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

Weiskopf, Richard B. M.D.*; Feiner, John M.D.; Toy, Pearl M.D.

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In Reply:—

We thank Drs. Jutzi, Risch, Blumenthal, and Borgeat for their interest in the report of our finding that erythrocytes stored for 3 weeks are as efficacious as fresh erythrocytes (3.5 h storage) in reversing anemia-induced cognitive function deficits in healthy humans.1 The measured hemoglobin P50 at the time of cognitive testing, a few minutes after transfusion, support the lack of a physiologically significant increase in the stored erythrocytes’ P50from the measured low value of 15 mmHg, as is to be expected from the measured in vivo rate of regeneration of 2,3-diphosphoglycerate in erythrocytes stored in citrate-phosphate-dextrose-adenine.2 This is not in agreement with the conjecture3 based on 2,3-diphosphoglycerate data from erythrocytes stored in acid-citrate-dextrose and transfused more slowly.4
Jutzi et al. suggest that the neurocognitive deficit created by isovolemic anemia was secondary to iron deficiency and that the reversal of the cognitive deficit for erythrocytes of both storage durations was produced by transfusion of iron, rather than an increase of oxygen delivery by transfused hemoglobin. Although our results do not seem to be consistent with an inability of 2,3-diphosphoglycerate–depleted erythrocytes to release oxygen from hemoglobin, we do not believe that there is evidence to support the suggestion of Jutzi et al.
Beutler has concluded that it is unclear whether “’iron deficiency without anemia’ can cause symptoms.” As pointed out by Beutler, the lack of clarity is, at least in part, owing to the difficulty in separating these experimentally.5 When iron is administered to patients with a “normal” hemoglobin concentration (i.e., at the lower end of the normal range), the latter, nevertheless, can increase. 6 Although Jutzi et al. cite work showing that iron therapy improves exercise capacity and endurance, fatigue, and cognition in weeks to months, other studies have failed to find such improvement.5 Most importantly, the improvement found in those studies was among patients with chronic, not acute, iron deficiency, and the reported improvements occurred after weeks to months of therapy. We are unaware of reports of such improvement in the few-minute time frame of our study, or even within a few days. A systematic review found “no convincing evidence” of an effect of iron therapy on improvement of psychomotor development and cognitive function 5-11 days from the commencement of therapy.7 The sole study cited by Jutzi et al. as having demonstrated improved cognitive effects reported a very small effect in only one of four subanalyses (by multiple linear regression but not analysis of variance), but not the overall evaluation, after 8 weeks of iron therapy, with a concomitant increase in hemoglobin concentration that resulted in a greater hemoglobin concentration than in the control group.8
Decreased blood oxygen content and delivery caused by hypoxia decreases maximal oxygen consumption (exercise capacity) immediately,9 and acute isovolemic anemia to hemoglobin concentration of 5 g/dl alters central processing10 and cognitive function11 and increases fatigue,12 whereas increasing oxygen content at this critical level reverses these effects. Chronic iron-deficiency anemia alters central processing as determined by P300 latency,13 and 90 days of iron therapy reverses the iron deficiency and improves the anemia but does not improve the prolonged P300 latency.13 Increasing hemoglobin concentration immediately normalizes acute anemia-induced prolongation of P300 latency.10 Breathing oxygen for 5 min, without alteration of iron stores, completely reverses anemia-induced cognitive deficits.11 These results indicate that oxygen, not iron, is responsible for the improved cognitive function. Acute anemia to the identical degree does not alter peripheral or central nerve conduction,14 which also argues against an immediate direct neural effect of an acute decrease in blood iron content.
As we stated in our article, we do not have data to support or refute the several possible explanations we discussed.1 However, we do not feel compelled to add iron deficiency and replacement as a possible cause of our findings.
Richard B. Weiskopf, M.D.*
John Feiner, M.D.
Pearl Toy, M.D.
*Novo Nordisk A/S, Bagsvaerd, Denmark. rwes@novonordisk.com
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References

1. 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

2. Heaton A, Keegan T, Holme S: In vivo regeneration of red cell 2,3-diphosphoglycerate following transfusion of DPG-depleted AS-1, AS-3 and CPDA-1 red cells. Br J Haematol 1989; 71:131–6

3. Spahn DR, Madjdpour C: Physiologic transfusion triggers: Do we have to use (our) brain? Anesthesiology 2006; 104:905–6

4. 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

5. Beutler E: Disorders of iron metabolism, Williams Hematology, 7th Edition. Edited by Lichtman MA, Beutler E, Kipps TJ, Seligsohn U, Kaushansky K, Prchal JT, New York, McGraw-Hill, 2006, pp 511–53.

6. Beutler E, Larsh SE, Gurney CW: Iron therapy in chronically fatigued, nonanemic women: A double-blind study. Ann Intern Med 1960; 52:378–94

7. Martins S, Logan S, Gilbert R: Iron therapy for improving psychomotor development and cognitive function in children under the age of three with iron deficiency anaemia. Cochrane Database Syst Rev 2001:CD001444.

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

9. Horstman D, Weiskopf R, Jackson RE: Work capacity during 3-wk sojourn at 4,300 m: effects of relative polycythemia. J App Physiol 1980; 49:311–8

10. 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 Neurophysio 2005; 116:1028–32

11. Weiskopf RB, Feiner J, Hopf HW, Viele MK, Watson J, 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

12. Toy P, Feiner J, Viele MK, Watson J, Yeap H, Weiskopf RB: Fatigue during acute isovolemic anemia in healthy resting humans. Transfusion 2000; 40:457–60

13. Bandhu R, Shankar N, Tandon OP, Madan N: Effects of iron therapy on cognition in anemic school going boys. Indian J Physiol Pharmacol 2003; 47:301–10

14. 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

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