No Exacerbation of Perihematomal Edema with Intraventricular Tissue Plasminogen Activator in Patients with Spontaneous Intraventricular Hemorrhage

Introduction

In severe spontaneous intraventricular hemorrhage (IVH), intraventricular (IVR) administration of tissue plasminogen activator (rtPA) clears blood from the ventricles more rapidly than with external ventricular drainage (EVD) alone. However, experimental studies suggest tPA may be neurotoxic in compromised brain tissue and may exacerbate perihematomal edema.

Methods

We used computerized volumetrics to assess change in intracerebral hemorrhage (ICH), IVH, ventricular, and perihematomal edema (PHE) volumes at 2–4 (T1) and 5–9 (T2) days following diagnostic CT scans (T0) of 24 patients (12 tPA-treated; 12 controls) with IVH requiring EVD. Controls from a hospital registry were matched by IVH and ICH volume to tPA-treated patients who came from a multicenter trial involving 52 patients with IVH.

Results

There were no significant differences between matched pairs in admission ICH and IVH volumes. IVR tPA resulted in more rapid clearance of IVH as determined by T2–T0 decrease in median IVH volume (tPA: ?18.7 cc, iqr 14.9; control:?6.9 cc, iqr 6.4; P = 0.002). Median ratios of PHE to ICH volume were not significantly different in control versus tPA-treated patients at T1 and T2 [control:tPA = 0.55:0.56 (T1); P = 0.84 and 0.81:0.71 (T2); P = 1.00]. Total ventricular volume was significantly larger in the control group at T2 (mean: 57.57 ± 10.32 vs. tPA: 24.80 ± 2.67 cc; P = 0.01). Bacterial ventriculitis was more frequent in the control group (5 vs. 1 episodes; P = 0.06) as was shunt dependence (4 vs. 0 cases; P = 0.03).

Conclusions

For case matched large IVH with small ICH volume, IVR tPA enhances lysis of intraventricular blood clots and has no significant impact on PHE.     

Morphological changes following experimental intraventricular haemorrhage and intraventricular fibrinolytic treatment with recombinant tissue plasminogen activator

Intraventricular haemorrhage (IVH) occurs in up to 50% of patients with primary intracerebral haemorrhage and aneurysmal subarachnoid haemorrhage. It is a significant and independent contributor to mortality and morbidity in these intracranial haemorrhages. Using a model of isolated IVH, we assessed the morphological changes induced by intraventricular bleeding and investigated the effects of intraventricular fibrinolytic treatment following IVH. IVH was induced in 32 pigs by intraventricular infusion of 10 ml autologous blood along with thrombin. The treatment group received an intraventricular injection of 1.5 mg (1 mg/ml) tissue plasminogen activator (tPA) following the injection of blood. The placebo group received the same volume of normal saline. Morphological examinations of the brains were carried out 7 days and 6 weeks following IVH. The ventricles were incompletely filled with blood and significantly enlarged in the placebo group 7 days after the IVH. In contrast, no residual intraventricular clots were visible in the animals treated with tPA, and the diameters of the lateral ventricles had returned to normal within 7 days. Marked losses of the ependymal covering of the ventricular walls were found in the placebo-treated animals, while the ependymal layer was largely intact in the animals treated with tPA. No haemorrhages induced by tPA were observed. The results indicate that intraventricularly administered tPA significantly enhances the lysis of intraventricular blood clots, accelerates the resolution of acute posthaemorrhagic hydrocephalus, and preserves the integrity of the ependymal layer. Received: 6 October 1999 / Revised, accepted: 26 January 2000     

Role of red blood cell lysis and iron in hydrocephalus after intraventricular hemorrhage

Thrombin and iron are two major players in intracerebral hemorrhage-induced brain injury and our recent study found that thrombin contributes to hydrocephalus development in a rat model of intraventricular hemorrhage (IVH). This study investigated the role of red blood cell (RBC) lysis and iron in hydrocephalus after IVH. There were three parts to this study. First, male Sprague-Dawley rats received an injection of saline, packed, or lysed RBCs into the right lateral ventricle. Second, rats had an intraventricular injection of iron or saline. Third, the rats received intraventricular injection of lysed RBCs mixed with deferoxamine (0.5 mg in 5 μL saline) or saline. All rats underwent magnetic resonance imaging at 24 hours and were then euthanized for brain edema measurement, western blot analysis, or brain histology. We found that intraventricular injection of lysed RBCs, but not packed RBCs, resulted in ventricular enlargement and marked increases in brain heme oxygenase-1 and ferritin at 24 hours. Intraventricular injection of iron also resulted in ventricular enlargement and ventricular wall damage 24 hours later. Coinjection of deferoxamine reduced lysed RBC-induced ventricular enlargement (P<0.01). These results suggest that iron, a degradation product of hemoglobin, has an important role in hydrocephalus development after IVH.     

Effects of traumatic brain injury on regional cerebral blood flow in rats as measured with radiolabeled microspheres

To clarify the effect of experimental brain injury on regional CBF (rCBF), repeated rCBF measurements were performed using radiolabeled microspheres in rats subjected to fluid-percussion traumatic brain injury. Three consecutive microsphere injections in six uninjured control rats substantiated that the procedure induces no significant changes in hemodynamic variables or rCBF. Animals were subjected to left parietal fluid-percussion brain injury of moderate severity (2.1-2.4 atm) and rCBF values were determined (a) prior to injury and 15 min and 1 h following injury (n = 7); and (b) prior to injury and 30 min and 2 h following injury (n = 7). At 15 min post injury, there was a profound reduction of rCBF in all brain regions studied (p less than 0.01). Although rCBF in the hindbrain had recovered to near-normal by 30 min post injury, rCBF in both injured and contralateral (uninjured) forebrain areas remained significantly suppressed up to 1 h post injury. At 2 h post injury, recovery of rCBF to near-normal values was observed in all brain regions except the focal area of injury (left parietal cortex) where rCBF remained significantly depressed (p less than 0.01). This prolonged focal oligemia at the injury site was associated with the development of reproducible cystic necrosis in the left parietotemporal cortex at 4 weeks post injury. Our results demonstrate that acute changes in rCBF occur following experimental traumatic brain injury in rats and that rCBF remains significantly depressed up to 2 h post injury in the area circumscribing the trauma site.     

大鼠脑室系统出血模型的建立

目的 探讨建立稳定、制作过程简单、创伤小的大鼠脑室系统出血模型的方法 . 方法 取大鼠自体动脉血立体定向下注入右侧侧脑室建立大鼠腩室系统出血模型,对模型组和对照组大鼠在不同时间点进行神经行为学评分,并观察脑室及室周脑组织病理变化. 结果本方法 模型成功率为88.9%(16/18),注血后6h大鼠出现行为异常,7d后行为异常好转;光镜下观察发现注血后24h模型组大鼠室管膜连续性遭到破坏,细胞间隙增宽,室周脑组织轻度水肿及出现红色坏死神经元. 结论 本研究采用的造模方法 模型稳定,制作创伤小,病理变化接近临床.     

大鼠脑室系统出血模型的建立

目的 探讨建立稳定、制作过程简单、创伤小的大鼠脑室系统出血模型的方法 . 方法 取大鼠自体动脉血立体定向下注入右侧侧脑室建立大鼠腩室系统出血模型,对模型组和对照组大鼠在不同时间点进行神经行为学评分,并观察脑室及室周脑组织病理变化. 结果本方法 模型成功率为88.9%(16/18),注血后6h大鼠出现行为异常,7d后行为异常好转;光镜下观察发现注血后24h模型组大鼠室管膜连续性遭到破坏,细胞间隙增宽,室周脑组织轻度水肿及出现红色坏死神经元. 结论 本研究采用的造模方法 模型稳定,制作创伤小,病理变化接近临床.     

大鼠脑室系统出血模型的建立

目的 探讨建立稳定、制作过程简单、创伤小的大鼠脑室系统出血模型的方法 . 方法 取大鼠自体动脉血立体定向下注入右侧侧脑室建立大鼠腩室系统出血模型,对模型组和对照组大鼠在不同时间点进行神经行为学评分,并观察脑室及室周脑组织病理变化. 结果本方法 模型成功率为88.9%(16/18),注血后6h大鼠出现行为异常,7d后行为异常好转;光镜下观察发现注血后24h模型组大鼠室管膜连续性遭到破坏,细胞间隙增宽,室周脑组织轻度水肿及出现红色坏死神经元. 结论 本研究采用的造模方法 模型稳定,制作创伤小,病理变化接近临床.     

大鼠脑室系统出血模型的建立

目的 探讨建立稳定、制作过程简单、创伤小的大鼠脑室系统出血模型的方法 . 方法 取大鼠自体动脉血立体定向下注入右侧侧脑室建立大鼠腩室系统出血模型,对模型组和对照组大鼠在不同时间点进行神经行为学评分,并观察脑室及室周脑组织病理变化. 结果本方法 模型成功率为88.9%(16/18),注血后6h大鼠出现行为异常,7d后行为异常好转;光镜下观察发现注血后24h模型组大鼠室管膜连续性遭到破坏,细胞间隙增宽,室周脑组织轻度水肿及出现红色坏死神经元. 结论 本研究采用的造模方法 模型稳定,制作创伤小,病理变化接近临床.     

大鼠脑室系统出血模型的建立

目的 探讨建立稳定、制作过程简单、创伤小的大鼠脑室系统出血模型的方法 . 方法 取大鼠自体动脉血立体定向下注入右侧侧脑室建立大鼠腩室系统出血模型,对模型组和对照组大鼠在不同时间点进行神经行为学评分,并观察脑室及室周脑组织病理变化. 结果本方法 模型成功率为88.9%(16/18),注血后6h大鼠出现行为异常,7d后行为异常好转;光镜下观察发现注血后24h模型组大鼠室管膜连续性遭到破坏,细胞间隙增宽,室周脑组织轻度水肿及出现红色坏死神经元. 结论 本研究采用的造模方法 模型稳定,制作创伤小,病理变化接近临床.     

大鼠脑室系统出血模型的建立

目的 探讨建立稳定、制作过程简单、创伤小的大鼠脑室系统出血模型的方法 . 方法 取大鼠自体动脉血立体定向下注入右侧侧脑室建立大鼠腩室系统出血模型,对模型组和对照组大鼠在不同时间点进行神经行为学评分,并观察脑室及室周脑组织病理变化. 结果本方法 模型成功率为88.9%(16/18),注血后6h大鼠出现行为异常,7d后行为异常好转;光镜下观察发现注血后24h模型组大鼠室管膜连续性遭到破坏,细胞间隙增宽,室周脑组织轻度水肿及出现红色坏死神经元. 结论 本研究采用的造模方法 模型稳定,制作创伤小,病理变化接近临床.     

大鼠脑室系统出血模型的建立

目的 探讨建立稳定、制作过程简单、创伤小的大鼠脑室系统出血模型的方法 . 方法 取大鼠自体动脉血立体定向下注入右侧侧脑室建立大鼠腩室系统出血模型,对模型组和对照组大鼠在不同时间点进行神经行为学评分,并观察脑室及室周脑组织病理变化. 结果本方法 模型成功率为88.9%(16/18),注血后6h大鼠出现行为异常,7d后行为异常好转;光镜下观察发现注血后24h模型组大鼠室管膜连续性遭到破坏,细胞间隙增宽,室周脑组织轻度水肿及出现红色坏死神经元. 结论 本研究采用的造模方法 模型稳定,制作创伤小,病理变化接近临床.     

大鼠脑室系统出血模型的建立

目的 探讨建立稳定、制作过程简单、创伤小的大鼠脑室系统出血模型的方法 . 方法 取大鼠自体动脉血立体定向下注入右侧侧脑室建立大鼠腩室系统出血模型,对模型组和对照组大鼠在不同时间点进行神经行为学评分,并观察脑室及室周脑组织病理变化. 结果本方法 模型成功率为88.9%(16/18),注血后6h大鼠出现行为异常,7d后行为异常好转;光镜下观察发现注血后24h模型组大鼠室管膜连续性遭到破坏,细胞间隙增宽,室周脑组织轻度水肿及出现红色坏死神经元. 结论 本研究采用的造模方法 模型稳定,制作创伤小,病理变化接近临床.     

大鼠脑室系统出血模型的建立

目的 探讨建立稳定、制作过程简单、创伤小的大鼠脑室系统出血模型的方法 . 方法 取大鼠自体动脉血立体定向下注入右侧侧脑室建立大鼠腩室系统出血模型,对模型组和对照组大鼠在不同时间点进行神经行为学评分,并观察脑室及室周脑组织病理变化. 结果本方法 模型成功率为88.9%(16/18),注血后6h大鼠出现行为异常,7d后行为异常好转;光镜下观察发现注血后24h模型组大鼠室管膜连续性遭到破坏,细胞间隙增宽,室周脑组织轻度水肿及出现红色坏死神经元. 结论 本研究采用的造模方法 模型稳定,制作创伤小,病理变化接近临床.     

重组组织型纤溶酶原激活剂治疗脑室内出血

目的 探讨利用重组组织型纤溶酶原激活剂(rt-PA)脑室内给药治疗脑室出血的疗效和安全性. 方法 对自2005年11月至2007年10月收入我院的10例脑室出血患者CT确诊后,进行(单侧或双侧)脑室穿刺置管,4～6 h后经弓l流管缓慢注入rt-PA 4～8 mg,12～24 h重复1次,每24～48小时复查CT了解脑室内血肿清除情况,直至头颅CT扫描显示脑室内高密度影像消失.于脑室出血后30 d时对患者情况利用GOS评分进行评估. 结果 每个患者应用rt-PA总剂量为13～24 mg,30 d后GOS评分为良好4例,中残3例,重残2例,植物生存1例,无患者死亡,无出血、颅内感染等并发症,未发生引流管被血块堵塞情况. 结论 选择适宜剂量和方法的rt-PA脑室内给药能够加速脑室内血块溶解,保持脑室引流管通畅,减少血块占位效应.该方法能够安全有效地改善患者的预后.     

Effects of unilateral intrathecal administrations of low dose tissue-type plasminogen activator on clot lysis,vasospasm and brain phospholipid hydroperoxidation in a primate model of bilateral subarachnoid hemorrhage

Abstract

In order to clarify the effect of clot lysis by recombinant tissue-type plasminogen activator (tPA) on the brain lipid peroxidationl we measured phosphatidylcholine hydroperoxide (PCOOH) and phosphatidylethanolamine hydroperoxide (PEOOH) levels in a primate model of subarachnoid hemorrhage (SA H). Monkeys were assigned into two groups; a tPA-treated group receiving intrathecal injections of 0.02 mg tPAI and a placebo-treated group receiving saline. The tPA or placebo was injected into the right side of the basal cistern every 8 h for 6 days following bilateral SAH induction. The tPA cleared the right side clots (p < 0.0007)1 but not the left side clots. The degree of vasospasm in the right middle cerebral artery and the rCBF decrease in the right parietal cortex were significantly attenuated in the tPA group (p < 0.05). In the placebo groupi more severe vasospasm and marked rCBF reduction were noted in comparison with those in the tPA group. PCOOH levels in the parietal cortex were significantly higher in the placebo group than in the tPA group (p < 0.05). There were no significant changes in brain PEOOH levels. These results may explain the limitations for clinical application of unilateral intrathecal administration of tPA. [Neural Res 1998; 20: 625–631]     

Alterations in regional cerebral blood flow following brain injury in the rat

To elucidate the temporal changes in regional cerebral blood flow (rCBF) after experimental traumatic brain injury, serial rCBF measurements were made during a 24-h period following fluid-percussion (F-P) traumatic brain injury in the rat. Brain injury of 2.2 atm was induced over the left parietal cortex and serial measurements of rCBF were performed using the radiolabeled microsphere method. rCBF values were obtained prior to injury and at 15 and 30 min and 1, 2, 4, and 24 h postinjury. At 15 min postinjury, there was a profound, wide-spread reduction in rCBF in all brain regions studied (p less than 0.05). At 30 min and 1 h postinjury, all brain regions except pons-medulla and cerebellum showed significantly reduced rCBF compared to the preinjury values (p less than 0.05). By 2 h postinjury, however, a significant focal reduction of rCBF was observed only in the cerebral tissue surrounding the trauma site (p less than 0.05); rCBF in the remaining brain regions had recovered to the preinjury levels. By 4 h postinjury, rCBF had returned to normal in all brain regions studied. This recovery of rCBF was still evident at 24 h postinjury. The present study demonstrates that, following the experimental traumatic brain injury in the rat, (a) an initial global suppression of rCBF occurs up to 1 h postinjury; (b) at the trauma site, a more persistent focal reduction of rCBF occurs; and (c) these alterations in rCBF after trauma dissolve by 4 h postinjury.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cerebrovascular responses to pentylenetetrazol: time and dose dependent effects.

The effects of subconvulsant and convulsant doses of pentylenetetrazol (PTZ) on cerebral blood flow (rCBF), permeability-capillary surface area products (rPS), and brain vascular spaces (BVS) were examined in 15 brain regions at 1 h, 24 h and 1 week after injection in male Sprague-Dawley rats. Brain histology was examined 3 days after injection. A dose of PTZ (50 mg/kg, i.p.), sufficient to trigger a single convulsive seizure, produced small regional changes in rCBF at 1 h, but not at 24 h or 1 week after injection. No significant changes in rPS or BVS were found at any time, and only mild histologic changes were observed. In contrast, a dose of PTZ (25 mg/kg) which failed to cause either convulsions or significant electrocorticographic changes, markedly increased rCBF and rPS. Some of these regional effects were still observed 1 week later. Similarly, more severe and extensive cellular changes followed treatment with the subconvulsive dose. These findings indicate that PTZ treatment can have prolonged effects on cerebrovascular functions and neuronal integrity even in the absence of convulsive activity.     

Periventricular/intraventricular hemorrhage in neonatal mouse cerebrum

Periventricular/intraventricular hemorrhage (PVH/IVH) into brain can occur in premature infants and is associated with poor developmental outcome. The purpose of this study was to develop and characterize a model of PVH/IVH in newborn mouse. We hypothesized that periventricular germinal matrix would exhibit reduced cell proliferation. PVH/IVH was induced in 1-day-old mice by injection of autologous blood into the periventricular tissue. Magnetic resonance images (MRI) were obtained from 15 minutes to 14 days later. Mice were killed 4 hours to 28 days later. Cell proliferation, dying cells, astrocyte and microglial reactions, neutrophils, and lymphocytes were quantified. Histological studies showed that MRI accurately localizes the hematoma but overestimates its size. The hematoma, located in the striatum and germinal tissue, always extended into the lateral ventricles. Cell proliferation, measured by Ki67 immunoreactivity, was suppressed bilaterally in germinal matrix and beyond from 8 hours to 7 days. Increased cell death was observed in the ipsilateral striatum and germinal matrix 1 and 2 days after PVH/IVH. Astrocyte and microglia reaction peaked at 2 days and persisted up to 28 days. Inflammatory response was minimal. Extravasated blood might play an important role in brain damage following PVH/IVH through suppression of cell proliferation.     

Effect of nimodipine on cerebral blood flow and metabolism in rats during hyperventilation

Nimodipine shws promise in the prevention and treatment of brain ischemia. We examined the interaction of nimodipine pretreatment in a dose sufficient to prevent postischemic hypoperfusion and hyperventilation. We studied four groups of rats: normocarbia plus vehicle (Group 1, n = 5), hypocarbia plus vehicle (Group 2, n = 4), normocarbia plus nimodipine (Group 3, n = 7), and hypocarbia plus nimodipine (Group 4, n = 6). Groups 3 and 4 received 1 mg/kg i.p. nimodipine, and Groups 1 and 2 received an equivalent amount of vehicle. Ventilation was left unaltered in Groups 1 and 3 or increased to lower PaCO2 to 21-24 mm Hg in Groups 2 and 4. Determination of regional cerebral glucose utilization (rCGU) was carried out using the [3H]2-deoxyglucose method, and regional cerebral blood flow (rCBF) was determined by the indicator fractionation method using [14C]iodoantipyrine. The brain regions studied were the cerebral hemispheres, the diencephalon, the cerebellum, and the brainstem. Hyperventilation in Groups 2 and 4 from approximately 38 to 22 mm Hg reduced rCBF to 60% of normocarbic levels (p less than 0.05). The slope and intercept of this response were similar in vehicle- and nimodipine-pretreated rats. Nimodipine modestly decreased mean arterial blood pressure by 20% and increased plasma glucose concentration by 60% (p less than 0.05). Although nimodipine tended to increase rCBF and decrease regional cerebrovascular resistance (rCVR), this was significant only for hemispheric rCVR (p less than 0.05). There was a borderline effect for nimodipine to increase rCGU, especially during hypocarbia.(ABSTRACT TRUNCATED AT 250 WORDS)     

Magnet-targeted delivery of bone marrow-derived mesenchymal stem cells improves therapeutic efficacy following hypoxic-ischemic brain injury

hypoxicischemic brain injury;however,the therapeutic efficacy of bone marrow-derived mesenchymal stem cells largely depends on the number of cells that are successfully transferred to the target.Magnet-targeted drug delivery systems can use a specific magnetic field to attract the drug to the target site,increasing the drug concentration.In this study,we found that the double-labeling using superparamagnetic iron oxide nanoparticle and poly-L-lysine(SPIO-PLL)of bone marrow-derived mesenchymal stem cells had no effect on cell survival but decreased cell proliferation 48 hours after labeling.Rat models of hypoxic-ischemic brain injury were established by ligating the left common carotid artery.One day after modeling,intraventricular and caudal vein injections of 1×105 SPIO-PLL-labeled bone marrow-derived mesenchymal stem cells were performed.Twenty-four hours after the intraventricular injection,magnets were fixed to the left side of the rats’heads for 2 hours.Intravoxel incoherent motion magnetic resonance imaging revealed that the perfusion fraction and the diffusion coefficient of rat brain tissue were significantly increased in rats treated with SPIO-PLL-labeled cells through intraventricular injection combined with magnetic guidance,compared with those treated with SPIO-PLL-labeled cells through intraventricular or tail vein injections without magnetic guidance.Hematoxylin-eosin and terminal deoxynucleotidyl transferase dUTP nick-end labeling(TUNEL)staining revealed that in rats treated with SPIO-PLL-labeled cells through intraventricular injection under magnetic guidance,cerebral edema was alleviated,and apoptosis was decreased.These findings suggest that targeted magnetic guidance can be used to improve the therapeutic efficacy of bone marrow-derived mesenchymal stem cell transplantation for hypoxic-ischemic brain injury.This study was approved by the Animal Care and Use Committee of The Second Hospital of Dalian Medical University,China(approval No.2016-060)on March 2,2016.