, Dr. AuBuchon adds, “We truly didn’t know if older blood was worse for a patient than younger; in fact, some data suggested the opposite, so it was a comfortable situation to propose engaging in the study. Once you know which way was better, it becomes much more difficult to promote participating in the study.”

Is there a breakpoint when older blood is definitely worse? “We have no indication that the age of red cells has any impact on patient outcome. Most of the biochemical changes that occur in red cells over 42 days of storage are gradual; they do not occur precipitously, and so a dichotomous label such as young versus old or good versus bad does not seem to apply.”

“It was always possible that the accumulation of some analyte or loss of some compound of red cells might render the cells not as helpful to a patient, or potentially harmful to a patient. And again, whether that was at a definable single point does not seem to be the question at the moment.”

Is there any interest in extending the current FDA-approved shelf-life limitation of 42 days? “Most of the blood units that outdate today are Group AB, and if you doubled the storage time, there would still be outdated AB blood; it’s just a factor of the ABO group.” Still, he says, researchers are interested in understanding the changes that occur with storage. At the Bloodworks Northwest Research Institute, the focus is on identifying why the red cells of some donors appear to survive the storage period better than those of other donors.

“We would like to develop a simple test we could apply to a donor unit to identify the duration of storage most appropriate for that unit, and it might be less or more than 42 days. It might be theoretically possible to identify units that were better for patients in certain conditions. But the research has not progressed to that point yet.”

When he did research on red cell recovery and survival at Dartmouth College, where he worked previously, “It was easily observable that some of our subjects always gave superlative recoveries on the reinfusion, while others always had lower than average recoveries. We didn’t know why,” Dr. AuBuchon says. “But now we’re upon the point of unlocking that mystery, and we may be able to apply it to optimize the length of storage of each particular donor’s contribution.”

The idea of a “storage lesion” in reference to red blood cells may be on the way out, Dr. AuBuchon believes. “‘Storage lesion’ is a common shorthand that really reflects our ignorance as to what of importance is happening in red cells. We learn every day that there are so many things that change, yet we don’t really know which combination of these changes is potentially important to the survival of the cell or the outcome for the patient.”

To his knowledge, no one is considering altering the standard first-in, first-out usage algorithm, except for transfusing neonates. “It is common practice in most institutions to give the very youngest patients the youngest red cells, but they’re small and they usually don’t need very much. The approach commonly used is to dedicate a fresh unit to a patient, then take aliquots from that unit over the next five or six weeks, so the unit is aging as the patient is aging. That reduces exposure early.” This practice began when blood centers were dealing with concerns about HIV and it just continued, Dr. AuBuchon says.

At least potentially, as more study is directed to the metabolic profile of red cells during storage, “we may find some red cells are better able to carry and offload oxygen than others, or they may have capabilities in that regard only for a certain time. So it certainly might be possible that we end up segmenting our red cell inventory to offer red cells of different age and different capabilities in different situations. But it’s not going to happen anytime soon.”

Research might also show that donors, after a simple test, should be considered as better donors of one component, such as platelets, rather than another. “At the moment, it’s based more on ABO than anything else. But we may become more sophisticated in the future.”

The RBC storage controversy occurs as the use of red cells is in sharp decline. “It’s fallen quite dramatically over the last five or six years,” says Dr. AuBuchon, noting that RBC use has dropped by 25 percent to 30 percent and blood centers have constricted their recruitment and collection operations in response. “There’s no point in collecting it if you don’t need it.”