WE have all learned that 2,3-diphosphoglycerate (2,3-DPG) progressively decreases during storage of erythrocytes,1resulting in an increase of the affinity of hemoglobin for oxygen.2As a consequence, these erythrocytes seem to be less capable of releasing large amounts of oxygen to the tissue.3Therefore, it has been proposed to transfuse fresh rather than stored erythrocytes. For example, in a model of sepsis, only fresh (and not stored) erythrocytes could restore oxygen consumption.4Also, in septic patients with increased lactate levels, oxygen consumption did not increase after erythrocyte transfusions,5and gastric mucosal pH even decreased after the transfusion of erythrocytes older than 15 days.5Therefore, it is surprising that Weiskopf et al.  6in this issue of Anesthesiology found that transfusion of autologous erythrocytes stored for approximately 3 weeks is as efficacious as the transfusion of fresh (3–4 h) erythrocytes in reversing anemia induced cognitive dysfunction.

This finding is particularly surprising because the expected decrease in 2,3-DPG and the increase in the affinity of hemoglobin for oxygen was observed in the stored erythrocytes that reversed cognitive dysfunction.6Does this indicate that the retransfused stored erythrocytes had regained—at least partially—their 2,3-DPG levels at the time of testing? This is possible because Beutler and Wood7have shown that 1 h after transfusion, approximately 25–30% of prestorage 2,3-DPG was restored in donor erythrocytes. This does not necessarily mean that fresh and stored erythrocytes result in an equal increase of cerebral tissue oxygenation, which is the likely mechanism responsible for the reversal of the cognitive dysfunction after isovolemic hemodilution.8–10Perhaps the stored erythrocytes improved cerebral oxygenation sufficiently to reverse the cognitive dysfunction, whereas the fresh erythrocytes may have increased cerebral oxygenation to a greater extent. However, this did not translate into measurably better cognitive function. A more gradual increase of the hemoglobin concentration from 5 to 7 g/dl with intermittent neuropsychological testing might have resulted in a detectable difference in favor of fresh versus  stored erythrocytes. In addition, it is important to note that the study subjects were healthy young volunteers. Storage changes of erythrocytes may have had less impact on tissue oxygenation in these individuals than in patients with underlying diseases such as sepsis or coronary artery disease. Last but not least, a recent study has challenged the common understanding that 2,3-DPG levels in stored erythrocytes are the key factor for oxygen off-loading capacity of transfused erythrocytes.11In this study, human erythrocytes stored for 2–3 weeks and containing almost no 2,3-DPG were equally efficacious in maintaining intestinal microvascular oxygen partial pressure as erythrocytes that were stored for 2–6 days. Only erythrocytes stored for 5–6 weeks were less efficacious.11Although undoubtedly there are differences between the oxygenation of the intestine and the brain, both studies indicate that 2,3-DPG levels of transfused erythrocytes may not play a major role with respect to their capacity for tissue oxygenation.

Apart from their contribution to the discussion of old versus  fresh erythrocyte transfusions, Weiskopf et al.  8,9,12have opened the “window to the brain” with respect to monitoring the adequacy of cerebral oxygenation during acute anemia. Monitoring the effect of acute anemia on the cerebral function is essential because most experts would agree that erythrocyte transfusions are indicated to “treat or prevent imminent inadequate tissue oxygenation.”13Current monitoring assesses the heart for development of myocardial ischemia by electrocardiogram and transesophageal echocardiography. Also, the entire circulation can be evaluated by measuring mixed venous hemoglobin saturation in the presence of a pulmonary artery catheter and by calculating oxygen consumption using indirect calorimetry. With circulatory monitoring only, however, we have no direct access to the state of oxygenation and function of other organs. Monitoring the function of the brain in relation to the hemoglobin concentration is an important step toward physiologic transfusion triggers. However, cognitive testing with horizontal addition, digit symbol substitution, and memory tests6,8,9,12requires the cooperation of the patient and thus is unpractical during major operations or after trauma when patients normally are anesthetized. Anemia sensitive neurologic monitoring during general anesthesia is an area that requires further development,10,12,14–16 e.g. , analysis of evoked potentials aimed at central processing may in the future enable on-line monitoring of the adequacy of cerebral oxygenation.

The current study by Weiskopf et al.  6is therefore remarkable for several reasons. First, it is challenging the evolving way of thinking, that fresh erythrocytes are universally better than old erythrocytes. Second, it adds weight to the hypothesis that the 2,3-DPG level may not be the key factor determining the oxygen off-loading capacity of transfused erythrocytes. Finally, in conjunction with previous studies,8–10,12it suggests that on-line monitoring of the functional adequacy of cerebral oxygenation in relation to the hemoglobin concentration during acute anemia may be a valuable tool. Importantly, this study has established a very sensitive human model to monitor the early functional signs of oxygen supply–demand mismatch of the brain. This test can further be used to evaluate therapies that presumably increase oxygen delivery and tissue oxygenation such as hyperoxic ventilation9,10,17,18and artificial oxygen carriers.19 

After developing the capacity to monitor the functional adequacy of the oxygenation of the heart, the circulation, and the brain during acute anemia, physiologic transfusion triggers will progressively replace arbitrary hemoglobin based transfusion triggers. This will render allogeneic erythrocyte transfusions more efficacious because physicians will be capable of using goal-directed erythrocyte transfusions.

* Department of Anesthesiology, University Hospital Lausanne, Lausanne, Switzerland. donat.spahn@chuv.ch

Beutler E, Meul A, Wood LA: Depletion and regeneration of 2,3-diphosphoglyceric acid in stored red blood cells. Transfusion 1969; 9:109–15
Benesch R, Benesch RE: Intracellular organic phosphates as regulators of oxygen release by haemoglobin. Nature 1969; 221:618–22
Valtis DJ: Defective gas-transport function of stored red blood-cells. Lancet 1954; 266:119–24
Fitzgerald RD, Martin CM, Dietz GE, Doig GS, Potter RF, Sibbald WJ: Transfusing red blood cells stored in citrate phosphate dextrose adenine-1 for 28 days fails to improve tissue oxygenation in rats. Crit Care Med 1997; 25:726–32
Marik PE, Sibbald WJ: Effect of stored-blood transfusion on oxygen delivery in patients with sepsis. JAMA 1993; 269:3024–9
Weiskopf RB, Feiner J, Hopf H, Lieberman J, Finlay HE, Quah C, Kramer JH, Bostrom A, Toy P: Fresh blood and age stored blood are equally efficacious in immediately reversing anemia-induced brain oxygenation deficits in humans. Anesthesiology 2006; 104:911–20
Beutler E, Wood L: The in vivo  regeneration of red cell 2,3 diphosphoglyceric acid (DPG) after transfusion of stored blood. J Lab Clin Med 1969; 74:300–4
Weiskopf RB, Kramer JH, Viele M, Neumann M, Feiner JR, Watson JJ, Hopf HW, Toy P: Acute severe isovolemic anemia impairs cognitive function and memory in humans. Anesthesiology 2000; 92:1646–52
Weiskopf RB, Feiner J, Hopf HW, Viele MK, Watson JJ, Kramer JH, Ho R, Toy P: Oxygen reverses deficits of cognitive function and memory and increased heart rate induced by acute severe isovolemic anemia. Anesthesiology 2002; 96:871–7
Weiskopf RB, Toy P, Hopf HW, Feiner J, Finlay HE, Takahashi M, Bostrom A, Songster C, Aminoff MJ: Acute isovolemic anemia impairs central processing as determined by P300 latency. Clin Neurophysiol 2005; 116:1028–32
Raat NJ, Verhoeven AJ, Mik EG, Gouwerok CW, Verhaar R, Goedhart PT, de Korte D, Ince C: The effect of storage time of human red cells on intestinal microcirculatory oxygenation in a rat isovolemic exchange model. Crit Care Med 2005; 33:39–45
Weiskopf RB, Aminoff MJ, Hopf HW, Feiner J, Viele MK, Watson JJ, Ho R, Songster C, Toy P: Acute isovolemic anemia does not impair peripheral or central nerve conduction. Anesthesiology 2003; 99:546–51
Practice Guidelines for blood component therapy: A report by the American Society of Anesthesiologists Task Force on Blood Component Therapy. Anesthesiology 1996; 84: 732–47
Plourde G, Picton TW: Long-latency auditory evoked potentials during general anesthesia: N1 and P3 components. Anesth Analg 1991; 72:342–50
Sneyd JR, Samra SK, Davidson B, Kishimoto T, Kadoya C, Domino EF: Electrophysiologic effects of propofol sedation. Anesth Analg 1994; 79:1151–8
Jessop J, Griffiths DE, Furness P, Jones JG, Sapsford DJ, Breckon DA: Changes in amplitude and latency of the P300 component of the auditory evoked potential with sedative and anaesthetic concentrations of nitrous oxide. Br J Anaesth 1991; 67:524–31
Meier J, Kemming GI, Kisch-Wedel H, Wolkhammer S, Habler OP: Hyperoxic ventilation reduces 6-hour mortality at the critical hemoglobin concentration. Anesthesiology 2004; 100:70–6
Meier J, Kemming G, Meisner F, Pape A, Habler O: Hyperoxic ventilation enables hemodilution beyond the critical myocardial hemoglobin concentration. Eur J Med Res 2005; 10:462–8
Spahn DR, Kocian R: Artificial O2 carriers: Status in 2005. Curr Pharm Des 2005; 11:4099–114