Pathophysiology of brain edema formation.

A number of mechanisms seem to be involved in edema formation after an ICH. At least three phases of edema are involved in ICH. These include a very early phase (first several hours) involving hydrostatic pressure and clot retraction, a second phase (first 2 days) involving the activation of the coagulation cascade and thrombin production, and a third phase (after 3 days) involving RBC lysis and hemoglobin-induced neuronal toxicity. Activation of the complement system in brain parenchyma also plays an important role in the second and third phases. There are potential therapeutic strategies to address each of these mechanisms. Because the adverse effect of an ICH seems to result from a toxic effect of blood components on brain tissue, early clot removal may be the best strategy, because it results in the removal of all the toxic components [93]. Hematoma aspiration after tissue plasminogen activator (tPA) infusion has also been shown to be relatively safe and effective in animal models. Kaufman et al [94] reported that tPA lysed the hematoma in minutes and did not cause inflammation or bleeding in rabbits. Because clots lysed with tPA can be aspirated through a needle or catheter, mechanical brain injury by this method is minimized. In a rat model, aspiration of clot with tPA reduced clot volume and brain injury [95,96]. Recently, Wagner et al [97] infused tPA into hematomas in a porcine model at 3 hours after induction and aspirated the liquified clots 1 hour later. Clot removal after tPA treatment resulted in a 72% reduction in hematoma volume compared with untreated controls. Clot removal also reduced brain edema volume and BBB disruption and improved cerebral tissue pressure [93]. Six randomized trials have been accomplished, but surgical evacuation of the clot remains controversial [98-103]. Recently, thrombolysis and aspiration under CT guidance reduced the hematoma volume effectively [104]. Infusion of tPA directly into the hematoma before clot aspiration has also been used in human beings. Up to 90% of the original hematoma volume can be removed [105, 106]. Schaller et al [107] injected tPA directly into a hematoma 72 hours after the ictus in patients. The hematomas were lysed, and the liquified clots were drained in 14 patients. Two patients died, but none had recurrent hemorrhage. In conclusion, much has been learned about the basic mechanisms involved in edema formation after ICH. Animal models indicate that a number of components of blood are capable of inducing brain injury and brain edema. Now, it is time to translate that basic information into clinical trials.