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Abstract

Introduction: Polynitroxylated pegylated hemoglobin (PNPH), a bovine hemoglobin decorated with niroxide and polyethylene glycol moieties, demonstrated neuroprotection in vitro and in vivo vs. Lactated Ringer’s (LR) in experimental TBI plus hemorrhagic shock (HS). Hypothesis: We hypothesized that resuscitation with PNPH will reduce intracranial pressure (ICP) and brain edema vs. LR in experimental TBI+HS. Methods: C57/BL6 male mice (n=20) were anesthetized with isoflurane and underwent controlled cortical impact (CCI) followed by HS to mean arterial pressure (MAP) of 25-27mm Hg for 35 min. Mice (n=10/group) were then resuscitated with an initial bolus of 20ml/kg of either 4% PNPH or LR followed by 10ml/kg boluses every 5 min for MAP <70 mm Hg for 90min, mimicking pre-hospital care. Shed blood was then re-infused. ICP was monitored for the duration of the model after which the mice were sacrificed and percent brain water was quantified (wet/dry weight). Results: Mice resuscitated with PNPH vs. LR required less fluid for resuscitation (26 ± 0 vs. 167 ± 10.7 ml/kg, P<0.001) and had a higher MAP at the end of the pre-hospital phase (78 ± 4.7 vs. 60.1 ± 8.8 mm Hg, P<0.001). The PNPH mice required only the initial resuscitation bolus of 20 ml/kg, while the LR mice required multiple boluses during resuscitation for MAP <70mmHg. PNPH-treated mice also had a lower peak ICP (14.5 ± 3.1 vs 19.6 ± 3.5 mm Hg, P=0.003) and higher cerebral perfusion pressure (CPP) at the end of the pre-hospital phase (67.1 vs. 45 mmHg, P<0.001). The PNPH mice also had a reduced %brain water in the hemisphere ipsilateral to injury vs. LR (80.3 ± 0.1 vs. 80.9 ± 0.1%). Hemoglobin and lactate levels were not different between the groups at any time point. Methemoglobin levels were mildly elevated in the PNPH group in the pre-hospital and hospital phase (P<0.001). Conclusions: Resuscitation with PNPH dramatically lowers fluid requirements, improves ICP and CPP and reduces brain edema vs. LR resuscitation. Despite severe HS, PNPH-treated mice required only a single bolus of fluid and were adequately resuscitated while the LR mice were refractory to resuscitation. Our data support ongoing pre-clinical development of this novel resuscitation fluid for TBI resuscitation.