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.