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

Resuscitation with polynitroxylated pegylated hemoglobin (PNPH), a pegylated bovine hemoglobin decorated with nitroxides, eliminated the need for fluid administration, reduced intracranial pressure (ICP) and brain edema, and produced neuroprotection in vitro and in vivo versus Lactated Ringer's solution (LR) in experimental traumatic brain injury (TBI) plus hemorrhagic shock (HS). We hypothesized that resuscitation with PNPH would improve acute physiology versus whole blood after TBI+HS and would be safe and effective across a wide dosage range. Anesthetized mice underwent controlled cortical impact and severe HS to mean arterial pressure (MAP) of 25-27 mm Hg for 35 min, then were resuscitated with PNPH, autologous whole blood, or LR. Markers of acute physiology, including mean arterial blood pressure (MAP), heart rate (HR), blood gases/chemistries, and brain oxygenation (PbtO2), were monitored for 90 min on room air followed by 15 min on 100% oxygen. In a second experiment, the protocol was repeated, except mice were resuscitated with PNPH with doses between 2 and 100 mL/kg. ICP and 24 h %-brain water were evaluated. PNPH-resuscitated mice had higher MAP and lower HR post-resuscitation versus blood or LR (p < 0.01). PNPH-resuscitated mice, versus those resuscitated with blood or LR, also had higher pH and lower serum potassium (p < 0.05). Blood-resuscitated mice, however, had higher PbtO2 versus those resuscitated with LR and PNPH, although PNPH had higher PbtO2 versus LR (p < 0.05). PNPH was well tolerated across the dosing range and dramatically reduced fluid requirements in all doses-even 2 or 5 mL/kg (p < 0.001). ICP was significantly lower in PNPH-treated mice for most doses tested versus in LR-treated mice, although %-brain water did not differ between groups. Resuscitation with PNPH, versus resuscitation with LR or blood, improved MAP, HR, and ICP, reduced acidosis and hyperkalemia, and was well tolerated and effective across a wide dosing range, supporting ongoing pre-clinical development of PNPH for TBI resuscitation.

Emerging therapies in traumatic brain injury.

Despite decades of basic and clinical research, treatments to improve outcomes after traumatic brain injury (TBI) are limited. However, based on the recent recognition of the prevalence of mild TBI, and its potential link to neurodegenerative disease, many new and exciting secondary injury mechanisms have been identified and several new therapies are being evaluated targeting both classic and novel paradigms. This includes a robust increase in both preclinical and clinical investigations. Using a mechanism-based approach the authors define the targets and emerging therapies for TBI. They address putative new therapies for TBI across both the spectrum of injury severity and the continuum of care, from the field to rehabilitation. They discussTBI therapy using 11 categories, namely, (1) excitotoxicity and neuronal death, (2) brain edema, (3) mitochondria and oxidative stress, (4) axonal injury, (5) inflammation, (6) ischemia and cerebral blood flow dysregulation, (7) cognitive enhancement, (8) augmentation of endogenous neuroprotection, (9) cellular therapies, (10) combination therapy, and (11) TBI resuscitation. The current golden age of TBI research represents a special opportunity for the development of breakthroughs in the field.

Polynitroxylated-pegylated hemoglobin attenuates fluid requirements and brain edema in combined traumatic brain injury plus hemorrhagic shock in mice.

UNLABELLED: 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.