【作者】 谢东平；

【导师】 张敏州；

【作者基本信息】 广州中医药大学 ， 中西医结合临床， 2010， 博士

【摘要】 背景肠道在脓毒症的发病中具有非常重要的地位。脓毒症患者容易发生肠功能障碍,而肠功能障碍反过来又可以加重脓毒症,诱发多器官功能障碍综合征。对脓毒症患者发生肠功能障碍的相关危险因素进行调查,识别容易出现肠功能障碍的高危患者,对于脓毒症肠功能障碍的早期诊断、早期干预治疗具有重要的意义。辨证论治是中医的诊疗模式,也是中医学的精髓和核心。目前关于脓毒症的中医证候研究仍非常缺乏。对脓毒症的中医证候要素进行研究,总结脓毒症的中医证候特点,对于脓毒症中医诊疗方案的形成具有重要的意义。尽管目前中医在治疗脓毒症肠功能障碍方面取得了一定的效果,但脓毒症肠功能障碍的中医干预方案仍有待进一步完善。我们在既往调肠法研究的基础上,参照现代脓毒症集束化治疗的理论,形成干预脓毒症肠功能障碍的中医集束化调肠方案,在前期的临床实践中取得了较好的效果。现拟通过临床随机对照研究以证实其疗效,并对其疗效机制进行初步观察。目的1、对脓毒症患者发生肠功能障碍的相关危险因素进行调查,为临床防治脓毒症肠功能障碍提供参考。2、对脓毒症患者的中医证候要素进行调查,总结其证候要素的构成特点,为脓毒症的中医干预治疗提供证候学研究依据。3、评价中医集束化调肠方案治疗脓毒症肠功能障碍的临床疗效,并观察该方案对脓毒症患者全身炎症反应及相关炎症因子的影响。4、评价早期实现肠道治疗目标是否有助于改善脓毒症患者的预后及全身炎症反应。方法1、通过文献研究,总结脓毒症患者发生肠功能障碍的可能危险因素。其后采用临床横断面调查研究方法,纳入内科脓毒症患者73例,其中发生肠功能障碍者47例(肠功能障碍组),未发生肠功能障碍者26例(无肠功能障碍组)。在纳入时进行临床调查并采集相应的理化指标,具体包括肠功能障碍评分、APACHEⅡ评分、既往胃肠道疾病或腹部手术史、体循环水肿、休克、血乳酸浓度、血气分析、血清白蛋白、血清前白蛋白、血谷丙转氨酶及谷草转氨酶浓度。对两组患者的上述指标进行比较分析,探讨脓毒症患者发生肠功能障碍的危险因素。2、通过文献研究,总结脓毒症患者常见的中医证候要素。其后采用临床横断面调查研究方法,共纳入内科脓毒症患者73例,其中17例为一般脓毒症患者,24例为严重脓毒症患者,32例为脓毒症性MODS患者。在纳入时对中医基本证候要素进行调查,包括基本虚证类中的气虚证、血虚证、阴虚证、阳虚证,基本实证类中的痰证、火热证、血瘀证、水停证。同时调查下列内容：肠功能障碍评分、APACHEⅡ评分。对脓毒症、脓毒症不同病程阶段、脓毒症肠功能障碍的中医证候要素构成进行统计分析,同时对中医基本证候要素、APACHEⅡ评分进行相关性研究。3、采用前瞻性随机对照临床研究方法,共纳入脓毒症患者47例,应用简单随机数字表法进行随机分组,其中试验组24例,对照组23例。试验组、对照组的西医治疗均按照2008年国际脓毒症指南进行,试验组则在西医治疗的基础上加用中医集束化调肠方案进行干预,比较两组患者的临床疗效。以住院期间生存率、28天生存率作为主要疗效指标；以APACHEⅡ评分、肠功能障碍评分作为次要疗效评价指标。同时观察两组患者的中医基本证候要素的改善率、肠功能、血清前白蛋白及全身炎症反应相关指标。其中肠功能的观察指标主要为血浆二胺氧化酶；全身炎症反应方面则采用全身炎症评分、血乳酸浓度、C反应蛋白、TNF-a、IL-10作为观察指标。4、研究结束时,按照是否早期实现肠道治疗目标,将所有临床随机对照研究的纳入对象重新分组,分为早期实现肠道治疗目标组和未早期实现肠道治疗目标组,比较两组患者的临床疗效。以住院期间生存率、28天生存率作为主要疗效指标；以APACHEⅡ评分作为次要疗效评价指标。同时比较两组患者的血浆二胺氧化酶浓度、血清前白蛋白浓度及全身炎症反应相关指标。其中全身炎症反应相关指标包括全身炎症反应评分、血乳酸浓度、C反应蛋白、血TNF-a、血IL-10。结果1、对相关危险因素的分析发现,肠功能障碍组的休克发生率、呼吸衰竭发生率、血乳酸浓度升高发生率及APACHEⅡ评分均高于无肠功能障碍组。Logistic回归分析提示血乳酸浓度、APACHEⅡ评分可能是影响肠功能障碍是否发生的危险因素,其中血乳酸升高的OR值为7.056[95%CI(1.729-28.789)],APACHEⅡ评分的OR值为1.407[95%CI(1.169-1.693)]。相关性分析提示,肠功能障碍评分与血乳酸浓度、APACHEⅡ评分呈正相关,随着肠功能障碍评分的升高,血乳酸浓度、APACHEⅡ评分亦出现相应的升高。2、对73例脓毒症患者的中医证候要素进行调查,结果发现以虚实夹杂证多见,占83.6%,单纯实证的占16.4%,无1例患者表现为单纯的虚证。在虚证的基本证候要素中,气虚证出现频率最高(100%),其后依次为阳虚证(42.6%)、阴虚证(32.8%)、血虚证(9.8%)。在实证的基本证候要素中,痰证的出现频率最高(91.8%),其后依次为火热证(79.5%)、血瘀证(52.1%)、水停证(16.4%)。一般脓毒症患者与严重脓毒症患者的中医基本证候要素构成无明显差异,严重脓毒症患者与脓毒症性MODS患者的中医基本证候要素构成也无明显差异。而与一般脓毒症患者相比,脓毒症性MODS患者的阳虚证明显增多,经统计学分析差异有显著性意义(P<0.05)。对47例并发肠功能障碍脓毒症患者的中医证候要素进行分析,结果发现以虚实夹杂证多见,占83.0%,单纯实证的占17.0%,无1例患者表现为单纯的虚证。在虚证的基本证候要素中,气虚证出现频率最高(83.0%),其后依次为阳虚证(44.7%)、阴虚证(25.5%)、血虚证(12.8%)；在实证的基本证候要素中,痰证的出现频率最高(87.2%),其后依次为火热证(80.9%)、血瘀证(59.6%)、水停证(17.0%)。对不同证候要素的APACHEⅡ评分进行比较分析,结果发现,阳虚证脓毒症患者的APACHEⅡ评分高于未出现阳虚证的脓毒症患者(P<0.05)3、在前瞻性随机对照研究部分,试验组及对照组各有1例患者因自身原因中途退出,试验组2例患者及对照组1例患者在5天内死亡,资料收集不齐,均予以剔除,两组患者的脱落率经统计学分析差异无显著性意义。最终进入统计分析的受试者共42例,其中试验组21例,对照组21例。研究结果未能证实集束化调肠方案有助于改善脓毒症肠功能障碍患者的28天病死率。与对照组相比,集束化调肠方案在改善APACHEⅡ评分方面也并未显示出更大的优势。但应用集束化中医调肠方案有助于早期实现肠道治疗目标,进而改善脓毒症肠功能障碍患者的肠功能障碍评分,降低血清DAO浓度,改善肠道的屏障功能,并有可能相应的改善肠道的吸收功能。在炎症反应方面,研究观察到集束化调肠方案有助于降低血清CRP浓度,可能起到一定的减轻全身炎症反应的作用。但与对照组相比,治疗组在调节TNF-a、IL-10方面并未显示出更大的优势。在不良事件方面,集束化调肠方案的少数患者出现与治疗相关的腹泻,但组间比较差异无显著性意义。此外,研究结果提示血清DAO浓度与临床肠功能障碍评分相关性好,能够较好的反映肠功能障碍情况,血清DAO浓度与血乳酸浓度、休克的发生同样具有较好的相关性。4、将所有纳入对象按照是否早期实现肠道治疗目标进行重新分组、统计分析,结果提示,虽然两组患者的28天死亡率尚无明显差异,但能够早期实现肠道治疗目标的患者治疗后APACHEⅡ评分下降更明显,提示这些患者可能具有更好的预后结局。与未早期实现肠道治疗目标的患者相比较,能够早期实现肠道治疗目标的患者血清DAO浓度较低,提示血清DAO浓度可以反应肠功能障碍的严重程度。早期实现肠道治疗目标除了可以改善脓毒症患者的肠道屏障功能,还可能改善脓毒症患者的肠道吸收功能。在炎症反应方面,与未早期实现肠道治疗目标的患者相比,早期实现肠道治疗目标的患者治疗后的SIRS评分、血清CRP改善更明显。对TNF-a、IL-10的分析提示,早期实现肠道治疗目标的患者血清TNF-a浓度明显下降。因此,早期实现肠道治疗目标可能有助于改善全身炎症反应。结论1、血乳酸浓度、APACHEⅡ评分可能是影响肠功能障碍是否发生的危险因素,对于存在休克、血乳酸升高及高APACHEⅡ评分的脓毒症患者需要密切评估其肠功能状况,从而早期发现、早期干预肠功能障碍。2、脓毒症患者,尤其是老年脓毒症患者的中医证候以虚实夹杂证多见,在临床干预治疗中,除了“泻实”,需要兼顾“正虚”。在脓毒症性MODS阶段,阳虚证的发生有升高趋势,需注意“扶阳”治疗,防治阳气暴脱。3、中医集束化调肠方案有助于早期实现肠道治疗目标,进而改善肠功能障碍,并可能有助于减轻脓毒症患者的全身炎症反应。4、能够早期实现肠道治疗目标的脓毒症患者可能具有更好的预后结局。早期实现肠道治疗目标除了可以改善脓毒症患者的肠道屏障功能,还可能改善脓毒症患者的肠道吸收功能,并可能有助于改善全身炎症反应。5、在脓毒症肠功能障碍的中医干预治疗中,通过设定肠道治疗目标,针对不同严重程度的肠功能障碍实施不同强度的集束化调肠方案是可行的,这种干预方案能体现中医辨证论治、个体化施治的特点,也有可能通过发挥综合治疗效应,提高临床疗效。更多还原

【Abstract】 BackgroundIntestine is very important in the pathogenesis of sepsis. Patients with sepsis are prone to intestinal dysfunction where intestinal dysfunction in turn can aggravate sepsis and induced multiple organ dysfunction syndrome. Carrying out investigation on the risk factors of intestinal dysfunction to sepsis patients and identifying vulnerable patients at high risk of intestinal dysfunction have great significance to intestinal dysfunction in sepsis for early diagnosis and intervention.Syndrome differentiation is the method and essence of Chinese medicine. There are lack of Chinese medicine syndromes on study of sepsis at present. Therefore, carrying out research on the elements of Sepsis Chinese medicine syndromes, summarizing its characteristics have great importance to the formation of the Chinese medicine treatment for sepsis.Although Chinese medicine has achieved a certain effect in the treatment of intestinal dysfunction in sepsis, but its TCM intervention programs needs to be further improved. Forming the TCM Tiaochang bundles therapy to intervene intestinal dysfunction in sepsis based on the study of methods of bowel adjustments together with reference of the modern treatment of sepsis Tiaochang bundles therapy has achieved good result in the early clinical practice. This study-is going to confirm its efficacy through randomized controlled clinical trial, and preliminary observe on its efficacy mechanism.Object ives1. Carrying out investigation on the risk factors of intestinal dysfunction to sepsis patients, to provide reference of prevention and treatment for intestinal dysfunction in sepsis.2. Carrying out observation on the constitute elements of TCM syndromes on sepsis patients, to provide TCM syndromes research basis for Chinese medicine intervention treatment in sepsis.3. Evaluation on the clinical efficacy of TCM Tiaochang bundles therapy treatment plan of intestinal dysfunction in sepsis and observe its plan on sepsis patients with systemic inflammatory response and related inflammatory factors.4. Evaluation of whether early treatment could help to improve prognosis and systemic inflammatory response of sepsis patients.Methods1. Summarized the risk factors of sepsis patients with intestinal dysfunction through literature. Subsequently using clinical cross-sectional survey research methods and brought into 73 patients with sepsis. Among 73 cases,47 cases of which occurred intestinal dysfunction (intestinal dysfunction group), and 26 cases without intestinal dysfunction (non-intestinal dysfunction group). Carried out clinical investigations and collect the appropriate physical and chemical indicators, specifically including intestinal dysfunction score, APACHE II score, history of gastrointestinal disease or abdominal surgery, systemic edema, shock, blood lactate concentration, blood gas analysis, serum albumin, serum pre-albumin, serum alanine aminotransferase and aspartate aminotransferase. Compared the parameters of the two groups and conferred the risk factors of sepsis patients for intestinal dysfunction.2. Summarized the common elements of TCM syndromes of sepsis patients through literature. Subsequently using clinical cross-sectional survey research methods and brought into 73 patients with sepsis. Among 73 cases, 17 cases were general sepsis patients,24 cases were severe sepsis cases and 32 cases were septic MODS patients. To incorporate the basic TCM syndrome when investigating factors, including the basic deficiency:qi deficiency, blood deficiency, yin deficiency, yang deficiency, the basic excess class:phlegm, fiery, blood stasis, fluid-retention. While investigating the following: intestinal dysfunction score, APACHEⅡscore. Carried out statistical analysis of sepsis, sepsis at different stages, constitute elements of TCM syndromes of sepsis with intestinal dysfunction, moreover, carried out correlation study on the basic elements of the TCM Syndrome and APACHEⅡscore.3. Using prospective randomized controlled clinical research methods, brought into a total of 47 sepsis patients. Appling simple randomized method to divide into random groups,24 cases in trial group and 23 cases in control group. Experimental group and Western treatment control group treated in accordance with international guidelines of sepsis. While the experimental group was treated in Western medicine based on the use of TCM Tiaochang bundles therapy and compared the clinical efficacy of the two groups. The hospital survival rate-28 days survival as the primary endpoint; used APACHE II score, intestinal dysfunction score as a secondary efficacy evaluation.Simultaneously observed the improvement rate of the essential elements of the TCM syndrome, intestinal function, serum albumin and the relevant indicators of systemic inflammatory response of the two groups. Intestinal function was observed by plasma diamine oxidase while systemic inflammatory response was observed by inflammatory score, blood lactate concentration, C-reactive protein, TNF-a and IL-10.4. At the end of study, re-grouped all the randomized controlled clinical study into early treatment target group and non-early treatment target group, and compared their clinical efficacy. The hospital survival rate-28 days survival as the primary endpoint; used APACHE II score as a secondary efficacy evaluation. Simultaneously compared the plasma diamine oxidase, serum albumin concentration and the related indicators of systemic inflammatory response, including the systemic inflammatory response score, blood lactate concentration, C-reactive protein, serum TNF-a and serum IL-10 of the two groups.Results1. On the analysis of risk factors, the incidence rate of shock, respiratory failure, the incidence rate of blood lactate concentration and APACHEⅡscore of the intestinal dysfunction group was higher than the group without intestinal dysfunction. Logistic regression analysis showed that blood lactate concentration, APACHE II score of intestinal dysfunction may be the risk factors, the OR of increased blood lactic acid the was 7.056 [95% CI (1.729-28.789)], APACHE II score of the OR values was 1.407 [95% CI (1.169-1.693)]. Correlation analysis showed that intestinal dysfunction score and blood lactate concentration, APACHE II score was positively correlated. With the rate of increase in intestinal dysfunction, blood lactate concentration, APACHE II score would corresponding increase.2. Carried out investigation on the TCM syndromes of the 73 cases of sepsis patients, the results found out that the pattern of deficiency-excess complex was the most common, accounting for 83.6%,16.4% of pure excess, no patient was showed to be simple deficiency. In the basic elements of deficiency syndrome, qi deficiency was the most frequent (100%), followed by Yang Deficiency (42.6%), Yin deficiency syndrome (32.8%), blood deficiency (9.8%). In the basic elements of excess syndrome, the highest frequency of occurrence was phlegm (91.8%), followed by fiery (79.5%), blood stasis (52.1%), fluid-retention (16.4%). There is no significant difference in the constituent of the basic TCM syndromes in general and severe sepsis and also between severe sepsis and septic MODS patients. As compared with general sepsis patients, yang deficiency syndrome significantly increased in septic MODS patients which was statistically significant (P<0.05). Carried out investigation on the TCM syndromes of 47 cases of sepsis patients with complication of intestinal dysfunction, the results found out that the pattern of deficiency-excess complex was the most common, accounting for 83.0%,17.0% of pure excess, no patient was showed to be simple deficiency. In the basic elements of deficiency syndrome, qi deficiency the most frequent (83.0%), followed by Yang Deficiency (44.7%), Yin deficiency syndrome (25.5%), blood deficiency (12.8%); In the basic elements of excess syndrome, the most frequent was phlegm (87.2%), followed by fiery (80.9%), blood stasis (59.6 percent), fluid-retention (17.0%). APACHE II score of elements of different syndromes were compared, results showed that the APACHE II score was higher with patients which occurred yang deficiency than patients who had not occurred Yang Deficiency (P<0.05).3. From the prospective randomized controlled study,1 patient of each experimental group and control group dropped out due to their own reasons, 2 patients of the experimental group and 1 patient of the control group died within 5 days, data collection was incomplete, and to be removed, the loss rate of two groups was not statistically significant. A total of 42 cases eventually entered statistical analysis, of which 21 cases as experimental group,21 cases o control group. The results failed to confirm that cluster-based programs help to improve the 28-day mortality of sepsis patients with intestinal dysfunction. Compared with the control group, cluster-based program in improving APACHE II score of bowel also did not show greater advantages. But the application of the TCM bowel adjustments cluster-based program help to achieve early bowel treatment goals, thereby improving the intestinal dysfunction score of sepsis patients with intestinal dysfunction, lower serum DAO concentrations and improve intestinal barrier function, and may accordingly improve the intestinal absorption. In the inflammatory response, the study observed that the TCM bowel adjustments cluster-based program help reduce the concentrations of serum CRP which may play a certain role to reduce systemic inflammatory response. However, compared with the control group, treatment group in the regulation of TNF-a, IL-10 has not showed a greater advantage. In adverse events, small percentage of patients had diarrhea by treating by the TCM bowel adjustments cluster-based program, but difference between groups had no significance. In addition, the results suggest that serum DAO concentrations and the score of intestinal dysfunction had good clinical relevance, which could better reflect the situation of intestinal dysfunction, serum DAO concentrations and blood lactate concentration while the occurrence of shock also had good correlation.4. re-grouped and compared all the patients according to whether they achieve early bowel treatment, the results showed that although the 28-day mortality of the two groups had no significant difference, but the APACHEⅡscore decreased dramatically in patients who achieved early bowel treatment, suggesting that these patients may have a better prognosis of the outcome. Compared to patients with no early treatment, it was found that patients of early treatment had low serum DAO concentrations, suggesting that serum DAO concentrations can reflect the severity of intestinal dysfunction. In addition, early treatment could improve bowel intestinal barrier function and may improve intestinal absorption in sepsis patients. In the inflammatory response, in comparison with patients of no early treatment, there were significant improvements in the SIRS score, serum CRP of patients with early treatment. On the analysis of TNF-a and IL-10 showed that TNF-a serum levels significantly decreased in patients with early treatment. Therefore, early treatment may help to improve systemic inflammatory response.Conclusions1. Blood lactate concentration, APACHEⅡscore may be a risk factor of the occurrence of intestinal dysfunction. For septic patients who have a tendency of shock, increased blood lactate and high APACHEⅡscore needs closely assessment of their intestinal function. Thus for early detection and intervention of intestinal dysfunction.2. Sepsis patients, especially the elderly are found to be categorized as a pattern of deficiency-excess complex. In clinical intervention, "deficiency" other than "reducing excess" is more needed to be taken into account. At the stage of MODS in sepsis, the incidence of Yang deficiency tended to increase and so attention should be paid to "support the Yang" treatment in order to prevent the violence off of yang qi.3. TCM Tiaochang bundles therapy helps to achieve treatment goals early so as to improve the intestinal dysfunction. It may also help to reduce the systemic inflammatory response in sepsis patients.4. Sepsis patients who can be treated early may have a better prognosis outcome. Early bowel treatment not only can improve the intestinal barrier function, but may also improve intestinal absorption which therefore helps to improve the systemic inflammatory response.5. Through the setting up of bowel treatment goals, Tiaochang bundles therapy for different severity is feasible in the TCM intervention treatment of intestinal dysfunction in sepsis. Such an intervention program can reflect the diagnosis and treatment, the personalization characteristics of TCM while clinical efficacy can be improved through comprehensive treatment.更多还原