Controlled reperfusion prevents neurologic injury after global brain ischemia in a novel ischemic brain model

Introduction

Recent investigations have revealed that the state of post-ischemic brain recirculation is of major importance in recovery from sudden death, and we developed an isolated global ischemic brain model that excludes the confounding variables of bypass, donor blood, and whole body damage to investigate the strategy of controlled reperfusion. This study examines primary damage of cerebral function and tissue with uncontrolled brain reperfusion following 30 minutes of brain ischemia, and tests whether controlled brain reperfusion can attenuate the damage.

Methods

Sixteen pigs underwent 30 minutes of global brain ischemia by clamping major neck vessels via a small suprasternal incision. Seven pigs then received uncontrolled reperfusion with normal blood, while the other nine pigs received controlled reperfusion by infusing a modified (leukodepleted, hypocalcemic, hyperosmolar, alkalotic, normoglycemic, antioxidant enriched) warm blood solution into both carotid arteries for 20 minutes. Six pigs underwent Sham operation. Brain oxygen uptake and venous conjugated dienes (CD) were measured during reperfusion. The neurologic deficit score (NDS) (0 = normal, 500 = brain death) was determined at 24 hours after ischemia, and brain water contents and cerebral infarction by 2,3,5-triphenyl tetrazolium chloride staining were assessed post mortem.

Results

Sham pigs were neurologically normal at 24 hours. Uncontrolled reperfusion resulted in two early deaths with brain herniation, multiple seizures, low brain oxygen uptake*, high CD levels (1.64 ± 0.03 A₂₃₃ nm)*, and high NDS (244 ± 19 in survivors)* indicating marked functional neurologic impairment. Postmortem analysis showed marked brain edema (84.3 ± 0.6%)* and extensive brain infarcts*. In contrast, pigs receiving controlled reperfusion had high brain oxygen uptake, low CD levels (1.3 ± 0.07 A_{233 nm}), no post seizures, and low NDS (41 ± 11), with all pigs being able to sit and eat, and three showing complete recovery. Brain edema was reduced (81.8 ± 0.5%), and 2,3,5-triphenyl tetrazolium chloride staining showed no infarction. *P < 0.05 uncontrolled vs. controlled, mean ± SEM.

Conclusion

Our novel ischemic brain model provides an effective tool to study brain ischemia. More importantly, these data indicate that controlled reperfusion attenuates reperfusion injury in the brain as it has been applied in other organs, and introduces the potential of using controlled reperfusion as a new treatment for sudden death and stoke.