本文選題：急性百草枯中毒 + 胰腺　； 參考：《鄭州大學》2014年博士論文

【摘要】：百草枯(PQ)是一種廣泛使用的除草劑,自1960年以來在我國使用。1966年在英國醫(yī)學會雜志(British Medical Journal)上報道首例百草枯致死的患者,至今已經(jīng)過去近50年的時間。雖然經(jīng)過國內(nèi)外專家的不懈努力,百草枯中毒的病死率仍維持在40-60%以上,且多數(shù)發(fā)生在服毒后24至72小時。既往的研究發(fā)現(xiàn)最終導致急性百草枯患者死亡的最主要原因是急性呼吸衰竭、急性腎功能衰竭、急性肝功能衰竭等為主要表現(xiàn)的多器官功能不全(MODS)。PQ進入機體后,全身細胞結合,迅速的分布到全身的各個臟器。其中聚集于腎的濃度最高、最快,隨后再分布到肺、肝、心、大腦等各個臟器,PQ中毒可導致肺、肝、腎、心、腦、消化道等多個臟器的損傷。既往的研究發(fā)現(xiàn)PQ對肺泡細胞的親和力比較強,所以肺是PQ中毒損傷的主要靶器官,肺損傷多表現(xiàn)急性呼吸衰竭和肺纖維化。主要死亡原因有急性呼吸衰竭、肝功能衰竭、腎功能衰竭、心肌損害等。但是既往的文獻對其它的器官功能的損害報道、關注度、重視度均較少。針對百草枯的致病機理過去已經(jīng)作了些研究,主要集中在以下幾個方面：氧自由基的產(chǎn)生及氧化應激狀態(tài)；氧化應激的繼發(fā)效應：主要有脂質(zhì)過氧化、線粒體毒性、NADPH氧化作用、細胞凋亡等；炎癥反應：核轉(zhuǎn)錄因子(NF-kB)活化、細胞因子上調(diào)等。其中炎癥反應學說最受大家關注。已經(jīng)證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)、腫瘤壞死因子(TNF-α)、血小板源性生長因子(PDGF)及白介素6(IL-6)含量增加。但胰腺損傷的機制是什么,與急性胰腺炎的機制有什么不同,均不清楚。盡管目前針對急性百草枯中毒的治療有許多手段,例如增強排泄(血液灌流、床旁持續(xù)血液濾過)、腎上腺皮質(zhì)激素、免疫抑制劑、抗氧化劑等。但是即使全部用上,其死亡率仍居高不下。存在治療經(jīng)費巨大、醫(yī)護勞力投入多等眾多特點。因此,如何對急性百草枯中毒患者進行危險分層、病情程度判斷及預后分析是一個迫于解決的臨床問題。因此,急性百草枯中毒在內(nèi)的急危重癥患者如何早期判斷預后,從而合理地使用醫(yī)療資源是一個醫(yī)患、社會保障均關注的問題。目前應用的器官功能評估方法主要有以下幾種：急性生理學及慢性健康狀況評分(APACHE 2)、SOFA評分、中毒嚴重程度評分(poisoning severity score, PSS)等。APACHE2、SOFA評分系統(tǒng)雖然已經(jīng)被廣泛使用于急危重病患者,但對于急性中毒的應用卻存在以下兩個方面的缺陷。首先,急性百草枯中毒與其它非中毒性疾病存在一定的差別,例如服毒量、服毒后來診時間可能均與預后相關；另一方面,由于APACHE2、SOFA評分系統(tǒng)并不能對患者立即進行評估,項目繁多,不易實施,均需要至少24小時以上的時間來完成此項工作,更適合對于住院的危重患者進行評估,而不是急診工作中需要的簡潔、實用的方法來快速評估患者的預后。PSS評分則存在項目較為繁瑣的特點,不易開展。綜上所述,急性百草枯中毒致肺損傷已經(jīng)廣為大家關注,其致機體其它器官功能的變化如何尚沒有系統(tǒng)性的研究。其中胰腺功能損傷的報道較少。因此,探尋胰腺受損在急性百草枯中毒過程中的時間性、嚴重性、胰腺功能受損在其中扮演的角色以及對預后的影響很有必要。我們還將通過檢測NF-kB等炎癥因子,試圖探討百草枯中毒后導致患者出現(xiàn)多器官功能衰竭綜合癥的主要機制；并與急性胰腺炎患者進行對比,探尋其機制的不同。最后,我們還試圖建立能夠反映百草枯中毒特點的方便、實用、準確的預測模型。我們的研究分成三個部分。一、急性百草枯中毒致多器官功能不全的臨床觀察。方法：本研究前瞻性的選取2013年7月至2014年8月,收治于鄭州大學第一附屬醫(yī)院急診科救治的急性PQ中毒患者,了解其致全身各器官功能受損的情況,并分析這些器官功能受損的先后性、與患者預后的關系。觀察胰腺受損的發(fā)生率,以血淀粉酶超出正常值上限,也就是大于220U/L為界。以第一個淀粉酶為依據(jù),進行分組(正常值為220U/L以下),分為三個組,胰功正常組(淀粉酶為220U/L以下)、胰功輕度升高組(淀粉酶在220U/L至660U/L之間)、胰功升高組(大于660U/L)。比較這三組患者的生存曲線。各組患者死亡率。胰酶的高低與患者預后的關系。比較存活組與死亡組患者的胰腺功能變化,并對比兩組間各項臨床指標的不同。結果：研究期間鄭州大學第一附屬醫(yī)院急診內(nèi)科收治的PQ患者有共258例,符合入選標準且最終同意入選的患者最終有177例。依據(jù)胰腺功能的不同,我們把全部患者分成了三組,可以看出正常組、輕度升高組及升高組分別為125例、27例及25例。胰腺功能異常的患者占總患者數(shù)的29.06%。通過繪出三組患者的生存曲線可以看出,生存時間長短依次為胰功正常組胰功輕度升高組胰功升高組,并有統(tǒng)計學意義(P0.001)。對全部患者中有前9天血淀粉酶、血脂肪酶的患者進行進一步分析。共得到66患者,分成死亡組與存活組,存活組48例,死亡組18例。發(fā)現(xiàn)死亡組患者的胰功于來院第一天便開始升高,且一直呈上升態(tài)勢,至死亡；存活組患者的血胰功升高不明顯,于入院后第七天仍維持輕度升高。死亡組與存活組胰功差異有顯著性意義(P0.001),死亡組各期胰功水平顯著高于存活組各時間點的數(shù)值,兩組相比較有明顯的統(tǒng)計學差異(P0.001)�；颊叱霈F(xiàn)各器官損傷的順序依次是胰腺、消化道、肝臟、心臟、腎臟、肺。二、百草枯致胰腺功能受損的機制。方法：通過酶聯(lián)免疫吸附試驗(enzyme linked immunosorbent assay,ELISA)法測定百草枯病人血清中細胞因子IL-1β、IL-6、白介素13(IL-13)、白介素18 (IL-18)、 TNF-α及NF-kB的水平,對胰腺功能受損患者的細胞因子和NF-kB水平與急性胰腺炎的相同指標逐一進行比較,從而試圖解釋胰酶增高患者死亡率高的原因及其機制；對比死亡組、存活組上述指標變化的不同。結果：百草枯中毒存活組病人血清中細胞因子IL-1β、IL-6、IL-13、IL-18、TNFα及NF-kB均比死亡組患者低,二者差異有統(tǒng)計學意義,P0.05。存活組中,經(jīng)Pearson相關分析,NF-kB的水平和細胞因子IL-1β、IL-6,IL-13,IL-18, TNF a均成正相關,r值分別為0.497、0.756、0.837、0.972和0.716,P均小于0.05,差異有統(tǒng)計學意義。在百草枯病人死亡組中,NF-kB的水平和細胞因子IL-1β、 IL-6, IL-13, IL-18均無相關性,r值分別為0.411,0.156,0.452、0.159和0.114,P均大于0.05,差異無統(tǒng)計學意義。將患者分成胰腺功能正常組、輕重度增高組和增高組進行上述指標的比較分析,結果發(fā)現(xiàn)上述指標隨胰酶升高,而逐漸升高,并有顯著統(tǒng)計學差異。將患者分成存活組和死亡組,并與急性胰腺炎進行上述指標對照,結果發(fā)現(xiàn)急性胰腺炎組和存活組比較差異有統(tǒng)計學意義,P=0.006；胰腺炎組和死亡組比較,差異無統(tǒng)計學意義,P0.05。三、急性百草枯中毒患者預后模型的建立。方法：對第一部分的研究對象各項臨床指標進行深入研究。從死亡組、存活組兩組的各項指標對比、統(tǒng)計分析中找出具有統(tǒng)計學差異的指標,并從中優(yōu)化,試圖找到其中的三至五個關鍵因子。對這些指標進行ROC曲線分析,計算各項指標的最佳臨界值(cut off值)、特異度、敏感度、陽性預測值、陰性預測值、診斷正確率、約登指數(shù)及曲線下面積(area under the curve,AUC);并作出ROC曲線。得出曲線下面積最大的前3-5位指標,然后以此幾項指標為基礎,得出數(shù)學方程式。將此方程與SOFA和APACHE2、PSS的效力進行對比；初步探索急性百草枯中毒預后判斷的簡潔、可靠方法。結果：存活組和死亡組患者的各項指標對比,發(fā)現(xiàn)其中有差異的各項指標,它們分別是淀粉酶、脂肪酶、氧分壓、乳酸、白細胞計數(shù)、尿百草枯濃度等。根據(jù)ROC曲線結果提示,我們選出尿百草枯濃度、服毒量、血脂肪酶、血白細胞計數(shù)、動脈血乳酸為前五位的獨立危險因子。得出預測方程：h(t).h0(t)exp (0.0007215*PQconcentration+O.0062* ingestion volume+0.07954*WBC1+ 0.16764*Lacl+0.01610*lipase 1).將此方程與APACHE 2評分、SOFA評分及PSS評分進行比較,發(fā)現(xiàn)其效力居前二位,高于APACHE 2評分和SOFA評分。結論：急性PQ中毒不僅可以導致呼吸、肝、腎、功能受損,胰腺功能也可受到打擊。急性PQ中毒可以導致胰腺功能受損,其受損程度越重,患者的預后越差。存活組和死亡組的胰腺功能變化呈現(xiàn)不同的態(tài)勢,死亡組患者的胰功持續(xù)升高,存活組則維持較低水平。急性百草枯中毒后,IL-13,IL-18等細胞因子及NF-kB均可出現(xiàn)變化。較之存活組,這種變化在死亡組更為明顯。隨胰腺功能受損程度的加重,其變化更為明顯。急性百草枯中毒胰腺受損死亡組患者的上述因子變化與急性胰腺炎患者的因子變化類似。有待于更深入的研究,探尋其發(fā)病機制。我們的研究納入了血脂肪酶建立預測模型,并表明基于胰腺功能的預測模型在急性百草枯中毒患者的評估中效力可與傳統(tǒng)方法相似,但更簡潔、方便、快速。臨床工作中應重視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.
【學位授予單位】：鄭州大學
【學位級別】：博士
【學位授予年份】：2014
【分類號】：R595.4
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本文編號：2114292