Abstract
T-PA is expected to be used for cisternal drainage in subarachnoidal hemorrhage, because rapid and safe liquefaction and removal of clots are very important. We performed a pharmacological experimental study on the efficacy, administration method, and toxicity of various hematolytic agents, especially tissue-plasminogen activator (t-PA).
The hematolysis rate following a single administration was 88.9% with t-PA+Elase (Fibrinolysin+Deoxyribonuclease), 85.4% with t-PA, 84.6% with t-PA+urokinase, 80.2% with t-PA+urokinase+Elase, 27.5% with Elase+urokinase, 24.6% with Elase+urokinase+heparin, 17.2% with heparin+urokinase, 16.4% with urokinase, 12.6% with Elase, and 10.1% with the control (saline). Locally administered t-PA had remarkably greater hematolytic effects than urokinase on the hematoma (p<0.001). The effect of the local administration of t-PA seemed to reach a plateau at a dosage of 10×104 IU/ml. The local effects of each hematolytic agent continued for about 4-8 hours but markedly decreased thereafter.
Because of the low dose-dependency, frequent administrations of divided doses were more effective than a few administrations at a large dosage when the total dosage was the same (p<0.01). Intermittent repeated administration was also more effective than continuous administration (p<0.01).
A brain surface attachment test (patch test) of t-PA was negative, and light or scanning electron micrography after the intrathecal t-PA administration (10×104 IU/ml) showed no neurotoxicity, cell infiltration or arachnoid damage.
The pH of the t-PA general-purpose solution (for intravenous injection) is maintained at 4.6 to 4.8 because of its solubility and stability, and the osmotic pressure is also increased with an increase in concentration of t-PA. When the concentration of t-PA is 750×104 IU/ml, the osmotic ratio is 30 and the pH is 4.82. These features suggest that a locally administered t-PA solution at high concentration may induce meningeal irritations such as headache and vomiting, and exacerbation of the symptomatic cerebral vasospasm when it is used for cisternal drainage.
The pH and osmotic pressure of t-PA saline solution (10×104 IU/ml) were corrected to 7.23±0.072 and 1.45-1.48, respectively, with 6.0μl of Meylon, and those of t-PA Hartmann's pH: 8 solution (10×104 IU/ml) were corrected to 7.28±0.023 and 1.44-1.46, respectively, with 4.0μl of Meylon.
Therefore, the dosage and method of administration of the t-PA for cisternal drainage should be determined by taking into consideration not merely its histotoxicity but also its pH and osmotic pressure.
