AUGMENTED NEURONAL DEATH IN CA3 HIPPOCAMPUS FOLLOWING HYPERVENTILATION EARLY AFTER CONTROLLED CORTICAL IMPACT

Minimizing secondary injury after severe traumatic brain injury (TBI) is the primary goal of cerebral resuscitation. For more than two decad es, hyperventilation has been one elf the most often used strategies i n the management of TBI. Laboratory and clinical studies, however, hav e verified a post-TBI state of reduced cerebral perfusion that may inc rease the brain's vulnerability to secondary injury. In addition, it h as been suggested in a clinical study that hyperventilation may worsen outcome after TBI. Object. Using the controlled cortical impact model in rats, the authors tested the hypothesis that aggressive hyperventi lation applied immediately after TBI would worsen functional outcome, expand the contusion, and promote neuronal death in selectively vulner able hippocampal neurons. Methods. Twenty-six intubated, mechanically ventilated, isoflurane-anesthetized male Sprague-Dawley rats were subj ected to controlled cortical impact (4 m/second, 2.5-mm depth of defor mation) and randomized after 10 minutes to either hyperventilation (Pa CO2 = 20.3 +/- 0.7 mm Hg) or normal ventilation groups (PaCO2 = 34.9 /- 0.3 mm Hg) containing 13 rats apiece and were treated for 5 hours. Beam balance and Morris water maze (MWM) performance latencies were me asured in eight rats from each group on Days 1 to 5 and 7 to 11, respe ctively, after controlled cortical impact. The rats were killed at 14 days postinjury, and serial coronal sections of their brains were stud ied for contusion volume and hippocampal neuron counting (CA1, CA3) by an observer who was blinded to their treatment group. Mortality rates were similar in both groups (two of 13 in the normal ventilation comp ared with three of 13 in the hyperventilation group, not significant [ NS]). There were no differences between the groups in mean arterial bl ood pressure, brain temperature, and serum glucose concentration. Ther e were no differences between groups in performance latencies for both beam balance and MWM or contusion Volume (27.8 +/- 5.1 mm(3) compared with 27.8 +/- 3.3 mm(3), NS) in the normal ventilation compared with the hyperventilation groups, respectively. In brain sections cut from the center of the contusion, hippocampal neuronal survival in the CA1 region was similar in both groups; however, hyperventilation reduced t he number of surviving hippocampal CA3 neurons (29.7 cells/hpf, range 24.2-31.7 in the normal ventilation group compared with 19.9 cells/hpf , range 17-23.7 in the hyperventilation group [25th-75th percentiles]; p < 0.05, Mann-Whitney rank-sum test). Conclusions. Aggressive hyper ventilation early after TBI augments CA3 hippocampal neuronal death; h owever, it did not impair functional outcome or expand the contusion. These data indicate that CA3 hippocampal neurons are selectively vulne rable to the effects of hyperventilation after TBI. Further studies de lineating the mechanisms underlying these effects are needed, because the injudicious application of hyperventilation early after TBI may co ntribute to secondary neuronal injury.