| Thesis is divided into four partsPart I:Documental summary1.Diagnosis and treatment of severe community acquired pneumonia are reviewed:Severe community acquired pneumonia has a high mortality. Streptococcus pneumoniae, haemophilus influenzae, gram-negative bacteria, staphylococcus aureus, legionella bacteria and viruses are the main pathogenic bacteria. Kinds of scores such as PSI, CPIS, CURB-65 and some test indicators such as white blood cells, c-reactive protein, procalcitonin are commonly used to judge the disease severity. Abnormal serum sodium and abnormal blood sugar, blood cortisol levels and other biological indicators such as inflammatory factors, MR-proADM, MR-proANP, copeptin, CT-proET-1, endothelin, microRNA have good evaluating and predictive value. Diagnostic criteria for severe community acquired pneumonia in the 2007 IDSA/ATS guidelines of diagnosis and treatment of community acquired pneumonia in adults is now commonly used. Dual antibiotic therapy is the main treatment of severe community acquired pneumonia, antibiotic stewardship programmes is one of the important strategies to deal with antibiotic resistance crisis, hormone and statins may have auxiliary therapy effect.2. Research progress of severe pneumonia treated with traditional Chinese medicine:Because of high mortality of severe pneumonia and drug resistant bacteria, traditional Chinese medicine treatment is more and more paid attention to. At present,single Chinese herb, Chinese patent medicine, Chinese classical prescriptions, empirical prescriptions and treatment based on syndrome differentiation are all beneficial to severe pneumonia patients. They can inhibit inflammatory response, enhance immunity, improve oxygenation and circulation, relieve clinical symptoms. Acupuncture therapy, plastering therapy, enema therapy and spraying therapy can assist routine ones. But the definite curative effect of these therapies should be demonstrated by more quality studies.Part II:Theoretical discussion and summary of experienceTCM theory and clinical experience about severe pneumonia:Severe pneumonia can be learned from "wind-warm disorder and lung heat disease" in traditional Chinese medicine. Phlegm, heat, toxicity, blood stasis and deficiency are the main pathological features of severe pneumonia. Disorder of qi movement is the main pathological mechanism. Syndrome of phlegm-heat obstructing lung is the common one of severe pneumonia patients. Qinghua prescription was created according to the theory of ascending and descending of qi movement and professor Xue Boshou’academic ideas of regulating qi movement. Qinghua prescription includes ingredients of maxingshigan decoction, xiaoxianxiong decoction and shengjiang powder. Modern clinical and experiment researches prove that maxingshigan decoction, xiaoxianxiong decoction and shengjiang powder or single herbs in those prescriptions all can treat diseases of respiratory system. Qinghua prescription can restore normal lung function by dispersing lung qi to smooth wheezing, clearing heat and dissipating phlegm, ascending clear qi and descending turbid qi.Part III:Clinical studyQinghua prescription affects the state of illness related indicators in patients with severe pneumonia (Syndrome of phlegm-heat obstructing lung)Objective:To evaluate whether Qinghua prescription can affect the state of illness related indicators in patients with severe pneumonia (Syndrome of phlegm-heat obstructing lung).Methods:The study was prospective randomized control trial. The severe pneumonia patients admitted to ICU of the Guanganmen hospital between January 2013 and December 2015 were divided into the qinghua prescription group (conventional therapy add qinghua prescription) and the control group (conventional therapy) randomly, who conformed to eligibility. All patients were treated for three days. Comparing the baseline indicators:demographic data (gender, age), scores (APACHE II, PSI, CPIS), pneumonia type (CAP, HAP), underlying diseases (coronary heart disease, hypertension, diabetes mellitus, cerebrovascular disease, COPD, CRF), complications (respiratory failure, ARF, abnormal liver function, hypoalbuminemia, shock), clinic treatment [type of anti-infection drugs, type of vasoactive drugs, oxygen delivery devices, type of breathing machine, mode of breathing machine, parameters (Ppeak, PEEP), nutrition therapy, other support treatmeat (blood transfusion, imputing albumin, glucocorticoid, CRRT)], clinical manifestation [vital signs, sputum(colour, viscosity, volume)], accessory examination (sputum culture, blood routine examination, liver and renal function, CTNI, CRP, LC, PCT, PaO2/FiO2) between two groups on the first day in ICU. Comparing the main evaluation indicators:CRP, CPIS, PSI between two groups on the fourth day; Comparing the secondary evaluation indicators: ①sputum (color, viscosity, volume), body temperature, blood routine, LC, PCT, PaO2/FiO2 between two groups on the fourth day. ②ortality rate of ICU, length of ICU stay and ventilator application between two groups.Results:(1) 65 cases were selected, there were 33 cases in the control group and 32 cases in the qinghua prescription group.(2) There were not significant difference in the baseline indicators (gender, age, scores, underlying diseases, complications, clinical treatment, clinical manifestations) between two groups. There were not significant difference in the auxiliary examinations (sputum culture, blood routine, liver and kidney function, CTNI, CRP, LC, PCT) between two groups, PaO2/FiO2 was lower in the qinghua prescription group than in the control group on the first day (165 ± 48mmHg vs 207 ± 84mmHg, p= 0.028).(3) The main evaluation indicators:CRP were lower in the qinghua prescription group than in the control group on the fourth day (57 ± 47mg/L vs 81 ± 46mg/L, p= 0.033). PSI and CPIS were lower in the qinghua prescription group than in the contol group on the fourth day (121.8 ± 31.2 vs 154.2 ± 32.2, p= 0.000; 3.8 ± 1.2 vs 5.0 ± 1.5, p= 0.001).(4) The secondary evaluation indicators: ①Patients in the qinghua prescription group had lower viscocity and volume of sputum than those in the control group on the foruth day. LC were lower in the qinghua prescription group than in the control group on the fourth day (1.47 ± 0.6mmol/L vs 1.93 ± 0.86mmol/L, p= 0.046). PaO2/FiO2 in the qinghua prescription group rised significantly from the first day to the fourth day. Body temperature, blood routine examination and PCT were not different between two groups on the fourth day. ②ICU mortality rate of the qinghua prescription group was lower than that of the control group (21.9% vs 51.5%, p= 0.020). Length of ICU stay and ventilator application between two groups were not statistically different.Conclusions:Qinghua prescription maybe inhibit inflammatory reaction, improve tissue pefussion, reduce sputum volume and viscosity, improve oxygenation, relieve illness. Early application of qinghua prescription in treatment of severe pneumonia (Syndrome of phlegm-heat obstructing lung) maybe affect the prognosis of patients.Part IV:Experimental studyTo explore the inflammatory mechanism of qinghua prescription in treating severe pneumoniaObjectives:Observing how qinghua prescription influences lung bacteriology inflammatory factor of serum and lung tissue, lung tissue TLR4/MyD88/NF-κB pathway and MicroRNA146a, MicroRNA155 of severe pneumonia rat, exploring the inflammatory mechanism of qinghua prescription in treating severe pneumonia.Methods:Healthy SPF male SD rats were divided to the control group, the model group, the low dose of traditional Chinese medicine group, the middle dose of traditional Chinese medicine group, the high dose of traditional medicine Chinese group, the western medicine group randomly. There were eight rats in the control group, there were 15 rats in each other groups.To make the severe pneumonia rat model with ESBLs pneumonia klebsiella bacillus injected into trachea. Drugs were administrated after 24 hours. Three different concentration qinghua prescriptions were filled into stomach of rats in three traditional Chinese medicine groups respectively, distilled water were filled into stomach of rats in the control group, the model group and the western medicine group respectively. Imipenem and Cilastatin Sodium was injected into abdominal cavity of rats in the western medicine group, normal saline solution was injected into abdominal cavity of rats in the other groups. Dose volume was 10ml/kg/d, twice a day, treatment for three consecutive days. Observing rate of survival, behaviour, body temperature, blood routine, lung bacteriology and inflammatory factor of serum and lung tissue (IL-1β, IL-6, IL-8, IL-10, TNF-α), lung tissue TLR4/MyD88/NF-κB pathway and MicroRNA146a, MicroRNA155.Results:(1) There were more survival rats in the low dose of traditional Chinese medicine group, the middle dose of traditional Chinese medicine group, the western medicine group than in the model group, but there were not statistical difference.(2) Lung tissue bacterium colony count were obviously higher in the model group and the treatment groups than in the control group. There were not statistical difference between the treatment groups and the model group.(3) Serum IL-1β, IL-6, IL-8, IL-10 concentration of rats in the low dose of traditional Chinese medicine group, the middle dose of Chinese traditional medicine group, the western medicine group were lower than in the model group. Serum TNF-α concentration of rats in the treatment groups were not significantly lower than that in the model group. Lung tissue IL-1β, IL-10 concentration of rats in the low dose of traditional Chinese medicine group, the middle dose of traditional Chinese medicine group, the western medicine group were significantly lower than that in the model group. Lung tissue IL-6 concentration of rats in the middle dose of traditional Chinese medicine group were significantly lower than that in the model group. There were not statistical difference in the lung tissue IL-8, TNF-a concentration of rats between all the treatment groups and the control group.(4) TLR4 gene expression in lung tissue of rats in the low dose of traditional Chinese medicine group, the middle dose of traditional Chinese medicine group, the high dose of traditional Chinese medicine group, the western medicine group reduced significantly compared with that in the model group (3.70 ± 1.42x10-3 vs 0.74 ± 0.37×10-3,0.92 ± 0.96×10-3,0.45 ± 0.14×10-3,1.47 ± 0.74×10-3; p= 0.000,0.001,0.038,0.045). IRAKI gene expression in the lung tissue of rats in the low dose of traditional Chinese medicine group, the middle dose of traditional Chinese medicine group, the western medicine group reduced obviously compared with that in the model group (4.49 ± 2.53×10-8, 5.44 ± 5.03×10-8,2.24 ± 2.29×10-8 vs 21.73 ± 8.99×10-8;p= 0.028,0.001,0.021). TRAF6 gene expression in the lung tissue of rats in all treatment groups reduced compared with that in the model group, but there were not statistical difference. MyD88 gene expression in the lung tissue of rats in the middle dose of traditional Chinese medicine group, the western medicine group reduced obviously compared with that in the model group (3.85 ± 1.36×10-5,10.32 ± 3.04×10-5 vs 35.65 ± 25.80×10-5, p= 0.001,0.000). NF-κB gene expression in the lung tissue of rats in all treatment groups reduced compared with that in the model group, but there were not statistical difference.(5) MicroRNA 146a and MicroRNA155 gene expression in the lung tissue of rats in the low dose of traditional Chinese medicine group, the middle dose of traditional Chinese medicine group, the western medicine group were higher than those in the model group, there were statistical difference.Conclusions:Qinghua prescription may affect the state of illness of severe pneumonia rat, raising MicroRNA 146a and MicroRNA155 expression, inhibiting TLR4/MyD88/NF-KB pathway and controlling inflammation maybe are the action mechanism of qinghua prescription in treating severe pneumonia. |
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