TIRILAZAD MESYLATE DOES NOT IMPROVE EARLY CEREBRAL METABOLIC RECOVERY FOLLOWING COMPRESSION ISCHEMIA IN DOGS

Background and Purpose: Tirilazad mesylate (U74006F) has been reported to improve recovery following cerebral ischemia. We conducted a randomized blinded study to determine if the drug would improve immediate metabolic recovery after complete cerebral compression ischemia. Methods: Mongrel dogs were anesthetized with pentobarbital and fentanyl and treated with either vehicle (citrate buffer, n=8) or tirilazad (1.5 mg/kg i.v. plus 0.18 mg/kg/hr, n=8). Normothermic complete cerebral compression ischemia was produced for 12 minutes by lateral ventricular fluid infusion to raise intracranial pressure above systolic arterial pressure. Cerebral high-energy phosphate concentrations and intracellular pH were measured by phosphorus magnetic resonance spectroscopy. Cerebral blood flow was measured with radiolabeled microspheres, and oxygen consumption was calculated from sagittal sinus blood samples. Somatosensory evoked potentials were measured throughout the experiment. Results: During ischemia, both groups demonstrated complete loss of high-energy phosphates and a fall in intracellular pH (vehicle, 5.76+/-0.23; tirilazad, 5.79+/-0.26; mean+/-SEM). At 180 minutes of reperfusion, there were no differences between groups in recovery of intracellular pH (vehicle, 6.89+/-0.07; tirilazad, 6.88+/-0.18), phosphocreatine concentration (vehicle, 89+/-16%; tirilazad, 94+/-24% of baseline value), oxygen consumption (vehicle, 2.6+/-0.2 ml/min/100 g; tirilazad, 1.8+/-0.5 ml/min/100 g), or somatosensory evoked potential amplitude (vehicle, 11+/-6%; tirilazad, 7+/-4% of baseline value). Forebrain blood flow fell below baseline levels at 180 minutes of reperfusion in the tirilazad-treated animals but not in the vehicle-treated dogs (vehicle, 28+/-4 ml/min/100 g; tirilazad, 18+/-5 ml/min/100 g). Conclusions: We conclude that tirilazad pretreatment does not improve immediate metabolic recovery 3 hours following 12 minutes of normothermic complete ischemia produced by cerebral compression.