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 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.


OBJECTIVE
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.
Forbes
M L
ML
Safar Center for Resuscitation Research, The University of Pittsburgh Brain Trauma Research Center, and Department of Anesthesiology/Critical Care Medicine, Pennsylvania 15260, USA.
Clark
R S
RS
Dixon
C E
CE
Graham
S H
SH
Marion
D W
DW
DeKosky
S T
ST
Schiding
J K
JK
Kochanek
P M
PM
D018685:Anesthetics, Inhalation / Q000008:administration & dosage; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D001794:Blood Pressure / Q000502:physiology; D001831:Body Temperature / Q000502:physiology; D001924:Brain Concussion / Q000473:pathology* / Q000503:physiopathology / Q000628:therapy; D002245:Carbon Dioxide / Q000008:administration & dosage; D016923:Cell Death; D002470:Cell Survival; D002560:Cerebrovascular Circulation / Q000502:physiology; D004195:Disease Models, Animal; D005500:Follow-Up Studies; D006624:Hippocampus / Q000473:pathology*; D007442:Intubation, Intratracheal; D007530:Isoflurane / Q000008:administration & dosage; D008297:Male; D009474:Neurons / Q000473:pathology*; D004856:Postural Balance / Q000502:physiology; D011597:Psychomotor Performance / Q000502:physiology; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012121:Respiration, Artificial / Q000009:adverse effects / Q000379:methods*; D012151:Resuscitation; D016037:Single-Blind Method; D016896:Treatment Outcome
D018685:Anesthetics, Inhalation; D001786:Blood Glucose; D002245:Carbon Dioxide; D007530:Isoflurane