AMITRAZ

Classification | Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

1) Amitraz is an inhibitor of monamine oxidase in the rat liver.
2) Prostaglandin synthesis inhibition has also been reported.

Specific Substances

1) 1,5 di(2,4-dimethylphenyl)-3-methyl-1,3,5-
2) trizapenta-1,4-diene
3) N,N-(methyliminodimethylidyne) bis-2,4-xylidine
4) N'-(2,4-Dimethylphenyl)-N-(2,4-dimethylphenyl)
5) iminomethyl-N-methylmethanimidamide
6) N,N' ((Methylimino)dimethylidyne) di-2,4-xylidine
7) 2-methyl-1,3-di(2,4-xylylimino)-2-azapropane
8) ENT 27,967
9) BTS 27419
10) U-36059
11) CAS 33089-61-1
12) BAAM
13) BTS 27419 METHYLMETHANIMIDAMIDE

Available Forms Sources

1) Amitraz is a formamidine pesticide. Commercial preparations are formulated as a 20% solution (approximate concentration) in 75% xylene (Turnbull, 1983).
2) This compound is also available in aromatic mixtures containing up to 2.5% of epichlorhydrin, or may be formulated in toluene (Grossman, 1993), xylene, propylene oxide, and a blend of alkyl benzene sulfonates and ethoxylated polyethers (Jones, 1990).
3) Amitraz solutions are generally diluted 100 to 600-fold before applying to trees or livestock.
4) Amitraz is also available as an emulsifiable concentrate or wetable powder.

1) Amitraz is a formamidine pesticide with veterinary uses as an acaricide and insectide. It is used to control cattle ticks, mites, and other insects (lepidopterous species), and to treat generalized demodectic mange (Demodex canis) in dogs (Jones, 1990).
2) It has been used on pear trees as a pesticide (Gosselin et al, 1984) Bonsall & Turnbull, 1983; IRIS, 1995).

Overview

Life Support

Clinical Effects

0.2.1)

A) USES: Amitraz is an insecticide used on crops and topically for treatment of parasitic infections of farm animals. It is effective against mites, fleas, and other insects.
B) TOXICOLOGY: Amitraz acts as a central alpha-2 adrenergic agonist causing CNS depression, hypotension, and bradycardia.
C) EPIDEMIOLOGY: Exposure to amitraz is rare in the United States, but more common in other countries. Severe toxicity is uncommon, but deaths have been reported.
D) WITH POISONING/EXPOSURE

1) MILD TO MODERATE TOXICITY: Most patients will have mild to moderate gastrointestinal symptoms and mild sedation. Miosis is common; mydriasis may also occur. Hypersalivation is also common.
2) SEVERE TOXICITY: Severe toxicity may include bradycardia, hypotension, sedation, seizures, respiratory depression, and coma. Hyperglycemia, acidosis (both respiratory and metabolic) and mild elevation of serum transaminase activity have also been reported. Aspiration pneumonitis may develop from the solvent vehicle (commonly xylene). There is a single report describing torsade de pointes.

0.2.20)

A) There were no adverse effects reported in a pregnant woman or her fetus following an amitraz ingestion.

Laboratory Monitoring

Treatment Overview

0.4.2)

A) MANAGEMENT OF MILD TO MODERATE TOXICITY

1) Administer IV fluids and institute continuous cardiac monitoring. Treat vomiting with antiemetics.

B) MANAGEMENT OF SEVERE TOXICITY

1) Bradycardia has responded to atropine; repeated doses may be required. Hypotension should be treated with fluids; adrenergic vasopressors (such as dopamine) may be required in severe cases. Respiratory and CNS depression may necessitate intubation and mechanical ventilation. Seizures should be treated with benzodiazepines.

C) DECONTAMINATION

1) PREHOSPITAL: Remove contaminated clothing and wash exposed skin with soap and water. Gastrointestinal decontamination is not recommended as patients often have vomiting and sedation, and the risk of aspiration outweighs potential benefits.
2) HOSPITAL: Gastrointestinal decontamination is generally not recommended as patients often have vomiting and sedation and the risk of aspiration outweighs potential benefits. Remove contaminated clothing and wash exposed skin with soap and water.

D) AIRWAY MANAGEMENT

1) Patients often develop CNS depression that requires active airway management and ventilation. Intubate patients early.

E) ANTIDOTE

1) There is no proven antidote; some advocate treatment with central adrenergic antagonists (eg, yohimbine and atipamezole) but there are no clear data demonstrating the safety or efficacy of these therapies.

F) ENHANCED ELIMINATION

1) Dialysis is not indicated.

G) PATIENT DISPOSITION

1) HOME CRITERIA: Asymptomatic adults with inadvertent taste ingestions and patients with dermal exposures who are asymptomatic can be managed at home.
2) OBSERVATION CRITERIA: Children with inadvertent ingestions or large dermal exposures, adults with more than taste ingestions, any patient with a deliberate ingestion, and any symptomatic patient should be referred to a healthcare facility and monitored for a minimum of 6 hours. Patient with mild or moderate symptoms should be monitored until symptoms resolve.
3) ADMISSION CRITERIA: Patients with symptomatic bradycardia or CNS depression should be admitted.
4) CONSULT CRITERIA: Consult a medical toxicologist for patients with symptomatic bradycardia or CNS depression.

H) PITFALLS

1) Amitraz poisoning is frequently misdiagnosed as poisoning with a cholinesterase inhibitor.

I) TOXICOKINETICS

1) Oral absorption is rapid, dermal absorption may occur. Patients generally become symptomatic within 150 minutes of ingestion or dermal exposure. One report describes a serum half-life of 4 hours following an overdose.

J) DIFFERENTIAL DIAGNOSIS

1) Xylene, clonidine, guanabenz poisoning, poisoning with grayanotoxin or solanine, cholinesterase inhibitor poisoning.

0.4.5)

A) OVERVIEW

1) Remove contaminated clothing and wash exposed skin with soap and water.

Range Of Toxicity

Clinical Effects

Summary Of Exposure

Vital Signs

3.3.2)

A) WITH POISONING/EXPOSURE

1) Respiratory depression has been reported in patients with amitraz poisoning. Mechanical ventilation may be required (Veale et al, 2011; Demirel et al, 2006; Avsarogullari et al, 2006; Atabek et al, 2002; Yilmaz & Yildizdas, 2003; Gursoy et al, 2005).

3.3.3)

A) WITH POISONING/EXPOSURE

1) Hypothermia was reported in 4 of 8 pediatric cases of amitraz poisoning (Aydin et al, 1997). In another pediatric case series, hypothermia was reported in 4 out 11 cases following ingestion of a liquid concentrate of amitraz (12.5%) (Kursal et al, 1997).
2) Hypothermia (less than 36 degrees C) was reported in 29 of 45 patients (64.4%) following ingestion of an amitraz formulation containing 12.5% amitraz and 57.5% xylene in water (Demirel et al, 2006).
3) According to a 2-year survey of human amitraz poisoning cases that occurred in South Africa from 2008 to 2009, hypothermia was reported in 15.9% of patients (n=69) (Veale et al, 2011).
4) CASE REPORT: Hypothermia was reported in a 4-month-old infant following oral administration of 0.3 mL of a 5% amitraz solution (2.5 mg/kg) (Zoelen et al, 2001).
5) ANIMAL STUDIES: Hypothermia has been reported in rats (Turnbull, 1983; Moser, 1991) and dogs (Jones, 1990; Hovda & McManus, 1993). The onset of hypothermia in rats was a few hours after exposure to the amitraz/xylene product, and 24 to 48 hours after amitraz alone (Turnbull, 1983).
6) LACK OF DATA: There is insufficient information concerning hyperthermia in humans. Three out of 9 dogs who had excessive dermal or oral exposure to amitraz developed hyperthermia (Hovda & McManus, 1993).

3.3.4)

A) WITH POISONING/EXPOSURE

1) HYPOTENSION has been reported in several cases of pediatric and adult poisoning with amitraz (Veale et al, 2011; Hu et al, 2010; Avsarogullari et al, 2006; Aydin et al, 1997).
2) HYPOTENSION has occurred in humans following ingestion and injection of amitraz/petroleum distillate mixtures (Demirel et al, 2006; Gursoy et al, 2005; Kennel et al, 1996).
3) CASE REPORT: HYPERTENSION (200/100 mmHg) was reported in a 74-year-old man who had diabetes, evidence of old myocardial infarct and cerebrovascular atherosclerosis (Bonsall & Turnbull, 1983). No baseline blood pressure readings were provided.
4) DOGS: Dose-related HYPERTENSION has been reported in anesthetized dogs following intravenous injection of amitraz (Cullen & Reynoldson, 1988).

3.3.5)

A) WITH POISONING/EXPOSURE

1) BRADYCARDIA occurred in 6 of 8 pediatric cases of accidental amitraz ingestion (Aydin et al, 1997). It has also been reported following ingestion and injection of amitraz/petroleum distillates (Demirel et al, 2006; Gursoy et al, 2005; Kennel et al, 1996).
2) Bradycardia was reported in 2 of 23 adult patients (8.7%) with amitraz poisoning (Avsarogullari et al, 2006).
3) BRADYCARDIA has been reported in animals and may be due to a reflex response to hypertension or an alpha-2-adrenergic agonist effect (Cullen & Reynoldson, 1988; Hovda & McManus, 1993; Hsu & Kakuk, 1984).

Heent

3.4.3)

A) WITH POISONING/EXPOSURE

1) MIOSIS

a) Miosis has been reported in humans following ingestion of amitraz/petroleum distillates (Garnier et al, 1998; Kennel et al, 1996). Miosis was reported in 84% of 11 children who ingested a liquid concentrate formulation of amitraz (Yaramis et al, 2000). Miosis occurred in 6 of 23 adult patients (26%) with amitraz poisoning (Avsarogullari et al, 2006)
b) Miosis occurred in 31 of 45 patients (68.8%) following ingestion of an amitraz formulation containing 12.5% amitraz and 57.5% xylene in water (Demirel et al, 2006).
c) According to a 2-year survey of human amitraz poisoning cases that occurred in South Africa from 2008 to 2009, miosis was reported in 27.5% of patients (n=69) (Veale et al, 2011).
d) Miosis is an alpha-2-adrenergic agonist presynaptic effect of amitraz at low doses (Avsarogullari et al, 2006).

2) MYDRIASIS

a) Bilateral mydriasis (responsive to light) has been reported in one human poisoning case (Jorens et al, 1997). Higher doses of amitraz (alpha-2-adrenergic agonist as a postsynaptic effect) result in mydriasis, while lower doses, as a presynaptic effect, result in miosis (Avsarogullari et al, 2006; Garnier et al, 1998)
b) Mydriasis was reported in 3 of 23 adult patients (13%) with amitraz poisoning (Avsarogullari et al, 2006).
c) Mydriasis was reported in 6 of 45 patients (13.3%) following ingestion of an amitraz formulation containing 12.5% amitraz and 57.5% xylene in water. However, four of the 6 patients with mydriasis had received atropine to treat the bradycardia following amitraz ingestion; therefore, the mydriasis may have been a result of the atropine administration (Demirel et al, 2006).
d) According to a 2-year survey of human amitraz poisoning cases that occurred in South Africa from 2008 to 2009, mydriasis was reported in 10.1% of patients (n=69) (Veale et al, 2011).
e) Dose-related mydriasis has been reported in rats following IP (Moser, 1991) or IV administration (Hsu & Kakuk, 1984). Mydriasis has been reported in dogs following ingestion (Grossman, 1993) or IV administration of amitraz (Cullen & Reynoldson, 1988).
f) No reaction or irritation occurred after administration of 100 mg of powdered amitraz to rabbit eyes (Anon, 1980).

Cardiovascular

3.5.2)

A) HYPOTENSIVE EPISODE

1) WITH POISONING/EXPOSURE

a) SUMMARY

1) Hypotension, due to stimulation of central alpha-2-adrenergic receptors, is commonly reported in humans following amitraz ingestions. Onset of hypotension may be delayed by several hours following ingestions (Hu et al, 2010; Avsarogullari et al, 2006; Aslan et al, 2005; Yilmaz & Yildizdas, 2003; Atabek et al, 2002; Yaramis et al, 2000; Leung et al, 1999).

b) INCIDENCE

1) In several small case series of pediatric amitraz poisoning, hypotension developed in 44% to 67% of patients(Ertekin et al, 2002; Ertekin et al, 2002; Atabek et al, 2002).
2) In a series of 45 patients (44 adults, one child) who ingested a formulation containing 12.5% amitraz and 57.5% xylene in water, hypotension (less than 80 mmHg systolic) was reported in 21 (46.6%) . The hypotension resolved in all patients within 24 hours postingestion (Demirel et al, 2006).
3) According to a 2-year survey of human amitraz poisoning cases that occurred in South Africa from 2008 to 2009, hypotension was reported in 23.1% of patients (n=69) (Veale et al, 2011).

c) CASE SERIES

1) Hypotension occurred in 3 of 8 pediatric cases of amitraz poisoning (Aydin et al, 1997).
2) Hypotension was reported in two out of four cases involving ingestion of an amitraz/petroleum distillate mixture (Kennel et al, 1996).
3) Four of 11 children developed hypotension which responded to intravenous fluid hydration following the ingestion of a liquid concentrate of amitraz (12.5%) (Yaramis et al, 2000).
4) Hypotension was reported in 7 of 23 patients (30%) with amitraz poisoning (Avsarogullari et al, 2006).

d) CASE REPORTS

1) Hypotension (blood pressure 70/50) was reported approximately 8 hours after hospital admission in a 33-year-old man following ingestion of an undiluted amitraz solution. He recovered following IV fluid, atropine and supplemental oxygen (Leung et al, 1999).
2) Pronczuck et al (1986) also reported hypotension in a case involving amitraz/petroleum distillate ingestion (Kennel et al, 1996).
3) A 22-year-old woman presented to the emergency department comatose (GCS 3) with hypotension (70/40 mmHg) and bradycardia (42 bpm) approximately 90 minutes following intentional intravenous administration of 5 to 6 mL of a solution containing 12.5% amitraz and 57.5% xylene in water. The patient gradually recovered with supportive therapy (Gursoy et al, 2005).
4) A 54-year-old man became comatose with no response to painful stimuli, hypotensive (90/60 mmHg), bradycardic (60 beats per minute), bradypneic (7 breaths per minute), and hyperglycemic (28 mmol/L) after ingesting approximately 20 to 30 mL of a liquid amitraz concentrate. Following supportive treatment, the patient recovered and was discharged approximately 4 days post-ingestion (Elinav et al, 2005).
5) Hypotension (mean arterial pressure 50 to 55 mmHg) was reported in a 42-year-old man 3 days following exposure to a pesticide containing 12.5% amitraz. The hypotension resolved following vasopressor therapy (Batra et al, 2012).
6) CHILD: A 13-year-old boy was comatose (GCS 3) and hypotensive (70/50 mmHg) after ingesting 125 mL of a pesticide containing 12.5% amitraz. With symptomatic and supportive therapy, the patient gradually recovered without sequelae (Varma et al, 2013).

B) BRADYCARDIA

1) WITH POISONING/EXPOSURE

a) SUMMARY

1) Bradycardia, in amitraz poisoning, appears to be due to a central alpha-adrenergic agonist effect causing diminished peripheral sympathetic tone and resulting in a decreased heart rate (Aslan et al, 2005; Yilmaz & Yildizdas, 2003)

b) INCIDENCE

1) In several small case series of pediatric amitraz poisoning bradycardia developed in 29% to 86% of patients (Atabek et al, 2002; Kalyoncu et al, 2002; Caksen et al, 2003; Yilmaz & Yildizdas, 2003; Ertekin et al, 2002).
2) In a series of 45 patients (44 adults, one child) who ingested a formulation containing 12.5% amitraz and 57.5% xylene in water, bradycardia (less than 40 bpm) was reported in 35 (77.7%) (Demirel et al, 2006).
3) According to a 2-year survey of human amitraz poisoning cases that occurred in South Africa from 2008 to 2009, bradycardia was reported in 34.8% of patients (n=69) (Veale et al, 2011).

c) CASE REPORTS

1) Pronczuck et al (1986) also reported bradycardia in a case who ingested amitraz/petroleum distillate (Kennel et al, 1996).
2) Sinus bradycardia (heart rate, 28/min), unresponsive to atropine (3 mg) but responsive to isoprenaline or dopamine (5 mcg/kg/min), was reported in a 45-year-old man following ingestion of approximately 250 mg amitraz. His blood pressure remained stable and temporary pacing was not considered (Jorens et al, 1997).
3) Sinus bradycardia at 50 bpm was observed on ECG approximately 8 hours after admission in a 33-year-old patient following ingestion of about 20 mL of an undiluted amitraz solution. The patient recovered following 2 doses of atropine (0.6 mg each) and IV saline (Leung et al, 1999).
4) Bradycardia (80 bpm) was reported in a 4-month-old infant approximately 2 hours after ingestion of 0.3 mL of a 5% amitraz solution (2.5 mg/kg). The infant completely recovered following supportive care (Zoelen et al, 2001).
5) A 22-year-old woman presented to the emergency department comatose (GCS 3) with hypotension (70/40 mmHg) and bradycardia (42 bpm) approximately 90 minutes following intentional intravenous administration of 5 to 6 mL of a solution containing 12.5% amitraz and 57.5% xylene in water. The patient gradually recovered with supportive therapy (Gursoy et al, 2005).
6) A 54-year-old man became comatose with no response to painful stimuli, hypotensive (90/60 mmHg), bradycardic (60 beats per minute), bradypneic (7 breaths per minute), and hyperglycemic (28 mmol/L) after ingesting approximately 20 to 30 mL of a liquid amitraz concentrate. Following supportive treatment, the patient recovered and was discharged approximately 4 days post-ingestion (Elinav et al, 2005).
7) Multiple episodes of bradycardia occurred in a 42-year-old man following exposure to a pesticide containing 12.5% amitraz. The bradycardia resolved with atropine administration (Batra et al, 2012).

d) CASE SERIES

1) Bradycardia was reported in several pediatric exposures to amitraz (Atabek et al, 2002; Ertekin et al, 2002; Aydin et al, 1997).
2) Bradycardia (<60 beats/min) was reported in several children following ingestion of a liquid concentrate of amitraz (12.5%); bradycardia responded to 3 to 9 doses of atropine (Caksen et al, 2003; Yaramis et al, 2000).
3) Bradycardia occurred in 3 out of 4 cases who ingested a mixture of amitraz and petroleum distillate (Kennel et al, 1996).
4) In a series of 24 amitraz poisonings, bradycardia was reported in 29% of the cases (Bizovi et al, 1995).
5) Bradycardia was reported in 2 of 23 patients (8.7%) with amitraz poisoning (Avsarogullari et al, 2006).

C) HYPERTENSIVE EPISODE

1) WITH POISONING/EXPOSURE

a) CASE REPORTS

1) A 74-year-old diabetic man had a blood pressure of 200/100 mmHg after ingesting an estimated dose of 6 grams amitraz in <30 mL of amitraz/xylene (Bonsall & Turnball, 1983). No baseline blood pressure values were provided. Pre-existing health conditions included cerebral atherosclerosis and myocardial infarction.

2) A 37-year-old woman, with no previous history of hypertension, became hypertensive (160/120 mmHg) following ingestion of 50 mL of an amitraz formulation containing 12.5% amitraz and 57.5% xylene in water. The blood pressure normalized after 2 hours; however, 30 minutes later, the patient became hypotensive (75/40 mmHg) (Demirel et al, 2006).

CASE SERIES

3) Hypertension was reported in approximately 21% (n=29) of children following oral exposure to amitraz (Kalyoncu et al, 2002).

D) TACHYARRHYTHMIA

1) WITH POISONING/EXPOSURE

a) Tachycardia (> 100 bpm) was reported in 18 of 43 children following oral or dermal exposure to amitraz. The incidence of tachycardia appeared to be greater in the children following oral exposure to amitraz (48.3%, n=29) as compared with the children who were dermally exposed (28.6%, n=14) (Kalyoncu et al, 2002).

E) TORSADES DE POINTES

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 53-year-old woman presented to the hospital unresponsive with a Glasgow Coma Scale score of 3 approximately 1 hour after intentionally ingesting 500 mL of a pesticide containing 20% amitraz. An ECG revealed QTc interval prolongation that subsequently developed into torsades de pointes. Despite intensive supportive therapy, including repeated defibrillation, administration of magnesium sulfate and lidocaine, and overdrive pacing, as well as intravenous fluids and vasopressors for persistent hypotension, the patient died the following day (Hu et al, 2010).

3.5.3)

A) ANIMAL STUDIES

1) BRADYCARDIA

a) Bradycardia is a consistent dose-related finding in experimental animals (dogs, rats) following IV, IP, or oral administration of amitraz (Hsu & Kakuk, 1984; Cullen & Reynoldson, 1988; Bonsall & Turnball, 1983). Ingestion or dermal exposure to amitraz has produced bradycardia in pet dogs (Grossman, 1993; Jones, 1990; Hovda & McManus, 1993).

2) HYPOTENSION

a) Hypotension has been reported in experimental animals (Hsu & Kakuk, 1984; Cullen & Reynoldson, 1988; Bonsall & Turnball, 1983), and may be delayed and follow bradycardia. One proposed mechanism is alpha-2-adrenergic stimulation by the amitraz metabolite BTS 27 271 (Bonsall & Turnball, 1983).

3) HYPERTENSION

a) DOGS: Hypertension has been reported in anesthetized dogs following IV amitraz (Cullen & Reynoldson, 1988).

Respiratory

3.6.2)

A) PNEUMONITIS

1) WITH POISONING/EXPOSURE

a) Formulations which have high volumes of xylene or other solvents which have low viscosity may increase the risk of aspiration and chemical pneumonitis.
b) CASE REPORT: Ros and van Haken (1994) reported a case of ingestion (up to 100 ml of amitraz/petroleum distillate) which resulted in aspiration pneumonitis and significant CNS depression (Kennel et al, 1996).
c) CASE SERIES: In a series of 14 children with amitraz poisoning, two patients developed aspiration pneumonitis(Atabek et al, 2002).
d) Veterinary precautions address the possibility of aspiration pneumonitis (Jones, 1990).

B) ACUTE RESPIRATORY INSUFFICIENCY

1) WITH POISONING/EXPOSURE

a) Aydin et al (1997) reported that 7 of 8 pediatric cases of amitraz poisoning developed depressed respirations, with 2 requiring mechanical ventilation (Aydin et al, 1997).
b) In two small series of children with amitraz poisoning respiratory depression developed in four out of nine patients and five out of 14 patients; none of the patients in the first group and four patients in the second group required mechanical ventilation (Atabek et al, 2002; Yilmaz & Yildizdas, 2003).
c) INCIDENCE: According to a 2-year survey of human amitraz poisoning cases that occurred in South Africa from 2008 to 2009, respiratory depression was reported in 27.5% of patients (n=69) (Veale et al, 2011).
d) CASE REPORT: Central respiratory depression (pH 7.27, PCO2 9.6 KPa, and PO2 7.0 KPa), was reported in a 33-year-old man following the ingestion of about 20 mL of an undiluted amitraz solution. The patient recovered following supplemental oxygen, IV fluids and atropine (Leung et al, 1999).
e) CASE REPORT: A 22-year-old woman developed cyanosis with respiratory depression (respiratory rate 22 breaths/min, PO2 35.3 mmHg, PCO2 50.6 mmHg, O2sat 58%) following intentional intravenous administration of 5 to 6 mL of a solution containing 12.5% amitraz and 57.5% xylene in water. The patient gradually recovered with supportive care (Gursoy et al, 2005).
f) Five of 23 adult patients with amitraz poisoning developed respiratory depression, requiring mechanical ventilation for 36 to 72 hours (the mean duration was 50 +/-16 hours). (Avsarogullari et al, 2006).
g) Respiratory depression was reported in 20 of 45 patients (44.4%) following ingestion of an amitraz formulation containing 12.5% amitraz and 57.5% xylene in water (Demirel et al, 2006).
h) CASE REPORT: A 54-year-old man became comatose with no response to painful stimuli, hypotensive (90/60 mmHg), bradycardic (60 beats per minute), bradypneic (7 breaths per minute), and hyperglycemic (28 mmol/L) after ingesting approximately 20 to 30 mL of a liquid amitraz concentrate. Following supportive treatment, the patient recovered and was discharged approximately 4 days post-ingestion (Elinav et al, 2005).

C) DISORDER OF RESPIRATORY SYSTEM

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Rhonchi were present in the lung fields in an 82-year-old who ingested an unknown amount of an amitraz/petroleum distillate mixture (Kennel et al, 1996). The chest x-ray was normal.

3.6.3)

A) ANIMAL STUDIES

1) RESPIRATORY DISORDER

a) BRADYPNEA (Jones, 1990) and TACHYPNEA (Turnbull, 1983) have been reported in animals. Amitraz formulations which contain xylene or other solvents which have low viscosity may be aspiration hazards. Chemical pneumonitis can result (Jones, 1990).

Neurologic

3.7.2)

A) DROWSY

1) WITH POISONING/EXPOSURE

a) CNS depression, including drowsiness, unconsciousness and coma, is the most common presenting manifestation of amitraz poisoning (Hu et al, 2010; Demirel et al, 2006; Atabek et al, 2002; Yaramis et al, 2000; Leung et al, 1999; Garnier et al, 1998).
b) CNS depression generally resolves within 24 hours, following supportive care (Atabek et al, 2002).
c) INCIDENCE

1) In several small case series of children with amitraz poisoning, drowsiness or lethargy were very common, developing in 81% to 100% of children (Kalyoncu et al, 2002; Yilmaz & Yildizdas, 2003; Atabek et al, 2002).
2) According to a 2-year survey of human amitraz poisoning cases that occurred in South Africa from 2008 to 2009, CNS depression (ie, drowsiness, confusion, loss of consciousness, coma) was the most common clinical finding, occurring in 76.8% of patients (n=69) (Veale et al, 2011).

d) CASE SERIES

1) Drowsiness and unconsciousness were the first clinical findings in 7 pediatric exposures of amitraz, followed by coma in most patients (Aydin et al, 1997). Symptoms developed within 36 to 120 minutes following oral and dermal poisoning. Yaramis et al (2000) reported drowsiness and unconsciousness in 100% of 11 children who ingested a liquid concentrate of amitraz (12.5%). CNS depression resolved within 8.5 to 14 hours (Yaramis et al, 2000).
2) Drowsiness was present in all of 4 cases involving ingestion of amitraz/petroleum distillate mixtures (Kennel et al, 1996).
3) Decreased consciousness was reported in 5 of 8 pediatric patients following ingestion of a 12.5% amitraz solution. All the patients recovered following supportive care (Caksen et al, 2003).
4) Drowsiness was reported in 4 of 23 adult patients (17%) with amitraz poisoning and was one of the initial presenting symptoms (Avsarogullari et al, 2006). One of the four patients experienced severe drowsiness 14 hours after dermal application of amitraz for treatment of itching.

e) CASE REPORTS

1) Drowsiness which lasted for several hours occurred in a 3-year-old who had ingested a small but unspecified amount of an amitraz/xylene formulation. Recovery was spontaneous. No medical attention was required (Bonsall & Turnball, 1983).
2) A 4-month-old infant became drowsy and difficult to wake approximately 2 hours after ingesting 0.3 mL of a 5% amitraz solution (2.5 mg/kg). The infant completely recovered following supportive care (Zoelen et al, 2001).

B) COMA

1) WITH POISONING/EXPOSURE

a) CASE SERIES

1) Coma was reported in 5 of 8 pediatric (range, 2 to 4 years old) exposures to amitraz via the oral/dermal route (Aydin et al, 1997).
2) The most frequent finding in 24 amitraz poisonings was coma, reported in 33% of the cases (Bizovi et al, 1995).
3) Altered consciousness was reported in 4 of 23 adult patients (17%) with amitraz poisoning and was one of the initial presenting symptoms. The Glasgow Coma Scale (GCS) scores were 3 in each of 2 patients, and the GCS scores were 7 in each of the other 2 patients. The amitraz-containing product also contained xylene, which may have contributed to the altered consciousness in these patients (Avsarogullari et al, 2006).
4) Coma was reported in 20 of 45 patients (44.4%) following ingestion of an amitraz formulation containing 12.5% amitraz and 57.5% xylene in water (Demirel et al, 2006).

b) CASE REPORTS

1) A 74-year-old diabetic experienced decreased level of conscious, progressing to a 24-hour period of unconsciousness, after ingesting approximately 6 g of amitraz in a aromatic solvent base (Bonsall & Turnball, 1983).
2) A mentally handicapped 22-year-old man was comatose (Glasgow coma score of 3) within about 1 hour of ingesting approximately 12.5 g amitraz in a 25 to 100 mL solution. Treatment included gastric lavage, activated charcoal and sodium sulphate administration. The patient recovered the next day (Ros & van Aken, 1994).
3) CHILD: A 3-year-old girl who ingested 10.6 mL of amitraz/xylene was comatose and hyperglycemic upon presentation to the emergency department (ED). She had initially been discharged asymptomatic from the ED and had developed symptoms on the return trip home (Jones, 1990).
4) Jorens et al (1997) reported loss of consciousness, which reversed in 4 hours, in a 45-year-old male after ingestion of about 250 mg amitraz. He presented to the emergency department with lethargy, somnolence, ataxia and profound bradycardia (Jorens et al, 1997).
5) (REVIEW): Pronczuck et al (1986) reported a deep coma resulted from ingestion of 50 mL of an amitraz/petroleum distillate mixture (about 6 g of amitraz) by a 17-year-old (Kennel et al, 1996).
6) A 22-year-old woman presented to the emergency department comatose (GCS 3) with hypotension (70/40 mmHg) and bradycardia (42 bpm) approximately 90 minutes following intentional intravenous administration of 5 to 6 mL of a solution containing 12.5% amitraz and 57.5% xylene in water. The patient gradually recovered with supportive therapy (Gursoy et al, 2005).
7) A 36-year-old woman presented to the emergency department comatose (GCS10) with bradycardia and hypotension approximately 3 hours after ingesting a glass of water containing an unknown amount amitraz. The patient's neurological status improved following supportive therapy (Aslan et al, 2005).
8) A 54-year-old man became comatose with no response to painful stimuli, hypotensive (90/60 mmHg), bradycardic (60 beats per minute), bradypneic (7 breaths per minute), and hyperglycemic (28 mmol/L) after ingesting approximately 20 to 30 mL of a liquid amitraz concentrate. Following supportive treatment, the patient recovered and was discharged approximately 4 days post-ingestion (Elinav et al, 2005).
9) A 42-year-old man presented to the emergency department comatose with miotic and unreactive pupils, a respiratory rate of 10 breaths/minute, and bradycardic (52 beats/minute) following exposure to a pesticide containing 12.5% amitraz. Over the next 3 days, the patient also developed hypotension (mean arterial pressure 50 to 55 mmHg). With supportive care, the patient recovered and was discharged approximately 5 days post-exposure (Batra et al, 2012).
10) CHILD: A 13-year-old boy was comatose (GCS 3) and hypotensive (70/50 mmHg) after ingesting 125 mL of a pesticide containing 12.5% amitraz. With symptomatic and supportive therapy, the patient gradually recovered without sequelae (Varma et al, 2013).

C) SEIZURE

1) WITH POISONING/EXPOSURE

a) Generalized seizures have occurred in children following ingestion of amitraz. The children recovered after administration of diazepam (Yilmaz & Yildizdas, 2003; Ertekin et al, 2002; Atabek et al, 2002).
b) A seizure was reported in a 4-year-old child following ingestion of an amitraz formulation containing 12.5% amitraz and 57.5% xylene in water (Demirel et al, 2006).

3.7.3)

A) ANIMAL STUDIES

1) CNS STIMULATION

a) Amitraz produces CNS depression or stimulation in animals. The most common effects are decreased spontaneous activity, increased reactivity to stimuli, aggressive or irritable behavior, ataxia, and altered performance on behavioral tests (Moser, 1991; Moser, 1991; Turnbull, 1983; Moser & MacPhail, 1989; Florio et al, 1993). Coma and seizures have been reported. The CNS effects appear dose and species dependent.

2) CNS DEPRESSION

a) CNS depression, ataxia, head pressing and coma has been reported in dogs following excessive oral or dermal exposure to amitraz (Hovda & McManus, 1993). Seizures may occur in animals following dermal exposure to amitraz (Jones, 1990).
b) Toxicity of oral, IM or IP amitraz given to rats included depression, incoordination of movement, and paresis of the limbs (Al-Qarawi et al, 1999).

Gastrointestinal

3.8.2)

A) NAUSEA AND VOMITING

1) WITH POISONING/EXPOSURE

a) Vomiting after ingestion of amitraz or amitraz preparations which contain xylene may be expected (Bonsall & Turnball, 1983; Aydin et al, 1997). Vomiting in most cases is due to the petroleum distillates mixed with amitraz in commercial preparations (Avsarogullari et al, 2006; Garnier et al, 1998).
b) INCIDENCE

1) In a series of 45 patients (44 adults, one child) who ingested a formulation containing 12.5% amitraz and 57.5% xylene in water, nausea and vomiting were reported in 39 (86.6%) (Demirel et al, 2006).

c) CASE REPORTS

1) Brief immersion of an adult in a diluted amitraz cattle dip resulted in vomiting, headache, and malaise 36 hours later. A cause-effect relationship could not be concluded. A viral infection could not be ruled out (Bonsall & Turnball, 1983).

d) CASE SERIES

1) Vomiting occurred in 2 out of 4 cases who ingested a mixtures of amitraz and petroleum distillates (Kennel et al, 1996).
2) Vomiting was reported in 20% of 24 amitraz poisoning cases (Bizovi et al, 1995).
3) In a case series of 23 patients with amitraz poisoning, vomiting was one of the initial presenting symptoms, occurring within 5 to 30 minutes post-exposure in 6 patients (26%) (Avsarogullari et al, 2006).

B) EXCESSIVE SALIVATION

1) WITH POISONING/EXPOSURE

a) Poisonings may result in hypersalivation. Bizovi et al (1995) reported a 17% incidence of salivation in 24 amitraz toxicity cases(Bizovi et al, 1995).

C) ABDOMINAL PAIN

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 36-year-old woman presented to the emergency department comatose, hypotensive, and bradycardic, with vomiting and miosis, approximately 3 hours after ingesting a glass of water containing an unknown amount amitraz. The patient's signs and symptoms improved following supportive therapy. However, on day 2 post-admission, the patient experienced severe abdominal tenderness, distension, and pain, and decreased gastrointestinal motility, consistent with a diagnosis of Ogilvie's syndrome. Abdominal radiographs showed multiple air-fluid levels and distension of the large intestine. Following continuous nasogastric tube decompression and neostigmine administration, the patient completely recovered and was discharged seven days post-ingestion (Aslan et al, 2005).

3.8.3)

A) ANIMAL STUDIES

1) VOMITING

a) Vomiting, diarrhea, or decreased gastrointestinal motility and colonic impaction have been reported in some animal species (Hovda & McManus, 1993; Jones, 1990; Hsu et al, 1987; Hsu & McNeel, 1985).

Hepatic

3.9.2)

A) LIVER ENZYMES ABNORMAL

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Slight elevation in liver enzymes (SGOT=92, SGPT=35, alkaline phosphatase=166 ) were reported in a 74-year-old man who ingested about 6 grams of amitraz (Bonsall & Turnball, 1983).
b) Elevated liver enzyme levels were reported in several children following amitraz ingestion. The levels returned to normal within 72 hours of ingestion (Yilmaz & Yildizdas, 2003; Atabek et al, 2002; Ertekin et al, 2002).
c) Elevated liver enzyme levels were reported in several adult patients following amitraz poisoning. Four patients experienced elevated AST levels (81 +/- 28 units/liter) and 3 patients experienced elevated ALT levels (60 +/- 14 units/liter) (Avsarogullari et al, 2006).
d) Elevated transaminase levels were reported in 5 of 45 patients (11.1%) following ingestion of an amitraz formulation containing 12.5% amitraz and 57.5% xylene in water. The transaminase levels normalized within 72 hours in all patients (Demirel et al, 2006).
e) CASE REPORT: Elevated AST and ALT concentrations (74 units/liter and 47 units/liter, respectively) were reported in a 53-year-old woman who intentionally ingested 500 mL of a pesticide containing 20% amitraz (Hu et al, 2010).

3.9.3)

A) ANIMAL STUDIES

1) HEPATOCELLULAR DAMAGE

a) RATS: Doses of amitraz near the LD50 injected IP caused slight evidence of centrilobular hepatic degeneration in a study involving a small number of rats (Grilli et al, 1991). Intermediate doses produced minor morphological changes, and low doses did not produce any apparent effects.

2) HEPATIC NECROSIS

a) RATS - Peritoneal injection of xylenes in rats caused liver necrosis (NTP, 1986).

Genitourinary

3.10.2)

A) GLYCOSURIA

1) WITH POISONING/EXPOSURE

a) CASE SERIES: Glycosuria was reported in 5 of 8 pediatric cases of amitraz poisoning along with hyperglycemia (Aydin et al, 1997).
b) CASE SERIES: Glycosuria was reported in several children following ingestion of a concentrated product formulation containing amitraz (Atabek et al, 2002).
c) CASE REPORT: Glycosuria, in the absence of hyperglycemia, was reported in a 74-year-old diabetic man who ingested an estimated quantity of 30 mL of an amitraz/aromatic solvent mixture (approximately 6 g amitraz) (Bonsall & Turnball, 1983).

B) POLYURIA

1) WITH POISONING/EXPOSURE

a) Polyuria was reported in 3 of 8 pediatric cases of amitraz poisoning (Aydin et al, 1997).

C) BLOOD IN URINE

1) WITH POISONING/EXPOSURE

a) Hematuria occurred in a 22-year-old woman following intentional intravenous administration of 5 to 6 mL of a solution containing 12.5% amitraz and 57.5% xylene in water. The hematuria gradually resolved over the next several days (Gursoy et al, 2005).
b) Gross hematuria was reported in a 27-year-old woman who drank 75 mL of an amitraz formulation containing 12.5% amitraz and 57.5% xylene in water. The hematuria resolved within 3 days post-ingestion (Demirel et al, 2006).

3.10.3)

A) ANIMAL STUDIES

1) POLYURIA

a) Polyuria was reported in animals (Hovda & McManus, 1993; Anon, 1980), possibly as a result of hyperglycemia (Anon, 1980).

Acid-Base

3.11.2)

A) ACIDOSIS

1) WITH POISONING/EXPOSURE

a) In a series of 29 patients who ingested amitraz, 5 patients developed metabolic acidosis and 3 developed respiratory acidosis (Kalyoncu et al, 2002).
b) Respiratory acidosis occurred in a 22-year-old woman following intentional intravenous administration of 5 to 6 mL of a solution containing 12.5% amitraz and 57.5% xylene in water. Her initial arterial blood gas (ABG) results were as follows: pH 7.25, PO2 35.5 mmHg, PCO2 50.6 mmHg, HCO3 21.8, and O2sat 58%. Twelve hours later, following supportive care, her ABG results were pH 7.39, PO2 80 mmHg, PCO2 32 mmHg, HCO3 20.8 and O2sat 96% (Gursoy et al, 2005).

Dermatologic

3.14.2)

A) ERUPTION

1) WITH POISONING/EXPOSURE

a) Skin irritation and blistering may occur with prolonged dermal exposure to the amitraz formulations which contain xylene (Gosselin et al, 1984).

B) INJECTION SITE REACTION

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 22-year-old woman intravenously administered, in a suicide attempt, 5 to 6 mL of a solution containing 12.5% amitraz and 57.5% xylene in water and experienced hyperemia at the injection site as well as edema of the surrounding area. Amitraz is irritating to tissues and it is believed that the edema and hyperemia were a result of extravasation of the amitraz-containing solution during injection (Gursoy et al, 2005).

Endocrine

3.16.2)

A) HYPERGLYCEMIA

1) WITH POISONING/EXPOSURE

a) SUMMARY

1) Hyperglycemia is a common effect of amitraz poisoning, due to alpha-2-adrenoceptor stimulation which reduces insulin secretion (Garnier et al, 1998).

b) INCIDENCE

1) In several small series of children with amitraz poisoning, hyperglycemia developed in 60% to 71% of patients(Atabek et al, 2002; Yilmaz & Yildizdas, 2003; Kalyoncu et al, 2002).
2) Hyperglycemia was reported in two patients following amitraz ingestion, in amounts ranging from 1.8 grams to 12.5 grams (Doganay et al, 2002).
3) Blood glucose levels greater than 120 mg/dL (mean 191 +/-70 mg/dL) were reported in 62% of patients (n=23) following amitraz poisoning (Avsarogullari et al, 2006).
4) In a series of 45 patients (44 adults, one child) who ingested a formulation containing 12.5% amitraz and 57.5% xylene in water, hyperglycemia (blood glucose greater than 120 mg/dL) was reported in 29 (64%) (Demirel et al, 2006).
5) According to a 2-year survey of human amitraz poisoning cases that occurred in South Africa from 2008 to 2009, hyperglycemia was reported in 7.2% of patients (n=69) (Veale et al, 2011).

c) CASE REPORTS

1) A 3-year-old girl became hyperglycemic after ingesting about 2 grams of amitraz in a 10.6 mL solution (Jones, 1990).
2) Following a suicidal attempt by ingestion of approximately 20 mL of an undiluted amitraz solution, a 33-year-old man developed hyperglycemia (14 mmol/L) about 8 hours after hospital admission. The patient was given IV saline, oxygen and atropine, with blood glucose gradually returning to normal (Leung et al, 1999).
3) A 54-year-old man became comatose with no response to painful stimuli, hypotensive (90/60 mmHg), bradycardic (60 beats per minute), bradypneic (7 breaths per minute), and hyperglycemic (28 mmol/L) after ingesting approximately 20 to 30 mL of a liquid amitraz concentrate. Following supportive treatment, the patient recovered and was discharged approximately 4 days post-ingestion (Elinav et al, 2005).

d) CASE SERIES

1) Hyperglycemia occurred in 3 out of 4 cases involving ingestion of amitraz/petroleum distillate mixtures (Kennel et al, 1996).
2) Hyperglycemia (blood glucose >120 mg/dL) was reported in 9 out of 11 pediatric cases involving ingestion of a liquid concentrate of amitraz (12.5%) (Yaramis et al, 2000).
3) Aydin et al (1997) reported blood glucose levels greater than 120 milligrams/deciliter in 6 of 8 pediatric exposures along with glycosuria and polyuria occurring in some cases(Aydin et al, 1997).

3.16.3)

A) ANIMAL STUDIES

1) HYPERGLYCEMIA

a) RATS: Amitraz IP (1mg/kg) in rats decreased or prevented the insulin response to IV glucose at 5 and 15 minutes post glucose injection, and caused prolonged increased plasma glucose levels when compared to controls (Smith et al, 1990).
b) Inhibition of insulin release with subsequent development of hyperglycemia may be due to stimulation of alpha-2-adrenergic receptors by amitraz.

1) The alpha-2-adrenoceptor antagonist, yohimbine, prevented the effects of amitraz on insulin release and plasma glucose concentration. Prazosin, an alpha-1-adrenoceptor antagonist, did not alter the effects of amitraz.

Reproductive

3.20.1)

A) There were no adverse effects reported in a pregnant woman or her fetus following an amitraz ingestion.

3.20.2)

A) ANIMAL STUDIES

1) RATS - Offspring of rats given amitraz, 20 mg/kg PO every 3 days from days 1 through 19 of gestation, had earlier age of vaginal opening, earlier fur development, and delayed incisor eruption, compared with water-treated controls (Palermo-neto et al, 1994). These effects would not be regarded as structural malformations.

3.20.3)

A) LACK OF EFFECT

1) There were no adverse effects reported in a 27-year-old pregnant woman or her fetus (gestational age not reported) following ingestion of 10 mL of an amitraz formulation containing 12.5% amitraz and 57.5% xylene. Follow-up of the patient showed that she had given birth to healthy baby (Demirel et al, 2006).

Carcinogenicity

3.21.1)

A) IARC Carcinogenicity Ratings for CAS33089-61-1 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):

1) Not Listed

3.21.4)

A) CARCINOMA

1) Animal studies reviewed by Wang (1984) provided only weakly positive evidence of potential carcinogenicity.

a) The conclusions of one study were considered unsound, and another study showed increased incidence of liver tumors, but not lymphoreticular tumors.

Genotoxicity

Laboratory Monitoring

Monitoring Parameters Levels

4.1.1)

A) Monitor vital signs and mental status, and institute continuous cardiac and pulse oximetry monitoring.
B) Monitor serum electrolytes, glucose, and liver enzymes in symptomatic patients.
C) Obtain an ECG in patients with bradycardia.

4.1.2)

A) Monitor serum electrolytes, glucose, and liver enzymes in symptomatic patients.

4.1.3)

A) URINARY LEVELS

1) Xylene may be detected in the urine as methyl hippuric acid.
2) A metabolite of amitraz, 3-methyl-4-aminobenzoic acid is theoretically detectable in the urine of poisoned patients.

4.1.4)

A) OTHER

1) MONITORING

a) Monitor vital signs and mental status, and institute continuous cardiac and pulse oximetry monitoring.

2) ECG

a) Obtain an ECG in patients with bradycardia.

Methods

1) An improved method of measuring amitraz in the plasma using gas chromatography and nitrogen-phosphorus detection has been developed and used for pharmacokinetic studies in a dog (Ameno et al, 1991).
2) Jorens et al (1997) reported measuring human serum concentrations of amitraz by means of gas chromatography-mass spectrometry (Jorens et al, 1997).

Treatment

Life Support

Patient Disposition

6.3.1)

6.3.1.1) ADMISSION CRITERIA/ORAL

A) Patients with symptomatic bradycardia or CNS depression should be admitted.

6.3.1.2) HOME CRITERIA/ORAL

A) Asymptomatic adults with inadvertent taste ingestions and patients with dermal exposures who are asymptomatic can be managed at home.

6.3.1.3) CONSULT CRITERIA/ORAL

A) Consult a medical toxicologist for patients with symptomatic bradycardia or CNS depression.

6.3.1.5) OBSERVATION CRITERIA/ORAL

A) Children with inadvertent ingestions or large dermal exposures, adults with more than taste ingestions, any patient with a deliberate ingestion, and any symptomatic patient should be referred to a healthcare facility and monitored for a minimum of 6 hours. Patient with mild or moderate symptoms should be monitored until symptoms resolve.

Monitoring

Oral Exposure

6.5.1)

A) Remove contaminated clothing and wash exposed skin with soap and water. Gastrointestinal decontamination is not recommended as patients often have vomiting and sedation, and the risk of aspiration outweighs potential benefits.

6.5.2)

A) SUMMARY

1) Gastrointestinal decontamination is generally not recommended as patients often have vomiting and sedation and the risk of aspiration outweighs potential benefits.

B) ACTIVATED CHARCOAL

1) Administration of activated charcoal 0.5 g/kg to rats, 30 minutes after oral dosing of amitraz or amitraz/xylene mixture, had no effect on survival or severity of symptoms (Turnbull, 1983). The manufacturer states that experimental studies have shown that systemic effects have not been ameliorated by absorption retardants (Upjohn, 1984).

6.5.3)

A) SUPPORT

1) There is no known antidote for amitraz (Upjohn, 1984). Treatment is primarily symptomatic and supportive. Effects of amitraz resemble those caused by pure alpha-2-adrenergic agonist drugs, and because of this mechanism, phentolamine or yohimbine have been suggested as therapies following a large ingestion (Harvey et al, 1998), although data is lacking to confirm the effectiveness of these agents.
2) Initial symptoms may be due to xylene or other solvents in the amitraz formulation. Primary solvent related effects may include respiratory distress due to aspiration and pneumonitis, apnea, coma, hypotension, cardiac arrhythmia, hyperglycemia and vomiting. Solvent formulations may vary in different countries.
3) Delayed cardiovascular (e.g., bradycardia, hypotension or hypertension), CNS depression, endocrine (e.g., hyperglycemia, altered insulin response) and other effects (e.g., hypothermia) may result from the amitraz component of the formulations.

B) MONITORING OF PATIENT

1) Monitor vital signs and mental status, and institute continuous cardiac and pulse oximetry monitoring.
2) Monitor serum electrolytes, glucose, and liver enzymes in symptomatic patients.
3) Obtain an ECG in patients with bradycardia.

C) AIRWAY MANAGEMENT

1) Patients may require endotracheal intubation and mechanical ventilation because of respiratory depression, apnea, mental status depression or coma during the first 24 hours following ingestion of amitraz (Aydin et al, 1997; Harvey et al, 1998).

D) PULMONARY ASPIRATION

1) Administer 100% humidified supplemental oxygen with assisted ventilation as required.

E) BRADYCARDIA

1) Atropine may be useful for treatment of hemodynamically unstable bradycardia. An adult with bradycardia (heart rate 28/min), but normal blood pressure, was treated unsuccessfully with atropine; he later responded to infusions of isoprenaline or dopamine (Jorens et al, 1997). Bradycardia and myosis resolved after several doses of atropine in pediatric patients (n=6) exposed to amitraz (Aydin et al, 1997).

a) Atropine pretreatment prevented bradycardia but not hypotension in animals exposed to amitraz (Cullen & Reynoldson, 1988).

2) ATROPINE/DOSE

a) ADULT BRADYCARDIA: BOLUS: Give 0.5 milligram IV, repeat every 3 to 5 minutes, if bradycardia persists. Maximum: 3 milligrams (0.04 milligram/kilogram) intravenously is a fully vagolytic dose in most adults. Doses less than 0.5 milligram may cause paradoxical bradycardia in adults (Neumar et al, 2010).
b) PEDIATRIC DOSE: As premedication for emergency intubation in specific situations (eg, giving succinylchoine to facilitate intubation), give 0.02 milligram/kilogram intravenously or intraosseously (0.04 to 0.06 mg/kg via endotracheal tube followed by several positive pressure breaths) repeat once, if needed (de Caen et al, 2015; Kleinman et al, 2010). MAXIMUM SINGLE DOSE: Children: 0.5 milligram; adolescent: 1 mg.

1) There is no minimum dose (de Caen et al, 2015).
2) MAXIMUM TOTAL DOSE: Children: 1 milligram; adolescents: 2 milligrams (Kleinman et al, 2010).

3) ISOPROTERENOL INDICATIONS

a) Used for temporary control of hemodynamically significant bradycardia in a patient with a pulse; generally other modalities (atropine, dopamine, epinephrine, dobutamine, pacing) should be used first because of the tendency to develop ischemia and dysrhythmias with isoproterenol (Neumar et al, 2010).
b) ADULT DOSE: Infuse 2 micrograms per minute, gradually titrating to 10 micrograms per minute as needed to desired response (Neumar et al, 2010).
c) CAUTION: Decrease infusion rate or discontinue infusion if ventricular dysrhythmias develop(Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
d) PEDIATRIC DOSE: Not well studied. Initial infusion of 0.1 mcg/kg/min titrated as needed, usual range is 0.1 mcg/kg/min to 1 mcg/kg/min (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).

F) VENTRICULAR ARRHYTHMIA

1) VENTRICULAR DYSRHYTHMIAS SUMMARY

a) Obtain an ECG, institute continuous cardiac monitoring and administer oxygen. Evaluate for hypoxia, acidosis, and electrolyte disorders (particularly hypokalemia, hypocalcemia, and hypomagnesemia). Lidocaine and amiodarone are generally first line agents for stable monomorphic ventricular tachycardia, particularly in patients with underlying impaired cardiac function. Amiodarone should be used with caution if a substance that prolongs the QT interval and/or causes torsades de pointes is involved in the overdose. Unstable rhythms require immediate cardioversion.

2) LIDOCAINE

a) LIDOCAINE/INDICATIONS

1) Ventricular tachycardia or ventricular fibrillation (Prod Info Lidocaine HCl intravenous injection solution, 2006; Neumar et al, 2010; Vanden Hoek et al, 2010).

b) LIDOCAINE/DOSE

1) ADULT: 1 to 1.5 milligrams/kilogram via intravenous push. For refractory VT/VF an additional bolus of 0.5 to 0.75 milligram/kilogram can be given at 5 to 10 minute intervals to a maximum dose of 3 milligrams/kilogram (Neumar et al, 2010). Only bolus therapy is recommended during cardiac arrest.

a) Once circulation has been restored begin a maintenance infusion of 1 to 4 milligrams per minute. If dysrhythmias recur during infusion repeat 0.5 milligram/kilogram bolus and increase the infusion rate incrementally (maximal infusion rate is 4 milligrams/minute) (Neumar et al, 2010).

2) CHILD: 1 milligram/kilogram initial bolus IV/IO; followed by a continuous infusion of 20 to 50 micrograms/kilogram/minute (de Caen et al, 2015).

c) LIDOCAINE/MAJOR ADVERSE REACTIONS

1) Paresthesias; muscle twitching; confusion; slurred speech; seizures; respiratory depression or arrest; bradycardia; coma. May cause significant AV block or worsen pre-existing block. Prophylactic pacemaker may be required in the face of bifascicular, second degree, or third degree heart block (Prod Info Lidocaine HCl intravenous injection solution, 2006; Neumar et al, 2010).

d) LIDOCAINE/MONITORING PARAMETERS

1) Monitor ECG continuously; plasma concentrations as indicated (Prod Info Lidocaine HCl intravenous injection solution, 2006).

3) AMIODARONE

a) AMIODARONE/INDICATIONS

1) Effective for the control of hemodynamically stable monomorphic ventricular tachycardia. Also recommended for pulseless ventricular tachycardia or ventricular fibrillation in cardiac arrest unresponsive to CPR, defibrillation and vasopressor therapy (Link et al, 2015; Neumar et al, 2010). It should be used with caution when the ingestion involves agents known to cause QTc prolongation, such as fluoroquinolones, macrolide antibiotics or azoles, and when ECG reveals QT prolongation suspected to be secondary to overdose (Prod Info Cordarone(R) oral tablets, 2015).

b) AMIODARONE/ADULT DOSE

1) For ventricular fibrillation or pulseless VT unresponsive to CPR, defibrillation, and a vasopressor therapy give an initial dose of 300 mg IV followed by 1 dose of 150 mg IV. For stable ventricular tachycardias: Infuse 150 milligrams over 10 minutes, and repeat if necessary. Follow by a 1 milligram/minute infusion for 6 hours, then a 0.5 milligram/minute. Maximum total dose over 24 hours is 2.2 grams (Neumar et al, 2010).

c) AMIODARONE/PEDIATRIC DOSE

1) Infuse 5 milligrams/kilogram as a bolus for pulseless ventricular tachycardia or ventricular fibrillation; may repeat twice up to 15 mg/kg. Infuse 5 milligrams/kilogram over 20 to 60 minutes for perfusing tachycardias. Maximum single dose is 300 mg. Routine use with other drugs that prolong the QT interval is NOT recommended (Kleinman et al, 2010).

d) ADVERSE EFFECTS

1) Hypotension and bradycardia are the most common adverse effects (Neumar et al, 2010).

G) TORSADES DE POINTES

1) SUMMARY

a) Withdraw the causative agent. Hemodynamically unstable patients with Torsades de pointes (TdP) require electrical cardioversion. Emergent treatment with magnesium (first-line agent) or atrial overdrive pacing is indicated. Detect and correct underlying electrolyte abnormalities (ie, hypomagnesemia, hypokalemia, hypocalcemia). Correct hypoxia, if present (Drew et al, 2010; Neumar et al, 2010; Keren et al, 1981; Smith & Gallagher, 1980).
b) Polymorphic VT associated with acquired long QT syndrome may be treated with IV magnesium. Overdrive pacing or isoproterenol may be successful in terminating TdP, particularly when accompanied by bradycardia or if TdP appears to be precipitated by pauses in rhythm (Neumar et al, 2010). In patients with polymorphic VT with a normal QT interval, magnesium is unlikely to be effective (Link et al, 2015).

2) MAGNESIUM SULFATE

a) Magnesium is recommended (first-line agent) for the prevention and treatment of drug-induced torsades de pointes (TdP) even if the serum magnesium concentration is normal. QTc intervals greater than 500 milliseconds after a potential drug overdose may correlate with the development of TdP (Charlton et al, 2010; Drew et al, 2010). ADULT DOSE: No clearly established guidelines exist; an optimal dosing regimen has not been established. Administer 1 to 2 grams diluted in 10 milliliters D5W IV/IO over 15 minutes (Neumar et al, 2010). Followed if needed by a second 2 gram bolus and an infusion of 0.5 to 1 gram (4 to 8 mEq) per hour in patients not responding to the initial bolus or with recurrence of dysrhythmias (American Heart Association, 2005; Perticone et al, 1997). Rate of infusion may be increased if dysrhythmias recur. For persistent refractory dysrhythmias, a continuous infusion of up to 3 to 10 milligrams/minute in adults may be given (Charlton et al, 2010).
b) PEDIATRIC DOSE: 25 to 50 milligrams/kilogram diluted to 10 milligrams/milliliter for intravenous infusion over 5 to 15 minutes up to 2 g (Charlton et al, 2010).
c) PRECAUTIONS: Use with caution in patients with renal insufficiency.
d) MAJOR ADVERSE EFFECTS: High doses may cause hypotension, respiratory depression, and CNS toxicity (Neumar et al, 2010). Toxicity may be observed at magnesium levels of 3.5 to 4.0 mEq/L or greater (Charlton et al, 2010).
e) MONITORING PARAMETERS: Monitor heart rate and rhythm, blood pressure, respiratory rate, motor strength, deep tendon reflexes, serum magnesium, phosphorus, and calcium concentrations (Prod Info magnesium sulfate heptahydrate IV, IM injection, solution, 2009).

3) OVERDRIVE PACING

a) Institute electrical overdrive pacing at a rate of 130 to 150 beats per minute, and decrease as tolerated. Rates of 100 to 120 beats per minute may terminate torsades (American Heart Association, 2005). Pacing can be used to suppress self-limited runs of TdP that may progress to unstable or refractory TdP, or for override refractory, persistent TdP before the potential development of ventricular fibrillation (Charlton et al, 2010). In a case series overdrive pacing was successful in terminating TdP associated with bradycardia and drug-induced QT prolongation (Neumar et al, 2010).

4) POTASSIUM REPLETION

a) Potassium supplementation, even if serum potassium is normal, has been recommended by many experts (Charlton et al, 2010; American Heart Association, 2005). Supplementation to supratherapeutic potassium concentrations of 4.5 to 5 mmol/L has been suggested, although there is little evidence to determine the optimal range in dysrhythmia (Drew et al, 2010; Charlton et al, 2010).

5) ISOPROTERENOL

a) Isoproterenol has been successful in aborting torsades de pointes that was resistant to magnesium therapy in a patient in whom transvenous overdrive pacing was not an option (Charlton et al, 2010) and has been successfully used to treat torsades de pointes associated with bradycardia and drug induced QT prolongation (Keren et al, 1981; Neumar et al, 2010). Isoproterenol may have a limited role in pharmacologic overdrive pacing in select patients with drug-induced torsades de pointes and acquired long QT syndrome (Charlton et al, 2010; Neumar et al, 2010). Isoproterenol should be avoided in patients with polymorphic VT associated with familial long QT syndrome (Neumar et al, 2010).
b) DOSE: ADULT: 2 to 10 micrograms/minute via a continuous monitored intravenous infusion; titrate to heart rate and rhythm response (Neumar et al, 2010).
c) PRECAUTIONS: Correct hypovolemia before using; contraindicated in patients with acute cardiac ischemia (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).

1) Contraindicated in patients with preexisting dysrhythmias; tachycardia or heart block due to digitalis toxicity; ventricular dysrhythmias that require inotropic therapy; and angina. Use with caution in patients with coronary insufficiency (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).

d) MAJOR ADVERSE EFFECTS: Tachycardia, cardiac dysrhythmias, palpitations, hypotension or hypertension, nervousness, headache, dizziness, and dyspnea (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
e) MONITORING PARAMETERS: Monitor heart rate and rhythm, blood pressure, respirations and central venous pressure to guide volume replacement (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).

6) OTHER DRUGS

a) Mexiletine, verapamil, propranolol, and labetalol have also been used to treat TdP, but results have been inconsistent (Khan & Gowda, 2004).

7) AVOID

a) Avoid class Ia antidysrhythmics (eg, quinidine, disopyramide, procainamide, aprindine), class Ic (eg, flecainide, encainide, propafenone) and most class III antidysrhythmics (eg, N-acetylprocainamide, sotalol) since they may further prolong the QT interval and have been associated with TdP.

H) HYPOTENSIVE EPISODE

1) SUMMARY

a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.

2) CASE SERIES: Hypotension occurred in 3 of 8 pediatric patients exposed to amitraz, with 2 responding to intravenous fluids and 1 requiring several hours of dopamine therapy (Aydin et al, 1997).
3) Atropine pretreatment reversed bradycardia but not hypotension in animals exposed to amitraz (Cullen & Reynoldson, 1988).

I) HYPERTENSIVE EPISODE

1) Hypertension is generally transient and mild and does not require treatment. Aggressive therapy with hypotensive agents may result in profound and prolonged hypotension. If severe hypertension requires therapy use a short acting titratable agent.
2) Monitor vital signs regularly. For mild/moderate hypertension without evidence of end organ damage, pharmacologic intervention is generally not necessary. Sedative agents such as benzodiazepines may be helpful in treating hypertension and tachycardia in agitated patients, especially if a sympathomimetic agent is involved in the poisoning.
3) For hypertensive emergencies (severe hypertension with evidence of end organ injury (CNS, cardiac, renal), or emergent need to lower mean arterial pressure 20% to 25% within one hour), sodium nitroprusside is preferred. Nitroglycerin and phentolamine are possible alternatives.
4) SODIUM NITROPRUSSIDE/INDICATIONS

a) Useful for emergent treatment of severe hypertension secondary to poisonings. Sodium nitroprusside has a rapid onset of action, a short duration of action and a half-life of about 2 minutes (Prod Info NITROPRESS(R) injection for IV infusion, 2007) that can allow accurate titration of blood pressure, as the hypertensive effects of drug overdoses are often short lived.

5) SODIUM NITROPRUSSIDE/DOSE

a) ADULT: Begin intravenous infusion at 0.1 microgram/kilogram/minute and titrate to desired effect; up to 10 micrograms/kilogram/minute may be required (American Heart Association, 2005). Frequent hemodynamic monitoring and administration by an infusion pump that ensures a precise flow rate is mandatory (Prod Info NITROPRESS(R) injection for IV infusion, 2007). PEDIATRIC: Initial: 0.5 to 1 microgram/kilogram/minute; titrate to effect up to 8 micrograms/kilogram/minute (Kleinman et al, 2010).

6) SODIUM NITROPRUSSIDE/SOLUTION PREPARATION

a) The reconstituted 50 mg solution must be further diluted in 250 to 1000 mL D5W to desired concentration (recommended 50 to 200 mcg/mL) (Prod Info NITROPRESS(R) injection, 2004). Prepare fresh every 24 hours; wrap in aluminum foil. Discard discolored solution (Prod Info NITROPRESS(R) injection for IV infusion, 2007).

7) SODIUM NITROPRUSSIDE/MAJOR ADVERSE REACTIONS

a) Severe hypotension; headaches, nausea, vomiting, abdominal cramps; thiocyanate or cyanide toxicity (generally from prolonged, high dose infusion); methemoglobinemia; lactic acidosis; chest pain or dysrhythmias (high doses) (Prod Info NITROPRESS(R) injection for IV infusion, 2007). The addition of 1 gram of sodium thiosulfate to each 100 milligrams of sodium nitroprusside for infusion may help to prevent cyanide toxicity in patients receiving prolonged or high dose infusions (Prod Info NITROPRESS(R) injection for IV infusion, 2007).

8) SODIUM NITROPRUSSIDE/MONITORING PARAMETERS

a) Monitor blood pressure every 30 to 60 seconds at onset of infusion; once stabilized, monitor every 5 minutes. Continuous blood pressure monitoring with an intra-arterial catheter is advised (Prod Info NITROPRESS(R) injection for IV infusion, 2007).

9) NITROGLYCERIN/INDICATIONS

a) May be used to control hypertension, and is particularly useful in patients with acute coronary syndromes or acute pulmonary edema (Rhoney & Peacock, 2009).

10) NITROGLYCERIN/ADULT DOSE

a) Begin infusion at 10 to 20 mcg/min and increase by 5 or 10 mcg/min every 5 to 10 minutes until the desired hemodynamic response is achieved (American Heart Association, 2005). Maximum rate 200 mcg/min (Rhoney & Peacock, 2009).

11) NITROGLYCERIN/PEDIATRIC DOSE

a) Usual Dose: 29 days or Older: 1 to 5 mcg/kg/min continuous IV infusion. Maximum 60 mcg/kg/min (Laitinen et al, 1997; Nam et al, 1989; Rasch & Lancaster, 1987; Ilbawi et al, 1985; Friedman & George, 1985).

J) SEIZURE

1) Careful monitoring of blood pressure and cardiac rhythm should be conducted during treatment of seizures, since some of the drugs indicated for seizure control may cause hypotension and exacerbate the cardiovascular effects of amitraz.
2) SUMMARY

a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).

3) DIAZEPAM

a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .

4) NO INTRAVENOUS ACCESS

a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).

5) LORAZEPAM

a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).

6) PHENOBARBITAL

a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).

7) OTHER AGENTS

a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):

1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).

K) HYPERGLYCEMIA

1) Monitor glucose status and insulin regimen in diabetics. Hyperglycemia and glycosuria have been reported in humans exposed to amitraz. Animal studies have shown that amitraz inhibits insulin release in response to glucose challenge and may alter glucose metabolism. (Smith et al, 1990).

L) EXPERIMENTAL THERAPY

1) ALPHA-ADRENERGIC BLOCKADE

a) Various pharmacologic antagonists to amitraz have been successful in animals, but none have been reported to be used in human cases of amitraz overdose.
b) PHENTOLAMINE: Pretreatment with phentolamine in animals ameliorates the hypertension and bradycardia, but can exacerbate hypotension induced by amitraz (Cullen & Reynoldson, 1988).
c) YOHIMBINE: Administration of the specific alpha-2 receptor antagonist, yohimbine, reduces mydriasis, bradycardia, hyperglycemia, and decreased GI motility due to amitraz (Hsu & Kakuk, 1984; Hsu & McNeel, 1985; Smith et al, 1990).

Inhalation Exposure

6.7.1)

A) Move patient from the toxic environment to fresh air. Monitor for respiratory distress. If cough or difficulty in breathing develops, evaluate for hypoxia, respiratory tract irritation, bronchitis, or pneumonitis.
B) OBSERVATION: Carefully observe patients with inhalation exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.
C) INITIAL TREATMENT: Administer 100% humidified supplemental oxygen, perform endotracheal intubation and provide assisted ventilation as required. Administer inhaled beta-2 adrenergic agonists, if bronchospasm develops. Consider systemic corticosteroids in patients with significant bronchospasm (National Heart,Lung,and Blood Institute, 2007). Exposed skin and eyes should be flushed with copious amounts of water.

6.7.2)

A) PULMONARY ASPIRATION

1) Amitraz mixed with xylene or other solvents may produce aspiration pneumonitis following ingestion. Monitor respiratory status for at least 6 hours. Observe patients for initial symptoms of aspiration (coughing, choking, cyanosis).
2) Administer 100% humidified supplemental oxygen with assisted ventilation as required. Patients with symptoms of aspiration may develop delayed pulmonary edema. Extended monitoring is recommended in symptomatic individuals.

B) ACUTE LUNG INJURY

1) ONSET: Onset of acute lung injury after toxic exposure may be delayed up to 24 to 72 hours after exposure in some cases.
2) NON-PHARMACOLOGIC TREATMENT: The treatment of acute lung injury is primarily supportive (Cataletto, 2012). Maintain adequate ventilation and oxygenation with frequent monitoring of arterial blood gases and/or pulse oximetry. If a high FIO2 is required to maintain adequate oxygenation, mechanical ventilation and positive-end-expiratory pressure (PEEP) may be required; ventilation with small tidal volumes (6 mL/kg) is preferred if ARDS develops (Haas, 2011; Stolbach & Hoffman, 2011).

a) To minimize barotrauma and other complications, use the lowest amount of PEEP possible while maintaining adequate oxygenation. Use of smaller tidal volumes (6 mL/kg) and lower plateau pressures (30 cm water or less) has been associated with decreased mortality and more rapid weaning from mechanical ventilation in patients with ARDS (Brower et al, 2000). More treatment information may be obtained from ARDS Clinical Network website, NIH NHLBI ARDS Clinical Network Mechanical Ventilation Protocol Summary, http://www.ardsnet.org/node/77791 (NHLBI ARDS Network, 2008)

3) FLUIDS: Crystalloid solutions must be administered judiciously. Pulmonary artery monitoring may help. In general the pulmonary artery wedge pressure should be kept relatively low while still maintaining adequate cardiac output, blood pressure and urine output (Stolbach & Hoffman, 2011).
4) ANTIBIOTICS: Indicated only when there is evidence of infection (Artigas et al, 1998).
5) EXPERIMENTAL THERAPY: Partial liquid ventilation has shown promise in preliminary studies (Kollef & Schuster, 1995).
6) CALFACTANT: In a multicenter, randomized, blinded trial, endotracheal instillation of 2 doses of 80 mL/m(2) calfactant (35 mg/mL of phospholipid suspension in saline) in infants, children, and adolescents with acute lung injury resulted in acute improvement in oxygenation and lower mortality; however, no significant decrease in the course of respiratory failure measured by duration of ventilator therapy, intensive care unit, or hospital stay was noted. Adverse effects (transient hypoxia and hypotension) were more frequent in calfactant patients, but these effects were mild and did not require withdrawal from the study (Wilson et al, 2005).
7) However, in a multicenter, randomized, controlled, and masked trial, endotracheal instillation of up to 3 doses of calfactant (30 mg) in adults only with acute lung injury/ARDS due to direct lung injury was not associated with improved oxygenation and longer term benefits compared to the placebo group. It was also associated with significant increases in hypoxia and hypotension (Willson et al, 2015).

C) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Eye Exposure

6.8.1)

A) EYE IRRIGATION, ROUTINE: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, an ophthalmologic examination should be performed (Peate, 2007; Naradzay & Barish, 2006).

Dermal Exposure

6.9.1)

A) DERMAL DECONTAMINATION

1) Remove contaminated clothing.
2) DECONTAMINATION: Remove contaminated clothing and wash exposed area thoroughly with soap and water for 10 to 15 minutes. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).

Enhanced Elimination

1) Efforts to enhance elimination in animals have included diuretics and reduction of urine pH with ammonium chloride to enhance elimination of the toxic metabolite. None of these treatments were of benefit in terms of survival or severity of treatment (Turnbull, 1983).
2) Experimental studies have not shown induction of diuresis or alteration of urine pH to be effective in reversing the toxicity of amitraz (Upjohn, 1983).

Abstracts

Case Reports

1) A 74-year-old diabetic man who drank less than 30 mL (containing 6 g of amitraz) developed glycosuria, coma and hypertension (200/100 mmHg). Baseline blood pressure readings were not provided. Liver enzymes were slightly elevated (SGOT, 92, SGPT 35, alk phos 166) (Bonsall & Turnball, 1983).
2) Brief immersion of an adult in a diluted cattle dip formulation resulted in vomiting, headache and malaise 36 hours later. A cause-effect relationship was questionable. A viral infection could not be ruled out (Bonsall & Turnball, 1983).
3) A mentally handicapped 22-year-old man was comatose (Glasgow coma score of 3) within about 1 hour of ingesting approximately 12.5 g amitraz in a 25 to 100 mL solution. Treatment included gastric lavage, activated charcoal and sodium sulphate administration. The patient recovered the next day (Ros & van Aken, 1994).
4) A death occurred 6 days after a suicide attempt; no details were available (Bonsall & Turnball, 1983).

1) A 3-year-old child became drowsy for several hours after ingesting a small amount of an amitraz solution (Bonsall & Turnball, 1983).
2) A 3-year-old girl who ingested 10.6 mL of amitraz/xylene was comatose and hyperglycemic upon return presentation to the emergency department (ED). She had initially been discharged asymptomatic from the ED and had developed symptoms on the return trip home (Jones, 1990). Additional details were not provided.

Range Of Toxicity

Summary

Minimum Lethal Exposure

1) Very little human data exist regarding the range of toxicity for ingested amitraz. Death has been reported in an adult who intentionally ingested an unknown concentration of amitraz (Bonsall & Turnball, 1983).
2) CASE REPORT: A 53-year-old woman became comatose, developed persistent hypotension and torsades de pointes, and subsequently died after intentionally ingesting 500 mL of a pesticide containing 20% amitraz (Hu et al, 2010).

Maximum Tolerated Exposure

1) ADULT

a) A mentally handicapped 22-year-old man became comatose 1 hr after ingesting approximately 12.5 grams or less of amitraz in a solution. Gastric lavage, activated charcoal and sodium sulphate were administered. The individual recovered the next day (Ros & van Aken, 1994).
b) A 30-year-old man survived after ingesting 100 milliliters of an amitraz/petroleum distillate mixture believed to contain 12.5 grams of amitraz (Kennel et al, 1996). Spontaneous vomiting occurred.
c) A 74-year-old diabetic man believed to have ingested 6 grams or less of amitraz (30 milliliters of a xylene mixture) was unconscious for 24 hours (Bonsall & Turnball, 1983).
d) A 29-year-old man survived a three minute period of immersion to the shoulders in a dilute amitraz cattle dip (Bonsall & Turnball, 1983).
e) A 35-year-old man presented to the emergency department comatose (Glasgow Coma Scale 3) and hypothermic (34.5 degrees C) approximately 3 hours after intentionally ingesting approximately 50 to 100 milliliters of a product containing 12.5% amitraz in a xylene emulsion (6.25 to 12.5 grams total amount of amitraz ingested). The patient required mechanical ventilation after developing respiratory arrest. The patient also developed severe hypotension and bradycardia (35 bpm). Following supportive care, the patient gradually recovered and was extubated approximately 24 hours post-ingestion(Doganay et al, 2002).
f) An 80-year-old man developed drowsiness, miosis, mild hypothermia (35.5 degrees C), respiratory distress, hyperglycemia, polyuria, and elevated liver enzyme levels after unintentionally ingesting approximately 1.8 grams amitraz. The onset of symptoms occurred approximately 1 hour post-ingestion. The patient gradually recovered following supportive care(Doganay et al, 2002).
g) A 22-year-old woman developed hypotension, bradycardia, respiratory depression, and became comatose following intentional intravenous administration of 5 to 6 mL of a solution containing 12.5% amitraz and 57.5% xylene in water. The patient recovered following supportive therapy (Gursoy et al, 2005).

2) PEDIATRIC

a) A 3-year-old girl developed coma and severe hyperglycemia after ingesting approximately 10.6 milliliters of an amitraz containing solution (Jones, 1990).
b) A 17-year-old survived following ingestion of about 6 grams of amitraz (50 milliliters of amitraz/petroleum distillate) but was in a deep coma, was hypotensive and bradycardic (Kennel et al, 1996).
c) A 4-month-old infant developed hypothermia, drowsiness, and bradycardia after ingesting 0.3 mL of a 5% amitraz solution (2.5 mg/kg). The infant completely recovered following supportive care (Zoelen et al, 2001).
d) A 13-year-old boy was comatose (GCS 3) and hypotensive (70/50 mmHg) after ingesting 125 mL of a pesticide containing 12.5% amitraz. With symptomatic and supportive therapy, the patient gradually recovered without sequelae (Varma et al, 2013).

1) Dogs demonstrated no signs of toxicity after 0.25 milligram/kilogram orally and 16 milligrams/kilogram dermally. At parenteral doses of 20 mg/kg or greater, hypotension and bradycardia occurred (Anon, 1980).
2) Rats sprayed twice 14 days apart with up to a 2000 parts per million concentration of amitraz solution showed no evidence of toxicity (Al-Qarawi et al, 1999).

Serum Plasma Blood Concentrations

7.5.2)

A) TOXIC CONCENTRATION LEVELS

1) ADULT

a) Serum concentration of amitraz was reported to be 450 nanograms/milliliter in a 45-year-old male about one hour following an estimated ingestion of 250 milligrams (Jorens et al, 1997).
b) Serum concentration of amitraz was reported to be 500 nanograms/milliliter 2 hours after ingestion in a patient who only exhibited drowsiness (Garnier et al, 1998).
c) Serum concentration of 100 nanograms/milliliter of amitraz was reported 2 hours after ingestion in an asymptomatic patient (Garnier et al, 1998).

Workplace Standards

1) Not Listed

1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
2) EPA (U.S. Environmental Protection Agency, 2011): Not Assessed under the IRIS program. ; Listed as: Amitraz
3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
5) MAK (DFG, 2002): Not Listed
6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

1) Not Listed

Toxicity Information

7.7.1)

A) References: Anon, 1980 RTECS, 2001

1) LD50- (ORAL)MOUSE:

a) 1085 mg/kg

2) LD50- (ORAL)RAT:

a) 515-938 mg/kg

Pharmacology Toxicology

Toxicologic Mechanism

1) The primary mechanism of toxicity is stimulation of pre- and post- synaptic alpha(2) adrenergic receptors (effects similar to clonidine). The amitraz metabolite BTS 27 271 (N-2,4-dimethyl phenyl-N-methyl formamidine) is a partial agonist of alpha adrenergic receptors and an antagonist of norepinephrine receptors (reviewed in Bonsall & Turnbull, 1983). The specific toxic effects, following amitraz poisoning, and their mechanisms are as follows (Avsarogullari et al, 2006):

a) Bradycardia - Inhibition of presynaptic noradrenaline release and increased baroreflex activity.
b) CNS depression - Alpha2-adrenergic receptor stimulation.
c) Decreased intestinal motility - Inhibition of acetylcholine release in the parasympathetic nerve, which decreases gut motility.
d) Hyperglycemia - Inhibition of insulin secretion.
e) Hypotension - Presynaptic stimulation, central vasomotor effect, and endothelial-derived relaxation factor (EDRF).
f) Hypothermia - Through a direct effect on the thermoregulation center of the hypothalamus.
g) Increased urinary output - Decreased ADH and renin secretion, inhibition of ADH effect and enhanced diuresis through an increased glomerular filtration rate.
h) Pupil size - Miosis: presynaptic effect at low doses. Mydriasis: postsynaptic effect at higher doses.
i) Respiratory depression - Direct effect on the respiratory center with inhibition of the response to CO2.

2) Amitraz interacts with high potency and specificity with alpha (2) adrenoceptors in vitro and after in vivo administration in mouse models (Costa et al, 1988).
3) Amitraz competitively inhibits the binding of radiolabeled clonidine to alpha(2) adrenoceptors in mice and isolated mouse forebrains in a dose-related manner (Costa et a, 1988). Decreased affinity of clonidine at the receptors was shown, but the maximum binding capacity of clonidine was not altered.

1) Amitraz is a weak inhibitor of (MAO) activity in rat and mouse liver, brain and lung tissue. One of the major metabolites of amitraz, BTS-27271, is also an inhibitor of liver monoamine oxidase in vitro (Aziz & Knowles, 1973).
2) Neither amitraz nor the metabolite has significant central MAO inhibitor activity in vivo. The neurotoxic and other acute effects of amitraz are not believed to be mediated by MAO inhibition by amitraz or amitraz metabolites (reviewed in Bonsall & Turnbull, 1983; (Costa et al, 1988; Moser & MacPhail, 1989).
3) MAO inhibition may contribute to toxic effects occurring with very large doses.

Physicochemical

Physical Characteristics

Molecular Weight

Animal Toxicology

Clinical Effects

11.1.3)

A) Clinical signs of amitraz toxicity in a series of 8 dogs with dermal exposure included bradycardia, ataxia, depression, anorexia, bradypnea, hypothermia, vomiting, seizures, disorientation, and incoordination (Jones, 1990). Also reported are hypotension, distended abdomen, and hyperglycemia (Grossman, 1993).
B) Nine dogs with oral and dermal exposures exhibited CNS signs ranging from mild depression to head pressing and coma. Other signs and symptoms included bradycardia, bloating and ileus, diarrhea, mydriasis, polyuria hyperthermia, hypothermia, and vomiting (Hovda & McMcManus, 1993).
C) Hyperglycemia has been reported in dogs (Hsu & Schaffer, 1988). The onset of hyperglycemia was 4 hours after dermal application of concentrations as low as 2.1 g/7.56 L (277 ppm).

1) MECHANISM - Amitraz had no effect on baseline insulin levels, but markedly inhibited insulin release after a glucose load in a dose-dependent manner. After 1 g/kg IV in dogs, insulin release was totally blocked. This effect is reversed by the specific alpha-2-adrenergic inhibitor, yohimbine (Hsu & Schaffer, 1988; Smith et al, 1990).

11.1.5)

A) Three of 4 horses sprayed with a 3-week-old amitraz aqueous suspension developed sedation, depression, ataxia, and impaction colic lasting up to 6 days (Auer et al, 1984). Amitraz is contraindicated in horses.

Treatment

11.2.2)

A) GENERAL

1) MAINTAIN VITAL FUNCTIONS: Secure airway, supply oxygen, and begin supportive fluid therapy if necessary.

11.2.4)

A) GASTRIC DECONTAMINATION

1) GENERAL TREATMENT

a) Gastric lavage or nasogastric suction is probably indicated in most ingestions. Activated charcoal had no effect on clinical outcome in rats. Emesis is not indicated due to the xylene component and potential for aspiration and/or CNS depression.

11.2.5)

A) GENERAL TREATMENT

1) Treatment is primarily supportive. Following dermal exposure, dogs should be bathed and removed from stress for a least 24 hours. Yohimbine may be useful for bradycardia, hypertension CNS depression and gastrointestinal symptoms (Jones, 1990; Hovda & McManus, 1993). If yohimbine is unavailable atropine may be administered for severe bradycardia. Disadvantages of atropine include potentiation of pressor effects of amitraz, such as hypertension and cardiac arrhythmias, and aggravation of hypomotility leading to intestinal ileus or gastric distention (Grossman, 1993).

B) DOG

1) YOHIMBINE - 0.1 mg/kg IV slowly (Plumb, 1991). This dose has been repeated for a total of 3 doses in cases of persistent symptoms (Hovda & McManus, 1993).
2) ATROPINE - 0.02 mg/kg IM. This dose may be repeated for persistent bradycardia (Grossman, 1993).

Continuing Care

11.4.2)

11.4.2.2) GASTRIC DECONTAMINATION

A) GASTRIC DECONTAMINATION

1) GENERAL TREATMENT

References

General Bibliography

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AMITRAZ

Classification | Detailed evidence-based information

Therapeutic Toxic Class

Specific Substances

Available Forms Sources

Life Support

Clinical Effects

Laboratory Monitoring

Treatment Overview

Range Of Toxicity

Summary Of Exposure

Vital Signs

Heent

Cardiovascular

Respiratory

Neurologic

Gastrointestinal

Hepatic

Genitourinary

Acid-Base

Dermatologic

Endocrine

Reproductive

Carcinogenicity

Genotoxicity

Monitoring Parameters Levels

Methods

Life Support

Patient Disposition

Monitoring

Oral Exposure

Inhalation Exposure

Eye Exposure

Dermal Exposure

Enhanced Elimination

Case Reports

Summary

Minimum Lethal Exposure

Maximum Tolerated Exposure

Serum Plasma Blood Concentrations

Workplace Standards

Toxicity Information

Toxicologic Mechanism

Physical Characteristics

Molecular Weight

Clinical Effects

Treatment

Continuing Care

General Bibliography