Kramer Andreas H, Jenne Craig, Holodinsky Jessalyn K, Todd Stephanie, Roberts Derek J, Kubes Paul, Zygun David A, Hill Michael D, Leger Caroline, Wong John H
Department of Critical Care Medicine, University of Calgary, McCaig Tower, 3134 Hospital Drive N.W, Calgary, AB, T2N 2T9, Canada.
Department of Clinical Neurosciences, University of Calgary, Calgary, Canada.
Neurocrit Care. 2015 Dec;23(3):386-93. doi: 10.1007/s12028-015-0126-9.
Intraventricular hemorrhage (IVH) frequently complicates spontaneous intracerebral or subarachnoid hemorrhage (SAH). Administration of intraventricular tissue plasminogen activator (TPA) accelerates blood clearance, but optimal dosing has not been clarified. Using a standardized TPA dose, we assessed peak cerebrospinal fluid (CSF) TPA concentrations, the rate at which TPA clears, and the relationship between TPA concentration and biological activity.
Twelve patients with aneurysmal SAH and IVH, treated with endovascular coiling and ventricular drainage, were randomized to receive either 2 mg intraventricular TPA or placebo every 12 h (five doses). CT scans were performed 12, 48, and 72 h after initial administration, and blood was quantified using the SAH Sum and IVH Scores. CSF TPA and fibrin degradation product (D-dimer) concentrations were measured at baseline and 1, 6, and 12 h after the first dose using ELISA assays.
Median CSF TPA concentrations in seven TPA-treated patients were 525 (IQR 352-2129), 323 (233-413), and 47 (29-283) ng/ml, respectively, at 1, 6, and 12 h after drug administration. Peak concentrations varied markedly (401-8398 ng/ml). Two patients still had slightly elevated levels (283-285 ng/ml) when the second dose was due after 12 h. There was no significant correlation between the magnitude of CSF TPA elevation and the rate of blood clearance or degree of D-dimer elevation. D-dimer peaked at 6 h, had declined by 12 h, and correlated strongly with radiographic IVH clearance (r = 0.82, p = 0.02).
The pharmacokinetics of intraventricular TPA administration varies between individual patients. TPA dose does not need to exceed 2 mg. The optimal administration interval is every 8-12 h.
脑室内出血（IVH）常并发自发性脑出血或蛛网膜下腔出血（SAH）。脑室内注射组织型纤溶酶原激活剂（TPA）可加速血液清除，但最佳剂量尚未明确。我们使用标准化的TPA剂量，评估了脑脊液（CSF）中TPA的峰值浓度、TPA的清除速率以及TPA浓度与生物活性之间的关系。
12例患有动脉瘤性SAH和IVH的患者，接受了血管内栓塞和脑室引流治疗，被随机分为每12小时接受2mg脑室内TPA或安慰剂（共5剂）。在首次给药后12、48和72小时进行CT扫描，并使用SAH总和和IVH评分对血液进行定量。使用ELISA测定法在基线以及首次给药后1、6和12小时测量CSF中TPA和纤维蛋白降解产物（D-二聚体）的浓度。
7例接受TPA治疗的患者在给药后1、6和12小时的CSF中TPA中位数浓度分别为525（IQR 352-2129）、323（233-413）和47（29-283）ng/ml。峰值浓度差异显著（401-8398 ng/ml）。12小时后应给予第二剂时，有2例患者的水平仍略有升高（283-285 ng/ml）。CSF中TPA升高的幅度与血液清除速率或D-二聚体升高程度之间无显著相关性。D-二聚体在6小时达到峰值，12小时时下降，并且与影像学IVH清除密切相关（r = 0.82，p = 0.02）。
脑室内注射TPA的药代动力学在个体患者之间存在差异。TPA剂量无需超过2mg。最佳给药间隔为每8-12小时一次。
