急性百草枯中毒患者胰腺功能受损及其机制研究

发布时间：2018-07-10 18:29

  本文选题：急性百草枯中毒 + 胰腺　； 参考：《郑州大学》2014年博士论文

【摘要】：百草枯(PQ)是一种广泛使用的除草剂,自1960年以来在我国使用。1966年在英国医学会杂志(British Medical Journal)上报道首例百草枯致死的患者,至今已经过去近50年的时间。虽然经过国内外专家的不懈努力,百草枯中毒的病死率仍维持在40-60%以上,且多数发生在服毒后24至72小时。既往的研究发现最终导致急性百草枯患者死亡的最主要原因是急性呼吸衰竭、急性肾功能衰竭、急性肝功能衰竭等为主要表现的多器官功能不全(MODS)。PQ进入机体后,全身细胞结合,迅速的分布到全身的各个脏器。其中聚集于肾的浓度最高、最快,随后再分布到肺、肝、心、大脑等各个脏器,PQ中毒可导致肺、肝、肾、心、脑、消化道等多个脏器的损伤。既往的研究发现PQ对肺泡细胞的亲和力比较强,所以肺是PQ中毒损伤的主要靶器官,肺损伤多表现急性呼吸衰竭和肺纤维化。主要死亡原因有急性呼吸衰竭、肝功能衰竭、肾功能衰竭、心肌损害等。但是既往的文献对其它的器官功能的损害报道、关注度、重视度均较少。针对百草枯的致病机理过去已经作了些研究,主要集中在以下几个方面：氧自由基的产生及氧化应激状态；氧化应激的继发效应：主要有脂质过氧化、线粒体毒性、NADPH氧化作用、细胞凋亡等；炎症反应：核转录因子(NF-kB)活化、细胞因子上调等。其中炎症反应学说最受大家关注。已经证明急性百草枯中毒后NF-kB可以被活化。百草枯中毒后NF-kB活性增高,白介素1β(IL-1β)、肿瘤坏死因子(TNF-α)、血小板源性生长因子(PDGF)及白介素6(IL-6)含量增加。但胰腺损伤的机制是什么,与急性胰腺炎的机制有什么不同,均不清楚。尽管目前针对急性百草枯中毒的治疗有许多手段,例如增强排泄(血液灌流、床旁持续血液滤过)、肾上腺皮质激素、免疫抑制剂、抗氧化剂等。但是即使全部用上,其死亡率仍居高不下。存在治疗经费巨大、医护劳力投入多等众多特点。因此,如何对急性百草枯中毒患者进行危险分层、病情程度判断及预后分析是一个迫于解决的临床问题。因此,急性百草枯中毒在内的急危重症患者如何早期判断预后,从而合理地使用医疗资源是一个医患、社会保障均关注的问题。目前应用的器官功能评估方法主要有以下几种：急性生理学及慢性健康状况评分(APACHE 2)、SOFA评分、中毒严重程度评分(poisoning severity score, PSS)等。APACHE2、SOFA评分系统虽然已经被广泛使用于急危重病患者,但对于急性中毒的应用却存在以下两个方面的缺陷。首先,急性百草枯中毒与其它非中毒性疾病存在一定的差别,例如服毒量、服毒后来诊时间可能均与预后相关；另一方面,由于APACHE2、SOFA评分系统并不能对患者立即进行评估,项目繁多,不易实施,均需要至少24小时以上的时间来完成此项工作,更适合对于住院的危重患者进行评估,而不是急诊工作中需要的简洁、实用的方法来快速评估患者的预后。PSS评分则存在项目较为繁琐的特点,不易开展。综上所述,急性百草枯中毒致肺损伤已经广为大家关注,其致机体其它器官功能的变化如何尚没有系统性的研究。其中胰腺功能损伤的报道较少。因此,探寻胰腺受损在急性百草枯中毒过程中的时间性、严重性、胰腺功能受损在其中扮演的角色以及对预后的影响很有必要。我们还将通过检测NF-kB等炎症因子,试图探讨百草枯中毒后导致患者出现多器官功能衰竭综合症的主要机制；并与急性胰腺炎患者进行对比,探寻其机制的不同。最后,我们还试图建立能够反映百草枯中毒特点的方便、实用、准确的预测模型。我们的研究分成三个部分。一、急性百草枯中毒致多器官功能不全的临床观察。方法：本研究前瞻性的选取2013年7月至2014年8月,收治于郑州大学第一附属医院急诊科救治的急性PQ中毒患者,了解其致全身各器官功能受损的情况,并分析这些器官功能受损的先后性、与患者预后的关系。观察胰腺受损的发生率,以血淀粉酶超出正常值上限,也就是大于220U/L为界。以第一个淀粉酶为依据,进行分组(正常值为220U/L以下),分为三个组,胰功正常组(淀粉酶为220U/L以下)、胰功轻度升高组(淀粉酶在220U/L至660U/L之间)、胰功升高组(大于660U/L)。比较这三组患者的生存曲线。各组患者死亡率。胰酶的高低与患者预后的关系。比较存活组与死亡组患者的胰腺功能变化,并对比两组间各项临床指标的不同。结果：研究期间郑州大学第一附属医院急诊内科收治的PQ患者有共258例,符合入选标准且最终同意入选的患者最终有177例。依据胰腺功能的不同,我们把全部患者分成了三组,可以看出正常组、轻度升高组及升高组分别为125例、27例及25例。胰腺功能异常的患者占总患者数的29.06%。通过绘出三组患者的生存曲线可以看出,生存时间长短依次为胰功正常组胰功轻度升高组胰功升高组,并有统计学意义(P0.001)。对全部患者中有前9天血淀粉酶、血脂肪酶的患者进行进一步分析。共得到66患者,分成死亡组与存活组,存活组48例,死亡组18例。发现死亡组患者的胰功于来院第一天便开始升高,且一直呈上升态势,至死亡；存活组患者的血胰功升高不明显,于入院后第七天仍维持轻度升高。死亡组与存活组胰功差异有显著性意义(P0.001),死亡组各期胰功水平显著高于存活组各时间点的数值,两组相比较有明显的统计学差异(P0.001)。患者出现各器官损伤的顺序依次是胰腺、消化道、肝脏、心脏、肾脏、肺。二、百草枯致胰腺功能受损的机制。方法：通过酶联免疫吸附试验(enzyme linked immunosorbent assay,ELISA)法测定百草枯病人血清中细胞因子IL-1β、IL-6、白介素13(IL-13)、白介素18 (IL-18)、 TNF-α及NF-kB的水平,对胰腺功能受损患者的细胞因子和NF-kB水平与急性胰腺炎的相同指标逐一进行比较,从而试图解释胰酶增高患者死亡率高的原因及其机制；对比死亡组、存活组上述指标变化的不同。结果：百草枯中毒存活组病人血清中细胞因子IL-1β、IL-6、IL-13、IL-18、TNFα及NF-kB均比死亡组患者低,二者差异有统计学意义,P0.05。存活组中,经Pearson相关分析,NF-kB的水平和细胞因子IL-1β、IL-6,IL-13,IL-18, TNF a均成正相关,r值分别为0.497、0.756、0.837、0.972和0.716,P均小于0.05,差异有统计学意义。在百草枯病人死亡组中,NF-kB的水平和细胞因子IL-1β、 IL-6, IL-13, IL-18均无相关性,r值分别为0.411,0.156,0.452、0.159和0.114,P均大于0.05,差异无统计学意义。将患者分成胰腺功能正常组、轻重度增高组和增高组进行上述指标的比较分析,结果发现上述指标随胰酶升高,而逐渐升高,并有显著统计学差异。将患者分成存活组和死亡组,并与急性胰腺炎进行上述指标对照,结果发现急性胰腺炎组和存活组比较差异有统计学意义,P=0.006；胰腺炎组和死亡组比较,差异无统计学意义,P0.05。三、急性百草枯中毒患者预后模型的建立。方法：对第一部分的研究对象各项临床指标进行深入研究。从死亡组、存活组两组的各项指标对比、统计分析中找出具有统计学差异的指标,并从中优化,试图找到其中的三至五个关键因子。对这些指标进行ROC曲线分析,计算各项指标的最佳临界值(cut off值)、特异度、敏感度、阳性预测值、阴性预测值、诊断正确率、约登指数及曲线下面积(area under the curve,AUC);并作出ROC曲线。得出曲线下面积最大的前3-5位指标,然后以此几项指标为基础,得出数学方程式。将此方程与SOFA和APACHE2、PSS的效力进行对比；初步探索急性百草枯中毒预后判断的简洁、可靠方法。结果：存活组和死亡组患者的各项指标对比,发现其中有差异的各项指标,它们分别是淀粉酶、脂肪酶、氧分压、乳酸、白细胞计数、尿百草枯浓度等。根据ROC曲线结果提示,我们选出尿百草枯浓度、服毒量、血脂肪酶、血白细胞计数、动脉血乳酸为前五位的独立危险因子。得出预测方程：h(t).h0(t)exp (0.0007215*PQconcentration+O.0062* ingestion volume+0.07954*WBC1+ 0.16764*Lacl+0.01610*lipase 1).将此方程与APACHE 2评分、SOFA评分及PSS评分进行比较,发现其效力居前二位,高于APACHE 2评分和SOFA评分。结论：急性PQ中毒不仅可以导致呼吸、肝、肾、功能受损,胰腺功能也可受到打击。急性PQ中毒可以导致胰腺功能受损,其受损程度越重,患者的预后越差。存活组和死亡组的胰腺功能变化呈现不同的态势,死亡组患者的胰功持续升高,存活组则维持较低水平。急性百草枯中毒后,IL-13,IL-18等细胞因子及NF-kB均可出现变化。较之存活组,这种变化在死亡组更为明显。随胰腺功能受损程度的加重,其变化更为明显。急性百草枯中毒胰腺受损死亡组患者的上述因子变化与急性胰腺炎患者的因子变化类似。有待于更深入的研究,探寻其发病机制。我们的研究纳入了血脂肪酶建立预测模型,并表明基于胰腺功能的预测模型在急性百草枯中毒患者的评估中效力可与传统方法相似,但更简洁、方便、快速。临床工作中应重视胰腺功能在百草枯中的地位。
[Abstract]:Paraquat (PQ) is a widely used herbicide, which has been reported to be the first fatal case of paraquat in the British Medical Association (British Medical Journal) since 1960. It has been nearly 50 years ago. Despite the unremitting efforts of experts both at home and abroad, the mortality of paraquat poisoning remains at 40-60%. More than 24 to 72 hours after taking poison, previous studies found that the main cause of death in patients with acute paraquat was acute respiratory failure, acute renal failure, acute liver failure, and acute liver failure (MODS).PQ entered the body, and the whole body cell combination was rapidly distributed to the whole The concentration of various organs of the body, of which the concentration of the kidney is the highest, the fastest, and then redistributed to various organs such as lung, liver, heart and brain. PQ poisoning can cause damage to many organs such as lung, liver, kidney, heart, brain, and digestive tract. Previous studies have found that PQ has a strong affinity for alveolar cells, so the lung is the main target organ for PQ poisoning and lung injury. Acute respiratory failure and pulmonary fibrosis were manifested in many cases. The main causes of death were acute respiratory failure, liver failure, renal failure, and myocardial damage. However, previous literature has reported the damage to other organ functions, attention, and less attention. Some studies have been done on the pathogenesis of paraquat, mainly focused on the pathogenesis of paraquat. The next few aspects: oxygen free radical production and oxidative stress state; secondary effects of oxidative stress: lipid peroxidation, mitochondrial toxicity, NADPH oxidation, cell apoptosis and so on; inflammatory reaction: nuclear transcription factor (NF-kB) activation, cytokines up-regulated, among which inflammatory reaction theory is most concerned. It has been proved that acute NF-kB can be activated after paraquat poisoning. NF-kB activity increases after paraquat poisoning, interleukins 1 beta (IL-1 beta), tumor necrosis factor (TNF- alpha), platelet derived growth factor (PDGF) and IL-6 (IL-6) increase. But what is the mechanism of pancreatic injury and is not clear to the mechanism of acute pancreatitis. There are many ways to treat paraquat poisoning, such as enhancement of excretion (hemoperfusion, bedside continuous hemofiltration), corticosteroids, immunosuppressants, antioxidants, etc. but even if all, the mortality rate is still high. There are many characteristics such as huge cost of treatment and many medical labor and so on. Therefore, how to treat acute hundred grass The risk stratification of the patients with intoxication, the judgment of the severity of the disease and the analysis of the prognosis are a clinical problem which is solved. Therefore, how to judge the prognosis of acute critical patients with acute paraquat poisoning and how to use medical resources reasonably is a medical problem, and the social security is concerned. The present application of organ function assessment The main methods are as follows: acute physiology and chronic health status score (APACHE 2), SOFA score, poisoning severity score (PSS),.APACHE2, SOFA scoring system, although it has been widely used in acute severe disease patients, but there are two defects in the application of acute poisoning. There is a certain difference between acute paraquat poisoning and other non medium toxic diseases, such as the dose of poison, the time of subsequent diagnosis may be related to the prognosis; on the other hand, the APACHE2, SOFA scoring system can not be immediately evaluated, the project is numerous, and it is not easy to implement. It all takes at least 24 hours to complete the work. It is more suitable for assessing the critically ill patients in the hospital rather than in the emergency work. The practical method to quickly assess the patient's prognosis.PSS score is more complicated and difficult to carry out. In summary, the lung injury caused by acute paraquat poisoning has been widely concerned with the other organ functions of the body. There are few systematic studies. There are few reports of pancreatic dysfunction. Therefore, it is necessary to explore the time and severity of pancreatic damage in the process of acute paraquat poisoning and the role of pancreatic function damage and the impact on the prognosis. We will also try to detect NF-kB and other inflammatory factors. To discuss the main mechanism of multiple organ failure syndrome in patients with paraquat poisoning and to compare with patients with acute pancreatitis to explore the different mechanisms. Finally, we also try to establish a convenient, practical and accurate prediction model that can reflect the characteristics of paraquat poisoning. Our research is divided into three parts. Clinical observation of multiple organ dysfunction caused by Kat poisoning. Methods: a prospective study was made in this study from July 2013 to August 2014, treated in the emergency department of the First Affiliated Hospital of Zhengzhou University, with acute PQ poisoning, to understand the damage to various organs of the whole body, and to analyze the impairment of the function of these organs. The incidence of pancreatic damage was observed, with the blood amylase exceeding the upper limit of the normal value, that is, more than 220U/L. The first amylase was divided into three groups, the normal group of pancreatic work (the amylase is below 220U/L), the mild elevation of pancreatic work (amylase from 220U/L to 660U/L), pancreas work (amylase from 220U/L to 660U/L). The survival curves of the three groups were compared. The relationship between the mortality of the three groups, the relationship between the high and low levels of the pancreatin and the prognosis of the patients. Compare the changes of the pancreas function between the survival group and the death group, and compare the different clinical indexes between the two groups. Results: the emergency internal medicine, the First Affiliated Hospital of Zhengzhou University, was treated in the emergency internal medicine. There were 258 patients with a total of 258 patients who met the admission criteria and finally agreed to the admission of 177 cases. According to the difference of pancreas function, we divided all the patients into three groups. We can see that the normal group, the mild elevation group and the elevated group were 125 cases, 27 cases and 25 cases respectively. The total number of patients with the pancreas functional heterogeneity was drawn three groups by drawing three groups. The survival curve of the patients showed that the survival time was in the order of the group of mild pancreatic work in the normal group of pancreas work and the increase of pancreatic work in the group, and there was a statistical significance (P0.001). In all the patients, the patients with blood amylase and lipase were further analyzed in the first 9 days. A total of 66 patients were divided into the death group and the survival group, the survival group 48 cases, and the death group 18. It was found that the pancreatic work of the patients in the death group began to rise on the first day of the hospital, and continued to rise, to the death. The blood pancreatic work of the survivors in the survival group was not significantly higher than that in the seventh day after admission. The difference between the death group and the survival group was significant (P0.001), and the level of pancreatic work in the death group was significantly higher than that in the survival group. There was a significant statistical difference between the two groups (P0.001). The sequence of the organ damage in the patients was the pancreas, the digestive tract, the liver, the heart, the kidney, the lung. Two, the mechanism of the damage to the pancreas caused by paraquat. Methods: the enzyme linked immunosorbent assay (ELISA) method was used to determine the hundred grass by the enzyme linked immunosorbent assay (ELISA). The levels of cytokines IL-1 beta, IL-6, interleukin 13 (IL-13), interleukin 18 (IL-18), TNF- alpha and NF-kB in the patient's serum were compared with the same indexes of the cytokines and NF-kB levels in patients with impaired pancreatic function and the same index of the acute pancreatitis, thus trying to explain the cause and mechanism of high mortality in patients with increased trypsin and the comparison of death. Results: the serum cytokine IL-1 beta, IL-6, IL-13, IL-18, TNF, and NF-kB in the patients with paraquat poisoning were lower than those in the death group. The difference between the two groups was statistically significant. In the P0.05. survival group, the level of NF-kB and the level of IL-1 beta, IL-6, IL-13, and NF-kB were all in the P0.05. survival group. Positive correlation, R values of 0.497,0.756,0.837,0.972 and 0.716, P are less than 0.05, the difference is statistically significant. In the paraquat patient death group, the level of NF-kB and the cytokines IL-1 beta, IL-6, IL-13, IL-18 are not related, R values are 0.411,0.156,0.452,0.159 and 0.114, P are more than 0.05, the difference is not statistically significant. The patients are divided. The results showed that the above indexes were increased with the increase of trypsin, and there was a significant difference. The patients were divided into the survival group and the death group, and the above indexes were compared with the acute pancreatitis, and the results were found in the acute pancreatitis group and the survival group. The difference was statistically significant, P=0.006, the difference between the group of pancreatitis and the death group was not statistically significant, P0.05. three, the establishment of the prognosis model of patients with acute paraquat poisoning. Methods: the clinical indexes of the first part of the study were thoroughly studied. The indexes of the two groups in the death group and the survival group were compared and analyzed in the statistical analysis. Find out the index with statistical difference, and optimize it, try to find three to five key factors. The ROC curve analysis of these indexes, the optimum critical value (cut off value) of each index, specificity, sensitivity, positive predictive value, negative predictive value, diagnostic accuracy, the area of area under the and the area under the curve (area under the) Curve, AUC); and make a ROC curve. Get the top 3-5 index of the largest area under the curve, and then draw a mathematical equation based on several indexes. Compare the equation with the effectiveness of SOFA and APACHE2 and PSS; explore a simple and reliable method for judging the prognosis of acute paraquat poisoning. Results: the survival group and the death group. According to the results of ROC curve, we selected the independent risk factors of urinary paraquat concentration, dosage, blood lipase, blood leucocyte count and arterial blood lactate as the first five independent risk factors. Prediction equation: H (T).H0 (T) exp (0.0007215*PQconcentration+O.0062* ingestion volume+0.07954*WBC1+ 0.16764*Lacl+0.01610*lipase 1). Comparing this equation with APACHE 2 score, SOFA score and PSS score, it is found that its effectiveness is the top two, which is higher than that of the 2 score and the score. Aspiration, liver, kidney, impaired function, and pancreatic function can also be hit. Acute PQ poisoning can cause damage to the pancreas function, the worse the damage, the worse the patient's prognosis. The pancreatic function changes in the survival group and the death group are different, the pancreas work in the death group continues to rise, the survival group maintains a lower level. Acute paraquat poisoning. Later, IL-13, IL-18 and other cytokines and NF-kB were changed. Compared with the survival group, the changes were more obvious in the death group. The changes were more obvious with the aggravation of the damage of the pancreas function. The changes of these factors in the patients with acute paraquat poisoning were similar to those of the acute pancreatitis. Our study included the establishment of a prediction model for the establishment of blood lipase, and indicated that the predictive model based on pancreatic function in the assessment of acute paraquat poisoning can be similar to the traditional method, but more concise, convenient and rapid. In clinical work, the position of pancreatic function in paraquat should be paid attention to.
【学位授予单位】：郑州大学
【学位级别】：博士
【学位授予年份】：2014
【分类号】：R595.4
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