| Background:Chronic obstructive pulmonary disease (COPD) is a common progressive chronic inflammatory disease, with airflow limitation that is not fully reversible. End-stage COPD features rising incidence, high morbidity and high mortality, and the diagnosis and treatment enhance the social economic burden. The diagnosis and treatment of COPD, therefore, have become a serious problem in the world health.According to the analysis and statistics of WTO, by 2020, the global COPD will become the third leading cause of death. Because of its high morbidity, mortality, social and economic burden, COPD constitutes a serious threat to human public health, so it has gained more and more attention of the medical profession. As the main pathologic feature of COPD, emphysema has become the focus in the research of COPD.For advanced severe emphysema disease patients, LVRS is the operation method in the treatment proposed by America Dr. Brantigen in 1950s to cure end-stage diffuse emphysema, whose core concept is the removal of the non functional, the excessive expansion of the lung tissue, so as to correct pathological and physiological impacts caused by lung inflation and improve respiratory function. But the operation mortality was high back then, so the medical community did not accept this procedure. In the early 1990s, the scholar Cooper introduced minimally invasive endoscopic instruments to cut suture technique, improving the operation mode. The method strengthened the application of gasket closure margin, and reduce the operation risks.Since 1994 when China introduced lung volume reduction operation, it has become an effective therapy for end-stage pulmonary emphysema. Lots of literatures at home and abroad show that LVRS can significantly improve lung function, improve the life quality of the patients. According to the research results, LVRS can actually improve pulmonary function for heterogeneous emphysema, providing a new choice for surgical treatment of heterogeneous emphysema. With the development of medical basic theories of operation, the surgical treatments of emphysema are as follows:pulmonary bulla resection, lung tissue area target area resection and lung transplantation, all of which have certain clinical effect. At present, the main mechanism of surgical lung volume reduction surgery for emphysema is about local excision and folding the excessive emphysema lung tissues to remove the compression on the restoration of normal lung tissue, and resume lung elasticity, reduce airway obstruction, improve motor function of the diaphragm and chest, enhance ventilation/perfusion ratio and hemodynamics, eventually improving the lung the function of the patient and relieving the symptom of dyspnea. Thoracoscopic bullectomy applies only to some bullous emphysema patients. Double lung transplantation has some issues including limited number of donors, high difficulties of surgery, and high cost. Regional excision of lung tissue target area has wide indications, postoperative treatment satisfaction, so as to provide a promising new method for the treatment of heterogeneous emphysema.In recent years, with the rapid development of minimally invasive video-assisted thoracoscopic technique and anaesthetic technique, lung volume reduction surgery has many new operational methods. The operation mortality has been reduced and the indications of operation widened, making more emphysema patients have the opportunity to accept operation treatment. Minimally invasive surgery is the current focus of surgeons and anaesthetists, and reducing trauma, shortening the operation time and fastening the rehabilitation of patients will be the future directions of lung volume reduction surgery. In recent years many new ideas and operation modes of operation, such as minimally invasive bronchoscopic lung volume reduction (BLVR), have also showed better effects, expanding the range of COPD operation. However, the endoscopic stent for BLVR is expensive, and lobar bronchial communicating branches and inflammatory implant infection do exsit. The secretion can not be effectively discharged, even causing coughs or shifts. It therefore, is temporarily unable to be effectively promoted. With the development and promotion of VATS, the lung volume reduction surgery causes less trauma with shorter operation time. Surgery with fast rehabilitation is a new surgical concept, whose essence is the use of existing means of perioperative various treatment measures to improve and re-optimize, including the methods of anesthesia, analgesia and minimally invasive technique and postoperative rehabilitation. Therefore, how to optimize anesthesia and minimally invasive techniques and re-combination will is a hot issue in the research of thoracic surgery.In recent years, many foreign literatures show that, due to application of high doses of neuromuscular blocking drugs, patients with technical ventilations can have a long-time myasthenia and the muscle strength can not be restored in short terms. So they are forced to extend the mechanical ventilation time. In order to avoid the occurrence of the above mentioned problems, some scholars stipulated that, as far as possible, the anesthesia should be accompanied with spontaneous breathing. Autonomous respiration by thoracoscopic operation is defined as maintaining the spontaneous ventilation conditions to do the thoracoscopic operation after the implementation of the mild sedation. Its basic principle is to avoid the basic anesthesia tracheal intubation single lung ventilation and maintain the physiology of muscles, nerves and heart and lungs. At the same time, autonomous breathing will not need muscle relaxants, thereby minimizing operational and anesthesia trauma. Spontaneous breathing can play a greater role, avoiding mechanical ventilation, shortening the time of bed rest, reducing the cost and benefiting the patients more.At the same time, spontaneous respiration anesthesia, compared with tracheal intubation, reduces inflammatory injury of tracheal intubation,which is one of its biggest advantages. Therefore, we believe that spontaneous breathing and anesthesia VATS lung volume reduction surgery, under appropriate circumstances,are not different from the traditional operation in the curative effects, which will reduce patient trauma, shorten the hospitalization time, and reduce patient medical expenses. But its concrete operation indications, contraindications and the effects on the heart and lung function and airway inflammation are still in the stage of exploration and research.Many scholars at home and abroad have constructed animal model of pulmonary emphysema, and further explored and carried out surgery to provide the theoretical foundation for the treatment of emphysema. However, there are few researches on domestic animal experiments. Many domestic researches were based on different experimental purposes to employ experimental objects, such as mice, hamsters, guinea pigs, rats, rabbits and etc. But all small animal models have poor surgical operability. Using or copying animal models for lung swollen heterogeneous emphysema models can not achieve the basic research requirements and meet the need of clinical application. Domestically, non-heterogeneous emphysema large animal models are rarely reported, and there have been no reports related to spontaneous respiration anesthesia lung volume reduction surgery in basic research.Objective:We established a successful canine model of heterogeneous pulmonary emphysema by injecting papain,which was systematically assessed by vadous respiratory physiological indexes and coincided with pathophysiological changes of heterogeneous pulmonary emphysema. The results of the present investigation supported the conclusion that we can safely establish an canine model of heterogeneous pulmonary emphysema. In the present study with the animal model of heterogeneous pulmonary emphysema,We employed multiple profiles physiological evaluation including respiratory mechanics, gas exchange, iconography, hemodynamics and electromyologram of diaphragm, in attempt to evaluate the effects of lung volume reduction surgery on respiratory physiological mechanisms and airway inflammation. The results of the present investigation might provide important theoretical evidence for further clinical investigation.Methods:To investigate the effects of LVRS on respiratory physiological mechanisms and airway inflammation of heterogeneous pulmonary emphysema during spontaneous respiration anesthesia, we focused on the therapeutic effect of LVRS on pulmonary emphysema during spontaneous respiration anesthesia to study the following three aspects:1ã€The canine heterogeneous pulmonary emphysema model was induced by repeated endotracheal instillation of papain. Eligible animal model was evaluated by systematic physiology and photography to be applied for further LVRS during spontaneous breathing anesthesia.2ã€The balloon catheter systems for esophageal pressure and gastric pressure were placed by bronchoscopy to monitor the flow, volume, pressure and diaphragmatic electric potential. Multiple time points were settled for evaluation of respiratory mechanics, hemodynamics. gas exchange and myoelectrophysiology to reflect the effect of LVRS on respiratory physiology during spontaneous respiration anesthesia. The exact time points included 15 minutes before thoracotomy (T1), beginning of thoracotomy (T2),20minutes since thoracotomy (T3),15 minutes after surgery (T4), 90 minutes after surgery (T5).3ã€After finishing the foregoing experiment, the pathological samples of lung tissue were acquired for the examination of optical and electron microscope, enzyme-linked immunosorbent assay (ELISA), real-time quantitative PCR to to reflect the historical effect of LVRS on respiratory physiology during spontaneous breathing anesthesia.Results:Part I:Development and Systematic Analysis of a Canine Model of Heterogeneous Pulmonary Emphysema1. Imageology(1) Chest X-ray:The density of target area of the model was significantly lower, and the transmissivity was significantly enhanced, which presented as typical heterogeneous pulmonary emphysema.(2) Chest computed tomography (CT):The density of target area of the model was significantly lower, which formatted local emphysema. The rest lung was shown no signs of significant infection or pleural effusion.(3) Thoracoscopic exploration:The model of heterogeneous pulmonary emphysema was successfully established in experimental group. No signs of mediastinal shift or inflammation of mediastinal pleura were observed. Compared to the rest lung, the target lobe which had been injected papain was obviously swelling and lack of flexibility. There were no adhesion and fluid in the cavity, which was proper for operation in experimental group.(4) Quantitative CT:The CT value of the target area was calculated, which fits the criteria for emphysema. The area and percentage were measured to analysis the heterogeneous pulmonary emphysema.2. Pathological histology(1) The gross appearance of lung tissue of the target area:The volume of the lobe was significantly larger in experimental group than that in contrast group. In experimental group, the target lobe was lack of flexibility, and was unable to collapse after pressed or dissected; the margin of the target lobe was finely rounded; partial subpleural bleb were shown enlarged.(2) The optical microscopic appearance of lung tissue of the target area:in experimental group, the target lung tissue was rarefaction; alveolar septum was narrow; alveolar capillary was compressed; the breakdown or absence of alveolar septum led to distended alveolar spaces.(3) Quantitative analysis of the morphology of pulmonary alveoli:compared to contrast group, the mean number of pulmonary alveoli were significantly lower in experimental group (P<0.001)(4) The electron microscopic appearance of lung tissue of the target area:In experimental group, type â…¡ pulmonary alveoli were hyperplasia.3. Respiratory physiology(1) Life habit and daily activities:in experimental group, after modeling, the brightness of canine nose showed no difference, but the daily activities were significantly reduced during daytime.(2) Arterial blood gas analysis:In experimental group, the SaO2 (P<0.001) and PaCO2 (P<0.001) were significantly lower, so was after modeling.Part â…¡:The Respiratory Physiological Effects of Lung Volume Reduction Surgery on a Canine Model of Heterogeneous Pulmonary Emphysema During Spontaneous Respiration Anesthesia1. Respiratory mechanicsThe esophageal Pressure (Pes) and transdiaphragmatic pressure (Pdi) and gastric pressure (Pga) was significantly greater at T5 in experimental group than that in contrast group (P<0.001) The gastric pressure (Pga) at T4 showed no significant difference between two groups (P=0.127). Compared to contrast group, the tidal volume at T2 and T3 were significantly lower in experimental group; the tidal volume at T5 were significantly greater in experimental group (P<0.001); the respiratory rates at T5 were significantly greater in experimental group(P<0.001); the pulmonary elastic resistance at T5 were significantly greater in experimental group (P=0.003); and the respiratory compliance was significantly greater in experimental group (P=0.003)2. Diaphragmatic myoelectricityIn experimental group, there was diaphragmatic myoelectricity activities at T2 and T3, but absence of activity in contrast group. The root mean square (RMS) of diaphragmatic myoelectricity voltage at T4 and T5 were significantly greater in experimental group than that in contrast group (P=0.003)3. HemodialysisThere were no significant difference between two groups in terms of stroke volume (SV) (P=0.330), extravascular lung water index(ELWI) and heart rates (HR) at T5 (P=0.128)4. Arterial blood gas analysisCompared to contrast group, the PaCO2 was significantly greater at T2 and T3 (P<0.001). After the surgery, the PaCO2 was reduced in experimental group. The PaCO2 was significantly lower at T5 in experimental group than that in contrast group (P<0.001)Part â…¢:The Airway Inflammatory Effects of Lung Volume Reduction Surgery on a Canine Model of Heterogeneous Pulmonary Emphysema during Spontaneous Respiration Anesthesia1. Pathological histologyThe examination of optical and electron microscope:The pulmonary alveolus was intact both in mechanical ventilation group and spontaneous breathing group. The vessel of alveolar septum was hyperemia in both groups. There were sporadic lymphocytes around stroma and small vessels in both groups. There were inflammatory cell around bronchiole wall and diffusate in bronchiole lumen in mechanical ventilation group. The lung injury scores in spontaneous breathing group were significantly lower than that in contrast group.2. Molecular biology(1) Enzyme linked immunosorbent assay (ELISA):After thoracotomy, the plasma TNF-a in spontaneous breathing group was significantly lower than that in mechanical ventilation group (P=0.025); and the plasma IL-8 showed no difference between two groups (P=0.025).After surgery, the plasma TNF-a and IL-8 in spontaneous breathing group was significantly lower than that in mechanical ventilation group (P<0.001); and the cytokine in bronchoalveolar lavage fluid (BALF), lung tissue and tracheal tissue in spontaneous breathing group was significantly lower than that in mechanical ventilation group (P<0.001)(2) Real-time quantitative PCR:The gene expression level of TNF-α and IL-8 in spontaneous breathing group was significantly lower than that in mechanical ventilation group (P<0.001)3. PET/CTCircumferential tracheal hypermetabolism was observed four hours after tracheal intubation in mechanical ventilation group, which was not detected in spontaneous breathing group.Conclusion:1. This study suggested that canine heterogeneous pulmonary emphysema model could be induced by repeated endotracheal instillation of papain. This method is feasible, safe and effective.2. This study suggested that it is feasible to investigate the cardiorespiratory functional effects of lung volume reduction surgery on a canine model of heterogeneous pulmonary emphysema during spontaneous breathing anesthesia.(1) It is feasible, safe and effective to perform lung volume reduction surgery on a canine model of heterogeneous pulmonary emphysema during spontaneous breathing anesthesia.(2) Lung volume reduction surgery has less impact on hemodialysis, transdiaphragmatic pressure on a canine model of heterogeneous pulmonary emphysema during spontaneous breathing anesthesia, and the postoperative transdiaphragmatic pressure and respirator drive restored faster after spontaneous respiration anesthesia.(3) The potential beneficiary of spontaneous breathing anesthesia could be as follows:â‘ Patients who can tolerate certain hypoxemia and/or hypercapnia and establish a compensation mechanism under stable hemodialysis.â‘¡ Patients who can "escape " from the residual effect of muscle relaxantâ‘¢ Patients who has normal diaphragmatic myoelectricity.In this study, whole range of surgery was conducted on large animals, ELISA and quantitative real-time PCR was established to investigate the lung injury through the gene expression level of cytokine. Furthermore, we combined the method of pathology and molecular biology to comprehensively understand and analyze the change and interaction of airway inflammation. This study suggested that spontaneous breathing anesthesia brings less inflammatory reaction in both bronchiole and trachea than mechanical ventilation. TNF-a expresses faster than IL-8 in the inflammatory reaction tissue, indicate that TNF-a and IL-8 has different function in the process of inflammatory injury. |
