In this study, CPB combined with autologous salvaged RBC transfusion was not associated with changes in RBC deformability. In contrast, stored allogeneic RBC transfusion was associated with a dose-dependent loss of RBC deformability. The reversal of these changes was also dose-dependent, with return to baseline by POD 3 when the patients received <5 units of stored blood but incomplete reversal by POD 3 after ≥5 units of transfused blood. The decrease in RBC aggregation associated with CPB was unrelated to transfusion. It returned to baseline by POD 1 and never increased above baseline measurements.
These findings suggest that fresh autologous salvaged RBCs may be of higher quality than stored allogeneic RBCs regarding cell membrane deformability, an important determinant of blood flow in the microcirculation and thus of tissue oxygen delivery.31,35,39,40 The possibility that deformability of stored RBCs is impaired in a dose-dependent fashion may in part explain previous findings that the incidence of adverse outcomes is higher in patients who receive larger amounts of stored blood.4,11,41 If the laboratory-measured changes in our study do have clinical relevance, our findings would support the use of fresh autologous salvaged blood when possible, rather than stored allogeneic blood, especially when storage duration is prolonged.
Abundant evidence suggests that stored allogeneic transfused RBCs are functionally impaired relative to fresh circulating endogenous RBCs.16,26,32,42,43 Evidence also indicates that CPB adversely affects RBC structure and function,23–25 and 1 study has shown functional changes in salvaged autologous RBCs tested in vitro but not in blood sampled from patients after salvaged blood transfusion.44 In our study, we found that neither salvaged RBCs nor CPB, when studied in combination, had a detrimental effect on RBC deformability. It is of note that earlier studies showing a 50% to 60% loss of deformability with CPB were performed with older technology, such as bubble oxygenators, that have been implicated in RBC damage and loss of deformability.23,29 In the current study, all patients had CPB with membrane oxygenators, which have been shown to preserve RBC function without causing loss of deformability.30 One particular limitation of previous research into the effects of CPB is lack of information on whether the patients received allogeneic transfusion.23,25,29 Thus, one cannot exclude the possibility that transfusion of stored RBCs confounds the effects of CPB on RBC deformability.
Although the storage lesion with allogeneic blood has been well described, it is unclear whether the various detrimental changes that RBCs undergo during storage are reversible after transfusion. The loss of 2,3-diphosphoglycerate, for example, is thought to return to baseline levels by 2 or 3 days after transfusion.45 Although nitric oxide is rapidly depleted during RBC storage,42 it is controversial whether repletion occurs after transfusion, and how quickly the levels return to baseline.14,46 Some data suggest that the decrease in RBC cell membrane deformability is irreversible,26 but the evidence is insufficient to clearly answer the question. Our findings suggest that the effect of allogeneic blood transfusion is dose dependent, and that when large amounts of stored RBCs are administered; the loss of deformability may persist for as long as 3 days, although the data did show a trend toward return to baseline. Of course, it remains to be determined whether statistically significant changes in ektacytometry measurements reflect a clinically significant loss in overall RBC function.
In contrast to RBC deformability, little is known about the effects of CPB on RBC aggregation. CPB has been associated with a transient decrease in RBC aggregation, as shown in a study that compared patients who had undergone cardiac surgery either “on-pump” or “off-pump.”25 Although this particular study comprehensively measured changes in RBC morphology and aggregation (by 2 different methods), the authors provided no information on whether the patients were transfused. However, the findings regarding changes in aggregation were very similar to ours, with a transient decrease during CPB and return to baseline levels within 48 hours. Other investigators have shown that RBC aggregation in processed autologous salvaged blood, both before and after transfusion, is associated with no changes in aggregation.44 The changes that we measured were a transient decrease in aggregation that returned to baseline values by POD 1. We found no evidence of increased aggregation above baseline levels at any time point, an event that has been implicated in reduced blood flow in the microcirculation.47
Potential limitations in this study include the following. Because no patients had CPB without RBC transfusion, we are unable to comment about the effects of CPB alone on RBC characteristics. As autologous blood salvage has become routine practice for most cardiac surgical procedures, the 3 groups in our study likely represent the most common clinical scenarios, making our study design clinically relevant. A second limitation is that no patients received stored allogeneic RBCs in the absence of autologous salvaged RBCs. This scenario would also be uncommon, so again, the findings we report are most clinically relevant when considering routine practice. Another limitation is the potential confounding effect of longer-duration CPB in the Auto+Allo mod group. Hence, we cannot definitively state that the adverse changes in RBC deformability were attributable to increased transfusion. If CPB is harmful to RBC function, it is possible that confounding occurred, but we can conclude that the combination of prolonged CPB and increased stored blood transfusion appear to be detrimental. Although not definitive, the results of our multivariate analysis suggest that duration of CPB has less effect on RBC cell membrane deformability, compared with the effect of stored allogeneic blood transfusion. Last, our findings might have been different had we transfused allogeneic RBCs with shorter storage durations. The 24-day average duration of storage for blood administered in our study would be considered “older” blood according to the criteria used in the RECESS48 and ABLE49 studies, 2 ongoing clinical trials designed to compare outcomes in patients who receive RBCs with shorter or longer duration of storage.
In summary, for patients undergoing cardiac surgery with CPB, transfusion of salvaged autologous RBCs alone had no demonstrable adverse effect on RBC deformability or aggregation. When stored allogeneic RBCs were transfused, RBCs exhibited dose-dependent detrimental changes in deformability and a dose-dependent reversal of these changes. We also observed a transient decrease in RBC aggregation after CPB that was unrelated to transfusion. Our findings may have clinical implications for some patients, because transfusion of stored blood may not achieve the desired effect, namely improved oxygen delivery and improved outcome. In addition, the detrimental changes in RBC quality associated with storage may also explain the failure to show benefit in clinical trials that use stored allogeneic blood with a liberal transfusion strategy.
Dr. Charles Hogue is the Associate Editor-in-Chief for Cardiovascular Anesthesiology for the journal. This manuscript was handled by Dr. Steven L. Shafer, Editor-in-Chief, and Dr. Hogue was not involved in any way with the editorial process or decision.
The authors wish to thank the Johns Hopkins cardiac surgeons and the clinicians in the CVSICU (Cardiovascular Surgery Intensive Care Unit) for allowing the patients to participate in this study. They also greatly appreciate the efforts of Elizabeth Dackiw R.N. (Research Nurse Coordinator), and Claire Levine (editorial assistance).
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