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Society of Critical Care Medicine (SCCM) 39th Critical Care Congress
January 19, 2010 (Miami Beach, Florida) — Critically ill children transfused with red blood cell (RBC) units stored longer than 14 days have an increased incidence of multiple organ failure and a longer stay in pediatric intensive care units (PICU) than those receiving fresher blood, according to an analysis from a large observational study presented here at the Society of Critical Care Medicine (SCCM) 39th Critical Care Congress.
The results of this study, which was a Critical Care Congress Research Citation Finalist, were presented by lead author Oliver Karam, MD, PICU physician from CHU Sainte-Justine in Montreal, Quebec, during a poster presentation.
"Transfusion is a common treatment in pediatric intensive care. In fact, nearly 1 out of 2 children admitted for more than 48 hours in a PICU will be transfused," said Dr. Karam. "While past studies conducted with adults have suggested that prolonged length of RBC unit storage is associated with worse clinical outcomes, no such studies have been prospectively conducted in children."
Older Blood May Lead to MODS
In this secondary analysis of an observational study, the investigators evaluated 447 children younger than 18 years of age who stayed 48 hours or more in a PICU at 1 of 29 North American centers. Of these patients, 176 were transfused once and 271 were transfused multiple times.
An increase in multiple organ dysfunction syndrome (MODS) after transfusion was the primary outcome measure; 28-day mortality and PICU length of stay were secondary end points. The median length of RBC storage was 14 days.
The results showed an adjusted odds ratio [OR] of 1.87 (95% confidence interval [CI], 1.06 - 3.31; P = .03) for increased incidence of multiple organ failure for the group receiving blood stored for 14 days or more.
"At least 30% of the patients who received old blood, defined as over 14 days, had new or progressive MODS. They came in with respiratory failure and dynamic instability and then they experienced liver or kidney dysfunction, platelet problems, and other things," reported Dr. Karam.
These patients also had a significantly longer total PICU stay (adjusted median difference, +3.7 days; P < .001) and a trend toward developing new or progressive MODS faster (hazard ratio, 1.43; P = .08) than those who received fresher blood.
There was no significant difference in mortality between the 2 groups.
"In other words, transfusion of units stored for more than 2 weeks seems to be independently associated with an increased occurrence of multiple organ failure in critically ill children," said Dr. Karam during an interview with Medscape Critical Care.
"Patients who come into the [PICU] sicker have a higher probability of having more need of transfusions, and then have a higher probability of getting at least 1 old RBC unit," he noted. "So the sicker you are, the higher the probability of getting old blood and of having these outcomes. But independent of the severity of illness and the number of transfusions, the age of blood appears important for all patients."
Second Study, Similar Results
In a second study, also receiving a Research Citation, the same investigational team performed a secondary observational analysis of the Transfusion Requirements in Pediatric Intensive Care Units (TRIPICU) trial, which was conducted in 19 sites in Canada, the United States, the United Kingdom, and Belgium.
"The maximum recommended duration of RBC storage is presently 42 days," said Marisa Tucci, MD, also from the PICU at CHU Sainte-Justine, while presenting the results during a poster session. "We wanted to look at the association between RBC length of storage and the development of MODS."
In this study, the investigators examined data from 455 stable critically ill children enrolled in the TRIPICU trial who were randomized to either a restrictive (n = 145) or liberal (n = 310) RBC transfusion strategy. In addition to measuring increased MODS, they examined increased pediatric logistic organ dysfunction (PELOD) scores and 28-day mortality.
Cut-off storage thresholds of 7, 14, and 21 days were evaluated. For patients transfused multiple times (n = 135), storage time was defined as the oldest RBC unit used.
At the end of the analysis, the investigators found that new or progressive MODS was associated with an RBC storage time of more than 21 days (adjusted OR, 3.29; 95% CI, 1.21 - 9.04) in the restrictive group.
"That same association was found in the liberal group when the storage time was over 14 days [adjusted OR, 2.50; 95%, CI, 1.12 - 5.58]," reported Dr. Tucci.
In a meta-analysis that combined data from all transfused patients, increased MODS was associated with a storage time of more than 14 days (adjusted OR, 2.23; 95% CI, 1.20 - 4.15); increased daily PELOD scores (adjusted mean difference, 4.26; 95% CI, 1.99 - 6.53) and higher mortality (9.2% vs 3.8%) were associated with a storage time of more than 21 days.
"As with the other study, our findings from this analysis showed that stable critically ill children receiving RBC units with increased storage time may be at greater risk of developing new or progressive MODS," said Dr. Tucci. "However, definitive conclusions about a cause-and-effect relationship cannot be drawn from this secondary analysis. Rather, these data justify undertaking a randomized controlled trial to address this issue."
Dr. Karam agreed. "These 2 studies give the same signal — that older blood is probably less good for our patients. But as long as we don't do a pediatric [randomized controlled trial], there are always going to be biases."
When asked if clinicians should consider throwing out or just not using old blood right now, he gave an emphatic "no."
"Getting only blood that is less than 14 days old could have huge implications because blood banks would have to throw away a lot of old blood. And it's going to cost much more," said Dr. Karam. "These studies suggest that the length of storage is something important and something worth testing in a [randomized controlled trial]. But I wouldn't conclude anything yet and wouldn't change my practice based on just these studies."
More Studies Needed
"I think these findings are parallel to the adult situation in the sense that we believe that there are downsides to delivering any blood, but particularly blood that has had a long storage," said session comoderator Pamela Lipsett, MD, FCCM, codirector of the surgical intensive care units and professor of surgery, anesthesiology, and critical care medicine at Johns Hopkins University School of Medicine in Baltimore, Maryland, and the new president-elect of the SCCM. She was not involved with either study.
"To say simplistically that we should stop using old blood may have serious unintended consequences, including not having enough needed blood available," said Dr. Lipsett. "It's really a systems issue. Can we make it a safer, better, but still-adequate system by having a shorter duration of time from donation to administration? We just don't know."
She added that the age of blood is information that is not generally available to the clinician. "It's an interesting concept to note whether or not that would influence decision making. The parallel to that is that many institutions, including our own, are now looking at whether having cost information available for certain radiologic tests or even medications influence ordering behavior. This is similar, although slightly different. I'm still worried, though, that this possible influence will lead to an overall lack of blood availability."
Dr. Lipsett said that she'd be interested in knowing whether the effects from older blood are different for certain types of patients. "We saw that sicker patients have more of a chance of receiving older blood through their multiple transfusions, but does receiving that older blood itself cause a bigger effect if it's a sicker patient? What about age? Do the effects go down as a patient's age increases?"
She added that further studies are needed. "A large follow-up looking at these questions is the type of study we should invest our funding in because it could have a tremendous impact. Plus, anything that affects kids is a big deal. I personally think this should have a moderately high priority in where our dollars go. But, of course, that's a simplistic answer to a very complex problem."
Dr. Karam reported that his group has already started enrolling adult patients into the prospective randomized Age of Blood Evaluation (ABLE) trial. "We hope to include 2500 patients. The threshold for RBC storage in ABLE will be 7 days. We hope to have those results in a few years."
The same team has started the pediatric version of this trial, called Age of Blood in Children (ABC), which is currently in the pilot phase.
The original study for the first analysis was supported by Johnson & Johnson and Fonds de la Recherche en Santé du Québec (FRSQ). The second study was supported by FRSQ and the Canadian Institutes of Health Research. Dr. Karam, Dr. Tucci, and Dr. Lipsett have disclosed no relevant financial relationships.
Society of Critical Care Medicine (SCCM) 39th Critical Care Congress: Abstracts 100 and 106. Presented January 10, 2010.