Neuroprotective effect of preoperatively induced mild hypothermia as determined by biomarkers and histopathological estimation in a rat subdural hematoma decompression model

Shoji Yokobori, Shyam Gajavelli, Stefania Mondello, Jixiang Mo-Seaney, Helen M Bramlett, W Dalton Dietrich, M Ross Bullock
Journal of Neurosurgery 2013, 118 (2): 370-80

OBJECT: In patients who have sustained a traumatic brain injury (TBI), hypothermia therapy has not shown efficacy in multicenter clinical trials. Armed with the post hoc data from the latest clinical trial (National Acute Brain Injury Study: Hypothermia II), the authors hypothesized that hypothermia may be beneficial in an acute subdural hematoma (SDH) rat model by blunting the effects of ischemia/reperfusion injury. The major aim of this study was to test the efficacy of temperature management in reducing brain damage after acute SDH.

METHODS: The rats were induced with acute SDH and placed into 1 of 4 groups: 1) normothermia group (37°C); 2) early hypothermia group, head and body temperature reduced to 33°C 30 minutes prior to craniotomy; 3) late hypothermia group, temperature lowered to 33°C 30 minutes after decompression; and 4) sham group, no acute SDH (only craniotomy with normothermia). To assess for neuronal and glial cell damage, the authors analyzed microdialysate concentrations of GFAP and ubiquitin carboxyl-terminal hydrolase-L1 (UCH-L1) by using a 100-kD probe. Fluoro-Jade B-positive neurons and injury volume with 2,3,5-triphenyltetrazolium chloride staining were also measured.

RESULTS: In the early phase of reperfusion (30 minutes, 2.5 hours after decompression), extracellular UCH-L1 in the early hypothermia group was significantly lower than in the normothermia group (early, 4.9 ± 1.0 ng/dl; late, 35.2 ± 12.1 ng/dl; normothermia, 50.20 ± 28.3 ng/dl; sham, 3.1 ± 1.3 ng/dl; early vs normothermia, p < 0.01; sham vs normothermia, p < 0.01, analyzed using ANOVA followed by a post hoc Bonferroni test). In the late phase of reperfusion (> 2.5 hours after decompression), extracellular GFAP in the early hypothermia group was also lower than in the normothermia and late hypothermia groups (early, 5.5 ± 2.9 ng/dl; late, 7.4 ± 3.4 ng/dl; normothermia, 15.3 ± 8.4 ng/dl; sham, 3.3 ± 1.0 ng/dl; normothermia vs sham; p < 0.01). The number of Fluoro-Jade B-positive cells in the early hypothermia group was significantly smaller than that in the normothermia group (normothermia vs early: 774,588 ± 162,173 vs 180,903 ± 42,212, p < 0.05). Also, the injury area and volume were smaller in the early hypothermia group in which hypothermia was induced before craniotomy and cerebral reperfusion (early, 115.2 ± 15.4 mm(3); late, 344.7 ± 29.1 mm(3); normothermia, 311.2 ± 79.2 mm(3); p < 0.05).

CONCLUSIONS: The data suggest that early, preoperatively induced hypothermia could mediate the reduction of neuronal and glial damage in the reperfusion phase of ischemia/reperfusion brain injury.

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