扶正解毒化瘀法治疗老年肺炎的理论探讨与临床评价研究

【作者】 李猛；

【导师】 王成祥；

【作者基本信息】 北京中医药大学 ， 中医内科学， 2011， 博士

【摘要】 目的肺炎是老年人最为常见的肺部感染性疾病,一般病情严重,预后险恶。老年肺炎的发病率和病死率显著高于青年人。年龄、基础病、曾因CAP住院、营养不良等是其重要的危险因素。细菌感染是老年人肺炎最主要的病原菌,革兰氏阴性杆菌产生的内毒素,能引起严重的炎症级联反应,促使SIRS的发生,进而发展至MODS,导致老年肺炎患者死亡。这一病理过程与中医“风温肺热病”的核心病机比较一致。“热毒炽盛、痰瘀互结、正气亏虚”是贯穿老年肺炎始终的核心病机。风温毒邪是其主要致病因子,热毒之邢存在于病变的始终,热毒炽盛、气阴耗伤,导致痰瘀互结,胶着难去,是导致风温肺热病预后凶险的关键。我们抓住老年肺炎的核心病机,遵循扶正祛邪治则,确立扶正解毒化瘀治法,以期降低老年肺炎病死率。该论文研究目的主要是：①探讨老年肺炎的核心病机和扶正解毒化瘀治法；②评价扶正解毒化瘀法干预老年肺炎病死率的有效性和安全性；③分析总结老年肺炎的中医病因、发病特点以及中医证候分布规律等,为制定扶正解毒化瘀法治疗老年肺炎的诊疗技术规范提供临床证据。对象与方法论文的主要研究对象为≥65岁的老年人肺炎住院患者。老年肺炎归属于中医“风温肺热病”范畴,中医文献是中医理论知识与临床经验的载体,是中医学术研究和临床应用的基础,在文献学习粤临床实践的基础上对老年肺炎的中医病机和治法进行理论探讨。本研究为多中心随机双盲安慰剂对照试验。在5个分中心开展,将308例老年肺炎患者随机分为治疗组和对照组,两组各154例。治疗组采用西医基础抗感染治疗加扶正解毒化瘀颗粒治疗,对照组采用西医基础抗感染治疗加安慰剂治疗。本研究疗程为1月,死亡和治愈(或好转)出院为终点事件,用药时间不超过4周。分别于治疗后第7天评测症状积分、胸片、血常规、血气分析、体温；第14天评测症状积分、血常规、痰涂片、细菌培养、咽拭子找支原体、血气分析、体温；第21天评测症状积分、胸片、血常规、血气分析、体温；第28天评测症状积分、胸片、血常规、痰涂片、细菌培养、咽拭子找支原体、血气分析、生命体征、尿便常规、肝肾功、心电图。死亡事件粤不良事件随时记录。本论文主要统计分析基线资料；肺炎30天病死率；治疗后1周、2周的治愈率、症状积分、胸片吸收程度、血常规、血气分析及体温的变化情况。安全性评价采用报告表记录患者不良事件,并对治疗前后尿、大便常规,肝肾功能,心电图进行评价。结果通过文献学习、前期工作及临床实践总结,我们认为风温毒邪是老年性肺炎主要致病因素；热毒炽盛、痰瘀互结、正气亏虚是其核心病机。针对核心病机,治以扶正解毒化瘀法,中西医结合治疗可以提高疗效,具有降低病死率的趋势。临床试验共入组303例受试者。脱落17例,剔除2例,最后共有284例纳入统计分析。临床试验结果表明：1治疗组发生死亡20例(13.89%),与对照组死亡16例(11.43%)比较,无统计学意义(p>0.05),这与样本量较少可能有关。但治疗组总病死率低于文献报道的30%-50%这一平均病死率,仍具有降低病死率的临床趋势,进一步扩大样本量可能出现统计学差异。2两组第1周治愈率四分类等级分析,无统计学意义,但治疗组的趋势仍较对照组明显治疗组第2周有效率明显优于对照组,经X2检验,两组间有显著性差异(p=0.042)。结果表明,西医抗感染基础上配合中医扶正解毒化瘀法治疗老年肺炎,在一定程度上可以提高其临床疗效。3治疗组在治疗后第1周、第2周能够明显改善咯痰症状积分,与对照组比较有统计学意义(p>0.05)；其它症状(咳嗽、发热、胸闷痛、气短懒言、喘息、口干舌燥、大便干结等)治疗前后有明显差异,但组间比较则无显著差异(P>0.05)。扶正解毒化瘀法能够在第1周改善咳痰症状；在第2周能够明显改善喘息、气短懒言等症状；但咳嗽、胸闷痛、倦怠乏力、口干舌燥、大便干结等症状治疗后的起效时间不确定。4两组治疗后第1周、第2周外周血白细胞总数与中性粒细胞百分比均逐渐下降,治疗组下降趋势较对照组明显,但治疗组与对照组之间比较无显著差异(P>0.05)。扶正解毒化瘀法降低白细胞和中性粒细胞方面可能有一定优势,但是未发现统计学差异。5随着治疗时间延长,两组血氧分压逐渐上升,二氧化碳分压逐渐下降；治疗组在治疗后第1周二氧化碳分压下降较对照组差异有统计学意义(P=0.039)；但两组间血氧分压升高比较则无显著差异(P>0.05)。6本组资料中共有57例患者入组前有发热,对其服药后4h体温进行K-S检验,则4组数据都服从正态分布(P>0.05)。对两组间4个时间点作组间差异的t检验,则每个时间点上均无显著差异(P>0.05)。但从体温变化曲线来看,治疗组体温下降幅度略大于对照组,可以看出扶正解毒化瘀法具有即时退热的趋势。7本组老年肺炎患者影像学资料具有以下特点：①病变部位多在下肺野；②病灶形态多数表现为肺纹理增重、模糊、紊乱,网格状阴影,斑点状或斑片状阴影,一般病变范围比较广泛；③支气管肺炎者居多；④容易伴发胸腔积液、肺气肿、肺不张等。两组治疗后胸片显示均存在一定程度的吸收或进展,但治疗后两组间比较并无显著性差异(P>0.05)。老年肺炎患者的炎症消散粤吸收一般需要2～3月时间,本研究资料集中在10～14天,故没能明确反映出两组间的差异。8扶正解毒化瘀法安全性较好,治疗组144例患者中2例发生不良反应,发生率为1.39%；对照组140例患者中有3发生不良反应,发生率为2.14%；组间比较差别无统计学意义(P>0.05)。两组均未发生导致病例脱落的不良事件和严重不良事件。结论1老年肺炎的核心病机是热毒炽盛、痰瘀互结、正气亏虚,扶正解毒化瘀法是治疗老年肺炎的有效治法;2扶正解毒化瘀法可以在第2周明显提高老年肺炎的治愈率；能够改善咳痰等单项症状积分,对咳痰、气短懒言、喘息等起效时间较早,显示该治法可以有效改善老年肺炎主要临床症状3扶正解毒化瘀法能够改善老年肺炎的部分实验室指标,对降低外周血白细胞总数、中性粒细胞百分比等,具有一定的趋势；能够提高动脉血氧分压、降低二氧化碳分压,对于改善通气功能具有一定作用；4扶正解毒化瘀法治疗老年肺炎,是通过干预老年肺炎病变过程中的“热、毒、痰、瘀、虚”等病理变化起作用；5针对核心病机,确定扶正解毒化瘀法治疗老年肺炎,可以提高老年肺炎的治疗效果,在一定程度上反映出了老年肺炎发生、发展的内在规律；6扶正解毒化瘀法治疗老年肺炎,在降低病死率方面有一定趋势,但与对照组比较无显著差异,可能粤样本量小有关,有待扩大样本量进一步研究；7扶正解毒化瘀法治疗老年肺炎安全性较好,可以推广应用。更多还原

【Abstract】 ObjectiveSenile Pneumonia is the most common lung infection in old population, notorious with its serious condition and bad prognosis. Morbidity and mortality of Senile Pneumonia are significantly higher than that of pneumonia in young people. Age, underlying disease, hospitalization caused by CAP and malnutrition are major risk factors of Senile Pneumonia. Bacterial infection is the most important pathogens of Senile Pneumonia.Endotoxin produced by Gram-negative bacteria can cause severe inflamm-ation cascade which promote the occurrence of SIRS, even the development of MODS, leading to death of patients. This pathological process is accordant with that of lung heat disease with wind-warm syndrome. "exuberance of heat-toxicity、intermingled phlegm and blood stasis、deficiency of vital qi "is the core pathogenesis of senile pneumonia. Wind-warm and toxicity pathogen are the main pathogenic factor. Heat and toxicity pathogens are always present in the whole course of the disease. The entanglement of exuberance of heat-toxicity、intermingled phlegm and blood stasis、over consumption of qi and fluid is the key factor leading to the extremely dangerous progress of lung heat disease with wind-warm syndrome. In order to reduce the mortality of senile pneumonia, we grasp the core of the pathogenesis of senile pneumonia, follow the principle of "strengthening vital qi to eliminate pathogenic factor", and establish the treatment method of "strengthening vital qi,clearing toxicity,removing blood stasis". The purpose of our research is:①discuss the core of the pathogenesis of senile pneumonia and the treatment method of "strengthening vital qi,removing blood stasis";②evaluate the efficacy and safety of treatment method of "strengthening vital qi,clearing toxicity,removing blood stasis" in the intervention in elderly pneumonia mortality;③analyse causes, clinical features and distribution of syndromes, so as to provide clinical evidence for settlement of technical specifications of treatment method of "strengthening vital qi,clearing toxicity,removing blood stasis".MethodsThe main object of the study are hospitalized pneumonia patients who are more than 65 years old. Senile Pneumonia is attributed to "lung heat disease with wind-warm syndrome"in Chinese medicine. Literatures of Chinese medicine are carrier of Chinese medicine theory and clinical experience and the basis for research and clinical application. Through learning literatures and clinical practice, we study the pathogenesis and treatment method of senile pneumonia in the theoretical layer.Clinical research is conducted in five centers and the patients are divided into treatment group and control group according to the principles of randomization, with 154 cases of subjects in each group. The treatment group is interfered with anti-infection treatment and FuZhengJieDuHuaYu particle treatment, while the control group is interfered with anti-infection treatment and placebo. The treatment lasts for one month, death and discharge after cure (or improvement) are the end of the treatment and the time for medication is no longer than 4 weeks.7 days after treatment, symptom score evaluation、chest radiograph、blood routine、blood gas analysis and body temperature are obtained; 14 days after treatment, symptom score evaluation、blood routine、sputum smear, bacterial culture、throat swab to find mycoplasma、blood gas analysis and body temperature, are obtained; 21 days after treatment, evaluation of symptom score, chest radiograph, blood routine, blood gas analysis and body temperature are obtained; 28 days after treatment, evaluation of symptom score, chest radiograph, blood routine, sputum smear, bacterial culture, throat swab to find mycoplasma, blood gas analysis, vital signs, urine and stool routine, liver and kidney function, ECG are obtained. Deaths and adverse events are recorded whenever they occur.This study foucses on statistical analysis of baseline data; 30-day mortality of pneumonia; the cure rate, symptom score, chest X-ray absorption, blood routine, blood gas analysis and temperature changes 1 week and 2 weeks after treatment respectively. Safety evaluation is conducted by record of adverse reactions in patients, and evaluation of blood, urine and stool routine, liver and kidney function, ECG before and after treatment.ResultsThrough literature study, preliminary work and summary of clinical practice, we believe that wind-warm and toxicity pathogen are the major risk factor of senile pneumonia; exuberance of heat-toxicity、intermingled phlegm and blood stasis、deficiency of vital qi are the core pathogenesis. Interfered with "strengthening vital qi,clearing toxicity,removing blood stasis" treatment,which is aimed at the core pathogenesis, therapy combined with westen and Chinese medicine can improve the efficacy of treatment with lower mortality.303 cases of clinical trial subjects were enrolled in this research,17 cases of which are lost and 2 cases are excluded and finally 284 cases are statistically analysed. Clinical trial results show that:1 20 death cases in the treatment group (13.89%),16 death cases in the control group (11.43%) with no statistically significant difference (p>0.05), which may be related to small sample size. But overall mortality rate of the treatment group is lower than 30% to 50%, which is the average mortality rate reported by literature.If the sample size is enlarged, there may be statistical significance between the two groups.2 Four classification level analysis of cure rate lweek after treatment shows no significant statistical difference between the two groups; chi-square test shows efficacy of treatment group is higher than that of control group with significant difference (p=0.042). The results show that anti-infection treatment combined with traditional Chinese medicine, to some certain extent, can improve clinical efficacy in the treatment of senile pneumonia.3 Cough symptom score in treatment group can be obviously improved 1 week and 2 weeks after treatment with statistical significance compared with that of control group (p <0.05); other symptoms (cough, fever, chest pain, shortness of breath, disinclination to talk, breathe, dry mouth, dry stool, etc.) are significantly different before and after treatment, but between the two groups had no significant difference (p>0.05). The treatment method of "strengthening vital qi,clearing toxicity,removing blood stasis" can relieve sputum in the first week after treatment; Symptoms such as breathing, shortness of breath and disinclination to talk can be significantly improved 2 weeks after treatment; but the time when cough, chest pain, malaise, fatigue, dry mouth, dry stools and other symptoms are effectively improved after treatment is uncertain.4 WBC and neutrophil percentage have decreased in both groups with no significant difference (P>0.05).There may be some advantages for the treatment method of "strengthening vital qi,clearing toxicity,removing blood stasis" to reduce white blood cells and neutrophils, but there is no significant difference between the two groups.5 As treatment time passes, blood oxygen gradually increases and carbon dioxide partial pressure decreases in both groups; partial pressure of carbon dioxide of treatment group compared with the control group decreased significantly 1 week after treatment (P=0.039); but there was no significant difference of the elevated blood oxygen pressure compared between the groups (P>0.05).6 57 patients were with fever before they are enrolled, K-S test of their body tempera-ture 4 hours after taking the medicine shows the four sets of data are normally distributed (P> 0.05). Of the four time points between the two groups for differences between groups t-test, each time point were not significantly different (P>0.05). However, changes in body temperature curve show body temperature decrease in treatment group is slightly greater than that in the control group, which indicates real-time effect of decreasing body temperature with the use of the treatment method of "strengthening vital qi,clearing toxicity,removing blood stasis".7 Imaging data of this group of senile pneumonia has the following characteristics:①lesions are most common in lower lung field;②lesions manifest with blurred, disorder, grid-like shadow, the shadow of spots or patchy, usually the area of lesion is extensive;③bronchial pneumonia is the most common lesion;④usually associated with pleural effusion, emphysema, atelectasis, etc. Chest X-ray shows a degree of absorption and progress of the lesion, but there was no significant difference between the two groups after treatment (P> 0.05). Dissipation and absorption of inflammation in senile pneumonia usually takes 2 to 3 months and this research focuses on 10 to 14 days, thus this study did not clearly reflect the difference between the two groups.8 The safety of the treatment method of "strengthening vital qi,clearing toxicity, removing blood stasis" is certain, there are only two cases of adverse reactions in 144 cases of treatment group, with an adverse reaction rate of 1.39%; there are three cases of adverse reactions in 140 cases of control group, with an occurance rate of 2.14%; there is no statistically significant difference between the two groups(P>0.05). There are no adverse events or serious adverse events leading to loss of subjects in both groups.Conclusion1 Exuberance of heat-toxicity、intermingled phlegm and blood stasis、deficiency of vital qi is the core of the pathogenesis of senile pneumonia and the treatment method of "strengthen-ing vital qi,clearing toxicity,removing blood stasis" is an effective treatment in senile pneumo-ma;2 The treatment method of "strengthening vital qi,clearing toxicity,removing blood stasis" can significantly improve the cure rate of pneumonia two weeks after treatment; improve sputum and other individual symptom score; and has effect in the early stage to relieve cough, shortness of breath, disinclination to talk and breathing, indicating that the treatment method can effectively improve part of clinical symptoms in senile pneumonia;3 The treatment method of "strengthening vital qi,clearing toxicity,removing blood stasis" can improve part of the laboratory parameters in senile pneumonia, such as WBC, neutrophils and other inflammatory markers; increase blood oxygen partial pressure, reduce carbon dioxide partial pressure,and improve ventilation to certain extent;4 The treatment method of "strengthening vital qi,clearing toxicity,removing blood stasis" probably cures senile pneumonia by interfering with key factors in its pathological process, such as heat、toxicity、phlegm、blood stasis, deficiency";5 The treatment method of "strengthening vital qi,clearing toxicity,removing blood stasis" aimed at the core pathogenesis can improve the treatment effectiveness of pneumonia in the elderly, which to a certain extent, reveals the inherent regularity of pneumonia in the elderly;6 The fact that there is no significant statistical difference of mortality decrease between two groups may be related to the small sample size, thus sample size needs to be expanded in further study.7 The treatment method of "strengthening vital qi,clearing toxicity,removing blood stasis" has relatively higher safety in the treatment of senile pneumonia and can be applied extensively.更多还原