Decreased Damage From Transient Focal Cerebral Ischemia by Transfusion of Zero-Link Hemoglobin Polymers in Mouse

Abstract

Background and Purpose— Transfusion of large polymers of hemoglobin avoids the peripheral extravasation and hypertension associated with crosslinked tetrameric hemoglobin transfusion and may be more effective in rescuing brain from focal ischemia. Effects of transfusion of high-oxygen-affinity hemoglobin polymers of different weight ranges were determined. Methods— Hypervolemic exchange transfusion was performed during 2 hours of middle cerebral artery occlusion in mice. Results— Compared to transfusion with a 5% albumin solution or no transfusion, infarct volume was reduced 40% by transfusion of a 6% solution containing hemoglobin polymers in the nominal range 500 to 14 000 kDa. Infarct volume was not significantly reduced by transfusion of a lower concentration of 2% to 3% of this size range of polymers, 6% hemoglobin solutions without removal of polymers 14000 kDa, or crosslinked hemoglobin tetramers with normal oxygen affinity. Exchange transfusion with the 6% solution of the 500 to 14 000 kDa hemoglobin polymers did not improve the distribution of cerebral blood flow during focal ischemia and, in mice without ischemia, did not affect flow to brain or other major organs. Conclusion— An intermediate size range of polymerized bovine hemoglobin possessing high oxygen affinity appears optimal for rescuing mouse brain from transient focal cerebral ischemia. A minimum concentration of a 6% solution is required, the rescue is superior to that obtained with crosslinked tetrameric hemoglobin possessing normal oxygen affinity, and tissue salvage is not associated with increased blood flow. This polymer solution avoids the adverse effects of severe renal and splanchnic vasoconstriction seen with crosslinked tetrameric hemoglobin.