Use of indomethacin in brain-injured patients with cerebral perfusion pressure impairment: preliminary report

Abstract

The effect of indomethacin, a cyclooxygenase inhibitor, was studied in the treatment of 10 patients with head injury and one patient with spontaneous subarachnoid hemorrhage, each of whom presented with high intracranial pressure (ICP) (34.4 +/- 13.1 mm Hg) and cerebral perfusion pressure (CPP) impairment (67.0 +/- 15.4 mm Hg), which did not improve with standard therapy using mannitol, hyperventilation, and barbiturates. The patient had Glasgow Coma Scale scores of 8 or less. Recordings were made of the patients' ICP and mean arterial blood pressure from the nurse's end-hour recording at the bedside, as well as of their CPP, rectal temperature, and standard therapy regimens. The authors assessed the effects of an indomethacin bolus (50 mg in 20 minutes) on ICP and CPP; an indomethacin infusion (21.5 +/- 11 mg/hour over 30 +/- 9 hours) on ICP, CPP, rectal temperature, and standard therapy regimens (matching the values before and during infusion in a similar time interval); and discontinuation of indomethacin treatment on ICP, CPP, and rectal temperature. The indomethacin bolus was very effective in lowering ICP (p < 0.0005) and improving CPP (p < 0.006). The indomethacin infusion decreased ICP (p < 0.02), but did not improve CPP and rectal temperature. The effects of standard therapy regimens before and during indomethacin infusion showed no significant changes, except in three patients in whom mannitol reestablished its action on ICP and CPP. Sudden discontinuation of indomethacin treatment was followed by significant ICP rebound. The authors suggest that indomethacin may be considered one of the frontline agents for raised ICP and CPP impairment.

Indomethacin for Brain Edema following Stroke

“…In addition, a continuous infusion of indomethacin (which was tried twice) did not seem to be effective. In contrast to our observation, the effects on MAP and ICP persisted over hours in most of the reported patients with head trauma in whom the drug was continuously infused [2, 3, 4]. However, we employed indomethacin in a patient with malignant postischemic brain edema in whom all other treatments had failed, and, therefore, it is remarkable that we could detect an effect of indomethacin at all.…”

“…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.…”

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.…”

Cyclooxygenase-2-specific Inhibitor Improves Functional Outcomes, Provides Neuroprotection, and Reduces Inflammation in a Rat Model of Traumatic Brain Injury

“…In rat brain injury models, cyclooxygenase inhibitors limit prostaglandin production (88), suppress hypermetabolism (83), and decrease brain damage after temporary focal ischemia (10,62). Clinically, indomethacin has been suggested to improve intracranial pressure and cerebral perfusion pressure after brain injury in humans (6). Recent studies focusing on the role of COX2 in neuropathology, excitotoxicity, and control of cerebral microcirculation have used the third-generation, highly specific COX2 inhibitors in both basic and clinical investigations.…”