Delayed Hypoxemia After Traumatic Brain Injury Exacerbates Long-Term Behavioral Deficits

Hypoxemia during initial stabilization of patients with severe traumatic brain injury (TBI) has been associated with poorer outcomes. However, the effects of delayed hypoxemia occurring during intensive care post-TBI on outcome is unclear. Pre-clinical models of TBI have rarely shown cognitive or behavioral deficits beyond 6 weeks post-injury and commonly have not included modeling of secondary insults. We have previously developed a murine model of TBI followed by delayed hypoxemia to model the secondary insult of hypoxemia and brain hypoxia occurring in the intensive care setting. Understanding long-term effects of delayed hypoxemia post-TBI in our murine model is critical for future testing of candidate therapeutics targeting secondary brain hypoxia. For this study, forty 5-week-old male mice were randomized to controlled cortical impact (CCI; N=24) or sham surgery (N=16). One day later, awake animals were randomized to 60min of hypoxemia or normoxemia. Six months after initial injury, animals underwent behavior testing (Morris water maze, social interaction, and tail suspension) before euthanasia for immunohistochemistry (IHC) assessments. At 6 months post-injury, mice experiencing CCI and hypoxemia (CCI+H) had longer swim distances to the hidden platform (51cm) compared to CCI alone (26cm) or sham animals (22cm). During social interaction assessments, CCI+H mice spent less time interacting with novel stimulus mice (79sec) than CCI alone (101sec) or sham animals (139sec). CCI+H had larger lesion volumes compared to CCI alone (14.0% vs. 9.9%; p<0.003). Glial fibrillary acidic protein IHC at 6 months post-injury demonstrated increased astrogliosis in the ipsilateral white matter of CCI+H compared to CCI alone. To summarize, this clinically relevant model of delayed hypoxia post-TBI resulted in long-term behavioral deficits and evidence of exacerbated structural injury.