PATIENTS AND METHODS

Nine children poisoned with amitraz were admitted to Cukurova University Medical Faculty, Department of Pediatric Emergency Medicine between 1995 and 2002. The proprietary name of the ingested veterinary formulation, which contains 12.5% amitraz, is Kenaz, and all parents brought with them Kenaz bottles. We made the diagnosis according to a compatible exposure history and clinical findings. We reviewed their medical charts and detailed demographic data, intoxication route, ingested dose, onset and duration of effects, clinical and laboratory presentations, management, and outcome.

The major clinical signs were as follows: hypothermia (central body temperature <36°C), hypotension (2 standard deviations below the age appropriate mean²²), bradycardia, tachycardia, tachypnoea, bradypnoea below or above the appropriate average values,²³ miosis (pupils <2.5 mm²⁴), mydriasis (pupils >4 mm²⁴), hyperglycaemia (serum glucose >6.66 mmol/l (>120 mg/dl)), increased transaminase levels (serum transaminase level >50 IU/l (reference range 15–40 IU/l)), polyuria (urinary output >3 ml/kg/h).

We searched Medline, EMBASE, and SCI-Expanded (Web of science v4.3.1) up to July 2002 using the terms: amitraz AND (poisoning OR intoxication OR toxicosis). We concentrated on human amitraz poisoning articles (which were fewer than those regarding animals). We also looked for further cases by contacting the producer of Kenaz (Atabay Agricultural Chemicals and Veterinary Medicines Inc., Turkey) and the National Poisons Control Center. We checked the reference lists of all the studies and medical texts related to amitraz poisoning for additional case reports, and studied the abstracts of scientific meetings, but have not used them in our analysis.

RESULTS

Five boys and four girls aged 10 months to 8 years were admitted to our department. Table 1 shows the demographic, clinical, and laboratory data. Eight poisonings were accidental and one a suicide attempt. Intoxication occurred orally in all. The 10 month old baby boy was given one dose (5 ml) of amitraz solution mistakenly by his mother who confused it with the expectorant syrup in a similar bottle.

The estimated ingested dose ranged from 89.2 to 163 mg/kg in four of the cases and was unknown for the other five cases. Estimated time between ingestion and presentation was 30–120 minutes.

The paediatric Glasgow coma scores (GCS) of the cases were 7–14 (median 9). The predominant initial symptom in all was impaired consciousness. Eight patients presented with drowsiness, seven vomiting, and six were disorientated.

In the initial clinical evaluation six cases presented with miosis, two with mydriasis, and one with normal size pupils. Hypotension was present in four cases. There was bradycardia in four cases and tachypnoea in four. Three had a decreased body temperature (below 36°C). Short generalised seizures were observed in three cases; they responded to diazepam treatment.

Blood glucose was higher than 6.66 mmol/l (120 mg/dl) in six cases who also had glycosuria. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels increased minimally in three cases but all recovered to normal within two days. Urinary output was increased (>3 ml/kg/h) in four cases. Blood urea nitrogen, creatinine, serum sodium and potassium concentrations, and ECG were normal in all cases. None required mechanical ventilation support.

All cases received gastric lavage and activated charcoal. Six patients with hypotension received intravenous fluid repletion, with four improving and two requiring dopamine infusion for four hours. Atropine was used in cases V, VI, and VII, who had both bradycardia and hypotension. Cases VI and VII responded to the medication but case V required dopamine (5 μg/kg/min) as a second line therapy and recovered in two hours.

During hospitalisation one child developed fever (38.5°C). CNS depression resolved spontaneously within 4–28 hours (median 12 hours) in all patients. The length of hospital stay was two to three days. All the patients had good outcomes with no long term morbidity.

DISCUSSION

Amitraz is a pharmaceutical, veterinary, and agricultural product which is sold and used worldwide under numerous generic names.¹¹ It can cause poisoning in animals and humans when ingested, inhaled, or after skin exposure.^1,10 The minimal toxic dose previously reported was 3.57 mg/kg.² There have been two deaths reported in humans. One ingested 6 g amitraz; the dose in the other was not known.^25,26 Studies in animals showed the oral LD₅₀ as 523–800 mg/kg in rats and >1600 mg/kg in mice.²⁷ The dermal LD₅₀ was <1600 mg/kg for rats and >200 mg/kg for rabbits.²⁷

Table 2 describes the symptoms and the mechanisms of amitraz poisoning. Except for those reported by Kalyoncu and colleagues,²⁸ previous authors^{2,3,8,11,19–21} reported the onset and the duration of action for oral poisoning as 30–180 minutes, compatible with our results (table 1). However, Kalyoncu and colleagues²⁸ reported that it was 5 minutes to 6 hours, and that onset and the duration of action for dermal exposure was 5 minutes to 24 hours. Although the levels of BUN, creatinine, and serum sodium and potassium usually do not change,¹⁰ Kalyoncu and colleagues²⁸ reported hyponatraemia in three cases. Rarely there is a minimal increase in the level of serum ALT and AST.^8,10,13 No abnormality has been reported in the blood gasses except for the study by Kalyoncu and colleagues.²⁸ They reported respiratory alkalosis in two cases, respiratory acidosis in three cases, and metabolic acidosis in five cases. In the study by Aydin and colleagues,⁸ non-specific ST changes were reported in the ECGs of seven children with no history of cardiac disease who recovered completely in 24 hours. We did not observe any changes in ECG in our cases.

Seventeen of 137 cases (12.4%) suffered severe respiratory depression requiring mechanical ventilation for less than 24 hours.^1,3,8,10,13 The resolution time for CNS depression was reported to be 2–48 hours in the previous reports.^{2,3,8,19–21} Except for the two fatal cases, all, including our patients, were discharged uneventfully in less than a week.

Some other poisoning types can present with similar symptoms and signs which might lead to diagnostic confusion. These are caused by opioids, organophosphates, and centrally acting α₂ adrenergic agonist drugs, particularly clonidine. Sedative hypnotics such as barbiturates, benzodiazepines, phenothiazines, and tricyclic antidepressants may sometimes display similar signs and symptoms. Therefore, physicians should inform their diagnosis by combining the information obtained from the patients/parents/babysitter about the exposure history, observing the specific symptoms of poisoning and using the toxicological screening and more specific measurements.

As there is not a specific antidote for amitraz poisoning, management should be supportive and symptomatic. Particular attention must be given to monitoring and evaluation 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.¹³ The clinical presentations of our cases were relatively mild and did not require intubation or mechanical ventilation. Supportive measures include oxygen, supporting the blood pressure, and perfusion by administering fluids and/or vasopressors.¹ Inotropic agents (dopamine or noradrenaline) should be added as a second line therapy, but dopamine might potentiate MAO inhibiting drugs, so dosage should be as low as possible.^1,3,11,13

If present, seizures should be controlled by administering lorazepam or diazepam.^1,3,9 We do not recommend gastric lavage, unless the dose is massive, because of the presence of petroleum distillate in amitraz formulations. It should be performed after endotracheal intubation in order to avoid inhalation or aspiration pneumonitis, which should be checked by baseline chest x ray and follow up films in 6–24 hours.^1,9 Although the effects of activated charcoal and cathartics have not been studied, they may still be considered for treatment.¹

Using atropine is controversial.^{2,3,8,10,12,28} However, most studies reported that using atropine for those with both miosis and bradycardia resolved the problem.^3,8,19–21 Atropine is a first line therapy for the bradycardia that occurs from vagal stimulation and atrioventricular blocks, but not for that related to other mechanisms.²⁹ According to some animal studies α₂ adrenergic drugs cause bradycardia by stimulating the dorsal motor nucleus of the vagal nerve.^30–32 Hsu and colleagues³³ claimed that atropine (0.045 mg/kg intravenously) increased heart rate and prevented amitraz induced bradycardia in animals. Cullen and Reynoldson³⁴ showed that pressor responses to amitraz were slightly enhanced by atropine while bradycardia was reduced by it. In our study we used atropine on three of our patients who had bradycardia, hypotension, and miosis together and two of them recovered. The third case, a 10 month old baby, was given three doses of atropine which did not eliminate bradycardia; dopamine (5 μg/kg/min) had to be added to the therapy. We conclude that using atropine is effective when there is only symptomatic bradycardia in amitraz poisoning. However, asymptomatic bradycardia or miosis does not require atropine use.

To date there has been no specific antidote reported for amitraz poisoning in humans; several α₂ adrenergic receptor antagonists have been tried without success. However, in some experiments on animals α₂ adrenergic antagonists such as yohimbine and atimepazole have been effective in reversing most of the clinical and laboratory signs of amitraz poisoning.^35,36 These two agents might be considered for humans only in severe cases not responding to the usual measures.¹¹

Clonidine is a central α₂ adrenoceptor agonist which induces similar poisoning effects to amitraz.^2,8 Naloxone has been used successfully in clonidine overdose.³⁷ Two animal studies have looked specifically for the effects of naloxone on respiratory and CNS depression, but it did not prove to be successful.^38,39 Further investigation is needed to clarify its effectiveness.

A total of 84.6% of amitraz poisoning cases have been reported to occur accidentally and mainly among children. This emphasises the importance of taking serious precautions against this drug. We believe that action by producers, regulatory authorities, and national poisons control centres can minimise amitraz poisoning. For example: containers could be redesigned as childproof packages with striking and clear warning labels; 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.⁴⁰