Effect of the duration of middle cerebral artery occlusion on the risk of hemorrhagic transformation after tissue plasminogen activator injection in rats

Thrombolysis with tissue plasminogen activator increases the risk of brain hemorrhage after ischemic stoke. However, the relationship between the duration of ischemia and the risk of hemorrhagic transformation is still unclear. In the present study, we used a rat model of thrombolysis with tissue plasminogen activator after different periods of middle cerebral artery occlusion and we analyzed the effect of the duration of ischemia on the rate of hemorrhagic transformation, the extent of cerebral infarction and the degree of neurological impairment. Most of the rats reperfused before 3 h of ischemia did not develop intracerebral hemorrhages, while 90% of the rats occluded for more than 3 h developed cerebral hemorrhages ranging from benign hemorrhagic infarctions to severe parenchymal hemorrhages. After 6-hour occlusion, the proportion of parenchymal hemorrhages, as seen in 50% of the animals, was significantly augmented compared to the 11 to 13% of parenchymal hemorrhages observed in animals occluded for less than 6 h. Meanwhile, the quantity of hemoglobin measured in the brain parenchyma of animals showing hemorrhagic infarctions was doubled (0.19 mg/hemisphere in rats reperfused after 6 h of ischemia compared to 0.08 mg/hemisphere in rats reperfused earlier). Neurological outcome did also worsen with the duration of ischemia. However, the amplitude of cerebral infarction was not statistically different in animals subjected to short or longer time of ischemia. In addition, the risk of hemorrhagic transformation and the degree of neurological impairment were not statistically different between animals occluded for less than 3 h and animals permanently occluded. Our data clearly demonstrate a progression in the risk and gravity of hemorrhagic transformation that parallels the increase in the duration of transient cerebral ischemia. The results suggest a relationship, which is independent on the duration of ischemia, between neurological deficit and hemorrhagic transformation and confirm the expected but still debated principle that early recanalization of an occluded artery reduces the hemorrhagic risk after thrombolysis with tissue plasminogen activator.