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XYLAZINE AND RELATED AGENTS

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Xylazine and related agents including detomidine, medetomidine and dexmedetomidine hydrochloride are used in veterinary medicine as tranquilizers with sedative, analgesic, and muscle relaxant properties. They have characteristics similar to the phenothiazines. Their toxic actions are similar to clonidine and the phenothiazines.

Specific Substances

    A) XYLAZINE
    1) 2-(2,6-xylidino)-5,6-dihydro-4H-1,3 thiazine HCl
    2) CAS 7361-61-7
    DETOMIDINE
    1) 4-(2,3-Dimethylbenzyl)imidazole hydrochloride
    2) Detomidine Hydrochloride
    3) Demotidini Hydrochloridum
    4) Hidrocloruro de detomidina
    5) MPV-253-All
    6) CAS 76631-46-4 (detomidine)
    7) CAS 90038-01-0 (detomidine hydrochloride)
    MEDETOMIDINE
    1) MPV-1440
    2) Molecular Formula: C13-H16-N2,HCl
    3) CAS 86347-15-1 (Medetomidine hydrochloride)
    4) CAS 86347-14-0 (Medetomidine)

Available Forms Sources

    A) FORMS
    1) XYLAZINE
    1) XYLAZINE TRADE NAMES INCLUDE: BAY 1470, BAY VA 1470, Rompun(R)
    2) ROMPUN(R) FOR HORSES: 100 mg/mL, 50 mL vial.
    3) ROMPUN(R) FOR DOGS AND CATS: 20 mg/mL, 20 mL vial
    B) USES
    1) XYLAZINE
    a) SUMMARY
    1) Xylazine is an animal tranquilizer with sedative, analgesic, and muscle relaxant properties. Xylazine is not approved by the FDA for human use.
    2) It is a potent alpha(2)-adrenergic agonist that can produce sedation, muscle relaxation, nervous system depression, respiratory depression and cardiovascular effects (ie, hypotension, brady- or tachycardia, premature ventricular contractions) (Ruiz-Colon et al, 2014).
    b) VETERINARY USE
    1) Xylazine is an animal tranquilizer with sedative, analgesic, and muscle relaxant properties. It has characteristics similar to the phenothiazines (Lewis et al, 1983). Xylazine is not used in man due to marked hypotension. Its toxic actions are similar to clonidine and the phenothiazines (Gallanosa et al, 1981). Xylazine is used to induce vomiting in cats.
    c) ADULTERANT
    1) In recent years, xylazine has emerged as an adulterant in drugs of abuse, such as heroin or speedball (a cocaine and heroin mixture). Heroin abusers have reported a feeling of euphoria or a "rush" when heroin and xylazine is combined followed by a twilight state of sleep and wakefulness. Some individuals have died following exposure to xylazine when used as an adulterant (Ruiz-Colon et al, 2014).
    2) DETOMIDINE
    a) Detomidine is a selective alpha(2)-adrenoceptor agonist with anxiolytic, analgesic, and sedative properties used as a sedative/hypnotic agent in large animals (e.g., horses, cattle).
    3) DEXMEDETOMIDINE HYDROCHLORIDE
    a) Dexmedetomidine hydrochloride is a selective alpha2-adrenergic receptor agonist with anxiolytic, analgesic, and sedative properties used for the sedation of intubated and mechanically ventilated patients in the ICU setting (Prod Info PRECEDEX(R) injection, 2004). It has also been approved for use in dogs for sedation and analgesia (Sundlof, 2007).
    b) For further information see DEXMEDETOMIDINE HYDROCHLORIDE management.
    4) MEDETOMIDINE HYDROCHLORIDE
    a) Medetomidine hydrochloride is a selective alpha2-adrenergic receptor agonist used in veterinary medicine as a sedative-analgesic agent. It is a racemate to dexmedetomidine hydrochloride (Sweetman, 2007).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: VETERINARY: Xylazine is an animal tranquilizer with sedative, analgesic, and muscle relaxant properties. Xylazine is also used to induce vomiting in cats. Xylazine is not approved for human use. Detomidine and medetomidine are selective alpha(2)-adrenoceptor agonists with anxiolytic, analgesic, and sedative properties used as a sedative/hypnotic agent in veterinary medicine. ADULTERANT: In recent years, xylazine has emerged as an adulterant in drugs of abuse, such as heroin or speedball (a cocaine and heroin mixture). Heroin abusers have reported a feeling of euphoria or a "rush" when heroin and xylazine is combined followed by a twilight state of sleep and wakefulness. Some individuals have died following exposure to xylazine when used as an adulterant.
    B) PHARMACOLOGY: Xylazine is a potent alpha(2)-adrenergic agonist that can produce sedation, muscle relaxation, nervous system depression, respiratory depression and cardiovascular effects (ie, hypotension, brady- or tachycardia, premature ventricular contractions). Xylazine is NOT used in humans due to marked hypotension. Its toxic actions are similar to clonidine and the phenothiazines.
    C) TOXICOLOGY: Xylazine is NOT used in humans due to marked hypotension. Its toxic actions are similar to clonidine and the phenothiazines.
    D) EPIDEMIOLOGY: Exposure has occurred. These agents have been abused or misused by humans and exposure has occurred following inadvertent exposure in veterinary medicine.
    E) WITH POISONING/EXPOSURE
    1) OVERDOSE: Xylazine is NOT used in humans due to marked hypotension. The primary toxic effects seen after acute overdose with xylazine are hypotension, bradycardia, and respiratory depression. Dysrhythmias and hyperglycemia have also been reported. Xylazine is intended only as a veterinary drug but is occasionally abused by humans.
    2) OCULAR EXPOSURE: Inadvertent copious eye irrigation with xylazine (agent confused with eye irrigant) in an adult resulted in systemic toxicity approximately 2 hours after exposure which included bradycardia and hypotension; symptoms resolved within 25 hours following supportive care.
    3) DEXMEDETOMIDINE HYDROCHLORIDE is approved for sedation of intubated/mechanically ventilated patients in the ICU setting. For further information see DEXMEDETOMIDINE HYDROCHLORIDE management.
    0.2.20) REPRODUCTIVE
    A) At the time of this review, no data were available to assess the potential effects of exposure to this agent during pregnancy or lactation.

Laboratory Monitoring

    A) Monitor CNS and respiratory function.
    B) Monitor vital signs including blood pressure. Institute continuous cardiac monitoring and pulse oximetry monitoring. Obtain a baseline ECG and repeat as indicated.
    C) Although serum and urinary levels have been measured, their correlation to toxic manifestations is not well understood. Therefore, they have little utility in managing acute exposures.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Although xylazine is primarily an injectable drug, ingestion of the injectable formulation has occurred. Treatment is supportive and directed mainly at managing apnea or the loss of protective airway reflexes, bradycardia, and hypotension. Monitor vital signs including blood pressure. Bradycardia, hypotension and CNS depression often respond to physical stimulation. For mild hypotension begin IV 0.9% NaCl at 10 to 20 mL/kg. Bradycardia is typically mild and usually doesn't require any treatment. Naloxone has been used to reverse CNS depression with inconsistent success following clonidine exposure.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Severe bradycardia associated with hypotension and not responsive to physical stimulation should be treated with standard dose of atropine or cardiac pacing. Norepinephrine or dopamine may be beneficial in patients with severe bradycardia and hypotension not responding to physical stimulation, naloxone, intravenous crystalloid, and atropine. Patients with significant CNS and/or respiratory depression should be intubated. Paradoxical hypertension secondary to xylazine or related agents warrants caution due to the transient nature of this effect, which may be followed by hypotension. Aggressive therapy with antihypertensive agents may exacerbate hypotension. Life-threatening hypertension with end-organ effects should be managed with nitroprusside.
    C) DECONTAMINATION
    1) PREHOSPITAL: Gastrointestinal decontamination is unlikely to be necessary because these agents are available parenterally. If ingestion should occur, activated charcoal is not recommended because of the potential risk of altered mental status. If dermal exposure should occur, wash the exposed area with water.
    2) HOSPITAL: Xylazine is primarily an injectable drug; however, if ingestion of the parenteral product has occurred. Consider activated charcoal if the ingestion is recent and the patient is alert and the airway can be protected.
    D) AIRWAY MANAGEMENT
    1) Assess respiratory function. Airway protection including intubation and mechanical ventilation may be necessary if their is a loss of protective airway reflexes. Monitor pulse oximetry and obtain ABGs as indicated.
    E) ANTIDOTE
    1) There is no specific antidote. Although some patients have responded to naloxone (reversal of altered mental status, respiratory depression or apnea, and miosis) following clonidine exposure, not all patients respond. Naloxone should be administered to patients with significant CNS or respiratory depression; however, of the limited cases where it was used following xylazine exposure, the patients did not respond. Tolazoline (an alpha-2 adrenergic antagonist) has been suggested as an antidote, but there is little clinical experience with its use following a xylazine exposure. Most patients do well with supportive care.
    F) VENTRICULAR ARRHYTHMIAS
    1) Sinus tachycardia and multifocal PVCs have been reported following exposure to xylazine; ventricular dysrhythmias have not been reported. Institute continuous cardiac monitoring, obtain an ECG, and administer oxygen. Evaluate for hypoxia, acidosis, and electrolyte disorders. 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.
    G) ENHANCED ELIMINATION
    1) Xylazine has high lipid solubility and it is predicted that it has a large volume of distribution. Thus, like clonidine, it is unlikely that hemodialysis would remove significant amounts of xylazine. Forced diuresis is also NOT thought to significantly enhance elimination of xylazine.
    H) PATIENT DISPOSITION
    1) HOME CRITERIA: A patient with an inadvertent exposure (eg, occupational exposure via a needlestick) should be monitored in a healthcare center due to the risk of marked hypotension following human exposure.
    2) OBSERVATION CRITERIA: Patients with a deliberate overdose, and those who are symptomatic (ie, hypotension, bradycardia), need to be monitored until they are clearly improving and clinically stable.
    3) ADMISSION CRITERIA: Patients with severe, persistent symptoms (eg, hypotension, bradycardia, cardiac dysrhythmias) despite treatment should be admitted. An ICU setting may be necessary if the patient requires intubation and mechanical ventilation or if significant CNS depression is present.
    4) CONSULT CRITERIA: Consult a regional poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    I) PITFALLS
    1) Failure to obtain adequate history of exposure. Failure to detect airway compromise and to properly manage the patient's airway. Failure to detect dysrhythmias or hypotension.
    J) DIFFERENTIAL DIAGNOSIS
    1) Other chemicals or drugs that cause CNS and/or respiratory depression (eg, toxic alcohols, benzodiazepines, opiates/opioids, antipsychotic medications).
    0.4.4) EYE EXPOSURE
    A) DECONTAMINATION: 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, the patient should be seen in a healthcare facility.

Range Of Toxicity

    A) TOXICITY: XYLAZINE: A toxic dose is highly variable. Based on the literature, the known doses of toxicity and fatalities in humans has varied from 40 to 2400 mg. As little as 7 mg of xylazine IV has caused anesthesia and bradycardia. Doses as low as 0.73 mg/kg IM may produce mild symptoms. Intravenous administration of 1000 mg (15 mg/kg) produced coma and apnea and ingestion of 400 mg has caused profound sedation. DETOMIDINE: A woman was accidentally injected with 3 mg of detomidine that was intended for a horse, and developed asymptomatic bradycardia and sleepiness.

Clinical Effects

Summary Of Exposure

    A) USES: VETERINARY: Xylazine is an animal tranquilizer with sedative, analgesic, and muscle relaxant properties. Xylazine is also used to induce vomiting in cats. Xylazine is not approved for human use. Detomidine and medetomidine are selective alpha(2)-adrenoceptor agonists with anxiolytic, analgesic, and sedative properties used as a sedative/hypnotic agent in veterinary medicine. ADULTERANT: In recent years, xylazine has emerged as an adulterant in drugs of abuse, such as heroin or speedball (a cocaine and heroin mixture). Heroin abusers have reported a feeling of euphoria or a "rush" when heroin and xylazine is combined followed by a twilight state of sleep and wakefulness. Some individuals have died following exposure to xylazine when used as an adulterant.
    B) PHARMACOLOGY: Xylazine is a potent alpha(2)-adrenergic agonist that can produce sedation, muscle relaxation, nervous system depression, respiratory depression and cardiovascular effects (ie, hypotension, brady- or tachycardia, premature ventricular contractions). Xylazine is NOT used in humans due to marked hypotension. Its toxic actions are similar to clonidine and the phenothiazines.
    C) TOXICOLOGY: Xylazine is NOT used in humans due to marked hypotension. Its toxic actions are similar to clonidine and the phenothiazines.
    D) EPIDEMIOLOGY: Exposure has occurred. These agents have been abused or misused by humans and exposure has occurred following inadvertent exposure in veterinary medicine.
    E) WITH POISONING/EXPOSURE
    1) OVERDOSE: Xylazine is NOT used in humans due to marked hypotension. The primary toxic effects seen after acute overdose with xylazine are hypotension, bradycardia, and respiratory depression. Dysrhythmias and hyperglycemia have also been reported. Xylazine is intended only as a veterinary drug but is occasionally abused by humans.
    2) OCULAR EXPOSURE: Inadvertent copious eye irrigation with xylazine (agent confused with eye irrigant) in an adult resulted in systemic toxicity approximately 2 hours after exposure which included bradycardia and hypotension; symptoms resolved within 25 hours following supportive care.
    3) DEXMEDETOMIDINE HYDROCHLORIDE is approved for sedation of intubated/mechanically ventilated patients in the ICU setting. For further information see DEXMEDETOMIDINE HYDROCHLORIDE management.

Vital Signs

    3.3.2) RESPIRATIONS
    A) WITH POISONING/EXPOSURE
    1) Respiratory depression may occur; most patients with significant overdoses develop apnea (Capraro et al, 2001; Spoerke et al, 1986; Samanta et al, 1990).
    3.3.3) TEMPERATURE
    A) WITH POISONING/EXPOSURE
    1) Hypothermia has been reported in animals following injections of xylazine (Livingston et al, 1984) and in a human following intentional inhalation of xylazine powder (Capraro et al, 2001).
    3.3.4) BLOOD PRESSURE
    A) WITH POISONING/EXPOSURE
    1) Hypotension is the usual cardiovascular effect with toxicity (Spoerke et al, 1986; Samanta et al, 1990; Capraro et al, 2001).
    2) Transient paradoxical hypertension has been reported after human overdose (Spoerke et al, 1986).
    3.3.5) PULSE
    A) WITH POISONING/EXPOSURE
    1) Bradycardia is a common manifestation after overdose with xylazine (Spoerke et al, 1986; Samanta et al, 1990; Capraro et al, 2001; Hoffmann et al, 2001).

Heent

    3.4.3) EYES
    A) MIOSIS (Spoerke et al, 1986; Capraro et al, 2001; Hoffmann et al, 2001) and sluggishly reacting pupils were reported after human exposures (Gallanosa et al, 1981; Samanta et al, 1990).
    B) MYDRIASIS has been reported in animal models (Hsu, 1981).
    C) INTRAOCULAR PRESSURE: Unilateral instillation of xylazine lowered intraocular pressure bilaterally in rabbits, cats, and monkeys (Burke & Potter, 1986). Concurrent administration of xylazine and timolol in the eye produced significant ocular hypotension (Burke & Potter, 1986).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) BRADYCARDIA
    1) WITH POISONING/EXPOSURE
    a) XYLAZINE
    1) Sinus bradycardia frequently occurs with overdose. Heart rate may range from 35 to 45 beats/min (Lewis et al, 1983; Cummins, 2005).
    2) Bradycardia (45 beats/min) was reported in 2 teenagers following intentional inhalation of xylazine. Both patients recovered with supportive care (Elejalde et al, 2003; Capraro et al, 2001).
    3) CASE REPORT: A 27-year-old man developed bradycardia (heart rate 50 beats/min) after injecting 75 ml of 2% xylazine IM (Hoffmann et al, 2001).
    4) CASE REPORT: A 38-year-old man developed sinus bradycardia (heart rate 40 to 50 beats/min) approximately 2 hours after unintentional irrigation of both eyes with 8 mL of xylazine (100 mg/mL). The bradycardia resolved approximately 25 hours postexposure following the administration of IV fluids and supportive care (Velez et al, 2006).
    B) ELECTROCARDIOGRAM ABNORMAL
    1) WITH POISONING/EXPOSURE
    a) T-wave flattening and inversion were seen in one serious overdose (Carruthers et al, 1979).
    C) TACHYARRHYTHMIA
    1) WITH POISONING/EXPOSURE
    a) Sinus tachycardia occurred in one patient following intramuscular injection of 10 mL of 100 mg/mL xylazine solution (total dose 1000 mg) (Carruthers et al, 1979).
    D) CONDUCTION DISORDER OF THE HEART
    1) WITH POISONING/EXPOSURE
    a) PVCs (multifocal) were reported by Carruthers et al (1979) in a patient who injected 1000 mg intramuscularly.
    E) HYPOTENSIVE EPISODE
    1) WITH POISONING/EXPOSURE
    a) XYLAZINE
    1) Hypotension responsive to intravenous fluids has been reported in overdose (Gallanosa et al, 1981; Hoffmann et al, 2001; Elejalde et al, 2003; Cummins, 2005).
    2) CASE REPORT: Hypotension (90/60 mmHg) was reported in a 38-year-old man approximately 2 hours after unintentionally irrigating both eyes with 8 mL of xylazine solution (100 mg/mL). The patient recovered approximately 25 hours post exposure following administration of IV fluids and supportive care (Velez et al, 2006).
    F) HYPERTENSIVE EPISODE
    1) WITH POISONING/EXPOSURE
    a) XYLAZINE
    1) Transient paradoxical hypertension has been reported in animals and humans. The mechanism is similar to the hypertension caused by clonidine (Gallanosa et al, 1981).
    G) MYOCARDITIS
    1) WITH POISONING/EXPOSURE
    a) Based on elevated cardiac isoenzymes, it is suggested that a direct toxic effect on the myocardium by xylazine occurs (Carruthers et al, 1979).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) ACUTE RESPIRATORY INSUFFICIENCY
    1) WITH POISONING/EXPOSURE
    a) XYLAZINE
    1) Apnea was reported with a dose of 1 g administered intramuscularly (Carruthers et al, 1979), 400 mg orally (Gallanosa et al, 1981), and 200 mg subQ (Samanta et al, 1990).
    2) CASE REPORT: A 16-year-old boy intentionally inhaled xylazine powder and developed shallow breathing with intermittent episodes of apnea. He was intubated and transferred to a pediatric intensive care unit. Two hours after inhalation, his xylazine blood level was 0.54 mcg/mL. The patient was extubated 14 hours later and had no permanent sequelae (Capraro et al, 2001).
    3) CASE REPORT: A 14-year-old boy was inadvertently injected (incompletely injected) with an arrow containing xylazine and ketamine (the medications were intended for a deer) into his leg and lost consciousness. He required intubation and mechanical ventilation. Vital signs were stable. Ventilation was required for 4 hours. He developed symptoms of nightmares, nausea, vomiting and dizziness but recovered completely (Meyer et al, 2013).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) CENTRAL NERVOUS SYSTEM DEFICIT
    1) WITH POISONING/EXPOSURE
    a) XYLAZINE
    1) Coma, drowsiness, slurred speech, faintness, and fatigue have been reported (Meyer et al, 2013; Lewis et al, 1983; Velez et al, 2006).
    2) A feeling of disorientation may occur (Spoerke et al, 1986).
    3) Coma developed after intramuscular administration of 10 mL of a 100 mg/mL xylazine solution (total dose 1000 mg). There were no other coingestants involved. The patient did not regain complete consciousness for 60 to 72 hours(Carruthers et al, 1979).
    4) CASE REPORT: A 14-year-old boy was inadvertently injected (incompletely injected) with an arrow containing xylazine and ketamine (the medications were intended for a deer) into his leg and lost consciousness. He required intubation and mechanical ventilation. Vital signs were stable. Ventilation was required for 4 hours. He developed symptoms of nightmares, nausea, vomiting and dizziness but recovered completely (Meyer et al, 2013).
    5) CASE REPORT: A 16-year-old boy intentionally inhaled xylazine powder and subsequently developed stupor and lethargy. The patient presented to the ED unresponsive with hypotension and shallow breathing with intermittent apnea. The patient was given 2 mg naloxone with no response and he was intubated because of apnea and coma. Two hours after initial exposure, the patient's blood xylazine level was 0.54 mcg/mL. Twelve hours later, the patient was extubated. Symptoms fully resolved 20 hours after initial xylazine exposure (Capraro et al, 2001).
    6) CASE REPORT: A 27-year-old man was found comatose after injecting 75 mL of 2% xylazine intramuscularly (Hoffmann et al, 2001).
    b) Detomidine
    1) CASE REPORT: A 23-year-old woman was accidentally injected with 3 mg of detomidine (0.3 mL Domosedan(R)) intramuscularly, which had been intended for a 200 kilogram horse. She developed asymptomatic bradycardia (56 beats/min) and sleepiness. The patient was observed for 7 hours and then discharged (Pohjalainen et al, 2001).
    2) CASE REPORT: A 35-year-old farmer developed drowsiness and dizziness within 10 minutes of unintentionally injecting himself with detomidine hydrochloride in an attempt to sedate a bull. The patient presented with drowsiness, slurred speech, euphoria, bradycardia (44 beats/min), and hypotension (BP 106/48). An ECG showed sinus bradycardia without evidence of heart block or ischemia. The patient gradually recovered with supportive care (Cummins, 2005).
    B) HYPOREFLEXIA
    1) WITH POISONING/EXPOSURE
    a) Hyporeflexia is a common finding after overdose (Gallanosa et al, 1981).
    b) Hypotonia and diminished reflexes occurred following xylazine powder inhalation (Capraro et al, 2001).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) VOMITING
    1) WITH POISONING/EXPOSURE
    a) XYLAZINE
    1) Emesis has been a consistent side effect in animals, but it has not been a particularly prominent in humans.
    2) CASE REPORT: A 14-year-old boy was inadvertently injected (incompletely injected) with an arrow containing xylazine and ketamine (the medications were intended for a deer) into his leg and lost consciousness. He required intubation and mechanical ventilation. Vital signs were stable. Ventilation was required for 4 hours. He developed symptoms of nightmares, nausea, vomiting and dizziness but recovered completely (Meyer et al, 2013).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) LIVER ENZYMES ABNORMAL
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: LDH (529 units/L) and CPK (597 units/L) were both elevated for 5 to 7 days after an injection of 15 mg/kg xylazine (Carruthers et al, 1979).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) URINARY INCONTINENCE
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Incontinence was reported after an ingestion of 400 mg (Gallanosa et al, 1981).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) HYPERGLYCEMIA
    1) WITH POISONING/EXPOSURE
    a) Mildly elevated blood glucose levels have been reported in humans (Gallanosa et al, 1981; Carruthers et al, 1979; Samanta et al, 1990; Hoffmann et al, 2001).

Reproductive

    3.20.1) SUMMARY
    A) At the time of this review, no data were available to assess the potential effects of exposure to this agent during pregnancy or lactation.
    3.20.2) TERATOGENICITY
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the teratogenic potential of this agent.

Genotoxicity

    A) Xylazine was found to be weakly mutagenic in a laboratory model (Salmonella microsome test)(Preiss et al, 1982).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor CNS and respiratory function.
    B) Monitor vital signs including blood pressure. Institute continuous cardiac monitoring and pulse oximetry monitoring. Obtain a baseline ECG and repeat as indicated.
    C) Although serum and urinary levels have been measured, their correlation to toxic manifestations is not well understood. Therefore, they have little utility in managing acute exposures.
    4.1.2) SERUM/BLOOD
    A) TOXICITY
    1) Although serum and urinary levels have been measured, their correlation to toxic manifestations is not well understood. Therefore, they have little utility in managing acute exposures.

Methods

    A) CHROMATOGRAPHY
    1) Gas chromatography, gas-liquid chromatography, and mass spectrometry may be used to identify xylazine in biological fluids (Gallanosa et al, 1981) (Capraro et al, 1998) (Mittleman et al, 1998).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients with severe, persistent symptoms (eg, hypotension, bradycardia, cardiac dysrhythmias) despite treatment should be admitted. An ICU setting may be necessary if the patient requires intubation and mechanical ventilation or if significant CNS depression.
    6.3.1.2) HOME CRITERIA/ORAL
    A) A patient with an inadvertent exposure (eg, occupational exposure via a needlestick) should be monitored in a healthcare center due to the risk of marked hypotension following human exposure.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a regional poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with a deliberate overdose, and those who are symptomatic (ie, hypotension, bradycardia), need to be monitored until they are clearly improving and clinically stable.

Monitoring

    A) Monitor CNS and respiratory function.
    B) Monitor vital signs including blood pressure. Institute continuous cardiac monitoring and pulse oximetry monitoring. Obtain a baseline ECG and repeat as indicated.
    C) Although serum and urinary levels have been measured, their correlation to toxic manifestations is not well understood. Therefore, they have little utility in managing acute exposures.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) EMESIS/NOT RECOMMENDED
    1) EMESIS: Ipecac-induced emesis is not recommended because of the potential for CNS depression.
    B) SUMMARY
    1) Gastrointestinal decontamination is unlikely to be necessary because these agents are available parenterally. If ingestion should occur, activated charcoal is not recommended because of the potential risk of altered mental status. If dermal exposure should occur, wash the exposed area with water.
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) SUMMARY
    a) Xylazine is primarily an injectable drug; however, if ingestion of the parenteral product has occurred. Consider activated charcoal if the ingestion is recent and the patient is alert and the airway can be protected.
    2) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    3) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) MANAGEMENT OF MILD TO MODERATE TOXICITY
    a) Treatment is symptomatic and supportive. Although xylazine is primarily an injectable drug, ingestion of the injectable formulation has occurred. Treatment is supportive and directed mainly at managing apnea or the loss of protective airway reflexes, bradycardia, and hypotension. Monitor vital signs including blood pressure. Bradycardia, hypotension and CNS depression often respond to physical stimulation. For mild hypotension begin IV 0.9% NaCl at 10 to 20 mL/kg. Bradycardia is typically mild and usually doesn't require any treatment. Naloxone has been used to reverse CNS depression with inconsistent success following clonidine exposure.
    2) MANAGEMENT OF SEVERE TOXICITY
    a) Severe bradycardia associated with hypotension and not responsive to physical stimulation should be treated with standard dose of atropine or cardiac pacing. Norepinephrine or dopamine may be beneficial in patients with severe bradycardia and hypotension not responding to physical stimulation, naloxone, intravenous crystalloid, and atropine. Patients with significant CNS and/or respiratory depression should be intubated. Paradoxical hypertension secondary to xylazine or related agents warrants caution due to the transient nature of this effect, which may be followed by hypotension. Aggressive therapy with antihypertensive agents may exacerbate hypotension. Life-threatening hypertension with end-organ effects should be managed with nitroprusside.
    B) MONITORING OF PATIENT
    1) Monitor CNS and respiratory function.
    2) Monitor vital signs including blood pressure. Institute continuous cardiac monitoring and pulse oximetry monitoring.
    3) Obtain a baseline ECG and repeat as indicated.
    4) Although serum and urinary levels have been measured, their correlation to toxic manifestations is not well understood. Therefore, they have little utility in managing acute exposures.
    C) NALOXONE
    1) Naloxone has been used for treatment of paradoxical hypertension of clonidine overdose. Two reports using doses of 0.8 to 2 mg showed reversal of coma and apnea (Kulig et al, 1982), while another using 0.1 mg/kg did not show any benefit in clonidine overdose (Banner et al, 1983).
    2) Naloxone (0.015 mg/kg) was unsuccessful in reversing CNS depression and apnea following a xylazine exposure in one patient (Personal Communication, 1985).
    3) Naloxone was ineffective in 2 additional cases of xylazine intoxication (Spoerke et al, 1986).
    D) EXPERIMENTAL THERAPY
    1) YOHIMBINE
    a) Yohimbine has been tried in animals to reverse the effects of xylazine. There are a number of ongoing experiments evaluating yohimbine's ability to counteract the effects of xylazine. Studies have shown both a reduction in the bradycardia and in sedation (Guard & Schwark, 1984; Kitzman et al, 1982; Jensen, 1985). Yohimbine has not been tried in human overdose.
    E) 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) DOPAMINE
    a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    3) NOREPINEPHRINE
    a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
    b) DOSE
    1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
    2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
    3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).
    F) BRADYCARDIA
    1) Bradycardia and hypotension may respond to atropine alone (Gallanosa et al, 1981).
    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) TOLAZOLINE
    a) Although tolazoline is reported to reverse bradycardia and hypotension secondary to clonidine (Schieber and Kaufman, 1981), the efficacy in treating symptoms of clonidine overdose is not consistent (Anderson et al, 1981). Tolazoline is effective for reversing xylazine-induced sedation in cattle, chickens, deer, and dogs (Hsu, 1981; Mackintosh, 1985; Roming, 1984) (Ruckebusch & Toutain, 1984) (Tranquilli et al, 1984). It has yet to be tried in a xylazine overdose.
    b) Tolazoline may be considered for those patients who do not respond to fluids, dopamine, atropine, or other supportive measures. Tolazoline can be associated with toxic effects including marked hypertension, cardiac arrhythmias and tachycardia (Schieber & Kaufmen, 1981; Spoerke et al, 1986). The cardiovascular response to tolazoline is not always predictable. Its use should therefore be reserved for patients who remain hypotensive despite optimal supportive therapy.
    c) Tolazoline is given at a dose of 10 mg IV and repeated every 5 to 10 minutes as needed up to a maximum of 40 mg.
    G) HYPERTENSIVE EPISODE
    1) SODIUM NITROPRUSSIDE
    a) Management of paradoxical hypertension secondary to xylazine overdoses warrants great caution due to its transient nature. Aggressive therapy with hypotensive agents such as diaxozide may result in profound and prolonged hypotension (Anderson et al, 1981). Life threatening hypertension should be managed with sodium nitroprusside.
    b) SODIUM NITROPRUSSIDE/INDICATIONS
    1) 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.
    c) SODIUM NITROPRUSSIDE/DOSE
    1) 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).
    d) SODIUM NITROPRUSSIDE/SOLUTION PREPARATION
    1) 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).
    e) SODIUM NITROPRUSSIDE/MAJOR ADVERSE REACTIONS
    1) 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).
    f) SODIUM NITROPRUSSIDE/MONITORING PARAMETERS
    1) 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).
    2) PHENTOLAMINE
    a) Phentolamine has been considered the treatment of choice in clonidine poisoning when associated with paradoxical hypertension. Since clonidine and xylazine have similar toxicologic characteristics, it may be useful to consider phentolamine.
    b) CAUTION: Phentolamine, however, possesses sympathomimetic, parasympathomimetic, and histamine-like effects and can cause tachycardia, angina, and ventricular arrhythmias in some patients. Since some of the human xylazine poisoning cases have reported sinus tachycardia and multifocal PVC's these effects must be taken into consideration when administering phentolamine in xylazine poisonings.
    H) VENTRICULAR ARRHYTHMIA
    1) Sinus tachycardia and multifocal PVCs have been reported following exposure to xylazine; ventricular dysrhythmias have not been reported.
    2) The patient should be monitored for cardiac arrhythmias following an exposure (Gallanosa et al, 1981). Although ventricular arrhythmias have not been reported, intervention following a significant exposure may be necessary.
    3) 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.
    4) 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).
    5) 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).

Eye Exposure

    6.8.1) DECONTAMINATION
    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).
    6.8.2) TREATMENT
    A) SUPPORT
    1) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.
    B) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Enhanced Elimination

    A) HEMODIALYSIS
    1) Given xylazine's high lipid solubility, it is predicted that this agent has a large volume of distribution. Thus, like clonidine, it is unlikely that hemodialysis would remove significant amounts of xylazine (Ruiz-Colon et al, 2014; Gallanosa et al, 1981).
    B) DIURESIS
    1) Forced diuresis is not likely to significantly enhance elimination of xylazine (Gallanosa et al, 1981).

Abstracts

Case Reports

    A) ADULT
    1) A 19-year-old man veterinary nurse became comatose, hypotensive, bradycardic, and acidotic beginning about 30 minutes after he accidentally injected himself with 200 mg of xylazine. He required intensive supportive care including assisted ventilation for 8 hours. He fully recovered and was discharged about 24 hours after he was extubated (Samanta et al, 1990).

Range Of Toxicity

Summary

    A) TOXICITY: XYLAZINE: A toxic dose is highly variable. Based on the literature, the known doses of toxicity and fatalities in humans has varied from 40 to 2400 mg. As little as 7 mg of xylazine IV has caused anesthesia and bradycardia. Doses as low as 0.73 mg/kg IM may produce mild symptoms. Intravenous administration of 1000 mg (15 mg/kg) produced coma and apnea and ingestion of 400 mg has caused profound sedation. DETOMIDINE: A woman was accidentally injected with 3 mg of detomidine that was intended for a horse, and developed asymptomatic bradycardia and sleepiness.

Therapeutic Dose

    7.2.1) ADULT
    A) DEXMEDETOMIDINE HYDROCHLORIDE
    1) GENERAL
    a) Dexmedetomidine hydrochloride is used for sedation in patients in the intensive care setting (Prod Info PRECEDEX(R) injection, 2004).
    2) ADULTS
    a) SEDATION, Intubated/Mechanically ventilated ICU patient: Initial Dose: 1 mcg/kg IV over 10 minutes. Maintenance Dose: 0.2 to 0.7 mcg/kg/hour continuous IV infusion for a maximum of 24 hours (Prod Info PRECEDEX(R) injection, 2004).
    7.2.2) PEDIATRIC
    A) Safety and efficacy have not been established in children less than 18 years of age (Prod Info PRECEDEX(R) injection, 2004).

Minimum Lethal Exposure

    A) A specific toxic dose is highly variable. Based on the literature, the known doses to produce toxicity and fatalities in humans has varied from 40 to 2400 mg (Ruiz-Colon et al, 2014).
    B) In a literature review, 43 cases of human xylazine intoxication were identified from the years 1966 to 2013. Of all the cases, 21 (49%) were non-fatal and 22 (51%) were fatal Most exposures were via the parental route. Patients usually presented with CNS toxicity (ie, areflexia, asthenia, ataxia, blurred vision, disorientation, dizziness, drowsiness, dysarthria, dysmetria, faintness, hyporeflexia, slurred speech somnolence, staggering, tiredness, coma), respiratory depression (ie, apnea or shallow breathing), cardiovascular effects (hypotension, brady- or tachycardia, premature ventricular contractions), hyperglycemia and miosis. Rare effects included hypotonia, dry mouth, urinary incontinence and nonspecific electrocardiogram changes. In this study, the duration of effects lasted 8 to 72 hours compared to animals where the typical effects could last up to 4 hours (Ruiz-Colon et al, 2014).

Maximum Tolerated Exposure

    A) XYLAZINE
    1) As little as 7 mg IV has caused anesthesia and a heart rate of 44 beats/minute (Lewis et al, 1983).
    2) Intramuscular administration of 1000 mg (15 mg/kg) produced coma and apnea in a 34-year-old man (Carruthers et al, 1979).
    3) 400 mg orally also produce profound sedation in a 20-year-old woman (Gallanosa et al, 1981).
    4) A 37-year-old, 109 kg woman, developed apnea and CNS depression following intramuscular injection of 22 mg/kg of xylazine (Spoerke et al, 1986).
    5) Doses as low as 0.73 mg/kg intramuscularly may produce mild symptoms (Spoerke et al, 1986).
    B) DETOMIDINE
    1) CASE REPORT: A 23-year-old woman was accidentally injected with 3 mg of detomidine, which was intended for a horse. She developed asymptomatic bradycardia and sleepiness (Pohjalainen et al, 2001).

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) CONCENTRATION LEVEL
    a) A 16-year-old male developed bradycardia, apnea, and coma after intentionally inhaling xylazine powder and, two hours later, his xylazine blood level was 0.54 microgram/milliliter (Capraro et al, 1998).
    b) CASE REPORT - Two decomposed decapitated bodies of a 33-year-old male and a 23-year-old female with 32 milliliters of xylazine (in a 50-milliliter vial), syringes, and a hypodermic-dart gun found nearby. The severely decomposed heads were found approximately one month later.
    1) FEMALE - Toxicological testing revealed xylazine in the liver, kidney, and brain in concentrations of 42 milligrams/kilogram, 28 milligrams/kilogram, and 19 milligrams/kilogram, respectively. The authors concluded that these levels were consistent with a fatal overdose.
    2) MALE - Testing revealed xylazine in the liver, kidney, and brain in concentrations of 0.26 milligram/kilogram, 0.15 milligram/kilogram, and 0.16 milligram/kilogram, respectively. Death was likely due to blunt trauma, but xylazine could have been used for sedative purposes antemortem (Mittleman et al, 1998).
    c) A 27-year-old man developed coma, respiratory depression, bradycardia and transient hypotension after injecting 75 ml of 2% xylazine IM. Peak plasma level was 4.6 mg/L, urine level was 194 mg/L, and gastric fluid contained 446 mg/L (Hoffmann et al, 2001).

Toxicity Information

    7.7.1) TOXICITY VALUES

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Xylazine is a partial alpha-2-adrenergic agonist (Abdel El Motal & Sharp, 1985). The muscle relaxation is caused by inhibition, in the CNS, of interneural transmission of impulses (Gallanosa et al, 1981). Xylazine reduces sympathomimetic tone, both centrally and peripherally, but the central action predominates (Gallanosa et al, 1981).
    B) Xylazine has an inhibitory effect on glucose-induced insulin release. This effect could be completely eliminated by an alpha2-adrenergic antagonist, yohimbine, and was unaffected by an alpha1-adrenergic antagonist, prazosin (Abdel El Motal & Sharp, 1985).

Toxicologic Mechanism

    A) The hypotensive and bradycardic effects seen in animals are similar in action to that seen with clonidine. Xylazine has central alpha-adrenergic agonist properties which may produce inhibitory effects on the vasomotor brain stem centers and, therefore, decrease sympathetic tone (Schmitt & Fournadijiev Schmitt, 1970). Xylazine has both central and peripheral autonomic effects, diminishing centrally-mediated sympathetic tone by interneural blockage. This increases vagal tone producing bradycardia and hypotension (Gallanosa et al, 1981).

Physicochemical

Physical Characteristics

    A) Colorless, tasteless crystals.

Molecular Weight

    A) 220.33

Animal Toxicology

Clinical Effects

    11.1.6) FELINE/CAT
    A) A 10-year-old, 5.2 kg cat sedated with 4 mg/kg xylazine intramuscularly presented with a history of progressive ataxia and lethargy of 8 hours duration. Findings on physical exam were faint heart sounds at a rate of 60 beats/minute with normal rhythm, pale mucous membranes, cold extremities, and anisocoria with slow light reflexes and diminished response (Jensen, 1985).

Treatment

    11.2.2) LIFE SUPPORT
    A) GENERAL
    1) MAINTAIN VITAL FUNCTIONS: Secure airway, supply oxygen, and begin supportive fluid therapy if necessary.
    11.2.5) TREATMENT
    A) CATTLE
    1) 0.125mg/kg of yohimbine was administered intravenously to steers previously given 0.2 to 0.3mg/kg intramuscular injections of xylazine. The yohimbine produced a rapid return of reflexes, arousal, and a significant decrease in the mean standing time (the time until the animal can stand unaided) (Kitzman et al, 1982).
    2) CALVES - 0.25 mg/kg yohimbine was administered intravenously to calves that had previously been given 0.05 mg/kg xylazine. The yohimbine reduced the duration of xylazine-induced bradycardia, but did not affect the duration of sedation (Guard & Schwark, 1984).
    B) CAT
    1) A cat treated for suspected xylazine toxicosis with 0.1 mg/kg yohimbine, given intravenously, regained consciousness immediately and within 10 minutes was clinically normal (Jensen, 1985).
    C) SHEEP
    1) Yohimbine 0.18 to 0.2 mg/kg intravenously increased the rate and strength of contraction in big horn sheep that had bradycardia and cardiovascular collapse temporally related to excitement, exertion, and xylazine-induced sedation (Jessup et al, 1985).
    2) Atipamezole and yohimbine, 0.2 mg/kg, were administered intravenously to sheep in order to reverse the effects of sedation caused by the administration of medetomidine, 40 mcg/kg. The lowered heart rates, respiratory rates, and ruminal motility, caused by medetomidine administration, were also significantly increased by the administration of atipamezole and yohimbine (Mohammad et al, 1995).
    D) OTHER
    1) AFRICAN ELEPHANTS - Yohimbine hydrochloride 0.13 mg/kg (mean dose) intravenously via auricular vein reported useful in controlling duration of xylazine-ketamine sedation and immobilization in juvenile African elephants (Jacobson et al, 1985).
    2) CERVIDAE - Successive intravenous injections of yohimbine 0.15 mg/kg and 4-aminopyridine 0.26 to 0.29 mg/kg reversed maximal sedation induced with xylazine 0.63 to 1.29 mg/kg intramuscularly in deer and moose. Recumbency-to-arousal intervals were 1 to 15 minutes and recumbency-to-standing or walking intervals were 1 to 24 minutes. There were no observed relapses to recumbency (Renecker & Olsen, 1985).

Range Of Toxicity

    11.3.1) THERAPEUTIC DOSE
    A) CAT
    1) The therapeutic dose is 1 to 2.2 mg/kg IM (Knight, 1980) or 0.5 to 2 milligrams/pound (Gallanosa et al, 1981).
    B) DOG
    1) The therapeutic dose is 0.5 to 2 milligrams/pound (Gallanosa et al, 1981).
    C) HORSE
    1) The therapeutic dose is 0.5 milliliter/100 pounds intravenously (0.5 milligram/pound) or 1 milliliter/100 pounds intramuscularly (1 milligram/pound) (Gallanosa et al, 1981).
    11.3.2) MINIMAL TOXIC DOSE
    A) LACK OF INFORMATION
    1) No specific information on a minimal toxic dose was available at the time of this review.

Sources

    A) SPECIFIC TOXIN
    1) Rompun(R) Injectable (Haver) is available as 20 mg/mL in 20 mL vials and 100 mg/mL in 50 mL vials (Arnson, 1984).

References

General Bibliography

    1) Abdel El Motal SM & Sharp GWG: Inhibition of glucose-induced insulin release by xylazine. Endocrinology 1985; 116:2337-2340.
    2) American Heart Association: 2005 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2005; 112(24 Suppl):IV 1-203. Available from URL: http://circ.ahajournals.org/content/vol112/24_suppl/. As accessed 12/14/2005.
    3) Anderson RJ, Hart GR, & Crumpler CP: Clonidine overdose: report of 6 cases and review of the literature. Ann Emerg Med 1981; 10:107-112.
    4) Arnson CE: Veterinary Pharmaceuticals and Biologicals, 4th ed, Veterinary Publishing Company, Edwardsville, KS, 1984, pp 670.
    5) Banner W, Lund WE, & Clawson L: Failure of naloxone to reverse clonidine toxic effects. Am J Dis Child 1983; 137:1170-1171.
    6) Burke JA & Potter DE: The ocular effects of xylazine in rabbits, cats, and monkeys. J Ocular Pharmacol 1986; 2(1):9-21.
    7) Capraro AJ, Wiley JF, & Tucker JR: Severe intoxication from xylazine inhalation. Ped Emerg Care 2001; 17:447-448.
    8) Carruthers SG, Nelson M, & Wexler HR: Xylazine hydrochloride (Rompun) overdose in man. Clin Toxicol 1979; 15:281-285.
    9) Chyka PA, Seger D, Krenzelok EP, et al: Position paper: Single-dose activated charcoal. Clin Toxicol (Phila) 2005; 43(2):61-87.
    10) Cummins FH: Accidental human poisoning with a veterinary tranquiliser. Emerg Med J 2005; 22:524-525.
    11) Elejalde JI, Louis CJ, Elcuaz R, et al: Drug abuse with inhalated xylazine. Eur J Emerg Med 2003; 10:252-253.
    12) Elliot CG, Colby TV, & Kelly TM: Charcoal lung. Bronchiolitis obliterans after aspiration of activated charcoal. Chest 1989; 96:672-674.
    13) FDA: Poison treatment drug product for over-the-counter human use; tentative final monograph. FDA: Fed Register 1985; 50:2244-2262.
    14) Gallanosa AGE, Spyker DA, & Shipe JR: Human xylazine overdose: a comparative review with clonidine, phenothiazines, and tricyclic antidepressants. Clin Toxicol 1981; 18:663-678.
    15) Golej J, Boigner H, Burda G, et al: Severe respiratory failure following charcoal application in a toddler. Resuscitation 2001; 49:315-318.
    16) Graff GR, Stark J, & Berkenbosch JW: Chronic lung disease after activated charcoal aspiration. Pediatrics 2002; 109:959-961.
    17) Guard CI & Schwark KW: Influence of yohimbine on xylazine-induced depression of central nervous, gastrointestinal and cardiovascular function in California. Cornell Vet 1984; 74:312-321.
    18) Harris CR & Filandrinos D: Accidental administration of activated charcoal into the lung: aspiration by proxy. Ann Emerg Med 1993; 22:1470-1473.
    19) Hoffmann U, Meister CM, & Golle K: Severe intoxication with the veterinary tranquiizer xylazine in humans. J Analytical Toxicol 2001; 25:245-249.
    20) Hsu WH: Xylazine-induced depression and its antagonism by alpha adrenergic blocking agents. J Pharmacol Exp Ther 1981; 218:188-192.
    21) Jacobson ER, Allen J, & Martin H: Effects of yohimbine on combined xylazine-ketamine-induced sedation and immobilization in juvenile African elephants. J Am Vet Med Assoc 1985; 187:1195-1198.
    22) Jensen WA: Yohimbine for treatment of xylazine overdose in a cat. J Am Vet Med Assoc 1985; 187:627-628.
    23) Jessup DA, Jones K, & Mohr R: Yohimbine antagonism to xylazine in free-ranging mule deer and desert bighorn sheep. J Am Vet Med Assoc 1985; 187:1251-1253.
    24) Kitzman JV, Boot NH, & Hatch RC: Antagonism of xylazine sedation by 4-aminopyridine and yohimbine in cattle. Am J Vet Res 1982; 43:2165-2169.
    25) Kleinman ME, Chameides L, Schexnayder SM, et al: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Part 14: pediatric advanced life support. Circulation 2010; 122(18 Suppl.3):S876-S908.
    26) Knight AP: Xylazine. J Am Vet Med Assoc 1980; 176:454-455.
    27) Kulig K, Duffy JP, & Rumack BH: Naloxone for the treatment of clonidine overdose. JAMA 1982; 247:1697.
    28) Lewis S, O'Collaghan CLP, & Toghill PJ: Clinical curio: self medication with xylazine. Br Med J 1983; 287:1369.
    29) Link MS, Berkow LC, Kudenchuk PJ, et al: Part 7: Adult Advanced Cardiovascular Life Support: 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2015; 132(18 Suppl 2):S444-S464.
    30) Livingston A, Low J, & Morris B: Effects of clonidine and xylazine on body temperature in the rat. Br J Pharmacol 1984; 81:189-193.
    31) Mackintosh C: Potential antidote for Rompun (xylazine) in humans (letter). NZ Med J 1985; 2:714-715.
    32) Meyer GM, Meyer MR, Mischo B, et al: Case report of accidental poisoning with the tranquilizer xylazine and the anesthetic ketamine confirmed by qualitative and quantitative toxicological analysis using GC-MS and LC-MS(n.). Drug Test Anal 2013; 5(9-10):785-789.
    33) Mittleman RE, Hearn WL, & Hime GW: Xylazine toxicity - literature review and report of two cases. J Forensic Sci 1998; 43:400-402.
    34) Mohammad FK, Zangana IK, & Abdul-Latif AR: Reversal of medetomidine sedation in sheep by atipamezole and yohimbine. Vet Human Toxicol 1995; 37:97-99.
    35) Naradzay J & Barish RA: Approach to ophthalmologic emergencies. Med Clin North Am 2006; 90(2):305-328.
    36) Neumar RW , Otto CW , Link MS , et al: Part 8: adult advanced cardiovascular life support: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2010; 122(18 Suppl 3):S729-S767.
    37) None Listed: Position paper: cathartics. J Toxicol Clin Toxicol 2004; 42(3):243-253.
    38) Peate WF: Work-related eye injuries and illnesses. Am Fam Physician 2007; 75(7):1017-1022.
    39) Peberdy MA , Callaway CW , Neumar RW , et al: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care science. Part 9: post–cardiac arrest care. Circulation 2010; 122(18 Suppl 3):S768-S786.
    40) Personal Communication: Personal Communication: Michael Grimes, M.D. Michael Grimes, M.D., Laramie, Wyoming, 1985.
    41) Pohjalainen T, Pajarre S, & Harjola VP: Accidental parenteral exposure to detomidine, an alpha2-adrenergic agonist (abstract). J Toxicol - Clin Toxicol 2001; 39:298.
    42) Pollack MM, Dunbar BS, & Holbrook PR: Aspiration of activated charcoal and gastric contents. Ann Emerg Med 1981; 10:528-529.
    43) Preiss AM, Scheutwinkel-Deich M, & Fulle I: Investigation, with Salmonella/microsome test of psychopharmaceuticals used in meat production. Mutat Res 1982; 104:333-337.
    44) Product Information: Cordarone(R) oral tablets, amiodarone HCl oral tablets. Wyeth Pharmaceuticals Inc (per FDA), Philadelphia, PA, 2015.
    45) Product Information: Lidocaine HCl intravenous injection solution, lidocaine HCl intravenous injection solution. Hospira (per manufacturer), Lake Forest, IL, 2006.
    46) Product Information: NITROPRESS(R) injection for IV infusion, Sodium Nitroprusside injection for IV infusion. Hospira, Inc., Lake Forest, IL, 2007.
    47) Product Information: NITROPRESS(R) injection, sodium nitroprusside injection. Hospira,Inc, Lake Forest, IL, 2004.
    48) Product Information: PRECEDEX(R) injection, dexmedetomidine hcl injection. Hospira,Inc., Lake Forest, IL, 2004.
    49) Product Information: dopamine hcl, 5% dextrose IV injection, dopamine hcl, 5% dextrose IV injection. Hospira,Inc, Lake Forest, IL, 2004.
    50) Product Information: norepinephrine bitartrate injection, norepinephrine bitartrate injection. Sicor Pharmaceuticals,Inc, Irvine, CA, 2005.
    51) Rau NR, Nagaraj MV, Prakash PS, et al: Fatal pulmonary aspiration of oral activated charcoal. Br Med J 1988; 297:918-919.
    52) Renecker LA & Olsen CD: Use of yohimbine and 4-aminopyridine to antagonize xylazine-induced immobilization in North American Cervidae. J Am Vet Med Assoc 1985; 187:1199-1201.
    53) Roming LGP: Tolazolin as a xylazine-antagonist in cattle. Dtsch Tieraztl Wschr 1984; 91:154-157.
    54) Ruiz-Colon K, Chavez-Arias C, Diaz-Alcala JE, et al: Xylazine intoxication in humans and its importance as an emerging adulterant in abused drugs: A comprehensive review of the literature. Forensic Sci Int 2014; 240:1-8.
    55) Samanta A, Roffe C, & Woods KL: Accidental self administration of xylazine in a veterinary nurse. Postgrad Med J 1990; 66:244-245.
    56) Schieber RA & Kaufmen MD: Use of tolazoline in massive clonidine poisoning. Am J Dis Child 1981; 135:77-78.
    57) Schmitt H & Fournadijiev Schmitt HM: Central and peripheral effects of 2-(2,6-dimetylphenylamino)-4-H-5,6- dihydro-1-3-thiazines (Bayer 1470) on the sympathetic system. Eur J Pharmacol 1970; 10:230-238.
    58) Spoerke DG, Hall AH, & Grimes MJ: Human overdose with the veterinary tranquilizer xylazine. Am J Emerg Med 1986; 4:222-224.
    59) Sundlof, SF: Part 522 - Implantation or injectable dosage form new animal drugs - Dexmedtomidine. US Government Printing Office. Washington, DC. 2007. Available from URL: http://a257.g.akamaitech.net/7/257/2422/01jan20071800/edocket.access.gpo.gov/2007/pdf/E6-22508.pdf.
    60) Sweetman, S: Martindale: The Complete Drug Reference. London: Pharmaceutical Press. Electronic Version, Thomson Healthcare. Greenwood Village, CO. 2007.
    61) Vanden Hoek TL, Morrison LJ, Shuster M, et al: Part 12: cardiac arrest in special situations: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2010; 122(18 Suppl 3):S829-S861.
    62) Velez L, Shepherd G, Mills LD, et al: Systemic toxicity after an ocular exposure to xylazine hydrochloride. J Emerg Med 2006; 30(4):407-410.
    63) de Caen AR, Berg MD, Chameides L, et al: Part 12: Pediatric Advanced Life Support: 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2015; 132(18 Suppl 2):S526-S542.