Desmethyl tirilazad improves neurologic function after hypoxic ischemic brain injury in piglets

OBJECTIVE:Desmethyl tirilazad is a lipid-soluble free radical quencher. Deferoxamine reduces free radicals by chelating iron and reducing hydroxyl formation. Free radical inhibitors have shown promise in several hypoxic ischemic brain injury models, and we wished to see if this work could be extended to our newborn piglet model. DESIGN:Randomized controlled trial. SUBJECTS:Piglets (0 to 3 days old). INTERVENTION:Carotid snares and arterial and venous catheters were placed under 1.5% isoflurane anesthesia. In Experiment 1, piglets were randomly assigned to receive either 3 mg/kg desmethyl tirilazad or vehicle at −15 and 90 mins. In Experiment 2, piglets were randomly assigned to receive either 20 mg/kg desmethyl tirilazad at −15 mins followed by 8 mg/kg/hr for 90 mins or 100 mg/kg deferoxamine at −15 mins or vehicle. At time 0, both carotid arteries were clamped and blood was withdrawn to reduce the blood pressure to two-thirds normal. At 15 mins, inspired oxygen was reduced to 6%. At 30 mins, the carotid snares were released, the withdrawn blood was reinfused, and the oxygen was switched to 100%. On the third day after the hypoxic ischemic injury, the animals were killed by perfusing their brains with 10% formalin. We tested the timing of lipid peroxidation and inhibition of lipid peroxidation by these agents by freezing the brains of a subset of pigs in liquid nitrogen. MEASUREMENTS:Neurologic examination and brain pathology were scored by blinded observers. Thiobarbituric acid-reactive substance and oxidized and reduced glutathione were measured on frozen brains. MAIN RESULTS:Desmethyl tirilazad (20 mg/kg) and 100 mg/kg deferoxamine inhibit lipid peroxidation. Desmethyl tirilazad (20 mg/kg) improves neurologic exam, but 3 mg/kg Desmethyl tirilazad or 100 mg/kg deferoxamine does not. Neither desmethyl tirilazad nor deferoxamine improves pathologic results. CONCLUSIONS:High-dose desmethyl tirilazad improves neurologic function after hypoxic ischemic brain injury in the newborn piglet.