Quick Response Code: Systematic Review Indian J Med Res 144, September 2016, pp 348-358 DOI: 10.4103/0971-5916.198723 Amitraz, an underrecognized poison: A systematic review Sahajal Dhooria & Ritesh Agarwal Department of Pulmonary Medicine, Postgraduate Institute of Medical Education & Research, Chandigarh, India Received June 30, 2014 Background & objectives: Amitraz is a member of formamidine family of pesticides. Poisoning from amitraz is underrecognized even in areas where it is widely available. It is frequently misdiagnosed as organophosphate poisoning. This systematic review provides information on the epidemiology, toxicokinetics, mechanisms of toxicity, clinical features, diagnosis and management of amitraz poisoning. Methods: Medline and Embase databases were searched systematically (since inception to January 2014) for case reports, case series and original articles using the following search terms: ‘amitraz’, ‘poisoning’, ‘toxicity’, ‘intoxication’ and ‘overdose’. Articles published in a language other than English, abstracts and those not providing sufficient clinical information were excluded. Results: The original search yielded 239 articles, of which 52 articles described human cases. After following the inclusion and exclusion criteria, 32 studies describing 310 cases (151 females, 175 children) of human poisoning with amitraz were included in this systematic review. The most commonly reported clinical features of amitraz poisoning were altered sensorium, miosis, hyperglycaemia, bradycardia, vomiting, respiratory failure, hypotension and hypothermia. Amitraz poisoning carried a good prognosis with only six reported deaths (case fatality rate, 1.9%). Nearly 20 and 11.9 per cent of the patients required mechanical ventilation and inotropic support, respectively. The role of decontamination methods, namely, gastric lavage and activated charcoal was unclear. Interpretation & conclusions: Our review shows that amitraz is an important agent for accidental or suicidal poisoning in both adults and children. It has a good prognosis with supportive management. Key words Amitraz - intoxication - morbidity - overdose - pesticide - poisoning - toxicity Amitraz, chemically 1,5 di-(2,4-dimethylphenyl)- used as a solvent in most of the preparations4. Other 3-methyl-1,3,5-triazapenta-1,4-diene is a member of solvents include tetrachloroethylene and mixtures of the formamidine family of pesticides1. It is used as a petroleum products containing predominantly aromatic veterinary ectoparasiticide (acaricide) for dogs and hydrocarbons5. The United States Environmental livestock, and as an agricultural insecticide for fruit Protection Agency (US EPA) classifies oral amitraz crops2. It has been available for use since 19743, and exposure as ‘Class III- slightly toxic’ and a group C is marketed under various trade names. It is supplied ‘possible’ human carcinogen6. The first human case as a 12.5-50 per cent aqueous solution to be diluted of poisoning was reported in 19837 though amitraz in water in 1:100-1:1000 ratio before use. Xylene is is widely available in many regions worldwide. 348 DHOORIA & AGARWAL: AMITRAZ POISONING 349 This incongruity is probably attributable to under- of poison consumed; (vi) time of onset of symptoms; reporting of amitraz intoxication in remote rural (vii) clinical symptoms and signs reported; (viii) life areas, as awareness about amitraz, its toxicity and support (mechanical ventilation and inotropic support) its management remains poor among physicians5. In and specific treatment (including gastric lavage, addition, it is often misdiagnosed as organophosphate/ activated charcoal, atropine and others) offered carbamate (OPC) poisoning5,8. A sizeable number of to patients; (ix) time to recovery of sensorium, cases of human intoxication with amitraz have been extubation/weaning and discharge from intensive care reported over the past three decades. There have been unit (ICU) or hospital; and (x) death, if any. several reports from India in the past five years9-11. Yilmaz and Yildizdas had reviewed 137 cases of Results 12 amitraz poisoning in 2003 . Proudfoot published a The initial search retrieved a total of 239 articles 13 narrative review on amitraz poisoning in 2003 .Veale after excluding citations common to the two databases. 5 et al presented the worldwide demographic data of Fifty two articles describing human cases were found. amitraz poisoning in 2011, but they did not elaborate Twenty articles were excluded due to the following on the details of clinical features and management. This reasons: (i) four were abstracts14-17; (ii) four had systematic review on amitraz intoxication describes insufficient clinical details of cases18-21; (iii) one the demographics, toxicokinetics, mechanisms of report described cases, the details of whom were toxicity, clinical features and treatment modalities used included in a later paper with a larger sample size22,23; in amitraz poisoning. and (iv) 11 articles (33 patients) were published in a Material & Methods language other than English. The search thus yielded 32 studies reporting 310 cases of amitraz poisoning Search strategy: Medline and EmBase databases (since (Table I)1,3-5,7-12,23-44. Three cases from the series inception to January 23, 2014) were searched using described by Bonsall and Turnbull7 were excluded due the following search terms: ‘amitraz’, ‘poisoning’, to lack of clinical data. ‘toxicity’, ‘intoxication’, and ‘overdose’. Citations describing human cases of amitraz poisoning including Epidemiology: There was no gender predilection case reports, case series and original articles were (51.3% males and 48.7% females) among the cases. included. The cross references of these articles were A majority (56.5%) of the patients were children. The searched for more relevant articles. Articles published predominant route of exposure to the poison was by in a language other than English, those presented only ingestion (91.9%) followed by the percutaneous route as an abstract and those not providing sufficient clinical (7.4%). One patient had exposure by inhalation, while information, were excluded. another patient presented with intravenous injection of the toxin27,36. The manner of poisoning was accidental Initial review of studies: The initial database generated (56.5%) in the majority while 30 per cent of the patients from the electronic searches was compiled in the presented with suicidal ingestion. Sixteen patients had reference manager package Endnote (version X7; intentional percutaneous exposure as in some regions Thomson Reuters, New York, USA), and all duplicate in Turkey, amitraz had been used to treat scabies and citations were eliminated. The citations were first pediculosis in humans38. The manner of intoxication screened by both the authors and disagreement was was unknown or not reported in 8.4 per cent of the resolved by discussion. This database was then patients. One homicidal poisoning was also reported35. screened again to include only relevant articles. The No peculiarities of this poisoning were found in the full text of each selected citation was obtained and subgroups of females and children. reviewed in detail. Toxicokinetics: Majority of studies included (22/32, Data abstraction: Data were recorded on a standard 68.8%) reported an onset of symptoms within three data extraction form. The following items were hours (Table I). The duration of action is short as extracted: (i) publication details (title, authors and the elimination half-life in serum is only four hours, year of publication); (ii) country where the study the major terminal metabolite being 3-methyl-4- was conducted; (iii) number of females and children aminobenzoic acid, which is excreted by the kidneys1,7. (≤13 yr of age) reported in the study; (iv) route (oral, Appearance of symptoms was earlier, and the recovery dermal or other) and manner (accidental, suicidal, and was delayed with oral ingestion as compared to therapeutic misadventure) of poisoning; (v) amount percutaneous exposure38. 350 Table I. Details of studies included in this systematic review of amitraz poisoning Author Year Country No. of No. of Children Age Number in whom Amount Onset of symptoms individuals females the amount of poison has been mentioned Bonsall and 1983 NR 1* 0 0 74 yr 1 6 g 1 h Turnbull7 Jones4 1990 USA 1 0 1 3 yr 1 2 g NR Kennel et al39 1996 France 4 1 1 15 months - 82 yr 1 12.5 g NR Jorens et al1 1997 Belgium 1 0 0 45 yr 1 250 mg 1 h Leung et al40 1999 PR China 1 0 0 33 yr 1 4 g <1 h Yaramis et al44 2000 Turkey 11 4 11 2.5-6 yr 0 NA 30-90 min Ulukaya et al43 2001 Turkey 10 5 5 4-34 yr 2 6.3 g <1 h - several hours INDIAN JMEDRES, Atabek et al26 2002 Turkey 14 6 14 2-5 yr 0 NA 30-150 min Aydin et al23 2002 Turkey 24 8 24 2-6 yr 0 NR 30-120 min Doganay et al33 2002 Turkey 2 0 0 35-80 yr 2 1.8-12.5 g <3 h Ertekin et al35 2002 Turkey 21 8 21 5 months - 9 yr 0 NR 30-180 min Kalyoncu et al38 2002 Turkey 43 19 43 10 months - 13 yr 0 NA 5 min-24 h Caksen et al30 2003 Turkey 8 3 8 1-4 yr 8 1.3-1.9 g 1-4 h SEPTEMBER SEPTEMBER Yilmaz and 2003 Turkey 9 4 9 10 months - 8 yr 4 89-169 mg/ 30-120 min Yildizdas12 kg Agin et al24 2004 Turkey 7 2 7 2-6 yr 2 3.1-3.8 g 30-150 min Aslan et al25 2005 Turkey 1 1 0 36 yr 0 NA <3 h 2016 Elinav et al8 2005 Israel 1 0 0 54 yr 1 3.8 g 30 min Gursoy et al36 2005 Turkey 1 1 0 22 yr 1 0.8 g 1-2 min Avsarogullari et al27 2006 Turkey 23 14 0 16-78 yr 13 1.9-12.5 g 30-120 min Beyaztas et al29 2006 Turkey 1 0 0 46 yr 1 12.5 g 120 min Demirel et al32 2006 Turkey 45 35 1 4-97 yr 45 0.6-12.5 g <1 h in 28, >1 h in 17 Vucinic et al3 2007 Serbia 1 0 0 72 yr 1 10 g 30 min Hu et al37 2010 Taiwan 1 1 0 53 yr 1 100 g <1 h Shitole et al9 2010 India 3 3 1 2-40 yr 3 3.8 g 90-150 min Chakraborty et al31 2011 India 1 0 0 18 yr 1 6.3 g 150 min Eizadi-Mood et al34 2011 Iran 1 1 0 22 yr 1 40 g <1 h Contd.