Polynitroxylated-Pegylated Hemoglobin Attenuates Fluid Requirements and Brain Edema in Combined Traumatic Brain Injury Plus Hemorrhagic Shock in Mice

Abstract

Polynitroxylated-pegylated hemoglobin (PNPH), a bovine hemoglobin decorated with nitroxide and polyethylene glycol moieties, showed neuroprotection vs. lactated Ringer’s (LR) in experimental traumatic brain injury plus hemorrhagic shock (TBI + HS). Hypothesis: Resuscitation with PNPH will reduce intracranial pressure (ICP) and brain edema and improve cerebral perfusion pressure (CPP) vs. LR in experimental TBI + HS. C57/BL6 mice ( n = 20) underwent controlled cortical impact followed by severe HS to mean arterial pressure (MAP) of 25 to 27 mm Hg for 35 minutes. Mice ( n = 10/group) were then resuscitated with a 20 mL/kg bolus of 4% PNPH or LR followed by 10 mL/kg boluses targeting MAP > 70 mm Hg for 90 minutes. Shed blood was then reinfused. Intracranial pressure was monitored. Mice were killed and %brain water (%BW) was measured (wet/dry weight). Mice resuscitated with PNPH vs. LR required less fluid (26.0 ± 0.0 vs. 167.0 ± 10.7 mL/kg, P < 0.001) and had a higher MAP (79.4 ± 0.40 vs. 59.7 ± 0.83 mm Hg, P < 0.001). The PNPH-treated mice required only 20 mL/kg while LR-resuscitated mice required multiple boluses. The PNPH-treated mice had a lower peak ICP (14.5 ± 0.97 vs. 19.7 ± 1.12 mm Hg, P = 0.002), higher CPP during resuscitation (69.2 ± 0.46 vs. 45.5 ± 0.68 mm Hg, P < 0.001), and lower %BW vs. LR (80.3 ± 0.12 vs. 80.9 ± 0.12%, P = 0.003). After TBI + HS, resuscitation with PNPH lowers fluid requirements, improves ICP and CPP, and reduces brain edema vs. LR, supporting its development.