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

Laboratory investigation

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  • 1 Department of Neurosurgery, University of Miami Miller School of Medicine, Miami;
  • 2 Banyan Biomarkers, Inc., Alachua;
  • 4 Departments of Psychiatry and Neuroscience, University of Florida, Gainesville, Florida; and
  • 3 Department of Emergency and Critical Care Medicine, Nippon Medical School, Tokyo, Japan
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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 mm3; late, 344.7 ± 29.1 mm3; normothermia, 311.2 ± 79.2 mm3; 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.

Abbreviations used in this paper:LPR = lactate/pyruvate ratio; MABP = mean arterial blood pressure; NABISH II = National Acute Brain Injury Study: Hypothermia II; SDH = subdural hematoma; TBI = traumatic brain injury; TTC = 2,3,5-triphenyltetrazolium chloride; UCH-L1 = ubiquitin carboxyl-terminal hydrolase-L1.

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Contributor Notes

Address correspondence to: Shoji Yokobori, M.D., Ph.D., Department of Neurosurgery, University of Miami Miller School of Medicine, 1095 NW 14th Terrace, Miami, Florida 33136. email: SYokobori@med.miami.edu.

Please include this information when citing this paper: published online November 9, 2012; DOI: 10.3171/2012.10.JNS12548.

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