Intraventricular Thrombolysis

IVH is a poor prognostic factor in patients with ICH (20,21), and a large volume of IVH is predictive of mortality and unfavorable functional outcome (22). Although external ventricular drainage is effective in treating obstructive hydrocephalus, it has never been proven to accelerate resolution of the intraventricular clot. Furthermore, obstruction of the ventriculostomy catheter by the clot is a relatively frequent problem. Therefore, the use of thrombolytic drugs to hasten the removal of intraventricular blood is based on a solid rationale. The safety and efficacy of this strategy has been successfully tested in case series and cohort studies (23,24).

These initial favorable results were confirmed in a Phase 2, multicenter, prospective, controlled trial, in which 12 patients with IVH requiring ventriculostomy were randomized to receive intraventricular injections of urokinase (25,000 IU) or saline solution. Injections were administered every 12 hr starting at between 12 and 24 hr after bleeding onset. They were continued until the ventriculostomy catheter was removed following prespecified criteria (i.e., clamping of catheter for 24 hr without elevation of intracranial pressure above 15 mmHg). IVH volumes were measured on daily CT scans by examiners blinded to treatment assignment. Unfortunately, enrollment had to be stopped when the manufacturer withdrew urokinase from the market. Patients in the urokinase group received a mean of 7.7 injections (range, 4-11 doses). Clot resolution was significantly faster in patients treated with urokinase (p=0.02). After adjustment for baseline differences in gender distribution—which was necessary because faster IVH resolution was also associated with females—a reduction of 3.8 days in the intraventricular clot half-life was observed (i.e., time required for a 50% decrement in the initial volume of the clot). Mean duration of external ventricular drainage tended to be reduced in patients treated with urokinase (170 hr vs. 208 hr in the placebo group). No significant differences in adverse events between groups were observed, and no cases of expansion of ICH or IVH were reported.

A larger (n=48) Phase 2 trial using recombinant tissue plasminogen activator (rtPA) has also offered encouraging results (25). Infusion of rtPA strongly accelerated IVH resolution, and treated patients showed improved levels of consciousness more rapidly and tended to have better functional outcomes. Although symptomatic hemorrhages were more common in the rtPA

Figure 1 Survival at 90 days according to study group. Mortality was reduced by approximately 35% in each rFVIIa group, as compared to placebo group (p=0.10 by the log-rank test, comparing all 4 groups; p=0.02 by the chi-square test for the comparison of the three rFVIIa groups combined with placebo). Source: From Ref. 19.

group, this difference was not significant. In addition, nonhemorrhagic complications occurred more frequently in the placebo group. The results of this study justify the conduction of a Phase 3 trial to establish the role of intraventricular thrombolysis in daily practice.

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