Safety and efficacy of urokinase irrigation in deep intracerebral hemorrhage evacuation: a multicenter, open-label, dose-escalation trial

Background Urokinase irrigation (UI) for deep intracerebral hemorrhage (dICH) evacuation is prevalent in China. However, the optimal dosage remains controversial. This study aimed to determine the efficacy, safety and optimal dose of urokinase for intra-hematoma thrombolysis following stereotactic aspiration. Methods This was a multicenter, open-label, dose-escalation trial. Eligible patients underwent computed tomography angiography guided stereotactic aspiration and drainage within 36 hours of onset. If residual hematoma volume ≥ 10 ml at 6 hours post-surgery, intra-hematoma UI was initiated. Urokinase was administered every 12 hours through catheter until residual volume < 10 ml. The safety and optimal dose of urokinase were determined using a Utility-based Bayesian optimal interval (U-BOIN) phase I/II design. The dose-limiting toxicity (DLT) was defined as rebleeding occurring from the first UI to 72-hour after the last irrigation. Effective performance was defined as hematoma volume < 10 ml on the CT scan after the last irrigation, with irrigations ≤ 4. Results A total of 104 dICH patients were assessed for eligibility from June 2021 to December 2023. Six, twenty-four, and six patients were recruited into the 20,000 IU, 40,000 IU, and 60,000 IU irrigation group, respectively. The average interval from onset to first UI were 28.62 ± 8.59 hours. There was one patient (4.17%) from 40,000 IU group and one patient (16.67%) from 60,000 IU group who experienced rebleeding at surgical site during UI. In addition, two patients (8.33%) from the 40,000 IU group and one patient (16.67%) from the 60,000 IU group exhibited bleeding in puncture tract. The final utility score in the 20,000 IU, 40,000 IU, and 60,000 IU group were 76.43, 86.20, and 77.86, respectively. Comparison between the different irrigation groups by utility score indicated that 40,000 IU was the safe and optimal dose for irrigation. Conclusions Administering 40,000 IU of urokinase every 12-hour after stereotactic aspiration may be the optimal dose for hematoma evacuation. Trial registration URL https//clinicaltrials.gov/study/NCT04686877 ClinicalTrials.gov Identifier: NCT04686877