Prolonged Hypobaria during Simulated Aeromedical Evacuation Exacerbates Cognitive Deficits and Inflammatory Responses following Traumatic Brain Injury

Traumatic brain injury (TBI) is a common cause of injury and death in combat casualties. Aeromedical evacuation (AE), a crucial component in providing rapid care for these patients, exposes casualties to prolonged periods of hypobaria (HB). The effects of such exposure on pathophysiological changes and outcome following TBI are unknown. The effects of prolonged exposure to HB (6h duration of HB exposure; equivalent to 0.75 atmospheres) at 6h, 24h, 72h or 7d on short and long-term cognitive and pathological outcomes following TBI were evaluated using a lateral fluid percussion (LFP) model in adult male Sprague-Dawley rats. Additional groups were evaluated to determine the effects of both primary AE (6h duration of HB at 24h after injury) and secondary AE (10h duration of HB at 72h after injury) following TBI as well as the effects of breathing 100% inspired O2 concentrations (hyperoxia) during AE. HB exposure up to 3d following injury resulted in significant cognitive deficits, hippocampal neuronal cell loss and chronic microglial activation in comparison to injured controls not exposed to HB. Further characterization of the effects of AE following TBI on inflammatory responses demonstrated that HB exposure induced increases in levels of reactive oxygen species, cell cycle activation proteins and microparticles. Administration of a potent and selective CDK inhibitor CR8 3h after injury attenuated post-traumatic inflammatory responses caused by HB exposure and related injury exacerbation. These findings demonstrate that exposure to prolonged hypobaria up to 72hrs after TBI worsens long-term cognitive outcomes and is associated with increased neuroinflammation. Early transport without risk of further intensifying secondary injury processes could potentially be facilitated through the administration of an inhibitor of cell cycle activation which was shown to attenuate HB induced exacerbations in inflammation, neuronal cell loss, and cognitive dysfunction.