Amitraz, an underrecognized poison: A systematic review

Amitraz, chemically 1,5 di-(2,4-dimethylphenyl)-3-methyl-1,3,5-triazapenta-1,4-diene is a member of the formamidine family of pesticides1. It is used as a veterinary ectoparasiticide (acaricide) for dogs and livestock, and as an agricultural insecticide for fruit crops2. It has been available for use since 19743, and is marketed under various trade names. It is supplied as a 12.5-50 per cent aqueous solution to be diluted in water in 1:100-1:1000 ratio before use. Xylene is used as a solvent in most of the preparations4. Other solvents include tetrachloroethylene and mixtures of petroleum products containing predominantly aromatic hydrocarbons5. The United States Environmental Protection Agency (US EPA) classifies oral amitraz exposure as ‘Class III- slightly toxic’ and a group C ‘possible’ human carcinogen6. The first human case of poisoning was reported in 19837 though amitraz is widely available in many regions worldwide. This incongruity is probably attributable to under-reporting of amitraz intoxication in remote rural areas, as awareness about amitraz, its toxicity and its management remains poor among physicians5. In addition, it is often misdiagnosed as organophosphate/carbamate (OPC) poisoning58. A sizeable number of cases of human intoxication with amitraz have been reported over the past three decades. There have been several reports from India in the past five years91011. Yilmaz and Yildizdas had reviewed 137 cases of amitraz poisoning in 200312. Proudfoot published a narrative review on amitraz poisoning in 200313. Veale et al5 presented the worldwide demographic data of amitraz poisoning in 2011, but they did not elaborate on the details of clinical features and management. This systematic review on amitraz intoxication describes the demographics, toxicokinetics, mechanisms of toxicity, clinical features and treatment modalities used in amitraz poisoning.

Material & Methods

Search strategy: Medline and EmBase databases (since inception to January 23, 2014) were searched using the following search terms: ‘amitraz’, ‘poisoning’, ‘toxicity’, ‘intoxication’, and ‘overdose’. Citations describing human cases of amitraz poisoning including case reports, case series and original articles were included. The cross references of these articles were searched for more relevant articles. Articles published in a language other than English, those presented only as an abstract and those not providing sufficient clinical information, were excluded.

Initial review of studies: The initial database generated from the electronic searches was compiled in the reference manager package Endnote (version X7; Thomson Reuters, New York, USA), and all duplicate citations were eliminated. The citations were first screened by both the authors and disagreement was resolved by discussion. This database was then screened again to include only relevant articles. The full text of each selected citation was obtained and reviewed in detail.

Data abstraction: Data were recorded on a standard data extraction form. The following items were extracted: (i) publication details (title, authors and year of publication); (ii) country where the study was conducted; (iii) number of females and children (≤13 yr of age) reported in the study; (iv) route (oral, dermal or other) and manner (accidental, suicidal, and therapeutic misadventure) of poisoning; (v) amount of poison consumed; (vi) time of onset of symptoms; (vii) clinical symptoms and signs reported; (viii) life support (mechanical ventilation and inotropic support) and specific treatment (including gastric lavage, activated charcoal, atropine and others) offered to patients; (ix) time to recovery of sensorium, extubation/weaning and discharge from intensive care unit (ICU) or hospital; and (x) death, if any.

Results

The initial search retrieved a total of 239 articles after excluding citations common to the two databases. Fifty two articles describing human cases were found. Twenty articles were excluded due to the following reasons: (i) four were abstracts14151617; (ii) four had insufficient clinical details of cases18192021; (iii) one report described cases, the details of whom were included in a later paper with a larger sample size2223; and (iv) 11 articles (33 patients) were published in a language other than English. The search thus yielded 32 studies reporting 310 cases of amitraz poisoning (Table I)134578910111223242526272829303132333435363738394041424344. Three cases from the series described by Bonsall and Turnbull7 were excluded due to lack of clinical data.

Table I Details of studies included in this systematic review of amitraz poisoning

Epidemiology: There was no gender predilection (51.3% males and 48.7% females) among the cases. A majority (56.5%) of the patients were children. The predominant route of exposure to the poison was by ingestion (91.9%) followed by the percutaneous route (7.4%). One patient had exposure by inhalation, while another patient presented with intravenous injection of the toxin2736. The manner of poisoning was accidental (56.5%) in the majority while 30 per cent of the patients presented with suicidal ingestion. Sixteen patients had intentional percutaneous exposure as in some regions in Turkey, amitraz had been used to treat scabies and pediculosis in humans38. The manner of intoxication was unknown or not reported in 8.4 per cent of the patients. One homicidal poisoning was also reported35. No peculiarities of this poisoning were found in the subgroups of females and children.

Toxicokinetics: Majority of studies included (22/32, 68.8%) reported an onset of symptoms within three hours (Table I). The duration of action is short as the elimination half-life in serum is only four hours, the major terminal metabolite being 3-methyl-4-aminobenzoic acid, which is excreted by the kidneys17. Appearance of symptoms was earlier, and the recovery was delayed with oral ingestion as compared to percutaneous exposure38.

Dose-response relationship: The amount of poison consumed was reported in 99 (31.9%) cases (Table I). It ranged from 63 mg to 100 g. A dose of more than 12 g was reported in ten studies. The proposed lethal dose of the toxin is 200 mg/kg3545. Accordingly, with an average adult weight of 60 kg, a dose of 12 g is supposedly lethal. Of those ten studies with an intake of more than 12 g amitraz, death was reported in only two patients. The only death for which the information on the exact dose and clinical course was available and the death was attributable to the poisoning itself was the patient reported by Hu et al37. This patient was a 53 yr old female who had consumed 100 g of the poison and developed refractory torsades de pointes. The amitraz level in the serum of this patient was 0.78 mg/ml, while that of BTS-27271, a metabolite of amitraz was 0.49 mg/ml.

Clinical features: The clinical characteristics of the cases reported in the included studies are shown in Table II. The toxic effects of this compound on various organ systems of the human body are summarized below.

Table II Frequencies of various clinical features described in amitraz poisoning

Effects on the nervous system: Central nervous system (CNS) depression was the most common neurological abnormality in this poisoning. It occurs in the form of sleepiness, drowsiness, or complete loss of consciousness depending on the dose of the toxin consumed43. There was a positive correlation observed between the amount of amitraz taken and duration of CNS depression32. It is noteworthy that nearly all patients regain consciousness by 48 h (Table III). This is possibly due to the short elimination half-life of the toxin. If altered sensorium persists beyond this duration, alternative causes should be looked for. Cerebral oedema was documented by brain imaging in two studies925. Seizures occurred in <33 per cent of the patients (Table II). Amitraz exposure causes constriction of pupils at lower doses (in about 50% of the patients), but may cause dilation at higher doses due to different mechanisms of action (Table IV)4121321262732353638434647484950515253. Both miosis and mydriasis can occur in the same patient at different times. Rarely reported neurological defects include ataxia, hallucinations, and hypotonia384142.

Table III Various treatment modalities and outcomes reported for amitraz poisoning

Table IV Systemic effects of amitraz and their underlying mechanisms

Effects on the cardiovascular system: Bradycardia was the most common cardiovascular manifestation observed in >33 per cent of the patients. Hypotension occurred in a smaller proportion (<33%) of cases (Table II). Cardiovascular manifestations occur mainly due to the stimulation of presynaptic α₂-adrenergic receptors (Table IV)12464849. Hypertension was reported in one study32. Arrhythmias including atrial fibrillation and ventricular arrhythmias occurred, which responded to standard treatment333. Fatal torsades de pointes was reported in one case37.

Effects on the respiratory system: Respiratory depression occurred in >33 per cent of the cases (Table II). It occurred in the form of bradypnoea, respiratory acidosis, or respiratory arrest due to direct effect of the poison. Aspiration pneumonia was reported in a small proportion of patients.

Effects on the gastrointestinal system and liver: Vomiting was reported in >33 per cent of the patients. Asymptomatic rise in liver transaminases may occur usually with a normal bilirubin. Rarely reported features include dry mouth, decreased intestinal motility, and abdominal distension5222635. A case of Ogilvie's syndrome (acute colonic pseudo-obstruction) was also reported25 (Table II).

Effects on metabolism and homeostasis: Hyperglycaemia is a distinctive feature of this poisoning observed in almost half of the patients. Glycosuria was documented in a small proportion of the patients (Table II). Hypoglycaemia has been rarely reported3238. Hypothermia was relatively common, while fever was rarely seen3243. Polyuria may occur due to multiple mechanisms (Table IV).

About 33 per cent of the patients of amitraz poisoning developed respiratory depression (Table II) and 20 per cent of the patients required mechanical ventilation, although most of them were weaned off by 48 h (Table III). The case fatality rate was low (1.9%) with only six deaths reported among 310 cases (Table III). Only one of the six deaths could be directly attributed to the effects of the poison (Table V)37. One patient died 30 days after discharge possibly due to unrelated causes7. Two other deaths occurred due to pulmonary thromboembolism and ventilator-associated pneumonia on the third and fourth days of hospital admission, respectively; and thus, they were not attributable directly to the effects of the poison2742. The causes of two of the deaths were not available5.

Table V Characteristics of patients who expired after amitraz poisoning

Discussion

The results of this systematic review suggest that amitraz poisoning is a widely reported intoxication. It has multitudinous clinical manifestations and generally carries a good prognosis.

A large proportion of cases of amitraz poisoning has been reported from Turkey (15 articles, 220 cases). In the last five years, six reports on amitraz poisoning have been published from India91011283142. A large number of cases (69 patients) have been reported from South Africa5. A large survey of all acute poisonings in South Africa reported that around one per cent of the 4771 consultations sought from a poison information centre were concerning amitraz18.

Toxic exposure in humans may occur by ingestion, inhalation or skin contact. Absorption from the gut occurs at a high rate, as shown in animal studies5455. Amitraz concentrations are measurable in the plasma within two hours of ingestion121. Amitraz is metabolized rapidly in vivo to produce two primary metabolites: 2,4-dimethyl formanilide (BTS-27919) and an active metabolite N’-(2,4-dimethylphenyl)-N-methyl-formamidine (BTS27271), resulting in a rapid onset of symptoms6737. BTS-27271 acts through the octopamine receptors in invertebrates, which are responsible for its acaricidal and insecticidal activities. In vertebrates, it acts mainly on the α₂-adrenergic receptor which is structurally similar to the octopamine receptor4. It acts as an agonist on both pre- and post-synaptic α₂-adrenergic receptors4356. Presynaptic receptor stimulation inhibits norepinephrine discharge, while stimulation of postsynaptic receptors leads to effects similar to α₁-stimulation2643. It also acts as a monoamine synthesis inhibitor and an inhibitor of prostaglandin E2; however, the role of these actions in poisoning is unclear. Table IV shows the proposed mechanisms underlying the systemic effects of this toxin.

Amitraz has been classified as a ‘possible’ human carcinogen by the US EPA based on the studies on mice which have shown an increase in the risk of lymphoreticular malignancies and liver adenoma/carcinoma6. However, there are no reports of increased cancer risk in humans. Amitraz has been found to be teratogenic in frogs57, but there is a lack of human data. Among human cases, a pregnant woman who consumed amitraz at 18 wk of pregnancy subsequently made a complete recovery with treatment and gave birth to a healthy neonate at term58.

In a report from a poison information centre, the clinicians were unfamiliar with amitraz in 89 per cent of the instances18. Physicians should always insist on recovering the poison container and discerning the active compound in the preparation. Altered sensorium, miosis and bradycardia are three most common features of this poisoning. These features often mislead physicians into diagnosing the patient with OPC poisoning. Certain features point towards amitraz poisoning as opposed to OPC toxicity. These include presence of hyperglycaemia, hypothermia, and reduced gastrointestinal motility. Further, the absence of fasciculations and a hypersecretory state (salivation, lacrimation, perspiration, and diarrhoea) points against OPC poisoning. Smell of a solvent or a ‘mothball-like’ odour may be noticed on presentation in amitraz poisoning, while a garlic-like smell is encountered with OPC poisoning33859. Besides, serum cholinesterase levels remain normal in amitraz poisoning, while these are low in OPC poisoning52842. Gas chromatography-mass spectrometry and gas liquid chromatography have been used to detect the presence and measure the levels of amitraz and its metabolites in the serum and urine1337.

There is no specific antidote for amitraz poisoning. Management is supportive. Monitoring of respiratory, cardiovascular and CNS functions is essential12. In case of skin exposure, the contaminated clothing should be removed and the skin should be washed with soap and water. Endotracheal intubation should be done early in unconscious patients to avoid the risk of aspiration. Intravenous fluids and vasopressors/inotropes must be administered in hypotensive patients. There are no randomized controlled trials performed to date to clarify the true clinical benefit of gastric lavage and activated charcoal. In the studies included in this review, gastric lavage was performed in only 47.1 per cent of the patients (146/310) and activated charcoal was administered to only 37.4 per cent (116/310) of them (Table III). There are concerns that organic solvents present in the formulation may increase the risk of aspiration if gastric lavage is attempted13. Therefore, it should be performed only after endotracheal intubation, in cases of massive ingestion1221.

Activated charcoal is relatively safer; however the clinical benefit is again uncertain. Role of atropine is controversial. It has been shown to abrogate bradycardia in many of the patients, while in others dopamine was used for the treatment of bradycardia1122326. In this review, bradycardia was reported in 47.1 per cent of the patients, while only 36.5 per cent are reported to have received atropine (Table III). Yilmaz and Yildizdas12 suggest that atropine is effective only in patients with symptomatic bradycardia in amitraz poisoning and is not required for those with only asymptomatic bradycardia and/or miosis.

Although there is no antidote, animal studies have demonstrated that α₂-adrenergic antagonists such as yohimbine and atipamezole can reverse most of the clinical and laboratory signs of amitraz poisoning6061. These drugs, however, have not been used in human poisoning. Occasionally, patients receive pralidoxime for the mistaken diagnosis of OPC poisoning, which is however not recommended27. Naloxone used successfully for clonidine poisoning (α₂-adrenergic agonist) has proved to be ineffective in animal studies of amitraz poisoning6263.

Amitraz poisoning carries a good prognosis with a low case fatality rate. The most important factors affecting the clinical course and prognosis seem to be the dose and route of exposure to the poison. The possible reason for the low case fatality rate was that the compound was most commonly available in a 12.5 per cent solution. At this dilution, a large quantity needs to be consumed for a lethal effect.

There were a few limitations of this review. We did not have access to patient level data for all studies, therefore, certain factors such as the relationship of dose of poison consumed and the severity of the effects could not be analyzed for the entire patient population. As there are no randomized trials, no conclusions can be drawn on the ideal management strategy for this poisoning.

In conclusion, the present analysis shows that amitraz poisoning occurs in either accidental or suicidal manner and is more common in children than adults. Though majority of the cases have been reported from Turkey, there has been a recent rise in the number of cases reported from South Africa and India. There is no antidote for this toxin. It has an excellent prognosis with supportive management.