Clinical Fellow Johns Hopkins Medical Institution Baltimore, Maryland
Abstract Text:
Introduction: TBI is one of the leading causes of disability and death in the pediatric population. The most critically ill are admitted to the pediatric intensive care unit where they are exposed to necessary sedative medications and in often escalating doses. Benzodiazepines, which in preclinical studies have been shown to impair neurodevelopment and cognitive outcomes, are often used as an adjunctive class of sedatives in the care of these patients. We hypothesized that early exposure to midazolam following TBI would worsen outcomes in a pediatric pre-clinical model.
Methods: Male Sprague-Dawley rats (postnatal day, PND 17) were divided into four groups: naive (n=5), naive with sedation (n=9), TBI (n=12), and TBI with sedation (n=12). TBI groups underwent controlled cortical impact (CCI). Starting on post-injury day (PID) 1, sedation groups received 12 hours per day of sedation, using intra-peritoneal injections of midazolam, given at intervals to maintain sedation based on a standard rating scale. The rats were divided into short term, mid-term, and long-term groups and were sacrificed on post-injury day 4, 28 and 60-100 respectively. In our long-term behavioral studies, the rats underwent behavioral testing with visual discrimination touchscreen task, open-field and gait analysis. After completion of behavior tests, the rats were then sacrificed for ex-vivo brain MRI analysis.
Results: Previous works have shown short-term sedated rats following TBI had less neuro-inflammation and apoptotic cell death. On visual discrimination analysis, TBI-sedation rats had higher failure rates, committed more errors, and required more correction trials. With open field testing, TBI-sedation rats spent less time in the center of the field and had more deficits on gait analysis. MRI analysis is ongoing and includes measurements of total tissue loss, white matter volume loss and brain subregion injury analysis.
Conclusion: In our previous short-term histological studies, TBI-sedation rats had reduced microglial activation and reduced apoptotic activity compared to injured rats without sedation. These findings suggested potential neuroprotective properties of midazolam. However, this reduction in inflammation and neuronal cell death did not translate into improvements in cognitive function. Ongoing studies will use ex-vivo brain MRI analysis to measure tissue loss in our pediatric TBI model.
