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

Safety and efficacy of urokinase irrigation in deep intracerebral hemorrhage evacuation: a multicenter, open-label, dose-escalation trial | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Safety and efficacy of urokinase irrigation in deep intracerebral hemorrhage evacuation: a multicenter, open-label, dose-escalation trial Fuxin Lin, Qiu He, Ziyang Chen, Xinqun Luo, Yan Zheng, Zhuyu Gao, and 11 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9094666/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract 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 deep intracerebral hemorrhage stereotactic aspiration urokinase irrigation optimal dose Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Intracerebral hemorrhage (ICH) is a devastating disease characterized by bleeding into brain parenchyma. Although ICH is the second most common cause of stroke, it is the most serious form in terms of outcomes 1 – 3 . ICH is both a lethal and disabling disease, with an overall one-month case fatality of around 40–50% 1,3 . The Surgical Trial in Intracerebral Hemorrhage (STICH) trials revealed patients with supratentorial ICH could not be benefit from early surgery compared to conservative treatment. However, they did suggest that patients with superficial lobar hematomas (within 1 cm from the cortical surface) might benefit from surgery intervention 4 , 5 . In recent years, minimally invasive surgery (MIS) has gained recognition as a promising technique due to less damage to normal brain tissues during hematoma drainage compared to craniotomy 6 – 8 . Minimally Invasive Surgery with Thrombolysis in Intracerebral Haemorrhage Evacuation (MISTIE) serial trials demonstrated that image-guided MIS, combined with thrombolytic alteplase irrigation, was safe and potentially offered better functional outcomes than conservative treatment 9 , 10 . Additionally, subgroup analysis indicated that MIS plus thrombolysis might provide better outcomes than standard medical care when performed earlier (< 36 hours) 10 . In clinical practice, MIS with thrombolysis has shown beneficial effects and safety for ICH evacuation 11 , 12 . However, MISTIE highlighted the challenges: up to 15% of patient did not achieve large reductions of clot volume 9 . Furthermore, predefined reduction target could not be reached in up to 42% of the patients in MISTIE III 10 . These findings underscore the critical need to determine the timing, optimal irrigation dose and the number of irrigation procedures in MIS with thrombolysis to maximize patient outcomes. In China, many clinical trials have been conducted on MIS followed by thrombolysis, utilizing urokinase instead of alteplase as the thrombolysis agent. These studies demonstrated that minimally invasive craniopuncture with urokinase irrigation (UI) was safe and improved the survival and neurological function with fewer complications 13 – 15 . Moreover, several studies have found that the urokinase and tissue type plasminogen activators are similar in the efficacy and safety for thrombolytic evacuation. Additionally, urokinase appears to better ameliorate brain edema and promote an improved outcome after ICH 16 , 17 . However, the irrigation dose and frequency of UI varied greatly based on clinical experience in different medical centers and studies. This variability associated with unknown risks, including rebleeding, limited evacuation efficacy, and prolonged catheter implantation. To address these issues, we first designed a multicenter, open-label, dose-escalation trial. This trial aimed to determine the safety and optimal dose of urokinase for intra-hematoma thrombolysis following stereotactic clot aspiration. Our study builds upon previous research, seeking to establish more confirmed evidence for the UI in the treatment of deep ICH (dICH) to minimize risks and improve patient outcomes in China. Methods Ethics Approval and Consent to Participates The study protocol and informed consent forms had been approved by the Research Ethics Committee of the First Affiliated Hospital of Fujian Medical University, as well as the research ethics committee of each participating medical center in this study. The study protocol adheres to the SPIRIT guidelines 18 . In addition, the study also complies with the ethical principles outlined in the Declaration of Helsinki and the Good Practice Guidelines of the International Conference on Harmonization. The integrity, accuracy, and validity of clinical data are monitored by the Clinical Research Data Security Committee of Fujian Medical University. Written informed consent will be obtained from participants or their guardians. Study Design This study was a multicenter, open-label, dose-escalation trial consisting of two sequential steps. Step A was a dose-escalation phase designed to determine the safety and optimal dose of urokinase for intra-hematoma thrombolysis following stereotactic clot aspiration. Step B is a planned validation phase using the selected dose to evaluate the efficacy and long-term outcomes in a broader cohort. The trial was initiated by the Neurosurgery Department of the First Affiliated Hospital of Fujian Medical University and conducted at five medical centers: The First Affiliated Hospital of Fujian Medical University, Shunchang County Hospital, Anxi County Hospital, Huian County Hospital, Nan'an Hospital, and Longyan People's Hospital of Fujian. This study was registered in ClinicalTrials.gov under the number NCT04686877. The initial registration date was December 29th, 2020. Patient recruitment for Step A began on June 1st, 2021 and ended on September 30th 2023. Enrollment for Step B started on April 1st 2024 and is expected to be completed by December 1st 2024. The final follow-up is expected to be completed by November 30th . Participants and process of stereotactic aspiration The inclusion criteria for eligible patients underwent stereotactic aspiration were as follows: (1) Aged 40 years or older; (2) Duration from onset to the preoperative computed tomography angiography (CTA) scan is between 6 to 24 hours; (3) Patients with a spontaneous ICH in the deep brain parenchyma (≥ 1 cm from the cortical surface) and with hematoma volume more than 25 ml (measured using the ABC/2 method); without hydrocephalus caused by intraventricular hemorrhage and without cerebral herniation; (4) Preoperative Glasgow Coma Scale (GCS) score ranged from 9 to 15; (5) Patients with contralateral muscle strength grade 0 to 4; (6) The modified Rankin Score (mRS) ranges from 0 to1 before onset. Patients were excluded for the following reasons: (1) dICH is caused by aneurysms, arteriovenous malformations, tumors, or trauma; (2) Patients have a history of ICH or ischemic cerebral infarction; (3) Patients have severe coagulation disorders with international normalized ratio (INR) ≥ 1.5; (4) Patients have severe underlying diseases that may affect outcomes; (5) Pregnant or lactating patients; (6) Patients refuses to sign the informed consent or participate in follow-up. The surgery and UI protocols were summarized in Figure S1. All eligible patients underwent the CTA-guided stereotactic aspiration and drainage within 36 hours of onset. CTA guidance was used to avoid functional areas and vessels and to design the shortest path for placing an introducer cannula. After the introducer was removed, the hematoma was aspirated using a 10 ml syringe until there was no longer any clot in the aspirate or until resistance was encountered. If fresh bleeding appeared, the surgical cavity was flushed with saline until clear. If bleeding persisted, 1 kU of snake venom thrombin or 1 kU of epinephrine was irrigated. A size 12 soft catheter was then placed into the residual hematoma, and the drainage was initiated after a half-hour of observation. The participant flow throughout the study, including screening, enrollment, group allocation, and follow-up, is illustrated in Fig. 1 . IU, international unit Participants and process of urokinase irrigation All eligible patients underwent a computed tomography (CT) scan at 6 hours after surgery. Patients with one of the following conditions would not undergo intra-hematoma UI: (1) The side hole of the catheter was not located in the hematoma; (2) The residual hematoma volume were less than 10 ml; (3) Rebleeding, hemorrhage along the puncture tract, and/or hemorrhage in remote sites leading to a decrease in GCS score by ≥ 2 compared to the preoperative level. In cases where the GCS score decreases by < 2 from the preoperative level, continuous observation for 6 hours followed by a repeat CT scan and physical examination was warranted, with reassessment based on the aforementioned criteria. The other eligible patients underwent UI. Urokinase (100,000 IU/bottle, National Medicine Approval Number H10920040, Nanjing) was administered according to the Procedure of Dose Escalation . The first irrigation was recorded as the start point. Urokinase was dissolved in 2 to 3 mL of saline and irrigated through the catheter every 12 hours. Additionally, all patients underwent a CT scan every 24 hours before the same time point UI. The endpoints of UI including: (1) Residual hematoma volume ≤ 10 ml, or (2) Residual hematoma volume ≥ 10 ml but the time duration from the start point over 120 hours. And a CT scan was performed at 72 hours after the last UI. During the whole irrigation process, UI was stopped, if one of the following occurred: (1) Rebleeding, or bleeding in the puncture tract or distant areas, and/or cerebral edema increasing with a GCS score decreases by ≥ 2. (2) Intracranial infection. These patients were treated with appropriate conservative measures or craniotomy if necessary. The Procedure of Dose Escalation The safe and optimal dose of urokinase was determined using a Utility-based Bayesian optimal interval (U-BOIN) phase I/II design 19 . In this design, the dose-limiting toxicity (DLT) is defined as rebleeding occurring from the first UI to 72 hours after the last irrigation. Effective performance is defined as a achieving a hematoma volume < 10 ml on CT scan after the last irrigation, with the total number of irrigations not exceeding four. The dose escalation procedure is divided into two stages, with the standard operating procedure (SOP) provided in Figure S2 and Supplemental Methods. Dose escalation in Stage I is based on DLT, aiming to rapidly identify the acceptable safe doses. The data on effective performance is also collected in Stage I to inform the decision-making in Stage II. The starting dose of UI is 20,000 IU. Once the first group of standard subjects reaches six patients, the dose of the next group is determined according to the incidence of DLT in these patients, as referenced in Table S1. When the cumulative number of patients with a certain dose reaches twelve, the study progresses to Stage II. In Stage II, the following two conditions are evaluated: (1) The frequency of DLT occurrence at the currently highest dose is ≤ 0.118; (2) The dose has not yet reached 100,000 IU (the highest dose set in the protocol). If both of the conditions above are met, the subsequent group of six subjects will underwent UI of a higher dose. If either of the above conditions is not met, the utility score of each dose group will be calculated according to https://trialdesign.org/one-page-shell.html#UBOIN 19 , and the next group of subjects will undergo UI of dose with the highest utility score. The utility is defined as a score combining DLT and effective performance, calculated as shown in Tables S2 and S3. This decision loop will continue until the number of standard subjects in a dose group reaches 24, or the number of all standard subjects (including those from Stage I) reaches 48, at which point the dose escalation is terminated. Finally, the utility score of each dose group will be calculated, and the dose with the highest utility score is deemed to optimal for both safety and efficacy. Data Collection and Follow-up The research data were collected by the trained neurosurgeons (Qiu He and Xinqun Luo), including demographic information, medical history, physical examination results, imaging data, details of surgery and UI, complications, treatments, and survival information. These data were recorded during hospitalization. The participants were also scheduled to visit the outpatient clinic on the 30th day after enrollment in this study. The CT scan and the assessment of neurological outcomes will be recorded. In the event of a participants' death, the time and the cause of death should be collected. Statistical Analyses The normality of data distribution was tested using the Shapiro-Wilk test. Continuous variables were presented as mean ± standard deviation (SD) or median (Q1, Q3) based on the normality of the distribution. Categorical variables were presented as the number of cases and percentages. And the association between residual hematoma volumes and irrigation duration in different irrigation group was evaluated by fitting curves. All the analyses were performed using SPSS software, version 26.0 (IBM) and R software, version 4.3.2. Safety Monitoring In accordance with the International Conference on Harmonization-Good Clinical Practice (ICH-GCP) guidelines, adverse events (AEs) are defined as the occurrences of worsening symptoms, disease deterioration, new symptoms, new signs, or laboratory abnormalities. Serious adverse events (SAEs) must be documented in the SAE form and reported within 24 hours of occurrence. In this study, all SAEs were reviewed by the Clinical Event Arbitration Committee, and the Data and Safety Monitoring Committee provided the final evaluation. Results This study was conducted from June 2021 to September 2023. The participant flow has been illustrated in Fig. 1. A total of 104 dICH patients were initially assessed for eligibility. However, 67 patients were excluded as follows: 65 did not meet the inclusion criteria of UI after hematoma aspiration, and 2 refused to sign the consent form. Consequently, 37 patients were enrolled in the dose escalation trial. During the trial, one patient in 40,000 IU group was excluded due to early termination of treatment. According to the design of this study, we summarized the detailed process of dose escalation in Fig. 2. Initially, 6 patients were recruited into the 20,000 IU group, and the dose was then escalated to 40,000 IU. After enrolling 12 patients in the 40,000 IU group, the study progressed to Stage II. In this stage, 6 patients were recruited into the 60,000 IU group, and additional 12 patients were added to the 40,000 IU group. Comparison of the utility scores across different irrigation groups indicated that 40,000 IU was the safe and optimal dose for irrigation. Ultimately, 6, 24, and 6 patients were enrolled in the 20,000 IU, 40,000 IU, and 60,000 IU irrigation groups, respectively. Thus, 36 patients were monitored and followed-up in this study, and were included in the safety and efficacy analysis. Baseline characteristics A total of 36 patients were enrolled in this study, and their baseline characteristics were presented in Table 1. The study cohort comprised 27 (75.00%) men and 9 (25.00%) women, with an average age of 60.94 ± 11.46 years. Among the patients, 21 (58.33%) had hypertension history, 3 (8.33%) had diabetes mellitus. While none of the patients had history of stroke or were on either antiplatelet or anticoagulant medications. The average systolic blood pressure (SBP) was 180.08 ± 30.41mmHg, and the average diastolic blood pressure (DBP) was 103.94 ± 23.52 mmHg at admission. The average platelet count was (224.84 ± 69.74)×10 9 /L, and the average prothrombin time (PT) was 11.37 ± 0.94 seconds, and the average INR was 0.99 ± 0.08. Regarding neurological function, the median affected side upper and lower limb muscle strength at admission was 1.00 (0.00;2.00) and 1.00 (1.00;2.00), respectively. The median GCS score and the average National Institutes of Health Stroke Scale (NIHSS) score at admission were 10.00 (9.00;12.50) and 15.28 ± 5.40, respectively. Among the patients, 20 (55.56%) had left-side intracerebral hemorrhage, 13 (36.11%) had intraventricular hemorrhage. The median interval from onset to CTA was 6.90 (4.50;12.60) hours, and the average initial hematoma volume was 34.24 ± 6.33 ml. Details during hospitalization and at discharge The details of these patients during hospitalization and at discharge was presented in Table 2. All enrolled patient received blood pressure-lowering treatment. The average interval from onset to surgery was 19.53 ± 8.37 hours. The median residual hematoma volume after surgery was 20.85 (15.00;25.75) ml. The median number of UI procedures were 2.00 (2.00;4.00). The average interval from onset to first UI was 28.62 ± 8.59 hours. The median duration of UI was 12.75 (12.00;35.90) hours. In the analysis of residual hematoma volumes following the last irrigation of urokinase, the median residual hematoma volume was found to be 8.50 (7.30; 9.35) ml across all groups. Notably, the 40,000 IU group exhibited the smallest median residual hematoma volume, measured at 7.75 (6.15; 9.15) ml. Furthermore, the 40,000 IU group demonstrated the highest median hematoma evacuation rate, reaching 65.48% (55.30%; 70.56%). 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. However, all bleeding incidents were asymptomatic. The median length of hospital stay was 19.00 (15.50;24.00) days. At discharge, the median affected side upper and lower limb muscle strength was 1.00 (1.00;2.00) and 2.00 (1.00;3.00), respectively. The median GCS score, the average NIHSS score, and the median mRS at discharge was 15.00 (12.50;15.00), 9.33 ± 5.99, and 4.00 (4.00;5.00), respectively. Complication and neurological outcome at follow-up The complications and neurological outcomes at follow-up were summarized in Table 3. Within 30 days after onset, one patient from 60,000 IU group died. Among these patients enrolled, the following complications were observed within 30 days after onset, 28 (77.78%) patients had a pulmonary infection, 2 (5.56%) patients had an intracranial infection, 1 (2.78%) patient had a urinary infection, no (0.00%) patients experienced seizures, and 2 (5.56%) patients had a peptic ulcer. At follow-up, the median affected side upper limb muscle strength was 2.00 (1.00;3.00), and the median affected side lower limb muscle strength was3.00 (1.00;3.50). The median GCS score was 15.00 (15.00;15.00), the average NIHSS score was 6.58 ± 4.16, the median mRS was 4.00 (4.00;4.00), the average Barthel index (BI) score was 47.10 ± 22.54, and the median Glasgow Outcome Scale (GOS) score was 3.00 (3.00;3.00). Safety and efficacy analysis As shown in Fig. 3, we comprehensively analyzed the safety and efficacy of UI for every enrolled patient by examining hematoma volume. The DLT events happened in one patient from the 40,000 IU group and one patient from the 60,000 IU group. Patient S01-0010 in the 40,000 IU group experienced rebleeding at surgical site within 72 hours after the 6th UI, with hematoma expansion confirmed in repeated CT scans without any symptom. Meanwhile, Patient S07-0001 rebled during 60,000 IU UI, leading to severe brain herniation. Although this patient underwent emergency surgery for hematoma evacuation, she died from SAEs at follow-up, making the only one patient died in this study. In addition to the DLT events, there was 1 ineffective but safe irrigation (Patient S03-0003) in the 20,000 IU group and 2 ineffective but safe irrigation (Patient S01-0015 and S14-0002) in the 40,000 IU group. We analyzed the association between percentage change in residual hematoma volume (residual hematoma volume/ initial hematoma volume×100%) and duration of UI across the three groups (Fig. 4, Figure S3, and Figure S4). Actually, the residual hematoma volume from three groups showed the decreasing trend after UI. After comprehensive consideration of the safety and efficacy, the final utility score for the 20,000 IU, 40,000 IU, and 60,000 IU group were 76.43, 86.20, and 77.86, respectively (Fig. 2). Finally, 40,000 IU was determined to be the optimal dose of UI in stereotactic aspiration for patients with dICH in this study. Discussion In this study, we implemented a meticulously designed dose-escalation trial of urokinase, with the primary objective of precisely determining the optimal dosing strategy for its application in hematoma evacuation. By systematically incrementing the urokinase doses and rigorously monitoring the therapeutic responses, we have, for the first time, conclusively validated the regimen of administering 40,000 IU of urokinase into the hematoma cavity at 12 hours interval. This regimen was found to swiftly and significantly reduce the intracerebral hematoma volume to less than 10 ml. This discovery not only represents a substantial enhancement in treatment efficacy but also demonstrates a relatively low risk of complications, may paving a novel pathway for the management of patients with acute intracerebral hemorrhage. The recent ENRICH study, a pioneering investigation into minimally invasive treatments for intracerebral hemorrhage, has yielded encouraging positive outcomes 20 , fostering optimism regarding the potential of minimally invasive surgical interventions in this therapeutic domain. The combination of minimally invasive catheterization drainage and urokinase thrombolysis for the management of spontaneous intracerebral hemorrhage has gained widespread adoption across hospitals of all tiers in China. However, the administration of urokinase in these procedures remains largely empirical, with a notable lack of a standardized dosing protocol. The reported doses vary widely, ranging from 5,000 IU to 100,000 IU. Consequently, hematoma evacuation rates vary from 38.0% to 93.7%, while the incidence of rebleeding in the surgical cavity fluctuates between 2.4% to 21.2% 15,21–23 . Our findings indicate that in the 40,000 IU treatment arm, the incidence of postoperative hematoma rebleeding was 4.2%, accompanied by a median hematoma evacuation rate of 65.5%, ranging from 55.3% to 70.6%. Notably, 87.5% of patients achieved hematoma volumes below 10 ml after four administrations of UI. Consequently, this treatment protocol appears to be both safe and effective. The MISTIE series represent landmark advancements in the minimally invasive management of intracerebral hemorrhage, which leveraged alteplase with an every-8-hour irrigation protocol for thrombolytic. In MISTIE II, the incidence of asymptomatic hemorrhage reached 22.2%, with an average hematoma evacuation rate of 57% (± 25%) 9 . Furthermore, in MISTIE III, the median hematoma volume post-irrigation was 12.5 (7.6–21.0) ml, and approximately 42% of patients failed to achieve the predefined residual hematoma target of less than 15 ml 10 . Similarly, the ENRICH study also observed that over a quarter of patients did not meet the surgical target 20 . The primary destruction of neural fibers and tracts by hematoma is generally irreversible 24 ; nevertheless, prompt hematoma evacuation can alleviate the mass effect, thereby enhancing intracerebral circulation, mitigating cellular ischemia and hypoxia, as well as reducing secondary damage incurred by toxic byproducts of red blood cell degradation, ameliorating cerebral edema, potentially facilitating favorable neurological functional outcomes 25 – 28 . A subgroup analysis from the MISTIE III study concluded that a higher rate of hematoma evacuation may be associated with improved clinical outcomes 10 . Consequently, our trial aimed to restrict the residual intracerebral hematoma volume to within 10ml, with the intention of enhancing functional prognosis among patients. Our findings demonstrate that administering 40,000 IU effectively achieved this target in a rapid, safe, and efficient manner. Further validation of this UI protocol's impact on prognosis enhancement necessitates prospective, multicenter, randomized controlled studies. Our study remains several limitations and constraints. Firstly, the international recognition of urokinase for clot dissolution is relatively low compared to alteplase. However, several smaller clinical trials have affirmed the safety of urokinase 13 , 14 , 29 , whereas alteplase-mediated clot lysis may be accompanied by delayed cerebral edema, exhibiting neurotoxic effects that can induce brain injury, potentially limiting its positive impact on patients with intracerebral hemorrhage 30 , 31 . In contrast, urokinase may possess neuroprotective properties, capable of mitigating cerebral edema 16 , 32 . Given the rising incidence of intracerebral hemorrhage in China amidst an aging population, urokinase, with its affordable price, may well-suited for use in primary hospitals with relatively scarce medical resources, enhancing the treatment rates for cerebral hemorrhage. The conclusions drawn from our trial may aid clinicians in formulating thrombolytic protocols following stereotactic aspiration for cerebral hemorrhage. Secondly, although this study represents a multicenter dose-escalation investigation of urokinase, it is limited by a relatively small sample size and a lack of analysis on functional prognosis. Consequently, future studies with an expanded sample size are imperative to further substantiate our findings. Conclusions This is the first study to determine the optimal dose of urokinase irrigation after stereotactic clot aspiration. Stereotactic aspiration plus urokinase irrigation within 36 hours after onset is a safe and effective treatment for patients with dICH. Furthermore, administering 40,000 IU of urokinase every 12 hours may be the optimal dose for hematoma evacuation, which could decrease the residual hematoma to less than 10 ml within four irrigations and with few complications. Abbreviations dICH, deep intracerebral hemorrhage; DLT, dose-limiting toxicity; IU, international unit; MIS, minimally invasive surgery; U-BOIN, Utility-based Bayesian optimal interval; UI, urokinase irrigation; Declarations Acknowledgments: We are deeply grateful to Professor Siying Wu and Shaowei Lin 's team for their invaluable assistance in providing guidance on statistical methods, and to Xiaoxia Jiang's team for their efforts in data management and as clinical research coordinators. Contributors: D.-Z.K., W.-H.F. and Y.-X.L. contributed to study design. F.-X.L. administered the study and review the manuscript. Q.H., Z.-Y.C., X.-Q.L. wrote the first draft. Y.Z., Z.-Y.G., H.-C.S.-G., K.-M.S., J.-Y.H., J.-C.C., J.-J.H. and P.-K.H. contributed to data acquisition. S.-N.H. and K.M. did the data analysis and statistical analysis. All authors read and approved the final manuscript. Competing interests: None. Sources of Funding: This work was funded by the Fujian Provincial Health Commission (2022ZD01003), the National Natural Science Foundation of China (82371466), and the Key Scientific and Technological Initiatives for Stroke Prevention and Treatment (2024PSPT0903100, 2024PSPT0903104). Data availability: The data analyzed in this study are available from the corresponding author upon reasonable request. Ethics approval: The study protocol and informed consent forms had been approved by the Research Ethics Committee of the First Affiliated Hospital of Fujian Medical University, as well as the research ethics committee of each participating medical center in this study. 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Urokinase vs Tissue-Type Plasminogen Activator for Thrombolytic Evacuation of Spontaneous Intracerebral Hemorrhage in Basal Ganglia. Front Neurol 2017;8:371. Chan A-W, Tetzlaff JM, Altman DG, Laupacis A, Gøtzsche PC, Krleža-Jerić K, et al. SPIRIT 2013 statement: defining standard protocol items for clinical trials. Ann Intern Med 2013;158:200–7. Zhou Y, Lee JJ, Yuan Y. A utility-based Bayesian optimal interval (U-BOIN) phase I/II design to identify the optimal biological dose for targeted and immune therapies. Stat Med 2019;38:5299–316. Pradilla G, Ratcliff JJ, Hall AJ, et al. Trial of Early Minimally Invasive Removal of Intracerebral Hemorrhage. N Engl J Med . 2024;390(14):1277–1289. Montes JM, Wong JH, Fayad PB, Awad IA. Stereotactic computed tomographic-guided aspiration and thrombolysis of intracerebral hematoma: protocol and preliminary experience. Stroke . 2000;31(4):834–840. Zhao Z, Xiao J, Wang J, et al. Individualized CT image-guided free-hand catheter technique: A new and reliable method for minimally invasive evacuation of basal ganglia hematoma. Front Neurosci . 2022;16:947282. Published 2022 Aug 25. Wang L, Luo S, Ren S, et al. Irregular-Shaped Hematoma Predicts Postoperative Rehemorrhage After Stereotactic Minimally Invasive Surgery for Intracerebral Hemorrhage. Front Neurol . 2022;13:727702. Published 2022 Mar 11. Diringer MN. Intracerebral hemorrhage: pathophysiology and management. Crit Care Med . 1993;21(10):1591–1603. Qureshi AI, Mendelow AD, Hanley DF. Intracerebral haemorrhage. Lancet . 2009;373(9675):1632–1644. Kim JY, Bae HJ. Spontaneous Intracerebral Hemorrhage: Management. J Stroke . 2017;19(1):28–39. Urday S, Kimberly WT, Beslow LA, et al. Targeting secondary injury in intracerebral haemorrhage–perihaematomal oedema. Nat Rev Neurol . 2015;11(2):111–122. de Oliveira Manoel AL. Surgery for spontaneous intracerebral hemorrhage. Crit Care . 2020;24(1):45. Published 2020 Feb 7. Zhang X, Zhou S, Zhang Q, et al. Stereotactic aspiration for hypertensive intracerebral haemorrhage in a Chinese population: a retrospective cohort study. Stroke Vasc Neurol . 2019;4(1):14–21. Published 2019 Mar 2. Rohde V, Rohde I, Thiex R, et al. Fibrinolysis therapy achieved with tissue plasminogen activator and aspiration of the liquefied clot after experimental intracerebral hemorrhage: rapid reduction in hematoma volume but intensification of delayed edema formation. J Neurosurg . 2002;97(4):954–962. Figueroa BE, Keep RF, Betz AL, Hoff JT. Plasminogen activators potentiate thrombin-induced brain injury. Stroke . 1998;29(6):1202–1208. Cho E, Lee KJ, Seo JW, et al. Neuroprotection by urokinase plasminogen activator in the hippocampus. Neurobiol Dis . 2012;46(1):215–224. Tables Tables are available in the Supplementary Files section. Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9094666","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":607622922,"identity":"a34494a3-de82-43af-a72d-89df765e3dd4","order_by":0,"name":"Fuxin Lin","email":"","orcid":"","institution":"Neurosurgery Research Institute, The First Affiliated Hospital of Fujian Medical University","correspondingAuthor":false,"prefix":"","firstName":"Fuxin","middleName":"","lastName":"Lin","suffix":""},{"id":607622923,"identity":"a151941b-06f2-4a69-ae1d-913a7cd77424","order_by":1,"name":"Qiu He","email":"","orcid":"","institution":"Neurosurgery Research Institute, The First Affiliated Hospital of Fujian Medical University","correspondingAuthor":false,"prefix":"","firstName":"Qiu","middleName":"","lastName":"He","suffix":""},{"id":607622925,"identity":"bbc57ad9-aee7-4141-a773-20eacbb675a0","order_by":2,"name":"Ziyang Chen","email":"","orcid":"","institution":"Neurosurgery Research Institute, The First Affiliated Hospital of Fujian Medical University","correspondingAuthor":false,"prefix":"","firstName":"Ziyang","middleName":"","lastName":"Chen","suffix":""},{"id":607622926,"identity":"a40000dc-a2ab-44f2-9bba-17b3602793d3","order_by":3,"name":"Xinqun Luo","email":"","orcid":"","institution":"Neurosurgery Research Institute, The First Affiliated Hospital of Fujian Medical University","correspondingAuthor":false,"prefix":"","firstName":"Xinqun","middleName":"","lastName":"Luo","suffix":""},{"id":607622927,"identity":"21f059c2-ac47-4309-9ac9-625b1b99b132","order_by":4,"name":"Yan 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13:02:01","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9094666/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9094666/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":104998200,"identity":"b8952e73-b65d-4451-ac46-782767cce04b","added_by":"auto","created_at":"2026-03-19 16:25:42","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":282109,"visible":true,"origin":"","legend":"\u003cp\u003eFlowchart of patient screening, enrollment and follow-up\u003c/p\u003e\n\u003cp\u003eIU, international unit\u003c/p\u003e","description":"","filename":"image1.png","url":"https://assets-eu.researchsquare.com/files/rs-9094666/v1/dc11f5d278061bc4876ff587.png"},{"id":104998199,"identity":"4a29dcd9-7250-477f-bf8e-ae895d4820ea","added_by":"auto","created_at":"2026-03-19 16:25:42","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":131936,"visible":true,"origin":"","legend":"\u003cp\u003eProcess of dose escalation\u003c/p\u003e\n\u003cp\u003eIU, international unit\u003c/p\u003e","description":"","filename":"image2.png","url":"https://assets-eu.researchsquare.com/files/rs-9094666/v1/92c12e027dcb0fa6c0d97fca.png"},{"id":104998208,"identity":"fa76d7d9-d731-4bef-9910-adafd7bbca52","added_by":"auto","created_at":"2026-03-19 16:25:45","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":485164,"visible":true,"origin":"","legend":"\u003cp\u003eChange in hematoma volume for every enrolled patient\u003c/p\u003e\n\u003cp\u003eIU, international unit; DLT, dose-limiting toxicity\u003c/p\u003e","description":"","filename":"image3.png","url":"https://assets-eu.researchsquare.com/files/rs-9094666/v1/1c9752af5360b844926a0c75.png"},{"id":104998231,"identity":"41a3957a-af41-4c95-b814-200d964c3dc9","added_by":"auto","created_at":"2026-03-19 16:25:50","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":274399,"visible":true,"origin":"","legend":"\u003cp\u003ePercentage change in residual hematoma volume after first urokinase irrigation in 40,000 IU group (The red line indicates the fitting curve.)\u003c/p\u003e","description":"","filename":"image4.png","url":"https://assets-eu.researchsquare.com/files/rs-9094666/v1/a40453833e3bab6d2c90c09f.png"},{"id":104998405,"identity":"d24c45d8-998a-45f0-94c0-a458a0a9b2c9","added_by":"auto","created_at":"2026-03-19 16:26:32","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1898263,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9094666/v1/78240a0c-0834-4dbe-8cfd-8e47722a4861.pdf"},{"id":104998195,"identity":"36b8449d-c7c2-4cf1-871e-d051173aa4fc","added_by":"auto","created_at":"2026-03-19 16:25:42","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":26406,"visible":true,"origin":"","legend":"","description":"","filename":"Tables.docx","url":"https://assets-eu.researchsquare.com/files/rs-9094666/v1/c2ed2d5a97d77529055ec5b7.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003eSafety and efficacy of urokinase irrigation in deep intracerebral hemorrhage evacuation: a multicenter, open-label, dose-escalation trial\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eIntracerebral hemorrhage (ICH) is a devastating disease characterized by bleeding into brain parenchyma. Although ICH is the second most common cause of stroke, it is the most serious form in terms of outcomes\u003csup\u003e\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e. ICH is both a lethal and disabling disease, with an overall one-month case fatality of around 40\u0026ndash;50%\u003csup\u003e1,3\u003c/sup\u003e. The Surgical Trial in Intracerebral Hemorrhage (STICH) trials revealed patients with supratentorial ICH could not be benefit from early surgery compared to conservative treatment. However, they did suggest that patients with superficial lobar hematomas (within 1 cm from the cortical surface) might benefit from surgery intervention\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. In recent years, minimally invasive surgery (MIS) has gained recognition as a promising technique due to less damage to normal brain tissues during hematoma drainage compared to craniotomy\u003csup\u003e\u003cspan additionalcitationids=\"CR7\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. Minimally Invasive Surgery with Thrombolysis in Intracerebral Haemorrhage Evacuation (MISTIE) serial trials demonstrated that image-guided MIS, combined with thrombolytic alteplase irrigation, was safe and potentially offered better functional outcomes than conservative treatment\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e,\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. Additionally, subgroup analysis indicated that MIS plus thrombolysis might provide better outcomes than standard medical care when performed earlier (\u0026lt;\u0026thinsp;36 hours)\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. In clinical practice, MIS with thrombolysis has shown beneficial effects and safety for ICH evacuation\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e,\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e. However, MISTIE highlighted the challenges: up to 15% of patient did not achieve large reductions of clot volume\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. Furthermore, predefined reduction target could not be reached in up to 42% of the patients in MISTIE III\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. These findings underscore the critical need to determine the timing, optimal irrigation dose and the number of irrigation procedures in MIS with thrombolysis to maximize patient outcomes.\u003c/p\u003e \u003cp\u003e In China, many clinical trials have been conducted on MIS followed by thrombolysis, utilizing urokinase instead of alteplase as the thrombolysis agent. These studies demonstrated that minimally invasive craniopuncture with urokinase irrigation (UI) was safe and improved the survival and neurological function with fewer complications\u003csup\u003e\u003cspan additionalcitationids=\"CR14\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e. Moreover, several studies have found that the urokinase and tissue type plasminogen activators are similar in the efficacy and safety for thrombolytic evacuation. Additionally, urokinase appears to better ameliorate brain edema and promote an improved outcome after ICH\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e,\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e. However, the irrigation dose and frequency of UI varied greatly based on clinical experience in different medical centers and studies. This variability associated with unknown risks, including rebleeding, limited evacuation efficacy, and prolonged catheter implantation. To address these issues, we first designed a multicenter, open-label, dose-escalation trial. This trial aimed to determine the safety and optimal dose of urokinase for intra-hematoma thrombolysis following stereotactic clot aspiration. Our study builds upon previous research, seeking to establish more confirmed evidence for the UI in the treatment of deep ICH (dICH) to minimize risks and improve patient outcomes in China.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eEthics Approval and Consent to Participates\u003c/h2\u003e \u003cp\u003e The study protocol and informed consent forms had been approved by the Research Ethics Committee of the First Affiliated Hospital of Fujian Medical University, as well as the research ethics committee of each participating medical center in this study. The study protocol adheres to the SPIRIT guidelines\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e. In addition, the study also complies with the ethical principles outlined in the Declaration of Helsinki and the Good Practice Guidelines of the International Conference on Harmonization. The integrity, accuracy, and validity of clinical data are monitored by the Clinical Research Data Security Committee of Fujian Medical University. Written informed consent will be obtained from participants or their guardians.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eStudy Design\u003c/h3\u003e\n\u003cp\u003eThis study was a multicenter, open-label, dose-escalation trial consisting of two sequential steps. Step A was a dose-escalation phase designed to determine the safety and optimal dose of urokinase for intra-hematoma thrombolysis following stereotactic clot aspiration. Step B is a planned validation phase using the selected dose to evaluate the efficacy and long-term outcomes in a broader cohort. The trial was initiated by the Neurosurgery Department of the First Affiliated Hospital of Fujian Medical University and conducted at five medical centers: The First Affiliated Hospital of Fujian Medical University, Shunchang County Hospital, Anxi County Hospital, Huian County Hospital, Nan'an Hospital, and Longyan People's Hospital of Fujian. This study was registered in ClinicalTrials.gov under the number NCT04686877. The initial registration date was December 29th, 2020. Patient recruitment for Step A began on June 1st, 2021 and ended on September 30th 2023. Enrollment for Step B started on April 1st 2024 and is expected to be completed by December 1st 2024. The final follow-up is expected to be completed by November 30th .\u003c/p\u003e\n\u003ch3\u003eParticipants and process of stereotactic aspiration\u003c/h3\u003e\n\u003cp\u003eThe inclusion criteria for eligible patients underwent stereotactic aspiration were as follows: (1) Aged 40 years or older; (2) Duration from onset to the preoperative computed tomography angiography (CTA) scan is between 6 to 24 hours; (3) Patients with a spontaneous ICH in the deep brain parenchyma (\u0026ge;\u0026thinsp;1 cm from the cortical surface) and with hematoma volume more than 25 ml (measured using the ABC/2 method); without hydrocephalus caused by intraventricular hemorrhage and without cerebral herniation; (4) Preoperative Glasgow Coma Scale (GCS) score ranged from 9 to 15; (5) Patients with contralateral muscle strength grade 0 to 4; (6) The modified Rankin Score (mRS) ranges from 0 to1 before onset. Patients were excluded for the following reasons: (1) dICH is caused by aneurysms, arteriovenous malformations, tumors, or trauma; (2) Patients have a history of ICH or ischemic cerebral infarction; (3) Patients have severe coagulation disorders with international normalized ratio (INR)\u0026thinsp;\u0026ge;\u0026thinsp;1.5; (4) Patients have severe underlying diseases that may affect outcomes; (5) Pregnant or lactating patients; (6) Patients refuses to sign the informed consent or participate in follow-up.\u003c/p\u003e \u003cp\u003eThe surgery and UI protocols were summarized in Figure S1. All eligible patients underwent the CTA-guided stereotactic aspiration and drainage within 36 hours of onset. CTA guidance was used to avoid functional areas and vessels and to design the shortest path for placing an introducer cannula. After the introducer was removed, the hematoma was aspirated using a 10 ml syringe until there was no longer any clot in the aspirate or until resistance was encountered. If fresh bleeding appeared, the surgical cavity was flushed with saline until clear. If bleeding persisted, 1 kU of snake venom thrombin or 1 kU of epinephrine was irrigated. A size 12 soft catheter was then placed into the residual hematoma, and the drainage was initiated after a half-hour of observation. The participant flow throughout the study, including screening, enrollment, group allocation, and follow-up, is illustrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eIU, international unit\u003c/p\u003e\n\u003ch3\u003eParticipants and process of urokinase irrigation\u003c/h3\u003e\n\u003cp\u003eAll eligible patients underwent a computed tomography (CT) scan at 6 hours after surgery. Patients with one of the following conditions would not undergo intra-hematoma UI: (1) The side hole of the catheter was not located in the hematoma; (2) The residual hematoma volume were less than 10 ml; (3) Rebleeding, hemorrhage along the puncture tract, and/or hemorrhage in remote sites leading to a decrease in GCS score by \u0026ge;\u0026thinsp;2 compared to the preoperative level. In cases where the GCS score decreases by \u0026lt;\u0026thinsp;2 from the preoperative level, continuous observation for 6 hours followed by a repeat CT scan and physical examination was warranted, with reassessment based on the aforementioned criteria. The other eligible patients underwent UI.\u003c/p\u003e \u003cp\u003eUrokinase (100,000 IU/bottle, National Medicine Approval Number H10920040, Nanjing) was administered according to the \u003cem\u003eProcedure of Dose Escalation\u003c/em\u003e. The first irrigation was recorded as the start point. Urokinase was dissolved in 2 to 3 mL of saline and irrigated through the catheter every 12 hours. Additionally, all patients underwent a CT scan every 24 hours before the same time point UI. The endpoints of UI including: (1) Residual hematoma volume\u0026thinsp;\u0026le;\u0026thinsp;10 ml, or (2) Residual hematoma volume\u0026thinsp;\u0026ge;\u0026thinsp;10 ml but the time duration from the start point over 120 hours. And a CT scan was performed at 72 hours after the last UI. During the whole irrigation process, UI was stopped, if one of the following occurred: (1) Rebleeding, or bleeding in the puncture tract or distant areas, and/or cerebral edema increasing with a GCS score decreases by \u0026ge;\u0026thinsp;2. (2) Intracranial infection. These patients were treated with appropriate conservative measures or craniotomy if necessary.\u003c/p\u003e\n\u003ch3\u003eThe Procedure of Dose Escalation\u003c/h3\u003e\n\u003cp\u003eThe safe and optimal dose of urokinase was determined using a Utility-based Bayesian optimal interval (U-BOIN) phase I/II design\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e. In this design, the dose-limiting toxicity (DLT) is defined as rebleeding occurring from the first UI to 72 hours after the last irrigation. Effective performance is defined as a achieving a hematoma volume\u0026thinsp;\u0026lt;\u0026thinsp;10 ml on CT scan after the last irrigation, with the total number of irrigations not exceeding four. The dose escalation procedure is divided into two stages, with the standard operating procedure (SOP) provided in Figure S2 and Supplemental Methods.\u003c/p\u003e \u003cp\u003eDose escalation in Stage I is based on DLT, aiming to rapidly identify the acceptable safe doses. The data on effective performance is also collected in Stage I to inform the decision-making in Stage II. The starting dose of UI is 20,000 IU. Once the first group of standard subjects reaches six patients, the dose of the next group is determined according to the incidence of DLT in these patients, as referenced in Table S1. When the cumulative number of patients with a certain dose reaches twelve, the study progresses to Stage II.\u003c/p\u003e \u003cp\u003eIn Stage II, the following two conditions are evaluated: (1) The frequency of DLT occurrence at the currently highest dose is \u0026le;\u0026thinsp;0.118; (2) The dose has not yet reached 100,000 IU (the highest dose set in the protocol). If both of the conditions above are met, the subsequent group of six subjects will underwent UI of a higher dose. If either of the above conditions is not met, the utility score of each dose group will be calculated according to \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://trialdesign.org/one-page-shell.html#UBOIN\u003c/span\u003e\u003cspan address=\"https://trialdesign.org/one-page-shell.html#UBOIN\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003csup\u003e19\u003c/sup\u003e, and the next group of subjects will undergo UI of dose with the highest utility score. The utility is defined as a score combining DLT and effective performance, calculated as shown in Tables S2 and S3. This decision loop will continue until the number of standard subjects in a dose group reaches 24, or the number of all standard subjects (including those from Stage I) reaches 48, at which point the dose escalation is terminated. Finally, the utility score of each dose group will be calculated, and the dose with the highest utility score is deemed to optimal for both safety and efficacy.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eData Collection and Follow-up\u003c/h2\u003e \u003cp\u003eThe research data were collected by the trained neurosurgeons (Qiu He and Xinqun Luo), including demographic information, medical history, physical examination results, imaging data, details of surgery and UI, complications, treatments, and survival information. These data were recorded during hospitalization. The participants were also scheduled to visit the outpatient clinic on the 30th day after enrollment in this study. The CT scan and the assessment of neurological outcomes will be recorded. In the event of a participants' death, the time and the cause of death should be collected.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eStatistical Analyses\u003c/h3\u003e\n\u003cp\u003eThe normality of data distribution was tested using the Shapiro-Wilk test. Continuous variables were presented as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation (SD) or median (Q1, Q3) based on the normality of the distribution. Categorical variables were presented as the number of cases and percentages. And the association between residual hematoma volumes and irrigation duration in different irrigation group was evaluated by fitting curves. All the analyses were performed using SPSS software, version 26.0 (IBM) and R software, version 4.3.2.\u003c/p\u003e\n\u003ch3\u003eSafety Monitoring\u003c/h3\u003e\n\u003cp\u003e In accordance with the International Conference on Harmonization-Good Clinical Practice (ICH-GCP) guidelines, adverse events (AEs) are defined as the occurrences of worsening symptoms, disease deterioration, new symptoms, new signs, or laboratory abnormalities. Serious adverse events (SAEs) must be documented in the SAE form and reported within 24 hours of occurrence. In this study, all SAEs were reviewed by the Clinical Event Arbitration Committee, and the Data and Safety Monitoring Committee provided the final evaluation.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eThis study was conducted from June 2021 to September 2023. The participant flow has been illustrated in Fig. 1. A total of 104 dICH patients were initially assessed for eligibility. However, 67 patients were excluded as follows: 65 did not meet the inclusion criteria of UI after hematoma aspiration, and 2 refused to sign the consent form. Consequently, 37 patients were enrolled in the dose escalation trial. During the trial, one patient in 40,000 IU group was excluded due to early termination of treatment.\u003c/p\u003e\n\u003cp\u003eAccording to the design of this study, we summarized the detailed process of dose escalation in Fig. 2. Initially, 6 patients were recruited into the 20,000 IU group, and the dose was then escalated to 40,000 IU. After enrolling 12 patients in the 40,000 IU group, the study progressed to Stage II. In this stage, 6 patients were recruited into the 60,000 IU group, and additional 12 patients were added to the 40,000 IU group. Comparison of the utility scores across different irrigation groups indicated that 40,000 IU was the safe and optimal dose for irrigation. Ultimately, 6, 24, and 6 patients were enrolled in the 20,000 IU, 40,000 IU, and 60,000 IU irrigation groups, respectively. Thus, 36 patients were monitored and followed-up in this study, and were included in the safety and efficacy analysis.\u003c/p\u003e\n\u003ch2\u003eBaseline characteristics\u003c/h2\u003e\n\u003cp\u003eA total of 36 patients were enrolled in this study, and their baseline characteristics were presented in Table 1. The study cohort comprised 27 (75.00%) men and 9 (25.00%) women, with an average age of 60.94 ± 11.46 years. Among the\u003c/p\u003e\n\u003cp\u003epatients, 21 (58.33%) had hypertension history, 3 (8.33%) had diabetes mellitus. While none of the patients had history of stroke or were on either antiplatelet or anticoagulant medications. The average systolic blood pressure (SBP) was 180.08 ± 30.41mmHg, and the average diastolic blood pressure (DBP) was 103.94 ± 23.52 mmHg at admission. The average platelet count was (224.84 ± 69.74)×10\u003csup\u003e9\u003c/sup\u003e/L, and the average prothrombin time (PT) was 11.37 ± 0.94 seconds, and the average INR was 0.99 ± 0.08. Regarding neurological function, the median affected side upper and lower limb muscle strength at admission was 1.00 (0.00;2.00) and 1.00 (1.00;2.00), respectively. The median GCS score and the average National Institutes of Health Stroke Scale (NIHSS) score at admission were 10.00 (9.00;12.50) and 15.28 ± 5.40, respectively. Among the patients, 20 (55.56%) had left-side intracerebral hemorrhage, 13 (36.11%) had intraventricular hemorrhage. The median interval from onset to CTA was 6.90 (4.50;12.60) hours, and the average initial hematoma volume was 34.24 ± 6.33 ml.\u003c/p\u003e\n\u003cdiv id=\"Sec13\"\u003e\n \u003ch2\u003eDetails during hospitalization and at discharge\u003c/h2\u003e\n \u003cp\u003eThe details of these patients during hospitalization and at discharge was presented in Table 2. All enrolled patient received blood pressure-lowering treatment. The average interval from onset to surgery was 19.53 ± 8.37 hours. The median residual hematoma volume after surgery was 20.85 (15.00;25.75) ml. The median number of UI procedures were 2.00 (2.00;4.00). The average interval from onset to first UI was 28.62 ± 8.59 hours. The median duration of UI was 12.75 (12.00;35.90) hours. In the analysis of residual hematoma volumes following the last irrigation of urokinase, the median residual hematoma volume was found to be 8.50 (7.30; 9.35) ml across all groups. Notably, the 40,000 IU group exhibited the smallest median residual hematoma volume, measured at 7.75 (6.15; 9.15) ml. Furthermore, the 40,000 IU group demonstrated the highest median hematoma evacuation rate, reaching 65.48% (55.30%; 70.56%).\u003c/p\u003e\n \u003cdiv\u003eThere 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. However, all bleeding incidents were asymptomatic.\u003c/div\u003e\n \u003cp\u003eThe median length of hospital stay was 19.00 (15.50;24.00) days. At discharge, the median affected side upper and lower limb muscle strength was 1.00 (1.00;2.00) and 2.00 (1.00;3.00), respectively. The median GCS score, the average NIHSS score, and the median mRS at discharge was 15.00 (12.50;15.00), 9.33 ± 5.99, and 4.00 (4.00;5.00), respectively.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec14\"\u003e\n \u003ch2\u003eComplication and neurological outcome at follow-up\u003c/h2\u003e\n \u003cp\u003eThe complications and neurological outcomes at follow-up were summarized in Table 3. Within 30 days after onset, one patient from 60,000 IU group died. Among these patients enrolled, the following complications were observed within 30 days after onset, 28 (77.78%) patients had a pulmonary infection, 2 (5.56%) patients had an intracranial infection, 1 (2.78%) patient had a urinary infection, no (0.00%) patients experienced seizures, and 2 (5.56%) patients had a peptic ulcer.\u003c/p\u003e\n \u003cdiv\u003eAt follow-up, the median affected side upper limb muscle strength was 2.00 (1.00;3.00), and the median affected side lower limb muscle strength was3.00 (1.00;3.50). The median GCS score was 15.00 (15.00;15.00), the average NIHSS score was 6.58 ± 4.16, the median mRS was 4.00 (4.00;4.00), the average Barthel index (BI) score was 47.10 ± 22.54, and the median Glasgow Outcome Scale (GOS) score was 3.00 (3.00;3.00).\u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec15\"\u003e\n \u003ch2\u003eSafety and efficacy analysis\u003c/h2\u003e\n \u003cp\u003eAs shown in Fig. 3, we comprehensively analyzed the safety and efficacy of UI for every enrolled patient by examining hematoma volume. The DLT events happened in one patient from the 40,000 IU group and one patient from the 60,000 IU group. Patient S01-0010 in the\u003c/p\u003e\n \u003cp\u003e40,000 IU group experienced rebleeding at surgical site within 72 hours after the 6th UI, with hematoma expansion confirmed in repeated CT scans without any symptom. Meanwhile, Patient S07-0001 rebled during 60,000 IU UI, leading to severe brain herniation. Although this patient underwent emergency surgery for hematoma evacuation, she died from SAEs at follow-up, making the only one patient died in this study. In addition to the DLT events, there was 1 ineffective but safe irrigation (Patient S03-0003) in the 20,000 IU group and 2 ineffective but safe irrigation (Patient S01-0015 and S14-0002) in the 40,000 IU group.\u003c/p\u003e\n \u003cp\u003eWe analyzed the association between percentage change in residual hematoma volume (residual hematoma volume/ initial hematoma volume×100%) and duration of UI across the three groups (Fig. 4, Figure S3, and Figure S4). Actually, the residual hematoma volume from three groups showed the decreasing trend after UI. After comprehensive consideration of the safety and efficacy, the final utility score for the 20,000 IU, 40,000 IU, and 60,000 IU group were 76.43, 86.20, and 77.86, respectively (Fig. 2). Finally, 40,000 IU was determined to be the optimal dose of UI in stereotactic aspiration for patients with dICH in this study.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this study, we implemented a meticulously designed dose-escalation trial of urokinase, with the primary objective of precisely determining the optimal dosing strategy for its application in hematoma evacuation. By systematically incrementing the urokinase doses and rigorously monitoring the therapeutic responses, we have, for the first time, conclusively validated the regimen of administering 40,000 IU of urokinase into the hematoma cavity at 12 hours interval. This regimen was found to swiftly and significantly reduce the intracerebral hematoma volume to less than 10 ml. This discovery not only represents a substantial enhancement in treatment efficacy but also demonstrates a relatively low risk of complications, may paving a novel pathway for the management of patients with acute intracerebral hemorrhage.\u003c/p\u003e \u003cp\u003eThe recent ENRICH study, a pioneering investigation into minimally invasive treatments for intracerebral hemorrhage, has yielded encouraging positive outcomes\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e, fostering optimism regarding the potential of minimally invasive surgical interventions in this therapeutic domain. The combination of minimally invasive catheterization drainage and urokinase thrombolysis for the management of spontaneous intracerebral hemorrhage has gained widespread adoption across hospitals of all tiers in China. However, the administration of urokinase in these procedures remains largely empirical, with a notable lack of a standardized dosing protocol. The reported doses vary widely, ranging from 5,000 IU to 100,000 IU. Consequently, hematoma evacuation rates vary from 38.0% to 93.7%, while the incidence of rebleeding in the surgical cavity fluctuates between 2.4% to 21.2%\u003csup\u003e15,21\u0026ndash;23\u003c/sup\u003e. Our findings indicate that in the 40,000 IU treatment arm, the incidence of postoperative hematoma rebleeding was 4.2%, accompanied by a median hematoma evacuation rate of 65.5%, ranging from 55.3% to 70.6%. Notably, 87.5% of patients achieved hematoma volumes below 10 ml after four administrations of UI. Consequently, this treatment protocol appears to be both safe and effective.\u003c/p\u003e \u003cp\u003eThe MISTIE series represent landmark advancements in the minimally invasive management of intracerebral hemorrhage, which leveraged alteplase with an every-8-hour irrigation protocol for thrombolytic. In MISTIE II, the incidence of asymptomatic hemorrhage reached 22.2%, with an average hematoma evacuation rate of 57% (\u0026plusmn;\u0026thinsp;25%)\u003csup\u003e9\u003c/sup\u003e. Furthermore, in MISTIE III, the median hematoma volume post-irrigation was 12.5 (7.6\u0026ndash;21.0) ml, and approximately 42% of patients failed to achieve the predefined residual hematoma target of less than 15 ml\u003csup\u003e10\u003c/sup\u003e. Similarly, the ENRICH study also observed that over a quarter of patients did not meet the surgical target\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e. The primary destruction of neural fibers and tracts by hematoma is generally irreversible\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e; nevertheless, prompt hematoma evacuation can alleviate the mass effect, thereby enhancing intracerebral circulation, mitigating cellular ischemia and hypoxia, as well as reducing secondary damage incurred by toxic byproducts of red blood cell degradation, ameliorating cerebral edema, potentially facilitating favorable neurological functional outcomes\u003csup\u003e\u003cspan additionalcitationids=\"CR26 CR27\" citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e. A subgroup analysis from the MISTIE III study concluded that a higher rate of hematoma evacuation may be associated with improved clinical outcomes\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. Consequently, our trial aimed to restrict the residual intracerebral hematoma volume to within 10ml, with the intention of enhancing functional prognosis among patients. Our findings demonstrate that administering 40,000 IU effectively achieved this target in a rapid, safe, and efficient manner. Further validation of this UI protocol's impact on prognosis enhancement necessitates prospective, multicenter, randomized controlled studies.\u003c/p\u003e \u003cp\u003eOur study remains several limitations and constraints. Firstly, the international recognition of urokinase for clot dissolution is relatively low compared to alteplase. However, several smaller clinical trials have affirmed the safety of urokinase\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e,\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e,\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e, whereas alteplase-mediated clot lysis may be accompanied by delayed cerebral edema, exhibiting neurotoxic effects that can induce brain injury, potentially limiting its positive impact on patients with intracerebral hemorrhage\u003csup\u003e\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e,\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e. In contrast, urokinase may possess neuroprotective properties, capable of mitigating cerebral edema\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e,\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e. Given the rising incidence of intracerebral hemorrhage in China amidst an aging population, urokinase, with its affordable price, may well-suited for use in primary hospitals with relatively scarce medical resources, enhancing the treatment rates for cerebral hemorrhage. The conclusions drawn from our trial may aid clinicians in formulating thrombolytic protocols following stereotactic aspiration for cerebral hemorrhage. Secondly, although this study represents a multicenter dose-escalation investigation of urokinase, it is limited by a relatively small sample size and a lack of analysis on functional prognosis. Consequently, future studies with an expanded sample size are imperative to further substantiate our findings.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eThis is the first study to determine the optimal dose of urokinase irrigation after stereotactic clot aspiration. Stereotactic aspiration plus urokinase irrigation within 36 hours after onset is a safe and effective treatment for patients with dICH. Furthermore, administering 40,000 IU of urokinase every 12 hours may be the optimal dose for hematoma evacuation, which could decrease the residual hematoma to less than 10 ml within four irrigations and with few complications.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003edICH, deep intracerebral hemorrhage; DLT, dose-limiting toxicity; IU, international unit; MIS, minimally invasive surgery; U-BOIN, Utility-based Bayesian optimal interval; UI, urokinase irrigation;\u003c/p\u003e\n"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe are deeply grateful to Professor Siying Wu and Shaowei Lin \u0026apos;s team for their invaluable assistance in providing guidance on statistical methods, and to Xiaoxia Jiang\u0026apos;s team for their efforts in data management and as clinical research coordinators.\u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eContributors:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eD.-Z.K., W.-H.F. and Y.-X.L. contributed to study design. F.-X.L. administered the study and review the manuscript. Q.H., Z.-Y.C., X.-Q.L. wrote the first draft. Y.Z., Z.-Y.G., H.-C.S.-G., K.-M.S., J.-Y.H., J.-C.C., J.-J.H. and P.-K.H. contributed to data acquisition. S.-N.H. and K.M. did the data analysis and statistical analysis. All authors read and approved the final manuscript.\u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eCompeting interests: \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone.\u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eSources of Funding:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was funded by the Fujian Provincial Health Commission (2022ZD01003), the National Natural Science Foundation of China (82371466), and the Key Scientific and Technological Initiatives for Stroke Prevention and Treatment (2024PSPT0903100, 2024PSPT0903104).\u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eData availability:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data analyzed in this study are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study protocol and informed consent forms had been approved by the Research Ethics Committee of the First Affiliated Hospital of Fujian Medical University, as well as the research ethics committee of each participating medical center in this study. Approval No.: MRCTA, ECFAH of FMU [2019]294\u003c/p\u003e\n"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003evan Asch CJ, Luitse MJ, Rinkel GJ, van der Tweel I, Algra A, Klijn CJ. Incidence, case fatality, and functional outcome of intracerebral haemorrhage over time, according to age, sex, and ethnic origin: a systematic review and meta-analysis. \u003cem\u003eLancet Neurol\u003c/em\u003e 2010;9:167\u0026ndash;76.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCordonnier C, Demchuk A, Ziai W, Anderson CS. 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Stereotactic aspiration for hypertensive intracerebral haemorrhage in a Chinese population: a retrospective cohort study. \u003cem\u003eStroke Vasc Neurol\u003c/em\u003e. 2019;4(1):14\u0026ndash;21. Published 2019 Mar 2.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRohde V, Rohde I, Thiex R, et al. Fibrinolysis therapy achieved with tissue plasminogen activator and aspiration of the liquefied clot after experimental intracerebral hemorrhage: rapid reduction in hematoma volume but intensification of delayed edema formation. \u003cem\u003eJ Neurosurg\u003c/em\u003e. 2002;97(4):954\u0026ndash;962.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFigueroa BE, Keep RF, Betz AL, Hoff JT. Plasminogen activators potentiate thrombin-induced brain injury. \u003cem\u003eStroke\u003c/em\u003e. 1998;29(6):1202\u0026ndash;1208.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCho E, Lee KJ, Seo JW, et al. Neuroprotection by urokinase plasminogen activator in the hippocampus. \u003cem\u003eNeurobiol Dis\u003c/em\u003e. 2012;46(1):215\u0026ndash;224.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"deep intracerebral hemorrhage, stereotactic aspiration, urokinase irrigation, optimal dose","lastPublishedDoi":"10.21203/rs.3.rs-9094666/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9094666/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eUrokinase 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.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis 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 \u0026lt; 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 \u0026lt; 10 ml on the CT scan after the last irrigation, with irrigations ≤ 4.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA 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.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAdministering 40,000 IU of urokinase every 12-hour after stereotactic aspiration may be the optimal dose for hematoma evacuation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial registration\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eURL https//clinicaltrials.gov/study/NCT04686877\u003c/p\u003e\n\u003cp\u003eClinicalTrials.gov Identifier: NCT04686877\u003c/p\u003e","manuscriptTitle":"Safety and efficacy of urokinase irrigation in deep intracerebral hemorrhage evacuation: a multicenter, open-label, dose-escalation trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-19 16:23:34","doi":"10.21203/rs.3.rs-9094666/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"c942126d-afda-4deb-bfa5-ef87db785ca6","owner":[],"postedDate":"March 19th, 2026","published":true,"recentEditorialEvents":[{"type":"reviewerAgreed","content":"91716660719837787566372419096039463074","date":"2026-05-07T04:56:18+00:00","index":190,"fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-30T07:52:20+00:00","index":178,"fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-03-19T16:23:37+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-19 16:23:34","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9094666","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9094666","identity":"rs-9094666","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}