Masomi-Bornwassser Julia, Freguia Fabio, Müller-Werkmeister Hendrik, Kempski Oliver, Giese Alf, Keric Naureen
Department of Neurosurgery, University Medical Centre of the Johannes Gutenberg University of Mainz, Langenbeckstr. 1, 55131, Mainz, Germany.
Department of Neuropathology, University- and Knappschaft- Hospital Bochum, Bochum, Germany.
Acta Neurochir (Wien). 2018 Jun;160(6):1159-1165. doi: 10.1007/s00701-018-3517-9. Epub 2018 Mar 21.
Although fibrinolytic therapy is an upcoming treatment for intracerebral haemorrhage (ICH), standard guidelines are lacking, and some clinical issues persist. Here, we used our recently devised clot model of ICH to systematically analyse effects of irrigation and cerebrospinal fluid (CSF) on fibrinolysis.
In vitro clots of human blood (25 ml) were generated and a catheter irrigation system was applied to deliver fluid/treatment. Clots were weighed before and after treatment and compared to rtPA treatment alone. First various drainage periods (15, 30 and 60 min; n = 3 each) and irrigation rates (0, 15, 90 and 180 ml/h; n = 3-5 each) were tested, followed by rtPA administration (1 mg, 15 min incubation) at each irrigation rate. Potential fibrinolytic effect of CSF was examined by incubation with 5 ml healthy vs. haemorrhagic CSF (n = 3 each). To assess a washout effect treatment with saline (0.9%), rtPA (1 mg) and high-rate irrigation (180 ml/h) were compared with measuring plasminogen level before and after. Furthermore clots were treated with a combination of plasminogen (150% serum concentration) and rtPA (1 mg).
Relative clot end weights after 60 min irrigation system treatments were 66.3 ± 3.8% (0 ml/h), 46.3 ± 9.5% (15 ml/h), 46.5 ± 7.1% (90 ml/h) and 53.3 ± 4.1% (180 ml/h). At a lower irrigation rate (15 ml/h), relative end weights were lowest (49.5 ± 4.6%) after 60 min (15 min: 62 ± 4.3%, p = 0.016; 30 min: 62.90 ± 1.88%, p = 0.012). The combination of rtPA and irrigation produced following relative end weights: 0 ml/h, 35 ± 3.2%; 15 ml/h, 32.1 ± 5.7%; 90 ml/h, 36.7 ± 6.3% and 180 ml/h, 41.9 ± 7.5%. No irrigation (0 ml/h) versus rtPA alone showed a significant difference (p < 0.0001) in higher clot weight reduction by rtPA. Similar rtPA+15 ml/h irrigation achieved a significant higher weight reduction compared to 15 ml/h irrigation alone (p = 0.0124). No differences were evident at 90 and 180 ml/h irrigation rates with and without rtPA. Healthy (55.1 ± 5%) or haemorrhagic (65.2 ± 6.2%) CSF showed no fibrinolytic activity. Plasminogen levels in clots declined dramatically (> 80% initially to < 10%) after 1 mg single rtPA dosing and high-rate (180 ml/h) irrigation. The fibrinolytic benefit of adding plasminogen to rtPA was marginal.
In our in vitro clot model, irrigation combined with rtPA (vs. rtPA alone) conferred no added lytic benefit. Likewise, exposure to haemorrhagic CSF did not increase clot lysis.
尽管纤溶疗法是一种即将应用于脑出血（ICH）的治疗方法，但目前缺乏标准指南，一些临床问题仍然存在。在此，我们使用最近设计的ICH凝块模型，系统分析冲洗和脑脊液（CSF）对纤溶的影响。
制备人体血液（25ml）的体外凝块，并应用导管冲洗系统输送液体/进行治疗。治疗前后对凝块进行称重，并与单独使用rtPA治疗进行比较。首先测试不同的引流时间（15、30和60分钟；每组n = 3）和冲洗速率（0、15、90和180ml/h；每组n = 3 - 5），然后在每个冲洗速率下给予rtPA（1mg，孵育15分钟）。通过与5ml健康脑脊液和出血性脑脊液孵育（每组n = 3）来检查脑脊液的潜在纤溶作用。为了评估冲洗效果，比较用生理盐水（0.9%）、rtPA（1mg）和高速率冲洗（180ml/h）处理前后的纤溶酶原水平。此外，用纤溶酶原（血清浓度的150%）和rtPA（1mg）联合处理凝块。
冲洗系统处理60分钟后的相对凝块终重分别为：0ml/h时66.3±3.8%，15ml/h时46.3±9.5%，90ml/h时46.5±7.1%，180ml/h时53.3±4.1%。在较低冲洗速率（15ml/h）下，60分钟后的相对终重最低（49.5±4.6%）（15分钟时为62±4.3%，p = 0.016；30分钟时为62.90±1.88%，p = 0.012）。rtPA与冲洗联合处理后的相对终重分别为：0ml/h时35±3.2%，15ml/h时32.1±5.7%，90ml/h时36.7±6.3%，180ml/h时41.9±7.5%。不冲洗（0ml/h）与单独使用rtPA相比，rtPA导致的凝块重量减少差异显著（p < 0.0001）。与单独15ml/h冲洗相比，rtPA + 15ml/h冲洗导致的重量减少显著更高（p = 0.0124）。在90和180ml/h冲洗速率下，有无rtPA处理均无明显差异。健康脑脊液（55.1±5%）或出血性脑脊液（65.2±6.2%）均无纤溶活性。单次给予1mg rtPA和高速率（180ml/h）冲洗后，凝块中的纤溶酶原水平显著下降（从最初的>80%降至<10%）。在rtPA中添加纤溶酶原的纤溶益处微乎其微。
在我们的体外凝块模型中，冲洗与rtPA联合使用（相对于单独使用rtPA）并未带来额外的溶解益处。同样，接触出血性脑脊液也未增加凝块溶解。
