Improved intraischemic perfusion and pial arteriolar dilation by transfusion of pegylated hemoglobin in the carbon monoxide state

Abstract

Transfusion of chemically‐modifed, cell‐free hemoglobin (Hb) during middle cerebral artery occlusion (MCAO) can reduce infarct volume, but large amounts are typically required. We tested the concept that transfusion of Hb in the CO state would promote vasodilation during MCAO without requiring large amounts of Hb to be transfused. Transfusion of 10 ml/kg of a 4% solution of pegylated COHb (PEG‐COHb) in anesthetized rats resulted in rapid release of CO and equilibration of CO with red cell‐based Hb (2–3% COHb in whole blood and plasma). Plasma [Hb] was ~0.5 g/dL. Induction of MCAO initially produced 37±8% (±SD) dilation of pial arterioles in the MCA border region that gradually subsided to 7±7% at 2 h in controls. Transfusion of PEG‐COHb at 20 min of MCAO maintained pial arterioles in a dilated state (40±13%) at 2 h, whereas transfusion of albumin (25±13%) or PEG‐Hb without CO (22±8%) had intermediate effects. When transfusion of PEG‐COHb was delayed by 90 min, penumbral laser‐Doppler flow increased from 58% to 80% of pre‐ischemic baseline, whereas transfusion of albumin or PEG‐Hb produced no significant change. We conclude that PEG‐COHb can serve as a CO donor that effectively prevents time‐dependent loss of pial arteriolar dilation during MCAO and improves blood flow in the penumbral region to levels above the threshold typically associated with eventual infarction. (Supported by NIH NS38684).