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 brain lesions, and the efficacy of common non-surgical treatments has been questioned. Pharmacologically induced cerebral vasoconstriction aiming at a decrease of cerebral blood volume and brain edema has recently been suggested as an alternative. Limited clinical experience with indomethacin as a cerebral vasoconstrictor has been reported but dose- or concentration-effect relationships were not investigated. In particular, there is a lack of data showing whether a therapeutic window exists in which risk of cerebral ischemia is minimized.


METHODS
In a porcine model of intracranial hypertension induced with two epidural balloons to a level of 26-28 mmHg, 18 animals were randomized into three groups receiving 0.1, 0.3, and 3.0 mg.kg-1.h-1 indomethacin, respectively, as an infusion during 80 min. Intracranial pressure, mean arterial blood pressure, and electrocortical activity were recorded continuously and measurements of cerebral blood flow, arteriovenous difference 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. Baseline measurements, performed before the indomethacin infusion, were used as an internal control. The infusions were pharmacokinetically designed 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, venous pH, and electrocortical activity were observed in the group of animals 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 difference in oxygen content, and a slowing of the electrocortical activity. All changes were statistically significant.


CONCLUSIONS
Indomethacin, which is known to constrict precapillary resistance vessels, caused a decrease in intracranial pressure during experimental intracranial hypertension. This was accompanied by signs of cerebral ischemia when indomethacin was used in a dose that has previously been suggested for the treatment of increased intracranial pressure in patients.
Nilsson
F
F
Department of Anesthesia and Intensive Care, Malmö University Hospital, Sweden.
Björkman
S
S
Rosén
I
I
Messeter
K
K
Nordström
C H
CH
D000818:Animals; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D006935:Hypercapnia / Q000503:physiopathology; D007213:Indomethacin / Q000493:pharmacokinetics / Q000494:pharmacology*; D007427:Intracranial Pressure / Q000187:drug effects*; D013552:Swine; D014655:Vascular Resistance / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects*; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D014662:Vasoconstrictor Agents; D007213:Indomethacin