Minimally Invasive Surgery Plus Recombinant Tissue-type Plasminogen Activator For Hematoma Evacuation In Patients With Spontaneous Intracerebral Hemorrhage

Part ⅠDose finding of recombinant tissue-type plasminogen activator for hematoma evacuation in patients with spontaneous intracerebral hemorrhage treated with minimally invasive surgeryObjective:To test the feasibility and safety of minimally invasive surgery (MIS) plus recombinant tissue-plasminogen activator (rt-PA) for clot evacuation in patients with spontaneous intracerebral hemorrhage (ICH) and to explore the potential regimen of intraclot rt-PA in such context in China.Methods:Patients with ICH treated with MIS and intraclot rt-PA between July2012and November2013were retrospectively identified from our prospectively institutional ICH database. We manually conducted a semiautomated, computerized volumetric analysis to assess the change of ICH and PHE volumes at pre-and post-MIS CT scans. Glasgow Coma Scale score (GCS) was used to assess the level of consciousness. Clinical outcomes at day30were scored using the modified Rankin Scale (mRS). We compared the observed cohort mortality with its predicted30-day mortality using the ICH score.Results:Eighty patients were included with mean age53.6±12.3years. Mean time from symptom onset to MIS was40.5±18.5hours. The median dose and doses of rt-PA was1.0(1) mg and2(1), maximum cumulative dose of4.0mg. The ICH volume and PHE volume at post-MIS was significantly lower compared with pre-MIS respectively (9.2±7.4ml vs.45.6±20ml, P<0.01;31.0±14.4ml vs.41.3±17.8ml, P<0.01). There was a significantly negative correlation between the ratio of clot removal and the degree of catheter position accuracy (p=-0.45; P<0.01). GCS at post-MIS was significantly higher than pre-MIS (13(3) vs.9(5), P<0.01). The30-day mortality was significantly lower than its predicted (2.5%vs.40%, P<0.01). During the course of treatment, rebleeding events occurred in6patients and no cases with central nervous system infection.Conclusions:MIS plus intraclot low dose rt-PA for clot removal is feasible in patients with ICH, with a trend towards improved30-day survival. The dose of0.3mg-2.0mg seems to be helpful and the regimen of0.5mg/12h or0.5mg/24h with maximum dose of4.0mg might be favorable in such context in China. A large, randomized study addressing dose escalation and functional outcome is needed. Part ⅡNo exacerbation of perihematomal edema with intraclot recombinant tissue-type plasminogen activator in patients with spontaneous intracerebral hemorrhageObjective:Perihematomal edema (PHE) can worsen clinical outcomes in patients with spontaneous intracerebral hemorrhage (ICH). Studies have shown that clot degradation products can lead to PHE formation. We aimed to test the hypothesis that hematoma evacuation via minimally invasive surgery (MIS) will reduce PHE volume and that intraclot injection of recombinant tissue-type plasminogen activator (rt-PA) will not exacerbate it.Methods:Patients with ICH treated using MIS with or without intraclot rt-PA between October2011and November2013were retrospectively identified from our prospectively institutional ICH database. We manually conducted a semiautomated, computerized volumetric analysis on CT scans to assess the impact of clot evacuation on PHE and the effect of rt-PA on PHE at pre-MIS(T1) and post-MIS (T2).Results:Ninty MIS and36medical patients were analyzed. There was no significant difference in baseline characteristics in both MIS the two groups. The median dose and doses of rt-PA was1.0(0.85) mg and2(1), and a maximum dose of4.0mg. Mean T2ICH volume was11.5±8.7ml for the MIS group and34.4±11.0ml for the control group (P<0.01). PHE volume at the end of treatment was smaller for the MIS group:30.9±15.2ml than the control group:52.5±15.3ml (P<0.01). Positive correlation between reduction in PHE volume and ratio of ICH evacuation was identified (p=0.18, P=0.02). In addition, there was a significant correlation between T2PHE volume and T2ICH volume (p=0.61, P <0.01). There was no any significant correlation between T2PHE volume and cumulative rt-PA dose (p=-0.16, P=0.2). In the MIS group,65patients underwent MIS aspiration plus rt-PA, whereas25underwent MIS aspiration only. Median T2ICH volume was lower in MIS aspiration plus rt-PA than in MIS aspiration subgroup [8.1(10) ml vs.13.4(13.6) ml, P=0.007]. Median T2PHE volume in MIS aspiration plus rt-PA was29(17.5) ml and28.7(18.4) ml in MIS aspiration only (P=0.97).Conclusions:Hematoma evacuation leads to significant reduction in PHE. Furthermore, intraclot low dose rt-PA enhances clot evacuation and does not exacerbate PHE. The rt-PA dose administrated in this study seems to be safe for PHE. Part Ⅲ Minimally invasive surgery for hematoma evacuation reduces short-term mortality in patients with spontaneous intracerebral hemorrhageObjective:Treatment of intracerebral hemorrhage (ICH) is controversial. The effectiveness of minimally invasive surgery (MIS) in combination with thrombolytic removal of hematoma remains uncertain. We aimed to test the hypothesis that hematoma evacuation via MIS will reduce90-day mortality compared with medical treatment and that the clinical outcome in ICH patients treated with MIS plus intraclot rt-PA will be better than with MIS plus intraclot urokinase. Methods:Patients with spontaneous ICH treated using MIS with or without intraclot thrombolytics between October2011and November2013were retrospectively identified from our prospectively institutional ICH database. We manually conducted a semiautomated, computerized volumetric analysis to calculate ICH volume. The primary end point was death at3months. As secondary end points, ICH volume reduction and a dichotomised (favourable or unfavourable) outcome at3months measured by the modified Rankin scale (mRS) were chosen.The patients with mRS0-2were considered as favorable, mRS3-6unfavorable.The30-day complications were also compared between the groups.Results:A total of248patients [168cases in MIS group (80cases in rt-PA subgroup,32cases in only aspiration subgroup and56cases in urokinase subgroup) and80cases in control group] were included with mean age54.0±11.5years. Patients in the MIS group had worse neurological scores on admission as reflected in the Glasgow Coma Scale and NIH Stroke Scale scores. On average, the ICH volume and mass effect was smaller in the controls. MIS led to a significant reduction of30ml of hematoma reduction, a relative reduction of74%in the ICH volume, within about7days after ICH when compared with controls, which had a5-ml reduction (15%)(P<0.05). Compared with the controls, MIS treatment significantly reduced30-day (9.5%vs.30%,P<0.01) and90-day mortalities (10.7%vss.40%, P<0.01) in ICH patients. In addition, there were significantly differences in the ratio of clot removal[83.7%(20%) vs.69.5%(26%), P<0.01] and residual hematoma volume (9.2±7.4ml vs.13.8±8.3ml, P<0.01) in both rt-PA and urokinase subgroups. Importantly, the90-day mortality was significantly lower in the rt-PA subgroup than in the urokinase subgroup (2.5%vs.12.5%, P=0.03), and there was a tendency towards improved short-term prognosis measure by mRS score (32.5%vs.21.4%, P=0.16). There were no significant differences in related complications during the course of treatment between the rt-PA and urokinase subgroups (P>0.05).Conclusions:MIS can be performed safely and significantly reduce the clots, and therefore may improve90-day survival in patients with ICH. Furthermore, compared with urokinase treatment, intraclot low dose rt-PA leads to a significant reduction in3-month mortality and a trend to improved90-day outcome (mRS0-2) due to a higher ratio of clot removal. A prospective study is required to confirm our findings. SummaryThis current study finds that MIS combined with low dose rt-PA for clot evacuation is feasible and safe. The regimen of rt-PA,0.5mg/12h or0.5mg/24h, with a maximum dose of4.0mg, might be favorable in such context in China. In addition, clot evacuation leads to significant PHE reduction and intraclot rt-PA enhances ICH removal without exacerbate PHE. Importantly, compared with medical treatment, successful clot evacuation via MIS improves90-day survival in selected ICH patients. In addition, compared with urokinase treatment, intraclot rt-PA improves clot removal and thus leads to a significant reduction in3-month mortality and a trend to improved90-day outcome. A prospective study is needed to confirm these findings.