【作者】 周立艳；

【导师】 王萍；

【作者基本信息】 第三军医大学 ， 内科学呼吸病学， 2009， 硕士

【摘要】 背景慢性阻塞性肺疾病(chronic obstructive pulmonary disease,COPD)是一种以气流受限为特征的慢性气道疾病,其发病率不断上升,致残率、病死率高,给患者和社会造成沉重的直接和间接医疗负担。肺气肿是COPD的主要病理类型。在COPD的各个阶段均有不同程度的气体限闭在肺内,造成功能残气增加,表现为呼吸困难,活动后加重。晚期肺气肿患者药物治疗效果差,部分患者经肺减容治疗后,获得明显症状改善、生活质量提高,生存期延长。经支气管镜肺减容术(bronchoscopic lung volume reduction ,BLVR)因其具有微创性、安全性好的特点而备受关注,国外已有成熟的产品应用于临床。但因为材料及工艺等问题,国内尚未见到有关国产栓子可经支气管镜操作通道直视下置入成功的临床报道。目的评价自主研制的可经支气管镜操作通道直视下方便置入的单向活瓣栓子的安全性和有效性。材料单向活瓣栓子为解放军第三〇六医院呼吸内科与北京普益盛济科技有限公司合作研制,其材料为316L不锈钢、镍钛合金丝和聚氨酯硅胶。支气管径测量仪和推送器由北京普益盛济科技有限公司提供。研究对象实验动物为12～18个月龄的健康雄性山羊12只(解放军总医院动物实验中心提供),体重16～24 kg。方法实验羊术前72 h禁食,采用3%戊巴比妥钠0.7 ml/kg静脉注射麻醉。选用8.5～9号气管插管经口插管,术前穿刺耳背动脉取血进行动脉血气分析,保持静脉通畅,术中给青霉素钠320万U静脉滴注。选择右肺背侧3～4级支气管为靶肺段,通过支气管镜活检孔道置入支气管径测量仪,经显示屏观察并测量靶肺口径,选用型号FM4-FM8、直径4～8 mm的合适栓子,换入栓子输送系统。先将选定的栓子金属头端固定在装载器螺丝扣上,连同推送杆放入鞘管内,持镜者和术者配合,在活检孔道直视下依次将栓子输送系统放入靶肺段,定位满意后逆时针旋转推动杆释放栓子。每只羊放置3枚。同时通过电子屏幕观察瓣膜位置及其工作情况,使其达到支架嵌顿稳固、瓣膜完好,呼气时瓣膜口开放、吸气时瓣膜口闭合的状态。对个别位置不理想的栓子,可用支气管镜活检钳回收并再次置入。术后常规透视并记录栓子的位置和数量。术后30 min复查动脉血气分析。术后阿米卡星注射液0.2 g连续肌内注射3 d。分别于术后第2、4、8、12周,在静脉麻醉下(方法同上)对实验羊进行动脉血气分析和胸部CT扫描。各时间点取3只羊在麻醉状态下用无痛放血法处死。立即开胸取出完整肺组织,行大体标本观察,取栓子周围的支气管壁、栓子远端肺组织和左侧正常肺组织切片,HE染色观察病理表现,观察栓子对于支气管壁的损伤程度、肺泡萎陷情况及是否有感染等表现。结果(1)本实验共放置单向活瓣栓子36枚,置入顺利。12只羊均耐受良好,治疗中及治疗后没有出现呼吸困难。术后1只羊的进食量明显减少,体温较其基础值略高,呼吸频率无明显变化,1周后完全恢复。本组实验动物无气胸发生,均存活;(2)动脉血气分析结果:除术后30 min外,其他各时间点的动脉血气分析指标均无明显变化;(3)影像学检查结果:术后即行X线透视,1枚栓子因口径偏小而在手术台上咯出,其余栓子位置正常。至实验结束时,共有3枚栓子脱落。术后CT示栓子远端肺组织有不同程度的肺纹理聚拢现象,15/33(45%)的栓子远端有程度不等的肺萎陷和膨胀不全,部分动物肺内可见少许纤维条索影,未见气胸、阻塞性肺炎等影像学改变。(4)病理组织学检查结果:大体标本可见肺表面有瘢痕挛缩样改变,栓子固定良好,紧贴支气管黏膜,支气管黏膜表面光滑,无溃疡。有6枚(6/33)栓子周围有痰液附着,栓子远端肺组织有不同程度的萎缩。12周时可见少许纤维组织填充于栓子周围,栓子与支气管黏膜分离稍困难。HE染色示栓子周围支气管黏膜层略增厚,栓子远端肺组织萎陷,肺泡腔缩小,肺间质内有少许淋巴细胞和单核细胞浸润,可见少许纤维组织增生,未见肺组织坏死和脓肿等表现。将栓子清理取出后,可见栓子的表面光滑,弹性度良好,瓣膜无变形。12周时处死羊的部分栓子表面可见少许纤维素附着,剥离困难,栓子无变形、破损,瓣膜完整。结论(1)本实验采用自主研制的单向活瓣栓子,该栓子由血管内支架材料制成,可以经支气管镜操作通道直视下方便置入,操作简单,定位准确,与国外同类产品比较,操作简便性、组织相容性和安全性相似,且有更多型号可以选择,但其单向瓣膜功能不如国外产品灵敏、精致。(2)在实验中发现,植入栓子术后2周CT示近半数的栓子远端有一定程度的肺萎陷或膨胀不全,连续观察至术后12周,未见随时间延长肺组织塌陷逐渐增加的现象。(3)栓子置入12周时其周围有纤维素样物质增生,栓子与支气管黏膜粘连紧密,不易分离,提示如需术后取出栓子,应在术后1～2个月内进行;(4)本研究结果支持术后常规用3～5 d抗生素以预防肺部感染,并应用化痰药物有助于痰液咳出。(5)该操作创伤小,实验中羊耐受性好,术后未出现气胸、肺脓肿、阻塞性肺炎等并发症,无实验羊死亡。该国产栓子组织相容性好。(6)本实验采用自主研制单向活瓣栓子的安全性好,操作方便,费用低廉,有一定的肺减容效果,经过进一步改善有望用于临床治疗重度肺气肿。更多还原

【Abstract】 BackgroundChronic obstructive pulmonary disease (COPD) is a chronic airway disease characterized by inreversible limited air flow, It caused high mortality, mobidity and disability, COPD has lead to direct and indirect huge medical burden to both the families and society in the world.Emphysema is the main pathological types of COPD. In all stages of COPD, there is gas tripping in the lungs, which increasing lung residual volume and presented as dyspnea and short of breath especially when exercise. The drug therapy in patients with severe emphysema is not so effects. The NETT (National emphysema treatment trial) result shows lung volume reduction surgery (LVRS) are able to improve the patients’symptom, the quality of life and survival. In recent years, Bronchoscopic lung volume reduction (BLVR) has been paid much attention by physicians since its minimally invasive, safety and similar out comes with LVRS. So far, there are a few products has been used successfully in clinic trials outside of the countries. However, we have not see a research paper published in China about implant one- way valves directly through the bronchoscopy’s channel.ObjectiveTo evaluate the safety and effectivity of the self-made one-way valve which can be implanted in the target bronchi through the channel of bronchoscope.Laboratory animals:In this study, we use twelve healthy male goats of 12 to 18-month-old (provided by Animal Center of People’s Liberation Army General Hospital), weighing 16 ~ 24 kg.MaterialOne-way valves are designed and manufactured by the 306th Hospital of PLA and Beijing Puyishengji Science and Technology Co.,Ltd. It is made of 316L stainless steel, nickel titanium alloy wire and polyurethane gel. Caliper of bronchial diameter and the equipment of implanting are provided by Puyishengji Science and Technology Co.,Ltd Beijing.MethodsExperimental goats have been fasting for 72 h before operation, use 3% pentobarbital sodium 0.7 ml/ kg intravenous injection to anaesthetize. 8.5 or 9 tracheal tubes were put in through mouth, draw the arterial blood from ear artery of goats for arterial blood-gas analysis before the operation, and 3.2 million U of sodium penicillin intravenous drip during intraoperation.We choose right lung dorsal 3 ~ 4 ranks-bronchium as the target lungs, put the bronchial diameter measuring instrument through biopsy channel and observe and measure caliber of the target bronchium on screen of bronchoscope, select the suitable valves from FM4 to FM8 (diameter from 4mm to 8mm), fix the one way valves to the conveyer system with metal top of valve on screws, and put them into sheath tube together with the push rod. The holder of bronchoscope cooperates with operator to implant valve conveyer system into target bronchium through biopsy channel under the direct vision. And counterclockwisely rotate push rod to release valves after positioning the system appropriately. Each goat was implanted three valves. At the same time, the operator observe the valve position and working state, and make sure the valve steadily and in a stable working condition: keep open when expiration, close when inspiration. There are 3 of the valves at unsatisfactory location at the beginning. They were taken out by bronchoscope biopsy forceps and re-implanted. After operation, the location and number of valves were checked by X-ray transillumination. 30 minutes after the procedure, arterial blood gas analysis was test again. The goats were given intramuscular injection of amikacin 0.2g once a day for three days after operation, At the time point of 2, 4, 8, 12 weeks after the operation, the experimental goats were tested arterial blood gas analysis and chest CT scan under the intravenous anesthesia (method same as above). At each four time points, three goats were killed painless bleeding under anesthesia. Then, do thoracotomy immediately to resect the whole lung as the samples and observed them in the gross. The bronchial wall around the valves, the target lung and the normal left lung tissue were slice up, the later are observed as the normal control. All slices were HE stain. The pathological manifestations including valves themself injury to bronchial walls, alveolar collapses and the other representation, such as any infection, ulcer and so on. Results(1) 36 valves were implanted successfully. 12 goats were well toleranced. No dyspnea and short of breath were observed during and after the procedure .One goat take less food than before, the temperature is higher than the baseline, but there was no significant change in respiratory rate, and fully recovered one week later. There were no pneumothorax occurred, no goat died unexpected in this animals study.(2) Result of arterial blood gas analysis: Except the 30 min data, the arterial blood gas datas did not have significant changes in all other time points.(3)Imaging Results: X-ray transillumination was done shortly after the procedure. One valve was coughed out on the operating table, since the valve’s caliber is too small. Other valves remained in normal location. At the end of the experiment totally three valves was missing. Postoperative CT scan showed that 15/33 (45%) of the target lungs collapse and deteleotasis more or less, little fibrosis can be seen in the target lungs in some animals.There was no imaging showed pneumothorax, obstructive pneumonia, abscess and so on.(4)Histopathological findings: In the gross, there were visible scars contractures-like changes on the surface of some lungs. Valves were fixed well, close to bronchial mucosa, and bronchial mucosa surface was smooth without ulceration. We can see sputum adhesion around six valves (6/33) and distal lung tissue collapsed in varying degrees. A little fibrous tissue filled around the valves at 12 weeks. It is a little bit difficulty to separate the valves from the bronchus. HE staining slices showed that bronchus mucosa of peripheral of valve was become thicken, and distal lung tissue of the valves collapse and alveolar space become small and narrow. There are a few lymphocytes and mononuclear cells infiltrated in interstitial lung tissues, and a little fibrous tissue hyperplasia can been seen. But there was no lung tissue necrosis or abscess. The valves were smooth and flexible without deformation when cleaning-up and removed. In the lungs which were killed at 12 weeks, a little cellulose attached to the surface of some valves.Though it’s difficult to peel off, but there is no deformation and damage of valve and valve is integrity.Conclusion(1) The One-way valve which were adopted in this experiment, are designed independently, the valves are made of endovascular stent materials. It can be directly implanted in the target bronchus through a bronchoscopy’s biopsy channel. The procedure can be as easy as Emphasys’s valves. The operators can see if the valves is in the accurately position or not when performance. The compatibility with human tissue is well. The result shows that the self-made valve is secure and effective. Moreover, there are more size can be choose. However, the membrane of one-way valve isn’t as sensitive and exquisite as the foreign same kind of products.(2) CT scan showed that there were some grads of lung tissues collapse or atelectasis in nearly half of taget lungs at two weeks time point. But there were no extension lung tissues collapse at 12 weeks.(3) There are hyperplasia of the fibrous-like substance, which make the valve stick to the bronchial mucous membrane firmly and difficult to peel off at 12 weeks after the procedure. It indicated that if you need to take out the valve, it should be done within one to two monthes after the procedrue.(4) The results of this study support the routine use of antibiotics 3 ~ 5 days to prevent pneumonia. The applications of the expectorant drug can facilitately expectorate the sputums and phlegm.(5) It is a kind of minimal intervention technique with no severe postoperative complications, such as pneumothorax, pneumonia and no death in this experiment. The valves had good histocompatibility.(6) The one-way valve used in this experiment was independently designed and manufactured. It has showed the characteristic of good security, easy to procedrue and much cheaper than import products. It also showed a lung volum reduction outcome. We expecte the COPD patients with severe emphysema can get benefits from it in the near future.更多还原