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 At time 0, both carotid arteries were clamped and blood was withdrawn to reduce the blood pressure to two-thirds normal.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 At 30 mins, the carotid snares were released, the withdrawn blood was reinfused, and the oxygen was switched to 100%.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.

Use of polyethylene glycol-bound superoxide dismutase, polyethylene glycol-bound catalase, and nimodipine to prevent hypoxic ischemic injury to the brain of newborn pigs.

OBJECTIVE: To determine if polyethylene glycol-bound superoxide dismutase and catalase and nimodipine, alone or in combination, will ameliorate hypoxic ischemic injury to the brain. SUBJECTS: A total of 78 newborn (0 to 3 days) pigs were used. DESIGN: Prospective, blinded, randomized, controlled trial. INTERVENTIONS: The piglets were subjected to hypoxic ischemic brain injury. Carotid arteries were ligated at time 0 and BP was reduced one third by hemorrhage. At 15 mins, FIO2 was reduced to 0.6. At 30 mins, carotids were released, blood was reinfused, and FIO2 was increased to 1.0. Pigs were randomly assigned at time 35 mins to receive either: 10,000 U/kg of polyethylene glycol-bound superoxide dismutase and catalase (group 1); 0.5 mg/kg of nimodipine (group 2); both 10,000 U/kg of superoxide dismutase and catalase and 0.5 mg/kg of nimodipine (group 3); or no drugs (controls). MEASUREMENTS: The time after reoxygenation for return of electroencephalogram, respiration, blink and pain were recorded in minutes as well as a neurologic examination at 1, 2, and 3 days and pathologic examination of the brain at 3 days, both by blinded observers. MAIN RESULTS: There were no significant differences in the four groups. CONCLUSIONS: Polyethylene glycol-bound superoxide dismutase and catalase, and nimodipine, either alone or in combination, do not ameliorate hypoxic ischemic injury to the brain in the newborn pig when given 5 mins after reoxygenation.

Fructose-1,6-bisphosphate does not ameliorate hypoxic ischemic injury to the central nervous system in the newborn pig.

BACKGROUND AND METHODS: Fructose-1,6-bisphosphate has been shown to improve the outcome of hypoxic ischemic brain injury in adult rabbits. We wished to see if these results could be extended to a newborn animal. Twenty-four 0- to 3-day-old piglets were randomized to receive 300 mg/kg of fructose-1,6-bisphosphate 5 mins before injury, followed by a continuous infusion of 15 mg/kg/min of fructose-1,6-bisphosphate for the next 90 mins, or the equivalent volume of normal saline. Hypoxic ischemic central nervous system damage was induced by ligating both carotid arteries and reducing their BP to two thirds of the normal value for 30 mins. In the last 15 mins of this 30 mins, the FIO2 was reduced to 0.6. At 30 mins, the piglets were resuscitated with an FIO2 of 1.0, the carotid ligatures were released, and the removed blood was reinfused. RESULTS: The neurologic examination scores at 1, 2, and 3 days after injury and pathologic examination scores at 3 days after injury were not different in the fructose-1,6-bisphosphate-treated and the control animals. CONCLUSION: Fructose-1,6-bisphosphate does not ameliorate hypoxic ischemic brain injury in the newborn pig.