Amitraz Poisoning Management Essay

Amitraz, an insecticide/acaricide of the formamidine pesticide group, is a alpha 2 adrenergic agonist used to a great extent in veterinary and agricultural products for the treatment of ectoparasitic manifestations. In the current article we report the findings of a case of 22 year old female who consumed about 50 ml Amitraz poison by oral route as a suicidal attempt. On arrival to Emergency Department the patient presented in deep comatose state, respiratory depression, bradycardia, hypotension, miosis, hypothermia, and hyperglycemia.she recovered completely within 48 hours with adequate supportive care. Amitraz Poisoning Management Essay. The case report throws considerable light on the management of Amitraz poisoning, good prognosis with early recognition, initial stabilisation, reducing absorption, supportive management with Iv fluids, airway management, monitoring urine output and other supportive care, very few cases of intoxications in human beings due to the pesticide have been published in literature It has become imparative to intruct the pesticide manufacturers to initiate suitable measures to decrease the incidence of Amitraz poisoning by prominent and clear warning labels on the containers and potential hazards of the compound.

Key-words: Amitraz; poisoning ; alpha 2 adrenergic agonist; miosis

Key Messages [D1]: Introduction

Amitraz, a triazapentadiene compound and a member of the amidine chemical family is a formamidine pesticides which is increasingly being used as an insecticide and an acaricide to control animal ectoparasites [1-3]. The formulations available for chemical use contain 12.5-50% in an organic solvent called xylene, which itself is used in plant cleaners and glues[4].Amitraz is a Alpha 2 adrenergic agonist stimulating alpha 2 adrenergic receptors in the Central Nervous System(CNS).and both alpha 1 and alpha 2 adrenergic receptors in the periphery.Amitraz Poisoning Management Essay.  Poisoning occurs throgh oral, inhalational (the mostpotential), and dermal routes and is accompanied by numerous signs and symptoms varying from CNS depression (drowsiness, coma, and convulsion), to miosis, or rarely, mydriasis, respiratory depression, bradycardia, hypotension, hypothermia or fever, hyperglycemia, polyuria, vomiting, decreased gastrointestinal motility, and intestinal distension [4].Adverse effects and side effects have been reported in animals exposed to the product : however only few cases of human toxication have been published in Indian literature. we present a young female patient with Amitraz poisoning who was conservatively managed with complete recovery hence significantly contributing to the limited human toxicological data. Case History[D2]:

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An 22 year old female was brought to our Emergency Department (ED) with a history of suicidal consumption of about 50 ml Amitraz poison eight hours before being brought to our ED, her first symptom had begun about 30 minutes post ingesion and included nausea and vomiting, thus she was taken to a hospital in their locality where intravenous crystalloids were started and referred to our centre. On arrival to our department the patient was deeply comatose with a GCS scale of 4/15. Her pulse rate, respiratory rate, blood pressure and temperature were 50/min, blood pressure was 92/64 mm of Hg, 16/minand 36.8 degree celsius respectively. On examination of CNS her pupil were bilaterally constricted, all four limbs had hypotonia and there was bilateral flexor plantar response. Other systemic examination were normal, there was no exessive oral secretions or any fasciculations.Gastric lavage with activated charcoal was given and patients airway was secured with endotracheal intubation due to low GCS.she was then admitted to ICU for further management her lab tests (Complete blood count, serum electrolytes, renal function tests, liver function tests), serum pseudocholinestrase levels, electrocardiography, routine urine tests and chest xray were normal except glucose level of 192 mg/dl.A urine test for drugs of abuse was negative and blood alcohol levels were normal. Ct brain plain was done which was normal.She was treated with supportive care in the ICU with IV Flluids, respiratory and cardiac monitoring, Atropine (once 2mg stat) was adminitered for transient bradycardia.over the next 24 hours she gradually improved and was extubated. Her vitals signs were Heart rate of 70/min and blood pressure was 110/70 mm of Hg. By the following day she was completely concious and was able to answer the question and she was shifted to general ward and was discharged after consultation with a psychiatrist. Amitraz Poisoning Management Essay.

Discussion:

Amitraz is increasingly being used worldwide in veterinary and agricultural products for the treatment of ectoparasitic manifestations. Formamidines show reversible toxic effects on both animals and humans [1]. The present knowledge about Amitraz and Foramine pesticides is usually built on animal studies as the available human intoxication is limited. It can cause poisoning in animals and humans via oral, inhalational or dermal routes. The toxicity from this poisoning can be attributed both Amitraz and the solvent, xylene. Although the ingested dose of Amitraz can not be determined because it is diluted 1 part in 500 before usage. The acute oral medical lethal dose(LD50) for the rats is 800/kg body weight.[3, 4]. The clinical features of this poisoning reported in previous reports include CNS depression, drowsiness, vomiting, miosis, bradycardia, hypotension, and hyperglycemia. The duration of CNS depression has ranged from a few hours to 24 h [4]. CNS symptoms began within 120-180 minutes and resolved within 12-24 hrs in our case. Sedative effects of α2-agonists are dose dependent[1]. Coma, absence of light reflex, and respiratory failure are due to the ingestion of greater amounts of amitraz supporting its dose-dependent effects. Our patient was fully conscious after 48hrs. This time has been reported to be 2-48 h in previous reports.

The effect of amitraz on α1– and α2-receptors causes bradycardia [5]. In addition, literature reported hyperglycemia, hypotension, and bradycardia in amitraz poisoning and attributed them to the alpha-2 adrenoceptor agonist action of amitraz [6]. In our case, bradycardia was also present accompanying with miosis.

Co-existence of bradycardia, miosis, and the respiratory depression leads to confusion with organophosphate or opioid poisonings, both of which should be excluded. Using atropine for treatment of bradycardia is controversial.Amitraz Poisoning Management Essay.  Most studies, however, have reported atropine to resolve both miosis and bradycardia. Atropine is the first line therapy for the bradycardia resulted from vagal stimulation and atrioventricular blocks. Alpha-2 adrenergic drugs can also cause bradycardia by stimulating the dorsal motor nucleus of the vagus nerve. Studies have shown that atropine increases the heart rate and prevents Amitraz induced bradycardia in Animals(2). In our patient atropine was given once with the adult dose.

Amitraz and its active metabolites inhibits insulin and stimulate glucagon secretion, hyperglycemia was detected in our case as reported in previous studies by Demirel and colleagues[7]

Kalyoncu and colleagues have reported hyponatremia in their three cases[9], Usually BUN, creatinine, serum sodium and potassium do not change with this poisoning, in our case creatinine, serum potassium and sodium were normal. Kalyoncu and associates have reported respiratory alkalosis in two, respiratory acidosis in three and metabolic acidosis in five cases[9], in our patient the analysis of blood gases were normal. Avsarogullari et al reported hyperglycemia and fast deterioration of the patients with amitraz poisoning(within 5 minutes of ingestion of toxin)[8]

Whenever a patient presents with bradycardia and miosis, organophosphorus compound poisoning should be considered as a differential diagnosis a along with Amitraz. Other signs and symptoms of organophosphorus compound should be looked for and a cholinesterase level should be done. Amitraz levels in blood was not done because it was unavailable at our institute and other referral laboratories.

It is made clear that the basic approach to a patient with amitraz poisoning involves initial stabilisation, reducing absorption and increasing elimination of the toxin. there is no specific antidote[2] medical management involves supportive measures like gastric lavage, activated charcoal administration and securing the airway. Depending on the patients condition additional measures like oxygen supplementation or mechanical ventilation for respiratory depression, atropine for severe bradycardia, intravenous fluids and vasopressors for hypotension, diazepam or lorazepam for seizures.

This case report throws considerable light on the management of Amitraz poisoning, good prognosis with early recognition and timely supportive management as the available human toxicological data are limited. Amitraz Poisoning Management Essay. When appropriate timely supportive treatment is given, Amitraz intoxication in humans caries a low morbidity and mortality inspite of rapidly progressing and life threatening clinical picture. It has become imperative to instruct the pesticide manufacturers to initiate suitable measures to decrease the incidence of Amitraz poisoning by placing prominent and clear warning labels on containers.

References[D3]:

Queiroz-Neto A, Zamur GSC, Carregar O AB, 182 Motoqueiro MI, Harkins JD, Tobin T. Characterization of the 183 antinociceptive and sedative effect of amitraz in horses. J Vet 184 Pharmacol Ther 1998; 21:400-5. 1852.

Agin H, Calkavur S, Uzun H, Bak M. Amitraz poisoning: clinical and laboratory findings. Indian Pediatr 2004; 41:482-6.

Eizadi-Mood N, Sabzghabaee AM, Gheshlaghi F, Yaraghi A. Amitraz Poisoning Treatment: Still Supportive? Iran J Pharmaceut Res 2011; 10:155-8.

Shitole DG, Kulkarni RS, Sathe SS, Rahate PR. Amitraz poisoning-an unusual pesticide poisoning. J Assoc Physicians India 2010; 58:317-9.

Jorens PG, Zandijk E, Belmans L, Schepens PJ, Bossaert LL. An unusual poisoning with the unusual pesticide amitraz. Hum Exp Toxicol 1997; 16:600-1.

Jones RD. Xylene/amitraz: a pharmacologic review and profile. Vet Hum Toxicol 1990; 32:446-8.

Demirel Y, Yilmaz A, Gursoy S, Kaygusuz K, Mimaroglu C. Acute amitraz intoxication: retrospective analysis of 45 cases. Hum Exp Toxicol 2006; 25:613-7. Amitraz Poisoning Management Essay.

Avsarogullari L, Ikizceli I, Sungur M, Sözüer E, Akdur O, Yücei M. Acute amitraz poisoning in adults: clinical features, laboratory findings, and management. Clin Toxicol (Phila) 2006; 44:19-23.

Kalyoncu M, Dilber E, Okten A. Amitraz intoxication in children in the rural Black Sea region: analysis of forty-three patients. Hum Exp Toxicol2002; 21:269-72.

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Amitraz is a triazapentadiene, an α2 adrenergic agonist and a member of the amidine chemical family. A limited number of human intoxication cases have been published in the literature. Lack of a clear and specific protocol for the therapy of amitraz intoxication may make its successfully managed case reports useful and valuable for other clinical practitioners in poisoning departments. Amitraz Poisoning Management Essay.

The case is about a 22 years old female, single, university student, ingested a glass of amitraz poison (about 100 mL of a 20% solution) as a suicidal attempt on 11:30 am which was about 3.5 h before her hospital admission. She found nausea, vomiting, and dizziness. Immediately, her family took her to a clinic near their house. At that clinic (13:30 pm) she had miosis and they did gastric lavage , one adult dose of activated charcoal (50 g) and referred her to our Poisoning Emergency Department, where she was managed supportively and successfully.

Amitraz is a poisonous chemical which may cause central nervous system depression and also respiratory/cardiovascular symptoms as well. Several studies reported that using atropine for those amitraz poisoned patients with both miosis and bradycardia resolved the problem and recommend it as the first line of drug therapy when bradycardia occurs from vagal stimulation and atrioventricular block.

Management of amitraz poisoning is still considered to be supportive and symptomatic. Although the effects of activated charcoal and cathartics have not been studied, they may still be considered for treatment.

Key Words: Amitraz, Bradycardia, Miosis, Central nervous system, Isfahan
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Introduction
Amitraz is a triazapentadiene compound, a member of the amidine chemical family (1). It is a member of formammidine pesticides and is used worldwide (1). Amitraz Poisoning Management Essay. Amitraz is used as an insecticide/acaricide for controling the ectoparasites in animals (2). Commercial formulations of amitraz generally contain 12.5-20% of the drug in organic solvents, especially Xylene, which is also used as a solvent in paints, cleaners, and glues (3).

Adverse reaction and side effects have been reported in animals exposed to the product, but only a limited number of human intoxication cases have been published in the literature. Amitraz is an α2 adrenergic agonist (1-3). It stimulates α2 adrenergic receptor sites in the central nervous system (CNS) and α1 adrenergic and α2 adrenergic receptor sites in the periphery (4). It also inhibits monoamine oxidase (MAO) enzyme activity and prostaglandin E2 synthesis (1).

Amitraz poisoning may occur through the oral or dermal routes and potentially through inhaling (5). Poisoning is accompanied with numerous symptoms varying from central nervous system depression (drowsiness, coma, and convulsion), to miosis, or, rarely, mydriasis, respiratory depression, bradycardia, hypotension, hypertension, hypothermia or fever, hyperglycaemia, polyuria, vomiting, decreased gastrointestinal motility, and intestinal distension (1).

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Experimental
A 22-year-old female, single, university student, ingested a glass of amitraz poison (20% solution) as a suicidal attempt on 11:30 am her first symptoms appear within an hour. At first, she had nausea, felt dizzy and vomiting followed afterward. Her family immediately took her to a clinic nearby. At that clinic they did gastric lavage and referred her to our Poisoning Emergency Department, in Noor Hospital, Isfahan, Iran. While being transferred to the hospital by emergency services, she lost her consciousness, had respiratory depression with shallow respiration, been intubated and received atropine because of bradycardia. On arrival to our center, her symptoms were coma with no response to painful stimuli, midriasis with negative light reflex. The vital signs were: (Blood pressure: 140/90), (Pulse rate: 84), (respiratory rate: 12), and (Temperature: 36.8°C). The analysis of blood gas was: (PaO2: 96.3), (O2 Saturation: 94), (pH: 7.15), (PCO2: 68.4) and (HCO3-: 23.5). Because of her shallow respiration and her ABG analysis, she required the mechanical ventilation support with SIMV mode. Furthermore, she received 50 g activated charcoal. Then the result of her ABG turned to: pH (7.44), PCO2 (34.2) and HCO3 (22.7). The other lab tests were: Amitraz Poisoning Management Essay.

BUN (13), Creatinine (0.9), Na+ (133; norm = 135-145), K+ (4.6), SGOT (61), SGPT (33), ALK. Phosphatase (182), Blood glucose (95 mg/dL; norm = 70-110 mg/dL), PT (13), PTT (40) and CBC (WBC: 9400, HCT: 40). Chest X-Ray was normal. We consulted with the neurologist, and everything seemed normal.

The following day at 5:00 am, her consciousness improved and she was extubated. At 8:00 am she gained her consciousness back and was able to answer to the questions. And finally, she completely recovered and discharged from the hospital in the afternoon.

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Results and Discussion
Amitraz is a pharmaceutical, veterinary, and an agricultural product which is used worldwide. It can cause poisoning in animals and humans when ingested, inhaled, or after skin exposure (1).

Central nervous system depression was the predominant sign in our case, constant with the effect of amitraz on α2-adrenergic receptors. The observation of respiratory depression concomitant with central nervous system depression may suggest a direct inhibitory effect of the agent on the respiratory center (6). The sedative effects of α2-agonists are dose dependent (7). Presence of coma, absence of light reflex, and respiratory failure are probably due to the ingestion of a greater amount of amitraz, which supports its dose-dependent effects on body systems. Our patient got conscious after 20 h. The resolution time for CNS depression was reported to be 2-48 h in the previous reports (1-10).

The α1– and α2-agonistic action of amitraz leads to bradycardia (1). In our case, bradycardia was also present, and miosis accompanied it. The co-existence of bradycardia and miosis and the respiratory depression may lead to confusion with some poisoning such as organophosphate or opioid poisoning; and both that are diagnosed should be excluded(11). Amitraz Poisoning Management Essay. Observation of miosis early in the intoxication followed by progression to mydriasis suggests that the presynaptic effect is dominant in the early phase and the postsynaptic effect in the late phase of the intoxication.

In our study atropine was used before reaching hospital to treat bradycardia. Using atropine for treatment of bradycardia is controversial (1, 5, 8, 12). However, most studies reported that using atropine for those with both miosis and bradycardia resolved the problem (8-10). Atropine is a first line therapy for the bradycardia that results from vagal stimulation and atrioventricular blocks, but not for those related to other mechanisms (13). The α2 adrenergic drugs can cause bradycardia by stimulating the dorsal motor nucleus of the vagal nerve (14). Hsu and colleagues claimed that atropine increased heart rate and prevented amitraz induced bradycardia in animals (15). We conclude that using atropine is effective when there is only bradycardia in amitraz poisoning.

Although amitraz and its active metabolite inhibit insulin and stimulated glucagon secretion from the perfused rat pancreas in a concentration-dependent manner (16), we did not find hyperglycemia in our case.

Slight hyponatremia was observed in our case. The levels of BUN, creatinine, and the serum sodium and potassium usually do not change in amitraz poisoning (5). However kalyoncu and colleagues also reported hyponatraemia in their three cases (12). Rarely there is a minimal increase in the level of serum ALT and AST (5, 8).

The analysis of blood gas showed respiratory alkalosis. The kalyoncu and colleagues reported respiratory alkalosis in two cases, respiratory acidosis in three cases, and metabolic acidosis in five cases (12).

We did not observe any changes in her ECG. However in the study by Aydin and colleagues, non-specific ST changes were reported in the ECGs of seven children with no history of cardiac disease who recovered completely in 24 h (8).

In conclusion, there is no specific antidote for amitraz poisoning and the management should be supportive and symptomatic. Although the effects of activated charcoal and cathartics have not been studied, they may still be considered for treatment (1). Particular attention must be given to monitoring and evaluating of the respiratory, cardiac, and central nervous systems. Since the sedative effects of α2 agonists are dose dependent, increased intake may lead to severe effects on the body systems causing coma and respiratory failure. The clinical presentations of our case were relatively severe and required intubation and mechanical ventilation.Amitraz Poisoning Management Essay.  With the supportive management, the prognosis is good and the patients may be discharged healthy without any organ dysfunction.

We believe that the action by producers, the regulatory authorities, and the national poisons control centers can minimize the amitraz poisoning. For example: the containers should be designed as childproof packages with striking and clear warning labels; the public education should be expanded on primary prevention of poisoning using media sources; and there should be new legislation for safety caps on poison containers (17).

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Acknowledgment
We would like to acknowledge the “Isfahan Poison Control and Research Center” team for their sincere efforts and collaboration.

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References
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