| Background and PurposeAs a kind of hemorrhagic cerebral vascular disease, intraventricular hemorrhage (IVH), especially total intraventricular hemorrhage of casting form, usually has poor prognosis, with mortality as high as 50%?75%. It is generally considered that the ventricle hematoma quantity and duration was closely correlated with the mortality and removing immediately the hematoma is the optimal result. The traditional treatments for IVH including surgical removal of hematoma and external ventricular drainage (EVD) haven't improve the survival due to complications such as trauma, infection, re-bleeding and drainage tube clogged etc. Thus, leads to a post-operation mortality of near 30%. Moreover, ventricle puncture has 1% to risk of re-bleeding, and 10%?20% to infection that increases with the prolonged drainage.In recent years, studies from animal experiments and clinical observations have showed that intraventricular fibrinolysis was probably safe and effective for IVH treatment with the benefits of improving prognosis, alleviating neural function defect and increasing survival rate.A series of clinical observations about Urokinase (UK) intraventricular fibrinolysis has indicated that it is effective on the treatment of IVH.Meanwhile, it has also been reported that UK is effective in treatment of traumatic subarachnoid hemorrhage (SAH). However, there are few studies of animal experiment or clinical observations about UK intrathecal injection in treating IVH. In this study, UK was intrathecally injected into subarachnoid space to resolve blood clot in the fourth ventricle, the third and the lateral ventricles through the Magendie's and the Luschka's foramina. The purpose of this study is to observe the effect of intrathecal UK injection in Rat model and patients with IVH.MethodsThere were two parts in this study.Part 1, Animal experiment:40 male matured Sprague-Dawley (SD) rats, weighted 250g?350g, were divided equally and randomly into the control group (A1) and the model group (B1). IVH model was established in 20 rats (B1) by autologous fresh femoral artery blood injecting into right lateral ventricle through skull drilling; the A1 rats accepted the drill only. Thereafter, the brain macroscopical tissue slice (1mm) and the light microscopical tissue section (5um) were made respectively to observe the ventricular blood residual in rats at 6h?24h?72h?120h?and 168h after ventricular blood injection through the macroscope observing and the light microscope viewing. Then, the other 40 male matured SD rats, weighted 250g-350g, were divided into normal group (A2)?physiological saline control group (A3)?model group (B2) and model+ intrathecal UK injecting group (C1) equally and randomly. The pathological changes and water contents of brain tissues, expression differences of heat shock protein 70(Hsp70)and S100 protein?(S100?) levels of cerebrospinal fluid (CSF) were observed after 24h of intrathecal injection..Part 2, Clinical study:A prospective, open and case-control clinical study was carried out to value the effect of intrathecal injection of UK on patients with IVH, based on the background of the animal experiment.27 cases of IVH, including subarachnoid hemorrhage (SAH) or intracerebral hemorrhage (ICH) extention into ventricle, admitted from Jan 2009 through May 2010 in neurological department, were enrolled. With informed-consent by the patient's family or the patient if possible,15 cases were trerated by intrathecal UK injection (C2) and the others with EVD plus UK irrigation or conservative treatment (A4). UK doses were adjusted,20000IU?50000IU, according to the volume of ventricular hematoma in C2 group at admission, and repeated or not by second-day's cranial tomography scan results; whilst,20000IU UK was used in A4 group per 12h until the CSF became clear. Glassgow coma scale (GCS), Mehta scale (MS), Glassgow outcome scale (GOS) and National Institute of Health Stroke scale (NIHSS) were applied to evaluate the therapy effect,including consciousness status?hydrocephalus?neurological deficits and disabilities.Results:Part 1, Animal experiment:2 rats were died of blood injection in B1 group, a death rate of 10%, and 16 of 18 rats were found blood residual in ventricles, meaning a 88.9% model rate. and, in B2 group, these pathological features had been found, including the epiependymal tissue looseness and disruption of ependymal lining,as well as increases of S100?in CSF, water contents in brain tissues and significant expression of Hsp 70 in cortex and subcortex areas; But these changes ameliorated significantly after UK intrathecal injection in C1 group, including decrease of Hsp70 expression in cortex and levels of S100?in CSF with descensus of water content in brain tissues, supporting the concept that it's effective of intrathecal UK injection on IVH.Part 2, Clinical study:There were no differences in GCS and MS at admission but different at discharge between C2 group and A4 group (GCS 10.36±1.75 vs 8.56±1.51; MS 0.6±0.23vs 1.2±0.45; P<0.01), so did the NIHSS (13.21±5.73 vs 19.32±4.52, P=0.002 at discharge). The time to arouse from coma was shorter in C2 group than that in the counterpart (t=5.07,P=0.000), and GOS in C2 group was better than that in A4 group at discharge (5.0±0.21 vs 3.8±1.1, P<0.01). In some C2 patients which had intracerebral hematoma, the changes of blood absorption rate accompanied with Uk intrathecal injections were: 3.25±1.17ml in first; 4.63±2.39ml in sceond; 6.29±2.63ml in third and 7.00±3.61ml in fourth treatment respectively. the difference was found between the first and the third treatment (t=2.801, P=0.031).No intracranial rebleeding was observed and no difference of coagulation functions, including prothrombin time?international normalized ratio?fibrinogen?activated partial thromboplastin time and thrombin time, was existing before and after UK treatment. This initial findings was a evidence to prove that intrathecal UK injection was effective in patients with IVH in this study.Conclusions:1. Prepared with autologous fresh femoral artery blood injection in rats, the IVH model is much similar to clinical situation and a higher IVH-rate;2. In this rat model of IVH, increases of S100?in CSF and significant expression of Hsp70 in cortex indicate that hematoma in ventricles do induce remote cortex damage;3. After intrathecal injecting of UK, these changes happen, including blood in ventricles complete resolving?lessened ependymal and epiependymal tissue damages?decrease of water content in brain tissues?S100?in CSF and HSP70 expression in cortex,which means the approach of intrathecal UK therapy can speed blood clot resolving in ventricles and ameliorate pathological changes associated with IVH in this model;4. primary clinical data, containing amelioration of conscious level, decurtation of consciousness recovery time and good functional outcome in IVH patients treated with intrathecal UK injection, indicate the improving effect of this therapy on IVH patients' prognosis;5. with intracerebral hematoma in IVH patients,the blood absorption rate is increased with intrathecal UK injections,especially after the third treatment,which implying that the optimal treatment frequency is more than 3 times in IVH UK therapy;6. Enlargement of hematoma and coagulation function abnormality were not observed in this study, indicating that intrathecal UK injection is safe in acute stage of these patients. |
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