Effect of indomethacin pretreatment on acute mortality in experimental brain injury

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✓ The effect of indomethacin administration on the mortality rate of brain-injured rats was studied in four groups of animals subjected to a level of injury with a fluid-percussion apparatus predetermined to cause 50% mortality (50% lethal dose, or LD50). There were 24 animals in each of the following groups: 1) a control group, on which the LD50 was evaluated; 2) an ethanol-treated group with a mean blood serum level of 0.32 ± 0.03 gm% (± standard error of the mean); 3) an indomethacin-treated group at a dose level of 3 mg/kg body weight administered intraperitoneally 10 to 15 minutes before injury; and 4) an indomethacin/ethanoltreated group. Significant differences in mortality rates were found in these experimental groups; namely, 50%, 58%, 8.3% (p < 0.005), and 25% (p < 0.05), respectively. The predetermined LD50 level of a 2.5- to 2.6-atm peak pressure pulse produced immediate apnea in all animals, which was either sustained (Type III), followed by temporary respiratory recovery (Type II), or followed by permanent resumption of breathing (Type I). The most important effect of indomethacin on respiratory function was manifested by a much higher percentage of Type I respiratory responses and a much lower percentage of Type II and III responses (hence a lower mortality rate). There was also a more rapid return to normal breathing in the postapneic period of recovery. Suppression of prostaglandin synthesis and of superoxide anion production at the onset of trauma may explain, at least in part, these favorable effects of indomethacin.

Article Information

Address for Dr. Kim: Department of Neurosurgery, Wonju College of Medicine, Yonsei University, Wonju, Republic of Korea.

Address reprint requests to: John L. Patterson, Jr., M.D., Division of Cardiopulmonary Laboratories and Research, Department of Medicine, Medical College of Virginia, MCV Station Box 282, Richmond, Virginia 23298.

© AANS, except where prohibited by US copyright law.

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Figures

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    Schematic drawing of the experimental preparation. A: The rat is intubated to allow end-tidal pCO2 sampling. PE 240 = polyethylene tubing. B: The burr hole is contoured just caudal to the coronal suture line. C: A commercial stainless steel screw is modified for use as a nonhindering anchor for the cranial connector. D: The relationship between the anchoring screws and the electroencephalographic wires.

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    Graphic outline of the three distinctive respiratory responses. Type I: spontaneous and sustained recurrence of breathing; Type II: spontaneous recurrence of breathing, not sustained; and Type III: permanent cessation of breathing.

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    Histogram of mortality rate: 50% in the control group; 58% in the ethanol (EtOH) group; 8.3% in the indomethacin group; 25% in the ethanol/indomethacin group. The difference is statistically significant between the control and indomethacin groups (p < 0.005) and between the ethanol and ethanol/indomethacin groups (p < 0.005).

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    Absorption profile from the intraperitoneal cavity to arterial blood for indomethacin. The time required for maximum drug concentration was about 10 minutes with an absorption rate constant of 0.195 min−1. There was no significant difference between the control and the brain-injured groups.

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    14C-labeled indomethacin content in brain normalized to arterial blood. The brain 14C content was significantly higher in the trauma group (p < 0.05).

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    Histogram of apneas showing combined Type I and II respiratory responses for each of the four groups: control, 11.7 ± 2.6 seconds; ethanol (EtOH), 16.0 ± 3.1 seconds; indomethacin, 8.0 ± 1.3 seconds; and ethanol/indomethacin, 12.7 ± 2.4 seconds. The differences are statistically significant only between the ethanol-treated group and the indomethacin-treated group (p < 0.05). The values are means ± standard error of the means.

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