CEREBRAL VASOCONSTRICTION BY INDOMETHACIN IN INTRACRANIAL HYPERTENSION - AN EXPERIMENTAL INVESTIGATION IN PIGS

Background: Uncontrolled increase in intracranial pressure is the most significant cause of mortality in patients with severe traumatic brai n lesions, and the efficacy of common nonsurgical treatments has been questioned. Pharmacologically induced cerebral vasoconstriction aiming at a decrease of cerebral blood volume and brain edema has recently b een suggested as an alternative. Limited clinical experience with indo methacin as a cerebral vasoconstrictor has been reported but dose- or concentration-effect relationships were not investigated. In particula r, there is a lack of data showing whether a therapeutic window exists in which risk of cerebral ischemia is minimized. Methods: In a porcin e model of intracranial hypertension induced with two epidural balloon s to a level of 26-28 mmHg, 18 animals were randomized into three grou ps receiving 0.1, 0.3, and 3.0 mg . kg(-1). h(-1) indomethacin, respec tively, as an infusion during 80 min. Intracranial pressure, mean arte rial blood pressure, and electrocortical activity were recorded contin uously and measurements of cerebral blood now, arteriovenous differenc e in oxygen content and cerebral venous pH were performed at 5, 20, 40 , 60, and 75 min during and 10 min after the indomethacin infusion. Ba seline measurements, performed before the indomethacin infusion, were used as an internal control. The infusions were pharmacokinetically de signed to mimic the reported clinical conditions. Results: An 11% mean decrease in intracranial pressure during the infusion, but no effects on cerebral blood flow, arteriovenous difference in oxygen content, v enous pH, and electrocortical activity were observed in the group of a nimals receiving 0.1 mg . kg(-1). h(-1). When the rate of infusion was 0.3 and 3.0 mg . kg(-1). h(-1), the decrease in intracranial pressure was 20 and 25%, respectively, but this was accompanied by a decrease in cerebral blood flow and venous pH, an increase in arteriovenous dif ference in oxygen content, and a slowing of the electrocortical activi ty. All changes were statistically significant. Conclusions: Indometha cin, which is known to constrict precapillary resistance vessels, caus ed a decrease in intracranial pressure during experimental intracrania l hypertension. This was accompanied by signs of cerebral ischemia whe n Indomethacin was used in a dose that has previously been suggested f or the treatment of increased intracranial pressure in patients.