摘要
有机磷农药(OP)中毒是全世界都关心的临床和社会问题。WHO曾统计每年有数百万的OP中毒病例,其大部分发生在中国、印度等发展中国家。急性有机磷农药中毒(acute organophosphorus pesticide poisoning, AOPP)的诊断主要依靠分析病人的接触史、典型的中毒症状、体征以及相关生化及毒物检测。基层医院常由于不具备检测设备等原因,不将毒物检测作为常规检查指标。作为有机磷毒物的靶酶,乙酰胆碱酯酶(acetylcholinesterase, AChE)活性成为现有的临床诊断及分级诊断标准。但是,由于AChE主要存在于神经肌肉接头、红细胞膜等位置,其失活快、标本处理繁琐,因此并不便于临床实际应用。而丁酰胆碱酯酶(butyrylcholinesterase, BuChE)虽并非OP作用的靶酶,但其主要存在于血浆(血清)中且性质较稳定,标本易于抽取、重复性好,检测流程简单,因此常被作为诊断依据。然而,大量的临床工作发现:使用BuChE作为诊断指标时,机械的套用理论上的AChE标准并不合理,而文献中对于其诊断价值一直争议不断,结论不一。因此,使用BuChE的活性来诊断及判断AOPP的病情是否准确可靠成为急诊科医生的一个亟待解决的问题。
我们前期已进行过相关动物体内OP染毒及人血体外OP染毒实验。本研究在已有的工作基础上,选取我院急诊科收入的AOPP口服患者作为研究对象,旨在正确评价BuChE的活性对AOPP的诊断及分级诊断价值。首先,测定了正常人血中AChE和BuChE的活性范围。然后,同步对比分析AOPP患者体内BuChE的活性与现行的“金标准”——AChE活性的关系。为进一步验证BuChE的临床应用价值,我们进一步回顾了113例AOPP患者病历,就BuChE的活性及其与临床其它主要指标的关系进行分析。
目前,测定胆碱酯酶(ChE)活性的方法繁多且无统一标准,各种检测方法结果之间数值差距巨大。ChE尤其是AChE活力检测时,所需样品处理较复杂、且失活较快,这给临床实际检验操作带来不少问题及挑战;同时,在样品采集过程中,影响ChE测定的临床因素较多,如患者在治疗过程中常常摄入多种药物成分,这些均给检测系统带来不利影响。我们在查阅文献、结合临床实际情况及符合医学伦理学的基础上,基于改良的Ellman比色法,建立并优化了一整套适合临床实际操作的采血、检测ChE活性的流程。
AChE和BuChE活性的关系研究中,理想的方法应将AOPP患者ChE的活力与其中毒前ChE活力做自身对照,来计算其活性,但这在实际研究中很难实现。因此,我们选取健康青年男性志愿者的血液样品建立了正常人全血AChE和血浆BuChE的活力范围,其中BuChE为15807±3495U/L,AChE为105±33U/Hb。
以2009年4月~9月入院的21例AOPP口服患者为研究对象,其中男性8例,女性13例,年龄(35.6±14.5)岁。中毒农药种类包括:敌敌畏13例,对硫磷1例,氧化乐果2例,甲拌磷4例,辛硫磷1例。同时监测这些患者初诊、中毒后各时间段的AChE及BuChE活性结果,分析AChE与BuChE的活性关系。结果显示:1、AOPP患者体内的AChE和BuChE的活性均受到OP不同程度的抑制,但两者并不能呈明显的直线回归关系,我们分析其原因主要为个体差异及AChE和BuChE对不同种类OP的敏感性不同。在大多数的情况下,BuChE受抑制程度要高于AChE的受抑制程度。统计发现,BuChE活性小于10%时,对应AChE活性基本小于30%;BuChE活性小于20%时则对应于AChE活性小于50%。根据现有的AChE分级诊断标准(中、重度为30%和50%),我们建议:以BuChE为标准时,可考虑将中、重度AOPP患者划定为BuChE活性在正常值的20%和10%。2、在病情恢复过程中,虽然AChE和BuChE活性的值存在差异,但两者的发展趋势是基本是相符的,即BuChE活性回升往往伴随着AChE活性的回升。因此,我们认为BuChE和AChE一样,可以作为跟踪病情发展趋势的指标,临床动态监测BuChE活性的发展趋势对预后的判断是有积极意义的。3、在对甲拌磷与敌敌畏中毒患者的观察中发现,不同种类的OP在对AChE及BuChE两者的抑制特异性上存在差别。虽然甲拌磷等剧毒农药受到国家限制使用或禁用,在临床中毒中越来越少见,但对于其中毒患者使用BuChE作为观察指标时需予以特别重视,其诊断标准应该更加严格。4、在治疗理想的敌敌畏中毒患者恢复过程中,BuChE活性呈线性回升,每日回升幅度约2.54%。
为了进一步验证BuChE这一效应生物学标志物的临床应用价值,我们观察了BuChE的活性及其与临床其它主要指标的关系。对2008年1月~2009年4月入院的113例AOPP患者进行了回顾性分析。我们发现:1、患者BuChE活性的抑制与OP暴露史密切相关,这对病史采集困难的患者及疑似病例情况下,可以提供重要的诊断线索,并为针对性毒物检测提供参考依据。2、临床病例显示,BuChE的活性与AOPP患者体内OP农药的血药浓度有明显的相关性。当BuChE的活性仍处在下降阶段或持续性压低时,预示患者体内OP农药的血药浓度维持较高水平;只有当OP的血药浓度下降到一定范围后,BuChE的活性才会出现回升,因此BuChE的活性监测可以提示体内农药的代谢情况。3、在病情的判断方面,BuChE活性的动态变化趋势比单次检测结果更具有意义。比如,当BuChE活性触底回升后,虽然其活性值仍然较低,但这一变化趋势预示着病情已经逐渐好转,并提示此时患者需给予严密的病情观察,并及时调整抗胆碱药剂量,否则易发生阿托品中毒。因此,我们认为在初诊时可以依据BuChE的活性进行病情分级,而在治疗过程中则需动态观测其活性曲线变化趋势,并及时调整治疗方案。4、预后较好的AOPP患者恢复过程中,BuChE活性呈直线回升,每日回升幅度达到或大于2.5%。5、我们发现BuChE活性持续小于5%时,往往提示服药量大(多为剧毒类),血药浓度高,此类AOPP患者多伴有呼吸衰竭、治疗困难、住院时间长、需要大量抗毒药物维持、并发症多、病死率高等情况,因此在临床上需给予足够重视。
综上所述,本研究初步论证了BuChE活性作为AOPP的诊断及分级诊断标准的可行性,并探讨了其对于病情及预后判断的价值。本研究的结论为:BuChE活性可以作为临床AOPP的诊断及分级诊断标准,但其标准数值低于AChE活性标准。其中、重度中毒的分级标准可划定为正常BuChE活性的20%、10%,并需结合农药种类综合考虑。在病情及预后的判断方面,BuChE活性的动态变化趋势比单次检测更有指导意义。在BuChE活性触底回升后,需严密观察病情并及时调整抗胆碱药剂量,以防发生阿托品中毒,BuChE活性日回升幅度在2.5%以上预示预后较佳。对于BuChE活性检测结果持续性小于5%的情况,提示患者具有体内血药浓度高、治疗困难、并发症多、病死率高等特征,需给予重点关注。
Organophosphorus pesticides (OP) poisoning is a clinical and social problem the whole world concerning about. The statistics data by WHO showed that there are millions cases of organophosphorus poisoning every year, mostly in China, India and other developing countries.The diagnosis of acute organophosphorus pesticide poisoning (AOPP) mainly depends on the patient's contact history, typical symptoms signs and biochemical and toxicological detection. However, in most primary hospitals the poison detection is often not as a routine way because of the lack of equipments. As the target enzyme of organophosphate poisons, the acetylcholinesterase (AChE) is the current diagnostic criteria for clinical diagnosis and classification of AOPP. However, AChE, mainly existing in the neuromuscular junction and red cell membrane, will be inactivated rapidly, and the protocol for preparing specimen is complicated. Therefore, AChE is not easy for clinical application. Although not as the target enzyme, butyrylcholinesterase (BuChE), mainly existing in plasma (or serum), is often as a diagnostic criteria because of its stable nature, easy-to-sample, reproducible and simple dectection procedure. However, a large number of clinical works discovered that BuChE is unreasonable to be applied as diagnostic indicator according to the existing standard of AChE mechanically. The controversy on the diagnostic value of BuChE was continued while without conclusion. Thus, whether BuChE can be used as a diagnostic indicator of AOPP is a pressing problem to physicians in emergency department.
This study, based on the existing groundwork including animals exposed to OP in vivo and human blood exposed to OP in vitro, aimed to evaluate the diagnosis and classification valuation of BuChE to AOPP by selecting AOPP patients in our hospital emergency department as research objects. Firstly, we detected the normal activity range of AChE and BuChE in heathy adults and then analysised the relationship between BuChE activity the the current "golded standard"—AChE in vivo in AOPP patients. To further validate the clinical value of BuChE, we have analysised the relationship between BuChE activity and some important clinical indicators by reviewing the medical records of 113 AOPP patients.
At present, there is no uniform standard among the various methods for determination of ChE activity of which results have large gap. The activity assay for ChE especially for AChE not only is easy to inactivate but also needs complex sample handling which brought a number of problems and challenges to clinical laboratory. At the same time, during the sample collection process, there are many clinical factors affecting determination of ChE. For example, patients often take in multi-drug ingredients during the treatment which has an adverse impact on the detection system. According to literatures, clinical circumstances and medical ethics, we have established and optimized a set of convenient protocal for blood collection and ChE activity detection based on the modified Ellman assay.
The ideal method for study the relationship between AChE and BuChE should compare ChE activity of patients with self-control before poisoning which is difficult to apply in practice. Therefore, we selected healthy young male volunteers to establish normal activity range of AChE in whole blood and BuChE activity in plasma which were 105±33U/Hb and 15807±3495U/L respectively.
We studied 21 cases of AOPP patients hospitalized from April, 2009 to September, 2009 of which 8 males, 13 females, at the age of 35.6±14.5. There are 13 cases of dichlorvos, parathion1 case, omethoate 2 cases, phorate 4 cases, phoxim 1 case devided by pesticide poisoning types. We simultaneous monitored the AChE and BuChE activity of these patients at the time of diagnosed and different time after poisoning inorder to further analyze the AChE-BuChE activity relationship. The results showed as follows. Firstly, activity of AChE and BuChE in vivo of AOPP patients were not a significant linear regression relationship, the reason of which would be individual differences and sensitivity difference of AChE and BuChE to different OP. In most cases, BuChE activity is lower than that of AChE. Statistics results showed that BuChE activity less than 10% correspond to AChE activity lower than 30% and BuChE activity less than 20% correspond to AChE activity lower than 50%. Therefore, we propose that when BuChE is used as criteria, the threshold of moderate or severe AOPP can be delimited at 20% or 10 % , according to the existing AChE classification criteria (moderate or severe at 50% or 30%). Secondly, during the recovery process, the activities of AChE and BuChE were different but both trends were basically consistent. The upswing of BuChE activity was often accompanied with AChE increasing. Therefore, we believe that BuChE, just liked AChE, can be used as indicators for tracking progression of disease which is positive for dynamic monitoring of disease and for judgment of prognosis. Thirdly, it was discovered that different types of OP had different suppression capability on AChE and BuChE activity which is concluded from observation of patients of phorate and dichlorvos poisoning. Now, phorate and other highly toxic pesticides are restricted by the goverment, thus the number of this kind poisoning is decreasing. Physicians should pay special attention to this kind of poisioning, and its diagnostic criteria should be more stringent in the case of using BuChE as indicator. During the recovery process of dichlorvos poisoning patients with with ideal prognosis, BuChE activity was linear rise at the rate of about 2.54% daily.
To further validate the clinical value of BuChE, we observe the relationship of BuChE activity and other major clinical index retrospectively by analyzing the 113 cases of AOPP patients hospitalized from January 2008 to April 2009. We found some useful informations. Firstly, the inhibition degree of BuChE activity was associated with the degree of OP exposure which provided important diagnostic clues and reference for specific toxicological detection especially for patients with difficult cases taking or suspected cases. Secondly, analysis of clinical cases showed that BuChE activity was significantly correlated with concentration of OP pesticides in blood of AOPP patients. When the BuChE activity was declining or keeping lower indicated the concentrations of OP in patients maintained at a high level. The BuChE activity will recovery only when blood concentration of OP decreased to a certain extent. Therefore, the biological activity of BuChE may prompt the body's metabolism of pesticides. Thirdly, dynamic change of BuChE activity was more significant than a single result for judgments of disease condition. For example, the recovering of BuChE activity after bottoming out, even though still low, indicated that conditions have gradually improved and the patients need more close observation and adjusting doses of anticholinergics in time, otherwise atropine poisoning would easily occurred. Therefore, we think that AOPP patients should be classified based on the activity of BuChE at preliminary diagnosis and in the course of treatment dynamic curve trend of BuChE activity should be observed according which adjust the treatment in time. Fourthly, in the recovery process of AOPP patients with ideal prognosis, BuChE activity was linear rise, the daily recovery rate was greater than 2.5%. Fifthly, activity of BuChE keeping less than 5% often indicated large amount of OP taking (mostly highly toxic class) and high OP concentration in serum. Such AOPP patients need be paid enough attention because they were always accompany with respiratory failure, difficult treatment, long hospital staying, needing a lot of anti-drug to maintenance, multiple complications and high mortality.
In summary, this study initially demonstrated the value of BuChE activity as the diagnostic and classification criteria for AOPP and its feasibility for estimating severity and prognosis of AOPP. The conclusion of this study is that BuChE activity can be used as clinical criteria for the diagnosis and classification of AOPP but numerus is lower than the standard AChE activity values. The classification criteria of moderate or severe poisoning can be classified by BuChE activity at 20% or 10% of normal and need be combined with pesticides types. Dynamic change of BuChE activity was more significant than a single result for judgment of disease condition. Patients need more close observation and adjusting doses of anticholinergics in time after BuChE activity bottoming out followed with upswing. Test continuing less than 5% for the BuChE activity indicated patients with high blood concentration in vivo, treatment difficulties, complications and high mortality characteristics, and need to be focused on. The patients need be paid enough attention when the activity of BuChE keeped less than 5% which indicated high serum concentration of OP, difficult treatment, multiple complications and high mortality.
引文
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