【作者】 周志强；

【导师】 菅向东；

【作者基本信息】 山东大学 ， 公共卫生（专业学位）， 2024， 硕士

【摘要】 研究背景敌草快与百草枯同属联吡啶类除草剂,自我国禁用百草枯后,敌草快因其除草效率高、环保无污染、遇土即失活等特点,迅速取代百草枯,广泛应用于我国的农业生产活动中,与此同时我国急性敌草快中毒患者的数量也在逐年增加。近年来有学者研究发现,口服包装成分标注为敌草快的除草剂中毒患者中有部分患者其实际诊断为百草枯中毒,而且我国农药销售市场中也存在以百草枯冒充敌草快进行销售的情况。目前尚无针对敌草快中毒和百草枯中毒的特效解毒剂,而且两者的病死率较高,初期临床表现相似,容易导致临床医生无法及时作出准确的诊断,这不仅是临床诊疗领域亟待解决的难题,同时也是公共卫生领域面临的重大挑战。研究目的本研究的第一部分首先总结口服包装成分标注为敌草快的除草剂中毒患者的人口统计学信息、中毒相关因素、实验室检测结果、治疗措施和生存结局的特点,进而分别分析影响敌草快中毒患者和百草枯中毒患者预后的危险因素,从而为临床医生的诊断和治疗提供科学依据;第二部分根据在临床诊疗过程中发现的口服包装成分标注为敌草快的除草剂中毒患者其实际诊断为百草枯中毒的现状,在山东省109个县(县级市、区)域内采集包装成分标注为敌草快的除草剂样品,采用液相色谱质谱法检测并分析其实际成分及浓度。研究方法本研究的第一部分选取2021年10月1日至2023年9月30日于山东省济南市某三甲医院急诊科就诊的口服包装成分标注为敌草快的除草剂中毒患者作为研究对象,回顾性收集其人口统计学信息、中毒相关因素、实验室检测结果、治疗措施和生存结局等资料。符合正态分布的计量资料使用均数±标准差(x±s)表示,组间比较使用独立样本t检验进行分析;不符合正态分布的计量资料使用中位数和四分位数间距[Median,(Q1,Q3)]表示,组间比较使用曼-惠特尼U检验(Mann-Whitney U test)进行分析。计数资料使用频数和百分比表示,组间比较使用卡方检验(χ2test)进行分析。此外,对单因素分析中表现出显著性的变量进一步作相关性分析,根据受试者工作特征曲线(receiver operating characteristic curve,ROC)下的面积及P值来筛选自变量。筛选出有意义的自变量将纳入多因素二元Logistic回归分析,其结果以OR值和95%置信区间表示,以P值<0.05表示差异具有统计学意义。最后将多因素二元Logistic回归分析中确定的有意义的自变量纳入ROC曲线分析,以确定预测患者生存结局的最佳指标。整个分析过程使用SPSS 25.0统计软件,检验水准α=0.05。本研究的第二部分是基于第一部分研究中发现的口服包装成分标注为敌草快的除草剂中毒患者中有部分患者其实际诊断为百草枯中毒的现状,于2022年9月至12月在山东省内的109个县(县级市、区)域内的东、南、西、北4个方向随机选取1家销售农药的农资店购买包装成分标注为敌草快的除草剂,利用液相色谱质谱法对采集的样品进行检测和分析,确定其实际成分及浓度。使用Analyst1.6.2分析软件进行数据处理和分析,使用SPSS 25.0进行分析和作图。研究结果第一部分:口服包装成分标注为敌草快的除草剂中毒患者的临床特征分析1.本研究共纳入375例口服包装成分为敌草快的除草剂中毒患者,其中诊断为急性敌草快中毒的患者274人,占比73.1%,病死率为36.9%,诊断为急性百草枯中毒的患者101人,占比26.9%,病死率为50.5%。2.单因素分析结果显示:(1)急性敌草快中毒患者的预后在性别、年龄、职业、服毒剂量、尿液浓度、血液浓度、敌草快中毒严重指数(Severity Index of Diquat Poisoning,SIDP)、病情分级、就诊时间、住院天数、白细胞计数(White blood cell count,WBC)、中性粒细胞比率(Neutrophil ratio,NEU%)、淋巴细胞比率(Lymphocyte ratio,LYM%)、中性粒细胞计数(Neutrophil count,NEU#)、淋巴细胞计数(Lymphocyte count,LYM#)、谷丙转氨酶(Alanine aminotransferase,ALT)、谷草转氨酶(Aspartate aminotransferase,AST)、γ-谷氨酰基转移酶(γ-glutamyltransferase,γ-GT)、总胆红素(Total bilirubin,TBIL)、总蛋白(Total protein,TP)、尿素氮(Urea nitrogen,BUN)、肌酐(Creatinine,Cr)、肌酸激酶(Creatine kinase,CK)、肌酸激酶同工酶(Creatine kinase isoenzyme,CK-MB)、乳酸脱氢酶(Lactate dehydrogenase,LDH)、淀粉酶(Amylase,AMY)、脂肪酶(Lipase,LIP)、洗胃、血液净化和使用糖皮质激素方面的差异具有统计学意义(P<0.05);(2)急性百草枯中毒患者的预后在年龄、职业、服毒剂量、尿液浓度、血液浓度、百草枯中毒严重指数(Severity Index of Paraquat Poisoning,SIPP)SIPP、病情分级、住院天数、WBC、NEU%、LYM%、NEU#、LYM#、ALT、AST、y-GT、TBIL、TP、BUN、Cr、CK、CK-MB、LDH、使用糖皮质激素方面的差异具有统计学意义(P<0.05)。3.多因素分析结果显示:(1)多因素二元Logistic回归分析显示服毒剂量(OR:1.030,95%CI:1.008～1.054)、血液浓度(OR:2.318,95%CI:1.274～4.217)、WBC(OR:1.202,95%CI:1.036～1.395)和CK(OR:1.007,95%CI:1.003～1.012)是影响急性敌草快中毒患者预后的独立危险因素,当急性敌草快中毒患者的服毒剂量>100ml、血液浓度>1.83μg/ml、白细胞计数>19.69× 109、肌酸激酶>142IU/L时提示患者的预后情况较差;(2)多因素二元Logistic回归分析显示服毒剂量(OR:1.027,95%CI:1.004～1.050)、ALT(OR:1.049,95%CI:1.010～1.090)是影响急性百草枯中毒患者预后的独立危险因素,当急性百草枯中毒患者的中毒剂量>100ml、谷丙转氨酶>50IU/L时提示患者的预后情况较差。第二部分:山东省市售包装成分标注为敌草快的除草剂检测分析1.本研究于山东省境内109个县(县级市、区)域内共采集包装成分标注为敌草快的除草剂样品417份,检测出实际成分为敌草快的样品为385份,检测出实际成分为百草枯的样品为32份;2.385份检测出敌草快成分的样品平均浓度为157.30±32.30g/L,32份检测出百草枯成分的样品中平均浓度为70.64±21.04g/L;3.检测出百草枯成分的敌草快除草剂的生产企业主要分布于河北、山西、广西、浙江、新疆、江苏等省份;检测出百草枯成分的敌草快除草剂的销售地区主要分布于山东省的枣庄市、潍坊市、济宁市、德州市、聊城市、临沂市和菏泽市。研究结论1.口服包装成分为敌草快的除草剂中毒患者中有部分患者其实际诊断为百草枯中毒,此类中毒事件应引起临床医务人员的重视;2.影响急性敌草快中毒患者预后的独立危险因素为服毒剂量、血液浓度、WBC和CK;影响急性百草枯中毒患者预后的独立危险因素为服毒剂量和ALT;3.目前山东省农药销售市场上存在假冒的敌草快除草剂,其实际成分为百草枯。对策与建议1.对于除草剂中毒事件,临床医生要深化对包装标注成分与实际成分可能存在差异的认识,在中毒患者入院后要在第一时间留取患者的尿液和血液进行毒物检测,尽快明确临床诊断,从而避免漏诊和误诊,提高患者的生存率;2.临床医生应详细了解患者的中毒史,在患者入院后立即给予洗胃、导泻、血液净化等综合治疗措施,尽快清除患者体内毒物。同时定期对中毒患者进行血液检查,密切监测各项血液指标的变化情况,以便及时评估患者的中毒严重程度和预后情况,采取更有效的治疗策略和措施;3.农业部门应该建立严格的监管和处罚机制,加大日常监管和执法力度,依法查处违法生产经营单位,对非法添加百草枯的除草剂追根溯源。更多还原

【Abstract】 BackgroundDiquat and paraquat belong to the same bipyridine herbicide,since China banned paraquat,diquat because of its high weed control efficiency,environmental protection and non-pollution,inactivation when encountered with soil and other characteristics,rapidly replaced paraquat,widely used in China’s agricultural production activities,at the same time,China’s acute poisoning of diquat the number of patients is also increasing year by year.In recent years,some scholars have found that some of the patients who were orally poisoned by herbicides whose packaging components were labelled as diquat were actually diagnosed with paraquat poisoning,and there were cases of paraquat being sold as diquat in the pesticide sales market in China.At present,there is no specific antidote for diquat and paraquat poisoning,and both of them have high morbidity and mortality rates,and their initial clinical manifestations are similar,which easily leads to the inability of clinicians to make timely and accurate diagnosis,which is not only a difficult problem to be solved in the field of clinical diagnosis and treatment,but also a major challenge faced by the field of public health.ObjectiveThe first part of this study firstly summarises the demographic information,poisoning-related factors,laboratory test results,treatment measures and survival outcomes of patients poisoned by herbicides whose oral packaging composition is labelled as diquat,and then analyses the risk factors affecting the prognosis of patients poisoned by diquat and those poisoned by paraquat,respectively,so as to provide a scientific basis for the clinicians’diagnosis and treatment;In the second part,based on the current situation that the actual diagnosis of paraquat poisoning is based on the patients who were found to have been poisoned by herbicides with the packaging ingredient labelled as diquat in the process of clinical diagnosis and treatment,samples of herbicides with the packaging ingredient labelled as diquat were collected in 109 counties in Shandong Province(county-level cities and districts),and the actual ingredient and concentration of the herbicides were detected and analysed using liquid chromatography-mass spectrometry,and the corresponding countermeasures and suggestions were put forward according to the results.MethodsIn the first part of this study,patients with herbicide poisoning by oral packaging ingredients labelled as diquat were selected as study subjects who attended the emergency department of a tertiary hospital in Jinan,Shandong Province,from October 1,2021,to September 30,2023,and information on their demographic information,factors associated with poisoning,laboratory test results,therapeutic measures,and survival outcomes was collected retrospectively.Measurement information that conformed to normal distribution was expressed using mean ± standard deviation(x±s),and comparisons between groups were analysed using the independent samples t test;measurement information that did not conform to normal distribution was expressed using median and interquartile spacing[Median,(Q1,Q3)],and comparisons between groups were analysed using the Mann-Whitney U test.Count data were expressed using frequencies and percentages and comparisons between groups were analysed using the chi-square test(χ2 test).In addition,variables that showed significance in the one-way analysis were further analysed for correlation,and the independent variables were screened with reference to the area under the receiver operating characteristic curve(ROC)and the P-value.Significant independent variables were included in the multifactor binary logistic regression analysis,and the results were expressed as ORs and 95%confidence intervals,with p-values<0.05 indicating statistically significant differences.Finally,the meaningful independent variables identified in the multifactorial binary logistic regression analysis will be included in the ROC curve analysis to determine the best predictor of patient survival outcomes.The entire analysis was performed using SPSS 25.0 statistical software with a test level of α=0.05.The second part of this study was based on the finding in the first part of the study that some of the patients who were poisoned by orally ingested herbicides with the packaging ingredient labelled as diquat were actually diagnosed with paraquat,and one agricultural shop selling pesticides was randomly selected in 109 counties(county-level cities and districts)in Shandong Province in four directions,namely,the east,the south,the west,and the north,to purchase herbicides with the packaging ingredient labelled as diquat from September to December 2022,and to determine their actual composition and concentration using liquid chromatography-mass spectrometry.Diquat was purchased from one randomly selected agricultural store selling pesticides in the four directions of east,south,west and north of Shandong Province,and the actual composition and concentration of diquat were determined by testing and analysing the collected samples using liquid chromatography-mass spectrometry.Data were processed and analyzed using Analyst 1.6.2 analysis software and analyzed and plotted using SPSS 25.0.ResultsPart Ⅰ.Clinical characterisation of patients poisoned by orally administered herbicides with packaged ingredients labelled as diquat1.In this study,a total of 375 patients with the main complaint of diquat poisoning were included,among which 274 patients were diagnosed with acute diquat poisoning,accounting for 73.1%,and the case fatality rate was 36.9%;101 patients were diagnosed with acute paraquat poisoning,accounting for 26.9%,and the case fatality rate was 50.5%.2.The results of single factor analysis show that:(1)There are statistically significant differences in the survival outcomes of acute diquat poisoning patients in terms of gender,age,occupation,dose of poison taken,urine concentration,blood concentration,SIDP(Severity index of diquat poisoning,),disease severity grading,time of hospital visit,length of hospital stay,WBC(White blood cell count),NEU%(Neutrophil ratio),LYM%(Lymphocyte ratio),NEU#(Neutrophil count),LYM#(Lymphocyte count),ALT(Alanine aminotransferase),AST(Aspartate aminotransferase),γ-GT(γ-glutamyltransferase),TBIL(Total bilirubin),TP(Total protein),BUN(Urea nitrogen),Cr(Creatinine),CK(Creatine kinase),CK-MB(Creatine kinase isoenzyme),LDH(Lactate dehydrogenase),AMY(Amylase),LIP(Lipase),gastric lavage,blood purification,and use of glucocorticoids(P<0.05);(2)There are statistically significant differences in the survival outcomes of acute paraquat poisoning patients in terms of age,occupation,dose of poison taken,urine concentration,blood concentration,SIPP,disease severity grading,length of hospital stay,WBC,NEU%,LYM%,NEU#,LYM#,ALT,AST,γ-GT,TBIL,TP,BUN,Cr,CK,CK-MB,LDH and use of glucocorticoids(P<0.05).3.The results of multivariate analysis shows that:(1)Multifactorial binary logistic regression analysis showed that the dose of poison(OR:1.030,95%CI:1.008～1.054),blood test concentration(OR:2.318,95%CI:1.274～4.217),WBC(OR:1.202,95%CI:1.036～1.395),and CK(OR:1.007.95%CI:1.003～1.012)were independent risk factors affecting the prognosis of patients with acute diquat poisoning.When the poisoned dose of acute diquat poisoning was>100 ml,the concentration of blood test was>1.83 μg/ml,the leukocyte count was>19.69 ×109,and the creatine kinase was>142 IU/L,it suggested that the patients had a poor prognosis;(2)Multifactorial binary logistic regression analysis showed that the dose of poison taken(OR:1.027,95%CI:1.004-1.050)and ALT(OR:1.049,95%CI:1.010-1.090)were independent risk factors affecting the prognosis of the patients with acute paraquat poisoning.When the poisoned dose of the acute paraquat poisoning was>100 ml and the glutathione aminotransferase>50IU/L suggests that the patients had a poor prognosis.Part Ⅱ.Detection and analysis of herbicides labelled as diquat on sale in Shandong Province1.In this study,a total of 417 samples of herbicides labelled as diquat were collected from 109 counties(county-level cities and districts)in Shandong Province;385 samples were detected as diquat and 32 samples were detected as paraquat;2.The average concentration of the 385 samples in which diquat was detected was 157.30±32.30 g/L,the average concentration of the 32 samples in which paraquat was detected was 70.64±21.04g/L;3.The production enterprises of diquat herbicides that were found to contain paraquat are mainly distributed in provinces such as Hebei,Shanxi,Guangxi,Zhejiang,Xinjiang,and Jiangsu.The sales areas of diquat herbicide with paraquat detected were mainly located in Zaozhuang,Weifang,Jining,Dezhou,Liaocheng,Linyi and Heze in Shandong Province.Conclusion1.Some of the patients who were poisoned by herbicides with the ingredient diquat in the oral package were actually diagnosed with paraquat poisoning,and this kind of poisoning should attract the attention of clinical medical personnel;.2.The independent risk factors affecting the prognosis of acute diquat poisoning were the dose of poison taken,blood concentration,WBC and CK.The independent risk factors affecting the prognosis of acute paraquat poisoning were the dose of poison taken and ALT;3.At present,there are fake and shoddy diquat herbicide in Shandong Province pesticide sales market,and its actual ingredient is paraquat.Countermeasures and Suggestions1.In the case of herbicide poisoning,clinicians should deepen their understanding of the possible differences between the labelled ingredients and the actual ingredients of the packages,and take the urine and blood of poisoned patients for toxicological testing at the first time after their admission to the hospital,so as to make a clear clinical diagnosis as soon as possible,thus avoiding omission and misdiagnosis and improving the survival rate of patients;2.Clinicians should know the patient’s history of poisoning in detail,and give comprehensive treatment measures such as gastric lavage,diarrhoea,blood purification and other measures as soon as possible after the patient is admitted to the hospital,so as to remove the poison in the patient’s body as soon as possible.Meanwhile,regular blood tests should be carried out on the poisoned patients,and the changes of various blood indexes should be closely monitored,so as to timely assess the severity of poisoning and the prognosis of the patients,and to take more effective treatment strategies and measures;3.The agricultural sector should establish a strict regulatory and penalty mechanism,increase daily supervision and law enforcement,investigate and deal with illegal production and operation units in accordance with the law,and trace back the roots of herbicides to which paraquat has been illegally added.更多还原