CO2 and indomethacin vasoreactivity in patients with head injury

Abstract

The purpose of this study was to compare the effect of hyperventilation and indomethacin on cerebral circulation, metabolism and pressures in patients with acute severe head injury in order to see if indomethacin may act supplementary to hyperventilation. Fourteen severely head injured patients entered the study. Intracranial pressure (ICP), mean arterial blood pressure (MABP) and cerebral perfusion pressure (CPP) were monitored continuously. Within the first four days after the trauma the CO(2) and indomethacin vasoreactivities were studied by measurements of cerebral blood flow (CBF) (Cerebrograph 10a, intravenous (133)Xe technique) and arterio-venous difference of oxygen (AVdO(2)). Ischaemia was evaluated from changes in CBF, saturation of oxygen in the jugular bulb (SvjO(2)), lactate and lactate/oxygen index (LOI). Data are presented as medians and ranges, results are significant unless otherwise indicated. Before intervention ICP was well controlled ,(14.8 (9-24) mmHg) and basic CBF level was 39.1 (21.6-75.0) ml/100 g/min). The arterio-venous oxygen differences were generally decreased (AVdO(2) = 4.3 (1.8-8.1) ml/100 ml) indicating moderate luxury perfusion. Levels of CMRO(2) were decreased (1.54 (0.7-3.2) ml/100 g/min) as well. During hyperventilation (delta PaCO(2)=0.88 (0.62-1.55) kPa) CBF decreased with 11.8 (-33.4-29.7) %/kPa and ICP decreased with 3.8 (0-10) mmHg. AVdO(2) increased 34.0 (4.0-139.2) %/kPa, MABP was unchanged, CMRO(2) and CPP increased (delta CPP = 3.9 (-10-20) mmHg). AVD (lactate) and LOI were unchanged. No correlations between CBF responses to hypocapnia and outcomes were observed. An i.v. bolus dose of indomethacin (30 mg) decreased CBF 14.7 (-16.7-57.4)% and ICP decreased 4.3 (-1-17) mmHg. AVdO(2) increased 27.8 (-40.0-66.7)%, MABP (delta MABP = 4.9 (-2-21) mmHg) and CPP (delta CPP = 8.7 (3-29) mmHg) increased while CMRO2 was unchanged. No changes in AVd (lactate) and LOI indicating cerebral ischaemia were found. Compared to hyperventilation (changes per 1 kPa, at PaCO(2) level = 4.05 kPa) the changes in MABP, CPP and CBF were significantly greater after indomethacin, while the changes in AVdO(2), ICP, SvjO(2) and LOI were of the same order of magnitude. No correlation between relative reactivities to indomethacin and CO(2), evaluated from changes in CBF and AVdO(2), or between the decrease in ICP after the two procedures were found. Thus, some patients reacted to indomethacin but not to hyperventilation, and vice versa. These results suggest that indomethacin and hyperventilation might act independently, or in a complementary fashion in the treatment of patients with severe head injury.

Prolonged Cyclooxygenase-2 Induction in Neurons and Glia Following Traumatic Brain Injury in the Rat

“…However, the role of COX2 in the pathophysiology of TBI is uncertain. Treatments that prevent COX2 induction (glucocorticoids) or inhibit enzyme activity (indomethacin) have had, at best, equivocal success in the clinical treatment of TBI (Benedek et al, 1987;Biestro et al, 1995;Dahl et al, 1996). If, contrary to current opinion, COX2 induction were beneficial, then inhibition might result in a worsened outcome.…”

Cerebral Metabolic Response to Low Blood Flow: Possible Role of Cytochrome Oxidase Inhibition

“…The only tomographic study on living animals (Schumann et al, 1996), found no change of the global CMR O 2 but interestingly (see below) a small and significant increase of CMR O 2 in thalamus and pons. In adult humans, the effect of indomethacin on CMR O 2 was assessed only by the arterio-venous difference (Wennmalm et al, 1981;Jensen et al, 1991;Dahl et al, 1996;Bundgaard et al, 1996) and no significant change was observed in any of these studies. However, a study of preterm infants with near-infrared-spectroscopy of cytochrome oxidase indicated reduced oxygenation (Benders et al, 1995).…”

“…We then tested the properties of the extended model equation by calculating the magnitude of the equation parameters, which would accurately predict the values of oxygen consumption measured in the course of drug-induced lowering of CBF. We used indomethacin, which lowers blood flow, probably by nonselectively inhibiting cyclooxygenase-1 (COX-1) and -2 (Jensen et al, 1991(Jensen et al, , 1993Dahl et al, 1996;Imberti et al, 1997;Zonta et al, 2003), although other mechanisms have also been proposed (Wang et al, 1993;Parfenova et al, 1995).…”

Indomethacin for Brain Edema following Stroke

“…Many experimental and clinical studies show that indomethacin acts as a potent vasoconstrictor on the cerebral vasculature [3, 4, 5, 6]. The mechanisms of the indomethacin-induced vasoconstriction are largely unclear.…”

“…A variety of therapies have been used in these patients, but unfortunately, these treatments frequently are not effective. There is increasing evidence from animal models and a few reports of patients with head trauma that indomethacin decreases elevated ICP [2, 3, 4]. Up to now, indomethacin has not been used in patients with brain edema following ischemic stroke.…”