1、農藥中毒,楊振昌醫師 國立陽明大學醫學系內科暨 臺北榮民總醫院內科部臨床毒物科,農藥 (Pesticides),保護農作物及其生產物或改良作物目的所用之化學藥品 農藥之種類： 殺菌劑 (Fungicide) 殺蟲劑 (Insecticide) 除草劑 (Herbicide) 殺蹣劑 (Acaricide, Miticide),農藥 (Pesticides),殺線蟲劑 (Nematocide) 殺鼠劑 (Rodenticide) 引誘劑 (Attractant) 忌避劑 (Repellent) 植物生長調節劑 (Plant growth regulator) 補助劑 (Supplemental
2、agent),歐洲及中國於公元前即有使用硫黃、東蕓草(Hellebore) 及紅海蔥(red squill) 之記錄 十九世紀後，農藥使用日益增加(CS2 、除蟲菊精、硫酸銅、砷酸鉛等) 1939年： DDT被發現具良好殺蟲效果 1944年：發現巴拉松 (Parathion) 1950年：殺菌劑保米黴素 (Blasticidin-S) 其後各種除草劑、殺蟲劑陸續被製造,農藥之沿革,殺蟲劑 (Insecticides),植物性殺蟲劑：如除蟲菊 有機氯劑：如安殺番 有機磷劑：如大滅松 氨基甲酸鹽：如安丹 有機氮劑：如培丹 有機氟素劑：如Fussol 其他及雜類：如溴化甲烷,除草劑/殺菌劑,選擇性除
3、草劑：如2-4-D 、草滅淨、嘉磷塞異丙胺鹽 非選擇性除草劑：如巴拉刈、五氯酚鈉 撒佈用殺菌劑：如波爾多、錳乃浦、三苯醋錫、快得寧 種子消毒劑：如免賴得 土壤消毒劑：如福馬林 果實保護劑：如硫尿素,其他農藥,殺蹣劑：如克氯苯 殺線蟲劑：如巴拉松、二溴氯丙烷 殺鼠劑：如殺鼠靈(短效)或得伐鼠 植物生長調節劑：植物荷爾蒙 補助劑：包括展著劑(spreader)、增量劑(diluent)、溶劑(solvent) 、乳化劑(emulsifier) 、協力劑(synergist) 、固著劑(sticker) 、分解防止劑(stabilizer),農藥型態,液劑：(1)液體狀： 溶液、乳劑、水懸：粉；(2
4、)粉狀：可濕性粉劑、可溶性粉劑 粉劑 粒劑 煙霧劑 燻蒸劑 錠劑 油劑.,理想的農藥 低毒性 效力大 無藥害 品質安定 價格低廉 物理性質好 使用簡單，可混用.,農藥 (Pesticides),可依據半致死劑量(LD50)作簡單之分類 5,000mg/kg：無毒性 500-5,000 mg/kg：低毒性 50-500 mg/kg：中毒性 5-50 mg/kg：強毒性 5 mg/kg：劇毒性,農藥毒性的分級,農藥中毒之流行病學：臺灣,Acute Pesticide Poisonings in Taiwan,n= 2,013) (n= 1,718) (n= 2,264) (n= 2,389) (n
5、= 2,885),Percentage of all pesticide poisonings,Figure 1. Distribution of poisoning substance by calendar time among 11,269 patients with acute pesticide poisonings in Taiwan,台灣地區的農藥中毒,中毒物質以有機磷殺蟲劑(23.3%) 、嘉磷塞異丙胺鹽除草劑(15.4%)、巴拉刈除草劑(11.9%) 、除蟲菊精殺蟲劑(11.6%) 、及氨基甲酸鹽殺蟲劑(6.7%)為主 中毒者以30-39歲者最多(19.5%)，其次為19-2
6、9歲(18.2%) 中毒途徑以口服為主(79.2%)，其次為吸入(13.3%),台灣地區的農藥中毒,中毒原因以自殺(66.7%)為主，職業相關者佔13.6% 中毒之死亡率為14.5% ，以巴拉刈居首(61.5%) ，其次為有機磷殺蟲劑(13.1%) 、氨基甲酸鹽殺蟲劑(8.2%)等 中毒死亡與暴露途徑、中毒物質、中毒原因、其他中毒物質、及年齡等因素有關,表十一、口服暴露中毒死亡與非死亡組間，基本資料之差異及相對之OR,表十一、口服暴露中毒死亡與非死亡組間，基本資料之差異及相對之OR,表十二、非口服暴露中毒死亡與非死亡組間，基本資料之差異及相對之OR,表十二、非口服暴露中毒死亡與非死亡組間，基本
7、資料之差異及相對之OR,農藥中毒之流行病學： 其他地區,農藥中毒之流行病學,每年約300萬嚴重的急性農藥中毒個案，其中約22萬人死亡(WHO 1990) 中毒個案95%發生在開發中國家，並導致約2500萬農夫之中毒個案 在已開發國家，農藥中毒不是大問題，但中毒而住院者，死亡率並不低。以英格蘭及威爾斯為例，中毒住院者之死亡率約12% (Vale JA 1987)，蘇格蘭則約19% (Proudfoot AT 1988),農藥中毒之流行病學,美國(1985-1990) 25,418人住院，其中78%為意外中毒 341人因農藥中毒死亡，其中64%為自殺 中毒住院及死亡者，皆以男性居多 同時期報告至毒
8、物中心之農藥中毒個案共338,170人，其中嚴重中毒者782人，死亡97人 除草劑佔中毒者之8%，但佔死亡者之25%,Ann Emerg Med 1997;29;232-8,農藥中毒之流行病學,美國(2002) 2,380,028名通報個案，其中1,153人死亡(死亡率約為0.04%) 96,112人為農藥中毒(4.0%)，多數無或僅有輕微症狀，其中僅18人死亡 農藥中毒以殺蟲劑(以氨基甲酸鹽為首)及殺鼠劑居多 中毒原因以意外佔絕大部份,Am Emerg Med 2003;21;353-421,*同時期共有87,385名中毒死亡個案，農藥中毒者以男性及自殺居多 * Hum Exp Toxico
9、l 1994;13:95-101,* 45% of fatal poisoning cases were attributed to pesticides * Vet Hum Toxicol 1996;38:366-367,Table 3. Pesticide groups identified by toxicological analysis among 1,138 fatal cases in Northern Greece,德國的Bonn毒物中心(1974-1993) 共111,313名資料完整之通報中毒個案 56%為兒童， 13.4%有產生毒性，藥物中毒居多(37.1%) ，其次為家
10、庭用品(31.2%)及植物(9.7%) 農藥中毒在成人僅佔7.6% 中毒物質之個別比重，在研究期間並無明顯之改變,農藥中毒之流行病學,* Vet Hum Toxciol 1995;37:367-8,日本的Hidaka毒物中心(1982-1995) 共1,000名住院中毒個案，其中89.5%為自殺個案 中毒死亡率為27% (意外者為1%，自殺者為30%) 農藥中毒佔518名，死亡率為51% 農藥中毒者以巴拉刈居多(291名個案，76%之死亡率)，其次為有機磷及氨基甲酸鹽殺蟲劑(155名個案，24%之死亡率),農藥中毒之流行病學,* Vet Hum Toxciol 1996;38:34-5,伊朗德
11、黑蘭的Loghman-Hakim醫院(1994) 7,000名中毒個案 中毒個案65%為成人、女性居多、89.8%服食一種毒性物質、自殺佔87.5% 、口服暴露為主(78%) 、藥物為主(60.2%) 農藥中毒僅佔4.9%，中毒物質以organophosphates(57%)、aluminum phosphide 及 zinc phosphide為主 死亡率以農藥中毒者居首,農藥中毒之流行病學,*J Toxicol-Clin Toxciol 1997;35:387-93,(1)土耳其Izmir市(1996-2000年) 4,251名解剖個案，其中331名為中毒死亡 男性居多、43%為殺蟲劑中毒
12、、自殺及口服暴露為主 殺蟲劑中以有機磷為主(78%) (2)1993-2001年25,572名中毒個案中，8.8%為農藥中毒，其中80.3%為殺蟲劑中毒，19.7%為殺鼠劑；中毒者以0-6歲及19-29歲為主；中毒死亡率僅0.4%,農藥中毒之流行病學,* Vet Hum Toxciol 2003;45:106-8,Table 2. Hospital admissions and deaths from poisoning in Sri Lanka, 1998,* Poisoning is the third leading cause of death in Sri Lanka * 4,070
13、 reports to the PCC between 1988-1997; 48.8% were suicidal; 34% were due to pesticide exposure (10% mortality rate among hospitalized patients),* J Toxicol-Clin Toxicol 2002;40:551-5,* Vet Hum Toxciol 1994;36:228-233,臺灣地區常見之農藥中毒,殺蟲劑 (Insecticides)有機磷殺蟲劑(Organophosphates)氨基甲酸鹽殺蟲劑(Carbamates)除蟲菊殺蟲劑(Py
14、rethrin and pyrethroids) 除草劑 (Herbicides)巴拉刈(Paraquat)嘉磷塞異丙胺鹽除草劑(Glyphosate-surfactant herbicide),有機磷農藥:美文松 (Mevinphos),殺狗蚤之有機磷製劑,低毒性之有機磷製劑:陶斯松,Acute cholinergic syndrome (crisis): muscarinic effect, nicotinic effect, CNS effect Intermediate syndrome: proximal muscle involvement Delayed polyneuropat
15、hy: distal muscle weakness, motor nerve predominant,Stage of clinical presentations,有機磷殺蟲劑中毒,有機磷殺蟲劑中毒,Symptoms are usually rapid onset and patients may die within 30 minutes due to respiratory failure Muscarinic effects ： Salivation, Lacrimation, Urinary incontinence, Diarrhea, Gastrointestinal cram
16、p, sweating, bronchorrhea, Emesis, bradycardia, hypotension, miosisNicotinic effects： muscle paralysis, weakness, fasciculation, hypertension, tachycardiaCentral nervous system effects： dizziness, lethargy, headache, delirium, seizures, coma Miscellaneous： Garlic-like odor, whitish vomitus , hyperam
17、ylasemia, pancreatitis,Clinical manifestations,左肺塌陷,左肺塌陷 (進步中),左肺塌陷 (恢復正常),左肺塌陷 (I) (one lung intubation),左肺塌陷 (II) (進步中),急性肺水腫 (I),急性肺水腫 (II),急性肺水腫 (III),有機磷致急性胰臟炎,Keep airway patent (intubation as needed)Decontamination (gastric lavage, skin and hair decontamination) & activated charcoalIV fluid a
18、nd dopamine for hypotensionBenzodiazepine, phenobarbital & dilantin for seizuresCharcoal hemoperfusion maybe useful in severely poisoned patients who were not responded to above treatment： usually not recommended! More aggressive treatment required for patients with moderate to severe poisoning Anti
19、dotes： atropine & pralidoxime,Treatment of poisoning,有機磷殺蟲劑中毒,Atropine,Indication： patients with muscarinic symptoms/signs Dosage： 2-4mg (pediatric dose 0.05 mg/kg), repeat every 10-15 minutes until atropinization; OR 0.004-0.016mg/kg/min, adjust the dosage by the amount of bronchial secretion (not
20、by heart rate or pupil size!) Course of therapy depends on the clinical severity Should be used with caution in patients with BPH, glaucoma, high fever, hypertension, hypothyroidismAdverse effects：anticholinergic manifestations, e.g. dry mouth, decreased intestinal motility, mydriasis, urine retenti
21、on, tachycardia, fever, psychosis, hallucination, seizures, coma, ventricular dysrrhythmias,Atropine,Continuous infusion Advantages less dosage required less incidents of overdose less complications less nursing careDisadvantages infusion pump is needed,有機磷殺蟲劑使用atropine之方式,輕度或無中毒 中度中毒 重度中毒 (輕微分泌物增加
22、(針瞳,fasciculation, (呼吸衰竭,昏迷, ,頭暈,腹痛等症狀 分泌物明顯增加等症狀 休克,抽搐等症狀 CHEase 20%-50% N)* CHEase 10-20% N)* CHEase 10% N)*,若無症狀則不用給 Atropine 5-10mg in Atropine 10-20mg in atropine, 否則 atropine IV bottle 500ml (= IV bottle 500ml (= 3-5mg in IV bottle 0.01 or 0.02mg/ml) 0.02 or 0.04mg/ml) 500ml (=0.006 or 0.01 St
23、art with 0.004 Start with 0.008mg mg/ml), Start with 0.002 mg/kg/hr (在50Kg的患 /kg/hr (在50Kg的患 mg/kg/hr (在50Kg的患者 者約 20 or 10ml/hr) 者約 20 or 10ml/hr) 約 17 or 10ml/hr),圖二. Atropine continuous infusion 之使用方式,根據患者的呼吸狀況 (有無 rales,痰量多寡,chest X-ray 是否有肺葉塌陷)以調整藥 量. 原則上勿以瞳孔及心跳快慢作為調藥之依據,但應注意避免因使用atropine後 可能引起
24、的心跳過速(=140/min) *cholinesterase佔標準值之比率,Atropine,In tachycardia：first correct the possible causes of tachycardia, such as dehydration, fever, hypoxemia, hypotension In tachycardia：If tachycardia persists or worsens after atropine usage and other possible factors have been corrected, decreased dose of
25、 atropine or change parenteral atropine to inhalation atropine should be warranted In fever：differential diagnosis between atropine overdose and infection (especially aspiration pneumonia) is indicated,Pralidoxime (2-PAM),Indication： reactivates acetylcholinesterase and antagonizes nicotinic effects
26、 of OPS poisoningDosage: 1-2gm (pediatric dose 25-50 mg/kg) over 30 minutes, repeat the dose every 6-12 hours; OR 500mg/hr (maximum dose 12gm/day)Usual treatment： 3 days; longer therapy maybe needed on few occasionsRapid infusion ( 500mg/min) or large dose： dizziness, headache, nausea, neuromuscular
27、 blockade, inhibition of cholinesterase, weakness, blurred vision, diplopia, tachycardia, CPK & ALTObidoxime or HI-6 maybe more potent than 2-PAM,Natural carbamate: physostigmine (calabar bean)Synthesized since 1940s Carbamate insecticides Carbamate herbicides Carbamte fungicides Toxicities of carba
28、mate insecticides are entirely different from carbamate herbicides and carbamate fungicides,氨基甲酸鹽殺蟲劑中毒,氨基甲酸鹽殺蟲劑中毒,最常見導致中毒之carbamate:納乃得,Reason of exposure： suicide, food residues.Route of exposure： GI tract, airway, & skin Interact with acetylcholinesterase (carbamylation of esteratic site) inhibiti
29、on of hydrolysis of acetylcholine acetylcholine excess cholinergic symptoms or signs Clinical manifestations are not easily distinguishable from organophosphate insecticide poisonings except Rapid reactivation of acetylcholinesterase No garlic-like odor,氨基甲酸鹽殺蟲劑中毒,Muscarinic effect： miosis, salivati
30、on, lacrimation, urinary incontinence, diarrhea, gastrointestinal cramping, emesis, bronchorrhea, bronchospasm, hypotension, bradycardia, pulmonary edema (“SLUDGE” or “DUMBELS” syndrome)Nicotinic effect： hypertension, tachycardia, dystonia, muscle paralysis, fasciculation CNS effect： anxiety, headac
31、he, dizziness, confusion, coma, seizure, respiratory depression Children are more likely to have CNS effects (e.g. seizure) instead of muscarinic effects,氨基甲酸鹽殺蟲劑中毒,Other manifestations： extrapyramidal signs, aspiration, hyperamylasemia, pancreatitis, DIC, metabolic acidosis,Mortality rate 5.8% and
32、cause of death mainly due to respiratory failure (airway obstruction, muscle paralysis, or respiratory depression)To date, intermediate syndrome hasnt been reported in patients with carbamate poisoningDelayed neuropathy (?)： possible since there were 2 case reports (carbaryl & m-tolyl methyl carbama
33、te),氨基甲酸鹽殺蟲劑中毒,Diagnosis： history and clinical manifestations; response to low-dose atropine, RBC & plasma cholinesterase (should be measured earlier after poisoning) Treatment： decontamination, maintain respiratory and cardiovascular function, IV fluid, diazepam, atropine, pralidoxime,. Laboratory
34、workup： CXR, arterial blood gases, CBC, biochemistry, ECG, and abdominal ultrasonograph (if needed),氨基甲酸鹽殺蟲劑中毒,Atropine,Indication： patients with muscarinic symptoms/signs Dosage: 2-4mg (pediatric dose 0.05 mg/kg), repeat every 10-15 minutes until atropinization; OR 0.004-0.016mg/kg/min, adjust the
35、dosage by the amount of bronchial secretion (not by heart rate or pupil size!) Course of therapy depends on the clinical severity Should be used with caution in patients with BPH, glaucoma, high fever, hypertension, hypothyroidismAdverse effects： anticholinergic manifestations, e.g. dry mouth, decre
36、ased intestinal motility, mydriasis, urine retention, tachycardia, fever, psychosis, hallucination, seizures, coma, ventricular dysrrhythmias,Pralidoxime (2-PAM),The use of PAM in patients with carbamate insecticide poisonings remains controversial Reasons proposed against the use of PAM (1). Rapid
37、hydrolysis of carbamylated acetylcholinesterase (2). PAM, in high concentration, can react with anionic site of acetylcholinesterase and then inhibit enzymatic hydrolysis of acetylcholine (3). In anecdotal reports, PAM has been reported to potentiate the toxic effects of carbaryl (4). Possible toxic
38、ities of PAM,Pralidoxime (2-PAM),Indication： concomitant organophosphate insecticide poisoning, severe toxic manifestations, requiring large dose of atropine, or insecticide poisoning with uncertain causeDosage： 1-2gm (pediatric dose 25-40 mg/kg with total dose 500mg/min) or large dose may lead to n
39、euromuscular blockade, inhibition of cholinesterase, weakness, blurred vision, diplopia, dizziness, headache, nausea, tachycardia, CPK & ALT,天然除蟲菊(pyrethrum)及人工除蟲菊酯(pyrethroids) 天然除蟲菊來自菊科植物Chrysanthemum flower，包括 pyrethrin I、II 、cinerin II 、jasmolin I 、II等成份 除蟲菊酯(pyrethroid)為人工合成的產品，如permethrin 、cym
40、ethrin 、allethrin 、fenothrin 、fenfluvalerate,除蟲菊精殺蟲劑中毒,Type I syndrome (T syndrome)： restlessness, incoordination, palpitation, paralysis, aggressive sparring, elevated startle response, tremor, hyperexcitation Example: pyrethrin I, allerthrin, tetramethrin, kadethrin, resmethrin, phenothrin, permet
41、hrin Type II syndrome (CS syndrome)： hyperactivity, convulsions, ataxia, choreoathetosis, dermal tingling, coarse tremor, paresthesia, profuse salivationExamples:cypermethrin, cyhalothrin, deltamethrin, fenvalerate, fluvalinate, decamethrin, cyfluthrin, flucythrinate, cyphenothrin,除蟲菊精殺蟲劑中毒,除蟲菊精殺蟲劑
42、(I),除蟲菊精殺蟲劑 (II),除蟲菊精殺蟲劑 (III),除蟲菊精殺蟲劑 (IV):噴香及拜貢,除蟲菊精殺蟲劑 (V): Type II製劑的賽滅寧,對於昆蟲及害蟲有極佳之效果 對於人體一般毒性很低，因此常作為家庭及住家附近環境之殺蟲劑 半致死劑量一般在數百至數千 mg/kg 支氣管痙攣及過敏性肺炎為較主要的毒性症狀 市面產品中常添加高比率之溶劑，但其成份多半不明,除蟲菊精殺蟲劑中毒,毒性症狀： facial dysthesia、corneal damage、rhinitis、sore throat、asthma、respiratory paralysis、pulmonary edema、
43、nausea、vomiting、paresthesia、contact dermatitis 嚴重病患：convulsion、coma 天然除蟲菊精較易導致過敏症狀,除蟲菊精殺蟲劑中毒,、,除蟲菊精導致皮膚紅疹,治療原則：洗胃活性碳(?)如有呼吸困難時，則使用氧氣，必要時給予氣管擴張劑，甚至於氣管插管有抽搐時以藥物控制抽搐其他支持性療法,除蟲菊精殺蟲劑中毒,巴拉刈(paraquat)除草劑 (I),巴拉刈(paraquat)除草劑 (II),巴拉刈除草劑致口腔潰瘍 (I),巴拉刈除草劑致口腔潰瘍 (II),巴拉刈除草劑致會陰部潰瘍,巴拉刈除草劑致眼睛發炎,Paraquat致急性肺泡炎(I),P
44、araquat致急性肺泡炎(II),Paraquat致肺纖維化(I),Paraquat致肺纖維化(II),Paraquat致肺纖維化(III),Paraquat致肺纖維化(IV),巴拉刈除草劑與檢驗試劑sodium dithionite反應 (I),巴拉刈除草劑與檢驗試劑sodium dithionite反應 (II),巴拉刈除草劑與檢驗試劑sodium dithionite反應 (III),Inducing emesis is not recommended (additive PP796, a phosphodiesterase inhibitor is emetic)If no cont
45、raindication (e.g. seizure, CNS depression with unprotected airway, GI tract not intact): early gastric lavage until return fluid is clear & administration of activated charcoal The effect of sodium polystyrene sulfonate (Kayexalate) remains inconclusive: survival in 6 of 22 patients (Yamashita 1987
46、)Whole bowel irrigation has not been shown to be of any benefit,Treatment,巴拉刈除草劑中毒,Do not administer supplemental oxygen unless the patient presents with marked hypoxic symptoms/signsForced diuresis has not been shown to modify the outcome; possible aggravation of pulmonary edema Hemoperfusion maybe
47、 useful if it can be commenced within 2 hours of ingestion Longer duration of hemoperfusion ? Possible complications of hemoperfusion: thrombocytopenia, hypocalcemia, hypotension, hypoglycemia, hypothermia,Treatment,巴拉刈除草劑中毒,N-acetylcysteine may be effective (limited evidence) Cyclophosphomide + cor
48、ticosteroid: (1). 68% (41/61) mortality rate in untreated group vs. 28% (20/72) in treatment group (Addo the data lost statistical significance when reanalyzed on an intention to treat basis (Buckley 2001),Treatment,巴拉刈除草劑中毒,(3). No difference in survival between groups (Perriens 1992) Possible comp
49、lications of therapy: septicemia, alopecia, acne, infertility in female patientsVitamin C, vitamin E, sodium thiosulfate, colchicine, superoxide dismutase, radiotherapy.: lack of supporting clinical evidenceNO inhalation maybe helpful (Koppel 1994)Hemodialysis if acute renal failure develops Lung transplantation： occasional survival,Treatment,巴拉刈除草劑中毒,
