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 þ HS). Hypothesis: Resuscitation with PNPH will reduce intracranial pressure (ICP) and brain edema and improve cerebral perfusion pressure (CPP) vs. LR in experimental TBI þ HS. C57/BL6 mice (n ¼ 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 ¼ 10/group) were then resuscitated with a 20 mL/kg bolus of 4% PNPH or LR followed by 10 mL/kg boluses targeting MAP470 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, Po0.001) and had a higher MAP (79.4 ± 0.40 vs. 59.7 ± 0.83 mm Hg, Po0.001). 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 ¼ 0.002), higher CPP during resuscitation (69.2 ± 0.46 vs. 45.5 ± 0.68 mm Hg, Po0.001), and lower %BW vs. LR (80.3 ± 0.12 vs. 80.9 ± 0.12%, P ¼ 0.003). After TBI þ HS, resuscitation with PNPH lowers fluid requirements, improves ICP and CPP, and reduces brain edema vs. LR, supporting its development. Keywords: blood substitute; cerebral edema; hemoglobin blood oxygen carrier; intracranial pressure; nitroxide; resuscitation INTRODUCTION Traumatic brain injury (TBI) is a leading cause of morbidity and mortality in civilian and military settings and is often accompanied by secondary insults such as hemorrhage. Optimum resuscitation is critical given the severe consequences of hemorrhagic shock (HS) after TBI. Early hypotension is a strong clinical predictor of mortality after TBI, doubling mortality rates with a reduction in systolic blood pressure of as small as 10 mm Hg. 1 In blast polytrauma victims in Operation Iraqi Freedom, sustained hypotension was associated with 100% mortality. 2 Ischemia as a consequence of hypotension greatly worsens outcomes in TBI models. 3 Hypotension leads to impaired energy metabolism, 4 reduced neuroprotective gene expression, 5 and increased neuronal death. 6-8 After TBI, cerebral blood flow (CBF) can also be reduced. 9 Animal models of TBI have revealed impaired autoregulation, exacerbating ischemic injury. 10 At autopsy, most TBI patients show evidence of cerebral ischemia, 11 implicating hypoperfusion in secondary injury after TBI. Journal of Cerebral BloodOptimized resuscitation of TBI patients is critical given the consequences of hypotension, and multiple fluids have been studied. Traditional resuscitation fluids for TBI patients include

Emerging Therapies in Traumatic Brain Injury

“…In a model of TBI plus hemorrhage, it dramatically reduced resuscitation fluid requirements compared with crystalloid. 220,221 It also reduced ICP, brain edema, and neuronal death. 220,221 Unlike conventional free hemoglobins, it has surprising in vitro neuroprotective effects.…”

“…220,221 It also reduced ICP, brain edema, and neuronal death. 220,221 Unlike conventional free hemoglobins, it has surprising in vitro neuroprotective effects. 221 It is in preclinical development.…”

Decompressive Craniectomy Reduces White Matter Injury after Controlled Cortical Impact in Mice

“…[24][25][26][27][28] The primary histologic focus of many of these investigations, however, has been cortical lesion volumes and neuronal injury. Recently, Lafrenaye and associates 26 investigated axonal injury in a central fluid percussion rat model of TBI with elevations in ICP.…”

Polynitroxylated Pegylated Hemoglobin—A Novel, Small Volume Therapeutic for Traumatic Brain Injury Resuscitation: Comparison to Whole Blood and Dose Response Evaluation

“…Polynitroxylation of the hemoglobin confers antioxidant effects and prevents NO scavenging, while the polyethylene glycol (PEG) side chains create a ''hydrating shell'' with a marked oncotic effect that is useful in resuscitation. [17][18][19] PNPH, in our prior studies, dramatically reduced resuscitation fluid requirements, ICP, and brain edema, and attenuated neuronal death in vulnerable hippocampal regions. Unlike conventional free hemoglobins, PNPH is not toxic to neurons and has surprising neuroprotective effects in vitro.…”