Hyperventilation early after controlled cortical impact augmented neuronal death in CA3 hippocampus

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Minimizing secondary injury after severe traumatic brain injury (TBI) is the primary goal of cerebral resuscitation. For more than two decades, hyperventilation has been one of the most often used strategies in the management of TBI. Laboratory and clinical studies, however, have verified a post-TBI state of reduced cerebral perfusion that may increase the brain's vulnerability to secondary injury. In addition, it has 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 hyperventilation applied immediately after TBI would worsen functional outcome, expand the contusion, and promote neuronal death in selectively vulnerable hippocampal neurons.

Methods. Twenty-six intubated, mechanically ventilated, isoflurane-anesthetized male Sprague—Dawley rats were subjected to controlled cortical impact (4 m/second, 2.5-mm depth of deformation) and randomized after 10 minutes to either hyperventilation (PaCO2 = 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 measured in eight rats from each group on Days 1 to 5 and 7 to 11, respectively, after controlled cortical impact. The rats were killed at 14 days postinjury, and serial coronal sections of their brains were studied 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 compared with three of 13 in the hyperventilation group, not significant [NS]). There were no differences between the groups in mean arterial blood pressure, brain temperature, and serum glucose concentration. There were no differences between groups in performance latencies for both beam balance and MWM or contusion volume (27.8 ± 5.1 mm3 compared with 27.8 ± 3.3 mm3, 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 the 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 hyperventilation early after TBI augments CA3 hippocampal neuronal death; however, it did not impair functional outcome or expand the contusion. These data indicate that CA3 hippocampal neurons are selectively vulnerable to the effects of hyperventilation after TBI. Further studies delineating the mechanisms underlying these effects are needed, because the injudicious application of hyperventilation early after TBI may contribute to secondary neuronal injury.

Article Information

Address reprint requests to: Patrick M. Kochanek, M.D., Safar Center for Resuscitation Research, 3434 Fifth Avenue, Pittsburgh, Pennsylvania 15260.

© AANS, except where prohibited by US copyright law.

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Figures

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    Graphs showing time course of (A) PaCO2 (mm Hg), (B) arterial pH, (C) MABP (mm Hg), and (D) brain temperature (°C) in all rats treated with either normal ventilation (triangles w/ solid line, 13 animals) or hyperventilation (squares w/ broken line, 13 animals) after controlled cortical impact. *p < 0.05 for normal ventilation compared with hyperventilation. Data are expressed as the mean ± standard error of the mean (SEM).

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    Graph showing mean beam balance performance latencies (mean ± SEM, in seconds) in rats before and on Days 1 to 5 after controlled cortical impact (4 m/second, 2.5-mm cortical deformation depth). Repeated-measures ANOVA revealed no difference in duration of balance maintained between the two groups (triangles = normal ventilation [eight rats]; squares = hyperventilation [eight rats]).

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    Graph showing MWM performance latency to find a hidden platform (mean ± SEM, in seconds) by rats on Days 7 to 11 after controlled cortical impact. There was no difference between groups (triangles = normal ventilation [eight animals]; squares = hyperventilation [eight animals]) when performances were compared using ANOVA with repeated measures.

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    Bar graph depicting mean lesion area (left y-axis, mm2) compared with distance from occiput (mm) measured 14 days after controlled cortical impact (open bars, normal ventilation [11 rats]; closed bars, hyperventilation [10 rats]). Contusion volume (mm3) was calculated as the sum of these areas in each group and is depicted as the cumulative volume (right y-axis) in the normal ventilation (triangles) and hyperventilation (squares) groups. There was no difference between groups in contusion volume (normal ventilation, 27.8 ± 5.1 mm3 compared with hyperventilation, 27.8 ± 3.1 mm3, mean ± SEM).

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    Box plots representing the number of surviving CA1 and CA3 hippocampal neurons in coronal brain sections cut from the center of the lesion in the hemisphere ipsilateral to the contusion. Cells were counted 14 days postinjury. The median line is placed within the shaded 25th to 75th percentile range. There was a reduction in the number of surviving CA3 hippocampal neurons after injury in normal ventilation (open boxes) compared with hyperventilation (solid boxes) groups (29.7 cells/hpf, range 24.2–31.7 compared with 19.9 cells/hpf, range 17–23.7). *p < 0.05, Mann—Whitney rank-sum test.

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