title: Neuroprotective effect of hypothermia on neuronal injury in diffuse traumatic brain injury coupled with hypoxia and hypotension.
abstract: It is well established in mechanical head trauma that posttraumatic secondary insults, such as hypoxia and hypotension exacerbate neuronal injury and lead to worse outcome. In this study, the neuroprotective effect of hypothermia on the reduction of supraventricular subcortical neuronal damage was evaluated using an impact-acceleration model of diffuse traumatic brain injury coupled with both moderate and severe periods of hypoxia and hypotension. A total of 135 adult male Sprague-Dawley rats (340-375 g) were divided into three experimental studies: (I) physiological evaluation (n = 36); (II) quantitative analysis of the effect of trauma coupled with moderate and severe hypotension on neuronal damage assessed at 4 (n = 39) and 24 h (n = 24); and (III) the neuroprotective effect of hypothermia following moderate secondary insult (n = 36). Induction of hypothermia occurred at 15 min postinjury, to a level of 30 degrees C for 60 min. At the designated time points (4 and 24 h), the animals were sacrificed via standard transcardial perfusion techniques for histological processing. Quantitative assessment of neuronal damage using routine H&E staining at 4 hours showed neuronal damage which correlated with the severity of secondary insult. Animals exposed to trauma alone had a mean number of damaged neurons of 7.61 +/- 3.08/high powered field (hpf) compared with a mean of 1.21 +/- 0.30/hpf in the sham operated group (p = 0.015). Animals exposed to trauma with 10 min of hypoxia and hypotension (THH-10) showed a statistically significant number of damaged neurons compared to the sham-operated animals (7.50 +/- 2.15 damaged neurons/hpf, p = 0.013), whereas, neuronal damage in animals undergoing trauma with a 30-min secondary insult of hypoxia and hypotension (THH-30) was markedly increased (100 +/- 30.20/hpf, p = 0.002). Statistical analysis showed no significant difference in neuronal damage in animals subjected to secondary insult alone. At 24 h, the evolution of neuronal damage in the trauma alone group (5.08 +/- 1.63/hpf) was relatively static; however, there was a remarkable increase in the neuronal damage of the THH-10 group (29.88 50 +/- 8.20/hpf). However, hypothermia provided nearly complete protection against secondary insults, and neuronal damage was equal to that of the trauma alone group (p = 0.42). The results of this study confirm that hypothermia provides remarkable protection against the adverse effects of neuronal damage exacerbated by secondary injury. This study also presents a new model of secondary insult, which can be used experimentally to further define the mechanism of increased vulnerability of the injured brain.
authors.affiliation: Division of Neurosurgery, Medical College of Virginia, Richmond, USA.
authors.forename: M
authors.initials: M
authors.lastname: Yamamoto
authors.forename: C R
authors.initials: CR
authors.lastname: Marmarou
authors.forename: M F
authors.initials: MF
authors.lastname: Stiefel
authors.forename: A
authors.initials: A
authors.lastname: Beaumont
authors.forename: A
authors.initials: A
authors.lastname: Marmarou
mesh_terms: D000818:Animals; D001930:Brain Injuries / Q000150:complications / Q000473:pathology / Q000628:therapy; D002540:Cerebral Cortex / Q000293:injuries / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D007022:Hypotension / Q000150:complications / Q000473:pathology; D007036:Hypothermia, Induced; D000860:Hypoxia / Q000150:complications / Q000473:pathology; D008297:Male; D009474:Neurons / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012720:Severity of Illness Index; D013997:Time Factors