Reducing Hemoglobin Oxygen Affinity Does Not Increase Hydroxyl Radicals After Acute Subdural Hematoma in the Rat

Abstract

Extensive evidence is available to show the importance of ischemia after severe human head injury. We have previously shown that pharmacologically increasing the release of oxygen in brain tissue where the local oxygen pressure is low reduces infarct size in animal models. To study the possible negative effects of this strategy, we tested the effect of an allosteric modifier of hemoglobin (RSR13) on free radical production in the rat acute subdural hematoma (ASDH) model, both under normoxic as well as under hyperoxic, normobaric conditions. When compared to baseline, induction of ASDH resulted in a significant increase (p < 0.05) in 2,3-DHBA (2,3 dihydroxybenzoic acid, produced from salicylate after attack by hydroxyl radicals) at 30 and 60 min postinduction, both for the control group (39% and 91%) as well as the RSR13-treated group (41% and 62%). The 2,5-DHBA also increased significantly (p < 0.05) in the drug-treated animals at the 30- and 60-min time points when compared to baseline (49% and 77%). At all time points, except the 30-min, the increase in 2,3-DHBA was less marked in the RSR13 animals than in the control group. Similarly, the 2,5-DHBA increase after ASDH was lower at all time points except for the 30-min time point in the RSR13-treated group. These results indicate that enhanced tissue oxygen release by the allosteric modifier of hemoglobin RSR13 does not increase hydroxyl radical production after ASDH. Clinical trials are needed to test this compound in humans after severe head injury.

Chronic cognitive effects of bilateral subdural haematomas in the rat

“…In this model, autologous blood is injected underneath the dura, forming a haematoma. As in SDH patients (Graham et al, 1978(Graham et al, , 1987Adams et al, 1983), cortical lesions and damage to the hippocampal formation have been observed in SDH rats (Bullock et al, 1991;Kuroda and Bullock, 1992;Doppenberg et al, 1999). Damage to these brain structures has been associated with cognitive decline in patients (Graham et al, 1978;Adams et al, 1983).…”

Small-volume Resuscitation with HBOC-201: Effects on Cardiovascular Parameters and Brain Tissue Oxygen Tension in an Out-of-hospital Model of Hemorrhage in Swine

“…33 Furthermore, direct measurement of free radical generation failed to reveal any difference in hydroxyl radical formation (2,3-DHBA, salicylate-trapping method) between control and treatment with the same allosteric modifier of hemoglobin. 34 While these studies are limited to animal models, to the best of our knowledge, no study has been performed in humans demonstrating an association with increased brain tissue oxygenation and free radical formation. 33,34 Future work identifying clinical outcomes in patients with brain tissue monitoring and laboratory experiments will determine the therapeutic potential of increases in brain tissue oxygen tension.…”

“…34 While these studies are limited to animal models, to the best of our knowledge, no study has been performed in humans demonstrating an association with increased brain tissue oxygenation and free radical formation. 33,34 Future work identifying clinical outcomes in patients with brain tissue monitoring and laboratory experiments will determine the therapeutic potential of increases in brain tissue oxygen tension.…”

A New Model for the Oxyhaemoglobin Dissociation Curve

“…Whatever the eventual answer, it is likely that the estimation of P50 as an indicator of oxygen-haemoglobin affinity, and hence tissue oxygen availability, will be a useful adjunct to the intensivists' diagnostic armamentarium. With knowledge of the P50, manipulation of this index may lead to significant reductions in the morbidity or mortality of critically ill patients [15][16][17][18][19][20][21][22][23][24] .…”