The rationale for, and effects of oxygen delivery enhancement to ischemic brain in a feline model of human stroke.
Reduced brain tissue oxygenation is frequently seen in severe head injury and after subarachnoid hemorrhage, and this is considered a major cause of secondary ischemic brain injury. In fact, in a previous study, we found a tight correlation between low brain tissue oxygen tension and poor outcome. Therefore, we tested the hypothesis that an allosteric modifier of hemoglobin, which improves oxygen transport to tissue, could reduce the size of an acute infarct in a feline model of human stroke. This compound produces a shift in the hemoglobin dissociation curve to the right and therefore facilitates the unloading of oxygen during low oxygen tension. Seventeen adult cats were studied. Ischemic stroke was induced through a transorbital, permanent, middle cerebral artery occlusion. Seven animals received saline, and 10 received the allosteric Hb modifier RSR-13. Three different endpoints were used to determine the effect of the allosteric modifier. Delta p50 values were measured in the arterial blood; the intra-infarct oxygen tension was measured, and finally, the volume of the infarct was assessed using TTC staining. Mean delta p50 changes varied from 10.4 +/- 9.2 mmHg up to 15.0 +/- 6.8 mmHg. Mean intra-infarct oxygen tension was 27 +/- 6 mmHg for the control group and 33 +/- 7 mmHg for the drug-treated animals. The mean infarct size (measured as percentage of hemisphere volume) in the control group was 32 +/- 9% and for the RSR-13 animals 22 +/- 10% (p < 0.05). A definitive trend towards improvement in brain oxygen tension was seen, such that animals pretreated with RSR-13 showed a higher infarct oxygen tension. Infarct size was significantly reduced in the drug group. Therefore, RSR-13 is potentially beneficial in the treatment of brain ischemia. Since human studies with this compound are already completed, and other compounds which increase oxygen delivery, such as perfluorocarbons, are already being evaluated, it is likely that oxygen delivery enhancement will rapidly become the first 'neuroprotective' modality, employed in patients with severe brain injury, stroke and subarachnoid hemorrhage.
Doppenberg
E M
EM
Department of Neurosurgery, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298-0631, USA. edoppenberg@gems.vcu.edu
Watson
J C
JC
Bullock
R
R
Gerber
M J
MJ
Zauner
A
A
Abraham
D J
DJ
D000328:Adult; D000368:Aged; D000814:Aniline Compounds / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D001930:Brain Injuries / Q000000981:diagnostic imaging / Q000503:physiopathology / Q000601:surgery; D002545:Brain Ischemia / Q000378:metabolism* / Q000473:pathology; D002415:Cats; D002543:Cerebral Hemorrhage / Q000000981:diagnostic imaging / Q000503:physiopathology* / Q000601:surgery; D002544:Cerebral Infarction / Q000473:pathology / Q000517:prevention & control; D002994:Clofibrate / Q000494:pharmacology; D004195:Disease Models, Animal; D005260:Female; D006408:Hematoma, Subdural / Q000000981:diagnostic imaging / Q000503:physiopathology / Q000601:surgery; D006801:Humans; D008297:Male; D010100:Oxygen / Q000097:blood*; D010101:Oxygen Consumption / Q000187:drug effects; D010108:Oxyhemoglobins / Q000378:metabolism; D011422:Propionates / Q000494:pharmacology*; D014057:Tomography, X-Ray Computed
D000814:Aniline Compounds; D010108:Oxyhemoglobins; D011422:Propionates; D002994:Clofibrate; C067396:efaproxiral; D010100:Oxygen