Abstract
BackgroundPolynitroxylated PEGylated hemoglobin (PNPH, aka SanFlow) possesses superoxide dismutase/catalase mimetic activities that may directly protect the brain from oxidative stress. Stabilization of PNPH with bound carbon monoxide prevents methemoglobin formation during storage and permits it to serve as a carbon monoxide donor. We determined whether small volume transfusion of hyperoncotic PNPH is neuroprotective in a polytrauma model of traumatic brain injury (TBI) plus hemorrhagic shock. Guinea pigs were used because, like humans, they do not synthesize their own ascorbic acid, which is important in reducing methemoglobin.ResultsTBI was produced by controlled cortical impact and was followed by 20 mL/kg hemorrhage to a mean arterial pressure (MAP) of 40 mmHg. At 90 min, animals were resuscitated with 20 mL/kg lactated Ringer’s solution or 10 mL/kg PNPH. Resuscitation with PNPH significantly augmented the early recovery of MAP after hemorrhagic shock by 10–18 mmHg; whole blood methemoglobin was only 1% higher and carboxyhemoglobin was 2% higher. At 9 days of recovery, unbiased stereology analysis revealed that, compared to animals resuscitated with lactated Ringer’s solution, those treated with PNPH had significantly more viable neurons in the hippocampus CA1 + 2 region (59 ± 10% versus 87 ± 18% of sham and naïve mean value) and in the dentate gyrus (70 ± 21% versus 96 ± 24%; n = 12 per group).ConclusionPNPH may serve as a small-volume resuscitation fluid for polytrauma involving TBI and hemorrhagic shock. The neuroprotection afforded by PNPH seen in other species was sustained in a species without endogenous ascorbic acid synthesis, thereby supporting potential translatability for human use.
Highlights
Polynitroxylated PEGylated hemoglobin (PNPH, aka SanFlow) possesses superoxide dismutase/catalase mimetic activities that may directly protect the brain from oxidative stress
One guinea pig was excluded from analysis because the lesion from the contusion extended into the hippocampus and interfered with the ability to perform stereology
Physiologic data Because hemorrhage was temporarily stopped when mean arterial pressure (MAP) decreased below 35–40 mmHg to avoid cardiogenic shock, the rate of hemorrhage differed among guinea pigs and, in some, was extended over an hour to achieve the goal of 20 mL/kg withdrawal
Summary
Polynitroxylated PEGylated hemoglobin (PNPH, aka SanFlow) possesses superoxide dismutase/catalase mimetic activities that may directly protect the brain from oxidative stress. Rapidly restoring and sustaining mean arterial pressure (MAP) in multi-trauma victims with TBI and hemorrhagic shock (HS) is of critical importance for initial treatment [1]. Definitive treatment with blood, platelets, coagulation therapy, and surgery can be delayed by many hours, especially in remote locations or in situations with large military and civilian casualties [1] In these situations, an ideal resuscitation fluid should have multiple targets. An ideal resuscitation fluid should have multiple targets It should serve as a resuscitation fluid that restores and sustains MAP in victims with TBI and HS, it should protect neurons and the entire neurovascular unit from secondary injury cascades, such as those resulting from reactive oxygen species. Fluids that require smaller volumes for successful resuscitation can have logistical advantages in these scenarios
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