Speaker abstracts

The age of stored erythrocytes has been implicated as a potential etiology of several adverse clinical outcomes: immunomodulation, transfusion-associated lung injury, multiple organ failure; and lack of efficacy: failure to provide adequate tissue oxygenation. The latter is based on two physiological changes occurring with erythrocyte storage. Erythrocyte concentrations of 2,3-diphosphoglycerate (2,3-DPG) decrease with duration of storage, and reach depleted concentrations of 1 lmol/g hemoglobin or less at 21 days of storage. 1-3 2,3-DPG is an important determinant of the affinity of hemoglobin for oxygen, with affinity increasing (P50 decreasing) as 2,3-DPG decreases 4,5 (and thus, as erythrocyte storage age increases). This has led some to postulate that transfused stored erythrocytes bind oxygen too tightly to allow for oxygen release at physiologic conditions 6 until 2,3-DPG increases, some hours after transfusion. 2,3,[6] 7][8] The second potential biophysical basis for the putative lack of immediate efficacy of transfused stored erythrocytes is that erythrocytic concentrations of adenosine triphosphate (ATP) decrease with storage duration. Decreased erythrocyte ATP concentrations have been associated with decreased erythrocyte deformability and in vivo survival secondary to impaired ability of erythrocytes to pass the microcirculation. 9,10 However, this hypothesis has been questioned by more recent data using laser technology. 11,12 Other studies in humans either have not been prospective and randomized, or have not tested humans using an appropriately sensitive measure when the subjects were in an oxygendependent state. We utilized our model of severe acute anemia, 13 in which cognitive function 14,15 and central neurophysiologic function as assessed by P300 16 are oxygen-delivery dependent, to test this hypothesis. With institutional approval and subjects informed consent, we studied nine volunteers (sample size determined by a priori power analyses) made acutely isovolemic anemic to a hemoglobin concentration of 50 g/L on two separate days, separated by 7 days. Cognitive function was tested with a computerized digit-symbol substitution test (DSST) each day before induction of anemia, at hemoglobin concentrations of 7 g/dL and 5 g/dL, and after transfusion of autologous erythrocytes, either stored for 3 h (fresh) or stored at usual blood bank conditions for 3 weeks, in sufficient quantity to increase the hemoglobin concentration to 7 g/dL. The type of erythrocytes transfused on each volunteer's first experimental day was randomly allocated; the alternate type of erythrocytes was transfused on the second experimental day. The subject and the person administering and evaluating the DSST were blinded as to type of erythrocyte transfused. Three weeks of storage reduced 2,3-DPG concentration from a normal value of 11.9 (10.4-13.4) lmol/g hemoglobin [mean (95% confidence interval)] to 1.1 lmol/g (0.7-1.5) (P < 0.001); 3 h of storage did not significantly change 2,3-DPG concentration. The P50 of the erythrocytes stored for 3 weeks was reduced from 27.4 mmHg (26.7-28.1 mmHg) to 15.0 (14.6-15.4) mmHg, and differed significantly (P < 0.001) from the P50 of the transfused erythrocytes stored for 3 h: 25.0 (24.5-25.5) mmHg. The DSST did not differ on the two experimental days before induction of anemia. The degree of anemia induced did not differ between the two experimental days (P = 0.69). Acute isovolemic anemia impaired (slowed response) (P < 0.001) the DSST equivalently on the two experimental days (P = 0.62). Transfusion of erythrocytes stored for 3 weeks significantly improved the DSST (P < 0.001), and the improvement did not differ between fresh erythrocytes and those stored for 3 weeks (P = 0.96). 17 The DSST results after transfusion produced an in vivo hemoglobin concentration of 7 g/dL that did not differ from the DSST results at an equivalent hemoglobin concentration during the production of anemia. Results for the secondary outcome measure, heart rate, were similar. We conclude that although 3 weeks of storage of erythrocytes depletes 2,3-DPG and increases hemoglobin affinity for oxygen (P50 = 15 mmHg) they are as efficacious as are erythrocytes stored for 3 h in reversing acute anemia-induced neurocognitive deficits. Potential Conflict of Interest Statement: The author was an employee of Novo Nordisk A/S, the manufacturer of recombinant activated coagulation factor VII (NovoSeven ) from February 2005 to March 2007, and currently is a consultant for Novo Nordisk A/S. The study described here was completed in 2004.

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