In a surprise finding that could just maybe be written into a future sequel to Twilight, transfusing one pint of fresh-from-the-vein red blood cells was no better than using stale blood from the back of the fridge, at least in its effects on pulmonary, coagulation, and immunologic parameters 2 hours after transfusion.
By embalming red blood cells in preservatives and refrigerating them, blood can be kept viable for weeks; the accepted storage time is now up to 42 days. Some investigators have blamed these long-stored zombie red blood cells for transfusion-related acute lung injury (TRALI) and have detected a possible association between receiving old blood and an increase in mortality.
The theory is that as red blood cells are stored, they slowly decompose and become harmful by accumulating pro-inflammatory mediators; becoming less deformable and liable to occlude the microcirculation; and losing 2,3 diphosphoglycerate, shifting leftward the hemoglobin dissociation curve and impeding oxygen delivery. The evidence to date for any meaningful impact of any of these experimental effects is not strong (observational, unblinded studies with possible unmeasured confounders).
What They Did
Daryl Kor et al randomized 100 mechanically ventilated patients requiring blood transfusion (but who hadn’t gotten any blood products yet) to receive one unit of fresh packed red cells (<= 5 days old) or “standard” age (~4 weeks old). The sample size was chosen a priori.
Outcomes were measured at the time of transfusion and 2 hours afterward: PaO2/FiO2, ventilatory mechanics, TNF-alpha, IL-8, C-reactive protein, platelet count, fibrinogen, and antithrombin consumption. Clinical outcomes (mortality, incidence of acute lung injury/ALI, organ failure scores, etc.) were also measured.
All transfused blood was leukocyte-reduced, which should reduce the risk for TRALI (agglutination/clumping of donor white blood cells with recipient antibodies is responsible for TRALI). There were unequal distributions of patients receiving less than perfectly matched blood (e.g. Rh incompatible) that didn’t reach statistical significance.
What They Found
There were no statistically significant differences between groups in the measured parameters: oxygenation, ventilatory mechanics, inflammatory mediators, or coagulation parameters. The standard-age-transfusion group had a decline in PaO2/FiO2 ratio of -11.5 mm Hg compared to the fresh-transfusion group, which was not statistically significant. However, the standard deviation for PaO2/FiO2 was 117 mm Hg (high above the predicted 17 mm Hg suggested by the a priori power analysis).
There were also no statistically significant differences in clinical outcomes.
What It Means
As the first randomized trial measuring these outcomes, this study is an important leap forward methodologically toward the goal of answering the question, “are older transfused red blood cells sometimes harmful?” Authors point out rightly that their trial shows this question can be studied ethically (patients’ families only had a perceived upside by participating, since their loved ones might get “fresher” blood).
However, they acknowledge their sample size was likely underpowered to detect the 5% difference in PaO2/FiO2 ratio they had sought (note the 117 mm Hg standard deviation in PaO2/FiO2). A post-hoc power analysis suggested only 80% power to detect differences in PaO2/FiO2 of >40 mm Hg between groups. They spin this as a minor defect to the trial that wouldn’t miss “clinically significant differences,” but what about the difference between a patient whose P/F fell from 110 to 100 and one who fell from 110 to 70 (a 30 point difference)? I would think the point of this type of physiology-grounded study would be to detect differences of this size, since you likely won’t be able to detect differences in clinical outcomes. I wouldn’t expect someone’s oxygenation to dramatically plummet 2 hours after getting a unit of blood, however old it was (unless it was the wrong blood type).
If you haven’t yet, check out Tim Hannon’s blog The Bloody Truth for a fresh take on the most current news in blood transfusions and blood banking.
Kor DJ et al. Fresh Red Blood Cell Transfusion and Short-Term Pulmonary, Immunologic, and Coagulation Status. A Randomized Clinical Trial. Am J Respir Crit Care Med 2012;185:842-850. (epub Jan 26, 2012).
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This interesting study finds no difference in the effects of a single transfused RBC unit with respect to length of storage over the next two hours after transfusion. However, patients in the course of a long ICU illness may receive many units of blood and we cannot rule out that a dose response relationship might exist both in amount of blood given and the duration of exposure. ‘Immunomodulation’ or immunosuppression is one of the possible many adverse consequences of allogeneic red cell transfusion and was not examined in this study, nor would it have been likely detected clinically in an investigation of this small size. One correction in the synopsis of the study- red cells in storage lose 2,3-DPG rather than acquire it.
Dr Swenson: thanks for these insightful comments. I find this line of research fascinating as it seems like one of the still-unsettled issues that could affect ICU outcomes, and the immunology, physiology, etc. are interesting to puzzle over. Although a large study would seemingly be challenging to do, I hope we see it someday. Thanks also for pointing out the error; I made the correction. -Matt