The authors are systematically exploring pharmacologic preservation for temporarily unresuscitable exsanguination cardiac arrest in dogs. They hypothesized that the antioxidant Tempol improves cerebral outcome when added to aortic saline flush at the start of cardiac arrest. In study A, no drug (n = 8), Tempol 150 mg/kg (n = 4), or Tempol 300 mg/kg (n = 4) was added to 25 mL/kg saline flush at 24 degrees C (achieving mild cerebral hypothermia) at the start of 20-minute cardiac arrest. In study B, no drug (n = 8) or Tempol 300 mg/kg (n = 7) was added to 50 mL/kg saline flush at 2 degrees C (achieving moderate cerebral hypothermia) at the start of 40-minute cardiac arrest. Cardiac arrest was reversed with cardiopulmonary bypass. Mild hypothermia lasted for 12 hours, controlled ventilation was sustained to 24 hours, and intensive care was provided for up to 72 hours. In study A, overall performance category 1 or 2 (good outcome) was achieved in all eight dogs treated with Tempol compared with three of eight dogs in the control group ( P = 0.03). In study B, good outcome was achieved in all seven dogs treated with Tempol versus only two of 8 dogs in the control group ( P = 0.007). In both studies, neurologic deficit scores were significantly better in the Tempol group, but not total histologic damage scores. At 72 hours, electron paramagnetic resonance spectroscopy of Tempol revealed direct evidence for its presence in the brain. Single- and double-strand DNA damage, nitrotyrosine immunostaining, total antioxidant reserve, and ascorbate acid levels were similar between groups, and thiol levels were decreased after Tempol in study B. The authors conclude that when added to aortic saline flush at the start of prolonged cardiac arrest, the antioxidant Tempol can enhance mild or moderate hypothermic cerebral preservation in terms of improved functional outcome. The mechanisms involved in this beneficial effect need further clarification.