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Anemia-induced Neurocognitive Dysfunction: Is Oxygen the Only Player?

Jutzi, Hans M.D.; Risch, Markus M.D.; Blumenthal, Stephan M.D.; Borgeat, Alain M.D.*

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To the Editor:—

Investigations dealing with blood transfusions and their components have recently been more and more focused on the risk-to-benefit issue. This has led to the investigation of specific organ functions under isovolemic anemia to define rational transfusion triggers. From these results, investigators have tried to define physiology-based parameters for transfusion triggers.1–7
In their recent article, Weiskopf et al.8 showed that erythrocytes stored for 3 weeks are almost as efficacious as are fresh erythrocytes for reversing the cognitive functions. Based of these results, the authors reject the current opinion that stored erythrocytes off-load oxygen less than fresh erythrocytes do.
As Spahn and Madjdpour argued in the corresponding editorial,9 the authors did not prove a direct correlation between better neurologic function and oxygen release by 2,3-diphosphoglycerate in the central nervous system. Spahn and Madjdpour emphasize that factors other than 2,3-diphosphoglycerate are responsible for the oxygen off-load.
These findings raised questions. Oxygen transport and release have been the main topic of research in this field. However, evidence is mounting8,9 that factors other than hemoglobin and 2,3-diphosphoglycerate are involved in explaining the benefits of blood transfusions. This is supported by the literature from the gynecological field.
It is well known that iron has functions other than hematologic functions. A common symptom, such as postoperative fatigue, can be explained by an iron deficiency: iron supplementation improves aerobic adaptation10 and endurance capacity11 in young iron-depleted but nonanemic women. Knee extensor exercise in nonanemic but iron-depleted women is also improved after iron supplementation.12 In the context of Weiskopf et al.’s investigation, it is of great interest to note that iron supplementation has been shown to improve some cognitive functions in nonanemic iron-depleted adolescent girls.13
Withdrawing one blood unit (450 ml), as described by the authors, corresponds to 250 mg of iron, which is almost 10% of the volunteer’s (mean weight 64 kg) functional iron. One unit has been withdrawn 4-5 weeks before the first experimental day (to gain stored blood for the experiments). Further blood units (iron included) were withdrawn to induce isovolemic anemia without (mentioned) iron substitution. According to previous articles,1–3 hemoglobin levels were roughly halved by withdrawing further blood in 450-ml steps for each experiment. Halving the hemoglobin concentration goes hand in hand with remarkable additional iron depletion. Unfortunately, no data concerning the volunteers’ iron status have been given.
Based on this view and supported by the literature,10–13 one could argue that, with the authors’ protocol, iron was withdrawn and retransfused in comparable amounts in both groups (“fresh” and “stored”). Iron could have been one of “the important” factors explaining the observed results, which are comparable to the cognitive test results reported by Bruner et al..13 Thus, one may wonder whether the results observed in Weiskopf et al.’s investigation could be partly explained by transient iron deficits.
For the future, it will be of great interest to investigate parameters other than hemoglobin levels and oxygen release by 2,3-diphosphoglycerate when dealing with the question of whether to transfuse blood or not.
Symptoms like fatigue or dizziness, which are frequently observed in postoperative orthopedic surgery, could be greatly reduced by improving iron status—preoperative and postoperative prescription—instead of postoperative blood transfusions.
Hans Jutzi, M.D.
Markus Risch, M.D.
Stephan Blumenthal, M.D.
Alain Borgeat, M.D.*
*Balgrist University Hospital, Zurich, Switzerland. alain.borgeat@balgrist.ch
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References

1. 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

2. Weiskopf RB, Feiner J, Hopf HW, Viele MK, Watson JJ, Lieberman J, Kelley S, Toy P: Heart rate increases linearly in response to acute isovolemic anemia. Transfusion 2003; 43:235–40

3. 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 increase heart rate induced by acute severe isovolemic anemia. Anesthesiology 2002; 96:871–7

4. Weiskopf RB, Viele MK, Feiner J, Kelley S, Liebermann J, Noorani M, Leung JM, Fisher DM, Murray WR, Toy P, Moore MA: Human cardiovascular and metabolic response to acute severe isovolemic anemia. JAMA 1998; 279:217–21

5. Madjdpour C, Spahn DR, Weiskopf RB: Anemia and perioperative red blood cell transfusion: A matter of tolerance. Crit Care Med 2006; 34:S102–8

6. Spahn DR, Zollinger A, Schlumpf RB, Stohr S, Seifert B, Schmid ER, Pasch T: Hemodilution tolerance in elderly patients without known cardiac disease. Anesth Analg 1996; 82:681–6

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8. Weiskopf RB, Feiner J, Hopf HW, Lieberman J, Finlay HE, Quah C, Kramer JH, Bostrom A, Toy P: Fresh blood and aged stored blood are equally efficacious in immediately reversing anemia-induced brain oxygenation deficits in humans. Anesthesiology 2006; 104:911–20

9. Spahn DR, Madjdpour C: Physiologic transfusion triggers. Anesthesiology 2006; 104:905–6

10. Brownlie T, Utermohlen V, Hinton PS, Giordano C, Haas JD: Marginal iron deficiency without anemia impairs aerobic adaptation among previously untrained women. Am J Clin Nutr 2002; 75:734–42

11. Brownlie T, Utermohlen V, Hinton PS, Haas JD: Tissue iron deficiency without anemia impairs adaptation in endurance capacity after aerobic training in previously untrained women. Am J Clin Nutr 2004; 79:437–43

12. Brutsaert TD, Hernandez-Cordero S, Rivera J, Viola T, Hughes G, Haas JD: Iron supplementation improves progressive fatigue resistance during dynamic knee extensor exercise in iron-depleted non-anemic women. Am J Clin Nutr 2003; 77:441–8

13. Bruner AB, Joffe A, Duggan AK, Casella JF, Brandt J: Randomized study of cognitive effects of iron supplementation in non-anemic iron-deficient adolescent girls. Lancet 1996; 348:992–6

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