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QUINUCLIDINYL BENZILATE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) 3-Quinuclidinyl benzilate (QNB; BZ) is a chemical warfare agent and is an anticholinergic agent that affects both peripheral and central nervous systems. BZ and its analogues are glycolic acid esters. It is one of the most potent anticholinergic psychomimetics known. BZ is classified as a hallucinogenic chemical warfare agent and would be disseminated as an aerosol, with the primary route of absorption through the respiratory system. It is odorless and its pharmacologic activity is similar to other anticholinergics, but with a much longer duration of action.

Specific Substances

    1) 1-Azabicyclo(2.2.2)octan-3-ol, benzilate (9CI)
    2) 3-(2,2-Diphenyl-2-hydroxyethanoyloxy)-quinuclidine
    3) 3-Chinuclidylbenzilate
    4) 3-Quinuclidinol benzilate
    5) 3-Quinuclidinyl benzilate
    6) 3-Quinuclidyl benzilate
    7) Agent 3
    8) Agent buzz
    9) Benzilic acid, 3-quinuclidinyl ester
    10) BZ
    11) CS 4030
    12) EA 2277
    13) QNB
    14) Ro 2-3308
    15) Molecular Formula: C21-H23-N-O3
    16) CAS 6581-06-2

Available Forms Sources

    A) FORMS
    1) BZ is a stable white crystalline powder that is only slightly soluble in water ((Anon, 1998)).
    B) USES
    1) BZ was initially used in experimental studies in the 1960's for therapy of gastrointestinal diseases. However, due to dose limiting adverse effects of confusion and hallucinations, even at lower doses, BZ was withdrawn from commercial study and given to the U.S. Army as a drug for potential interest as an incapacitating agent. It is likely that BZ would be dispersed by smoke-producing munitions or aerosols, using the respiratory tract as a portal of entry in a terrorist attack, with a secondary route of entry into the body through the digestive tract ((Holstege, 2001); (Anon, 1998); Ketchum & Sidell, 1997).
    2) Between 1962 and 1965 BZ was produced at Pine Bluff Arsenal. It was then discontinued from the chemical arsenal due to the varied and unpredictable effects the drug would have on enemy front-line troops ((Anon, 1998)).
    3) It was suspected, but not substantiated, that BZ was used in a terrorist attack on 15,000 civilians marching from Srebrenica to free territory in Bosnia in 1995. A large number of marchers suffered from hallucinations (Hay, 1998).

Overview

Life Support

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

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) Exposure to 3-quinuclidinyl benzilate (BZ) (most likely aerosol) causes an anticholinergic syndrome. Signs/symptoms are dependent on the dose and time postexposure. Prolonged effects may occur depending on the dose of BZ absorbed.
    B) CENTRAL NERVOUS SYSTEM - Restlessness, apprehension, abnormal speech, confusion, agitation, tremor, ataxia, stupor, and coma have been described. Hallucinations are prominent. Motor coordination, perception, cognition, and new memory formation are altered. Seizures may occur in severe poisoning.
    C) PERIPHERAL NERVOUS SYSTEM - Mydriasis resulting in photophobia is expected. Vision impairment occurs due to loss of accommodation. Following a splash exposure in the eye, conjunctival injection and eye pain may occur.
    1) Tachycardia is a prominent feature, rarely exceeding 150 beats/minute. Moderate increases in blood pressure may occur.
    2) Decreased intestinal motility occurs, with decreased secretions from the stomach, pancreas, and gallbladder. Nausea and vomiting may occur.
    3) Drying of oral mucous membranes occurs. Breath may develop a foul odor.
    4) Dry skin due to inhibition of sweat glands occurs. Red, flushed skin may occur.
    5) Urinary retention can occur. Enlarged bladder may be palpable on examination.
    6) Increased temperature from inability to sweat and dissipate heat is common. Marked hyperthemia may develop in hot environments.
    0.2.3) VITAL SIGNS
    A) Increased heart rate, respiratory rate and hyperthermia are expected following BZ exposures. Moderate increases in blood pressure may occur.
    0.2.5) CARDIOVASCULAR
    A) Sinus tachycardia is expected following BZ exposure.
    B) Moderate hypertension may occur.
    C) Decreased capillary tone may result in skin flushing.
    0.2.6) RESPIRATORY
    A) Respiratory depression and aspiration may occur following severe exposures.
    0.2.7) NEUROLOGIC
    A) Psychosis with prominent hallucinations is expected following an aerosol attack. Memory loss may be noted. Severe exposures may result in seizures, dystonic reactions, and dyskinesias.
    0.2.8) GASTROINTESTINAL
    A) Decreased gastric motility, diminished bowel sounds, and paralytic ileus may occur as a result of anticholinergic toxicity.
    0.2.10) GENITOURINARY
    A) Urinary retention may occur.
    0.2.14) DERMATOLOGIC
    A) Warm red skin with decreased sweating is expected.
    0.2.15) MUSCULOSKELETAL
    A) Rhabdomyolysis may occur as a complication in patients with seizure, marked agitation or coma.

Laboratory Monitoring

    A) There is no rapid test to diagnose exposure to 3-quinuclidinyl benzilate (BZ) (expected to be aerosol exposure in a terrorist attack).
    B) Obtain CBC, electrolytes, renal function tests, and liver transaminases in symptomatic patients.
    C) Monitor acid/base balance in symptomatic patients.
    D) Monitor creatine phosphokinase (CPK) in patients with marked agitation or who are comatose.
    E) Obtain an ECG in patients with preexisting cardiac disease who may be at risk of cardiac ischemia as their heart rates increase. BZ is associated with sinus tachycardia.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) Exposures are expected to be primarily inhalational. However, rare ingestion exposures may occur.
    B) GASTRIC EMPTYING may be successful even if delayed. Anticholinergics slow GI motility.
    C) ACTIVATED CHARCOAL: Administer charcoal as a slurry (240 mL water/30 g charcoal). Usual dose: 25 to 100 g in adults/adolescents, 25 to 50 g in children (1 to 12 years), and 1 g/kg in infants less than 1 year old.
    D) GASTRIC LAVAGE: Consider after ingestion of a potentially life-threatening amount of poison if it can be performed soon after ingestion (generally within 1 hour). Protect airway by placement in the head down left lateral decubitus position or by endotracheal intubation. Control any seizures first.
    1) CONTRAINDICATIONS: Loss of airway protective reflexes or decreased level of consciousness in unintubated patients; following ingestion of corrosives; hydrocarbons (high aspiration potential); patients at risk of hemorrhage or gastrointestinal perforation; and trivial or non-toxic ingestion.
    E) Treatment should include recommendations listed in the INHALATION EXPOSURE section.
    0.4.3) INHALATION EXPOSURE
    A) Quinuclidinyl benzilate (BZ) would be disseminated as an aerosol in a terrorist attack, with the primary route of absorption through the respiratory system. Without treatment following an incapacitating dose, recovery is gradual, requiring 72 to 96 hours. Onset of symptoms is seen in about one hour and symptoms peak in approximately 8 hours.
    B) PSYCHOMOTOR AGITATION: Intravenous benzodiazepines may be used to control agitation. Sedate patient with benzodiazepines as necessary; large doses may be required.
    C) PHYSOSTIGMINE
    1) Physostigmine is indicated to reverse the CNS effects caused by clinical or toxic dosages of agents capable of producing anticholinergic syndrome; however, long lasting reversal of anticholinergic signs and symptoms is generally not achieved because of the relatively short duration of action of physostigmine (45 to 60 minutes). It is most often used diagnostically to distinguish anticholinergic delirium from other causes of altered mental status. CAUTION: If tricyclic antidepressants are coingested, physostigmine may precipitate seizures and dysrhythmias.
    2) ADULT: 2 mg IV at a slow controlled rate, no more than 1 mg/min. May repeat doses at intervals of 10 to 30 min if severe symptoms recur. For patients with prolonged anticholinergic delirium consider a continuous infusion, start at 2 mg/hr and titrate to effect. CHILD: 0.02 mg/kg by slow IV injection, at a rate no more than 0.5 mg/minute. Repeat dosage at 5 to 10 minute intervals as long as the toxic effect persists and there is no sign of cholinergic effects. MAXIMUM DOSAGE: 2 mg total.
    D) TACHYCARDIA - Sinus tachydysrhythmias do not need to be routinely treated (slowed) unless the patient demonstrates signs and/or symptoms of hemodynamic instability. Tachydysrhythmias may respond to physostigmine or IV propranolol.
    E) VENTRICULAR DYSRHYTHMIAS/SUMMARY: 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.
    F) SEIZURES: Administer a benzodiazepine; DIAZEPAM (ADULT: 5 to 10 mg IV initially; repeat every 5 to 20 minutes as needed. CHILD: 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) or LORAZEPAM (ADULT: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist. CHILD: 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).
    1) Consider phenobarbital or propofol if seizures recur after diazepam 30 mg (adults) or 10 mg (children greater than 5 years).
    2) Monitor for hypotension, dysrhythmias, respiratory depression, and need for endotracheal intubation. Evaluate for hypoglycemia, electrolyte disturbances, and hypoxia.
    G) HYPERTHERMIA - Hyperthermia should be managed with external cooling and sedation if needed to control agitation. Avoid phenothiazines.
    H) MONITOR FLUID AND ELECTROLYTES carefully in symptomatic patients.
    I) RHABDOMYOLYSIS: Administer sufficient 0.9% saline (10 to 15 mL/kg/hour) to maintain urine output of at least 1 to 2 mL/kg/hour (or greater than 150 to 300 mL/hr). Monitor input and output, serum electrolytes, CK, and renal function. Diuretics may be necessary to maintain urine output, but should only be considered if urine output is inadequate after volume status is restored. Urinary alkalinization is NOT routinely recommended.
    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.
    B) Treatment should include recommendations listed in the INHALATION EXPOSURE section.
    0.4.5) DERMAL EXPOSURE
    A) OVERVIEW
    1) DECONTAMINATION: Remove contaminated clothing and jewelry and place them in plastic bags. Wash exposed areas with soap and water for 10 to 15 minutes with gentle sponging to avoid skin breakdown. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).
    2) When applied to the skin in a propylene glycol vehicle, apparent absorption is only 5% to 10%, with effects delayed by approximately 24 hours. Treatment should include recommendations listed in the INHALATION EXPOSURE section.

Range Of Toxicity

    A) The ID50 (dose that incapacitates 50% of adults) of BZ is about 6.2 mcg/kg.
    B) The range of toxicity is variable and unpredictable. Clinical judgment is more important than attempting to determine the amount inhaled.
    C) An absorbed dose of less than 1 mg produces delirium that lasts 2 to 3 days.

Clinical Effects

Summary Of Exposure

    A) Exposure to 3-quinuclidinyl benzilate (BZ) (most likely aerosol) causes an anticholinergic syndrome. Signs/symptoms are dependent on the dose and time postexposure. Prolonged effects may occur depending on the dose of BZ absorbed.
    B) CENTRAL NERVOUS SYSTEM - Restlessness, apprehension, abnormal speech, confusion, agitation, tremor, ataxia, stupor, and coma have been described. Hallucinations are prominent. Motor coordination, perception, cognition, and new memory formation are altered. Seizures may occur in severe poisoning.
    C) PERIPHERAL NERVOUS SYSTEM - Mydriasis resulting in photophobia is expected. Vision impairment occurs due to loss of accommodation. Following a splash exposure in the eye, conjunctival injection and eye pain may occur.
    1) Tachycardia is a prominent feature, rarely exceeding 150 beats/minute. Moderate increases in blood pressure may occur.
    2) Decreased intestinal motility occurs, with decreased secretions from the stomach, pancreas, and gallbladder. Nausea and vomiting may occur.
    3) Drying of oral mucous membranes occurs. Breath may develop a foul odor.
    4) Dry skin due to inhibition of sweat glands occurs. Red, flushed skin may occur.
    5) Urinary retention can occur. Enlarged bladder may be palpable on examination.
    6) Increased temperature from inability to sweat and dissipate heat is common. Marked hyperthemia may develop in hot environments.

Vital Signs

    3.3.1) SUMMARY
    A) Increased heart rate, respiratory rate and hyperthermia are expected following BZ exposures. Moderate increases in blood pressure may occur.
    3.3.2) RESPIRATIONS
    A) Increased respiratory rate may be expected following an acute exposure ((Anon, 1998)).
    3.3.3) TEMPERATURE
    A) Hyperthermia is a common effect of anticholinergics and is anticipated following significant exposure to BZ. The victim's temperature becomes elevated due to inhibition of sweating and ability to dissipate heat. In warmer climates, such as desert areas, this effect may result in marked hyperthemia ((Holstege, 2001); Ketchum & Sidell, 1997).
    3.3.4) BLOOD PRESSURE
    A) Moderate elevation of systolic and diastolic blood pressure may occur ((Holstege, 2001)).
    3.3.5) PULSE
    A) Elevated pulse rate is an initial effect and may be expected following significant exposures ((Holstege, 2001); (Anon, 1998); Ketchum & Sidell, 1997).

Heent

    3.4.3) EYES
    A) Mydriasis resulting in photophobia is expected following aerosol exposure. Vision impairment occurs due to loss of accommodation reflexes and decreased depth of field secondary to ciliary muscle paralysis and mydriasis ((Holstege, 2001); (Anon, 1998)).
    B) Conjunctival injection and eye pain may occur following a splash exposure ((Holstege, 2001)).
    C) Bilateral closed-angle glaucoma due to mydriasis is a possible complication in those patients who are predisposed ((Holstege, 2001)).
    3.4.6) THROAT
    A) Due to inhibition of glandular cells, dry mucous membranes of the mouth and throat may be expected and are dose related. Speech may be reduced to a whisper, and a foul odor may be noted on the victim's breath ((Holstege, 2001); (Anon, 1998)). Mouth and throat dryness are initial symptoms after one-half to four hours of exposure ((Anon, 1998)).

Cardiovascular

    3.5.1) SUMMARY
    A) Sinus tachycardia is expected following BZ exposure.
    B) Moderate hypertension may occur.
    C) Decreased capillary tone may result in skin flushing.
    3.5.2) CLINICAL EFFECTS
    A) TACHYARRHYTHMIA
    1) A prominent feature of BZ exposure is sinus tachycardia. Increased heart rate is an initial effect after one-half to 4 hours of exposure. Physical exertion may exacerbate heart rate responses. Tachycardia may be delayed in onset and may be cyclical. Patients with preexisting cardiac disease may be at risk of cardiac ischemia as their heart rates increase ((Holstege, 2001); (Anon, 1998); Ketchum & Sidell, 1997).
    B) HYPERTENSIVE EPISODE
    1) Moderate elevations of systolic and diastolic blood pressure may occur following an aerosol exposure. Hypertension may be delayed in onset and may be cyclical ((Holstege, 2001)).
    C) FLUSHING
    1) Cutaneous vasodilation with prominent skin flushing may be noted following aerosol exposures due to decreased capillary tone ((Holstege, 2001)). Skin flushing usually occurs only after salivation has been markedly depressed.

Respiratory

    3.6.1) SUMMARY
    A) Respiratory depression and aspiration may occur following severe exposures.
    3.6.2) CLINICAL EFFECTS
    A) PULMONARY ASPIRATION
    1) Respiratory depression and aspiration may occur in patients with seizures or mental status changes secondary to severe exposure ((Holstege, 2001)).

Neurologic

    3.7.1) SUMMARY
    A) Psychosis with prominent hallucinations is expected following an aerosol attack. Memory loss may be noted. Severe exposures may result in seizures, dystonic reactions, and dyskinesias.
    3.7.2) CLINICAL EFFECTS
    A) PSYCHOTIC DISORDER
    1) Psychosis (disorientation, delirium, hallucinations, and paranoia associated with anxiety, agitation, and hyperactivity) may occur following exposures. Hallucinations are prominent and usually visual. Motor skills, perception, and cognition may be affected due to inhibition of CNS muscarinic receptors ((Holstege, 2001); Ketchum & Sidell, 1997). Recovery from drug-induced delirium is gradual and dependent on the dose/exposure of BZ.
    B) SEIZURE
    1) Following severe and prolonged exposures, agitation, tremors and seizures may occur as CNS anticholinergic effects ((Holstege, 2001); Ketchum & Sidell, 1997).
    C) DYSTONIA
    1) Acute dystonic reactions following significant exposures may occur as an anticholinergic effect of BZ (Ketchum & Sidell, 1997).
    D) DYSKINESIA
    1) Dyskinesias, which are transient and usually resolve soon after removal from exposure, may occur following aerosol exposures (Ketchum & Sidell, 1997). Involuntary muscle movements are secondary effects which may occur after 3 to 5 hours of exposure ((Anon, 1998)).
    E) COMA
    1) Stupor followed by coma is a possible complication following severe and prolonged exposures, as a CNS muscarinic effect, but is not commonly expected ((Holstege, 2001)).

Gastrointestinal

    3.8.1) SUMMARY
    A) Decreased gastric motility, diminished bowel sounds, and paralytic ileus may occur as a result of anticholinergic toxicity.
    3.8.2) CLINICAL EFFECTS
    A) DRUG-INDUCED ILEUS
    1) Decreased gastric motility and diminished bowel sounds may be expected as a prolonged anticholinergic effect of BZ exposures. Nausea and vomiting may occur ((Holstege, 2001); Ketchum & Sidell, 1997).

Genitourinary

    3.10.1) SUMMARY
    A) Urinary retention may occur.
    3.10.2) CLINICAL EFFECTS
    A) RETENTION OF URINE
    1) Urinary retention and enlarged bladder, palpable on examination, may occur following exposure to BZ, and is a common anticholinergic effect ((Holstege, 2001); Ketchum & Sidell, 1997).

Dermatologic

    3.14.1) SUMMARY
    A) Warm red skin with decreased sweating is expected.
    3.14.2) CLINICAL EFFECTS
    A) VASODILATATION
    1) Warm red skin with decreased sweating and dry skin may occur as a peripheral effect of BZ ((Holstege, 2001); Ketchum & Sidell, 1997).

Musculoskeletal

    3.15.1) SUMMARY
    A) Rhabdomyolysis may occur as a complication in patients with seizure, marked agitation or coma.
    3.15.2) CLINICAL EFFECTS
    A) RHABDOMYOLYSIS
    1) A complication of severe exposures resulting in marked agitation or profound coma or prolonged seizures is tissue necrosis and resultant rhabdomyolysis. In extreme cases, if this remains undiagnosed, myoglobinuric renal failure could develop ((Holstege, 2001)).

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS6581-06-2 (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

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) There is no rapid test to diagnose exposure to 3-quinuclidinyl benzilate (BZ) (expected to be aerosol exposure in a terrorist attack).
    B) Obtain CBC, electrolytes, renal function tests, and liver transaminases in symptomatic patients.
    C) Monitor acid/base balance in symptomatic patients.
    D) Monitor creatine phosphokinase (CPK) in patients with marked agitation or who are comatose.
    E) Obtain an ECG in patients with preexisting cardiac disease who may be at risk of cardiac ischemia as their heart rates increase. BZ is associated with sinus tachycardia.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Serum levels of quinuclidinyl benzilate (BZ) are not clinically useful or readily available. Monitor serum electrolytes, renal function in symptomatic patients, and CPK levels in patients with prolonged seizures or coma.
    4.1.3) URINE
    A) URINALYSIS
    1) Follow urinalysis and urine output in patients with hypotension, dysrhythmias and those at risk for rhabdomyolysis.
    4.1.4) OTHER
    A) OTHER
    1) MONITORING
    a) Institute continuous cardiac monitoring and follow ECG in patients with persistent tachycardia, hemodynamic instability, seizures or severe mental status changes.

Radiographic Studies

    A) CHEST RADIOGRAPH
    1) Obtain a chest x-ray in symptomatic patients with CNS depression who are at risk for aspiration pneumonia.

Methods

    A) MULTIPLE ANALYTICAL METHODS
    1) Quinuclidinyl benzilate (BZ) may be detected with specific examinations in urine or blood, although with occasional difficulty due to low concentration. There are no rapid tests to diagnose exposure to BZ.
    2) Isotope dilution gas chromatography/mass spectrometry (GC/MS) has been used for the determination of BZ and its major metabolites (3-quinuclidinol and benzilic acid) in urine. Solid-phase extraction was used to isolate each analyte from urine and isotope dilution GC/MS was used for quantitation. Target levels of drug and metabolites were 5 ng/mL (Byrd et al, 1992).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Monitoring

    A) There is no rapid test to diagnose exposure to 3-quinuclidinyl benzilate (BZ) (expected to be aerosol exposure in a terrorist attack).
    B) Obtain CBC, electrolytes, renal function tests, and liver transaminases in symptomatic patients.
    C) Monitor acid/base balance in symptomatic patients.
    D) Monitor creatine phosphokinase (CPK) in patients with marked agitation or who are comatose.
    E) Obtain an ECG in patients with preexisting cardiac disease who may be at risk of cardiac ischemia as their heart rates increase. BZ is associated with sinus tachycardia.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) ACTIVATED CHARCOAL
    1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    2) 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).
    B) PERSONNEL PROTECTION
    1) CIVILIAN (paramedics, first responders) - "Off gassing" may occur from contaminated patients, putting paramedics or other health care providers at risk of contamination, particularly in the closed confines of an ambulance or helicopter. Decontamination of the exposed patient should occur prior to transfer or admittance to an emergency department. Water may be used for decontamination. Protective eye goggles and masks should be worn by all caretakers prior to decontamination ((Holstege, 2001); (Anon, 1998)).
    6.5.2) PREVENTION OF ABSORPTION
    A) SUMMARY
    1) Anticholinergics slow GI motility. Gastrointestinal decontamination may be worthwhile even if delayed.
    B) ACTIVATED CHARCOAL
    1) 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.
    2) 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).
    C) GASTRIC LAVAGE
    1) INDICATIONS: Consider gastric lavage with a large-bore orogastric tube (ADULT: 36 to 40 French or 30 English gauge tube {external diameter 12 to 13.3 mm}; CHILD: 24 to 28 French {diameter 7.8 to 9.3 mm}) after a potentially life threatening ingestion if it can be performed soon after ingestion (generally within 60 minutes).
    a) Consider lavage more than 60 minutes after ingestion of sustained-release formulations and substances known to form bezoars or concretions.
    2) PRECAUTIONS:
    a) SEIZURE CONTROL: Is mandatory prior to gastric lavage.
    b) AIRWAY PROTECTION: Place patients in the head down left lateral decubitus position, with suction available. Patients with depressed mental status should be intubated with a cuffed endotracheal tube prior to lavage.
    3) LAVAGE FLUID:
    a) Use small aliquots of liquid. Lavage with 200 to 300 milliliters warm tap water (preferably 38 degrees Celsius) or saline per wash (in older children or adults) and 10 milliliters/kilogram body weight of normal saline in young children(Vale et al, 2004) and repeat until lavage return is clear.
    b) The volume of lavage return should approximate amount of fluid given to avoid fluid-electrolyte imbalance.
    c) CAUTION: Water should be avoided in young children because of the risk of electrolyte imbalance and water intoxication. Warm fluids avoid the risk of hypothermia in very young children and the elderly.
    4) COMPLICATIONS:
    a) Complications of gastric lavage have included: aspiration pneumonia, hypoxia, hypercapnia, mechanical injury to the throat, esophagus, or stomach, fluid and electrolyte imbalance (Vale, 1997). Combative patients may be at greater risk for complications (Caravati et al, 2001).
    b) Gastric lavage can cause significant morbidity; it should NOT be performed routinely in all poisoned patients (Vale, 1997).
    5) CONTRAINDICATIONS:
    a) Loss of airway protective reflexes or decreased level of consciousness if patient is not intubated, following ingestion of corrosive substances, hydrocarbons (high aspiration potential), patients at risk of hemorrhage or gastrointestinal perforation, or trivial or non-toxic ingestion.
    6.5.3) TREATMENT
    A) GENERAL TREATMENT
    1) Treatment should include recommendations listed in the INHALATIONAL EXPOSURE section when appropriate.

Inhalation Exposure

    6.7.1) DECONTAMINATION
    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) TREATMENT
    A) SUPPORT
    1) Treatment is symptomatic and supportive. Without treatment following an incapacitating dose, recovery is gradual, requiring 72 to 96 hours.
    B) PSYCHOMOTOR AGITATION
    1) Patients with agitation or hallucinations should be sedated. Sedate patient with benzodiazepines as necessary; large doses may be required.
    2) INDICATION
    a) If patient is severely agitated, sedate with IV benzodiazepines.
    3) DIAZEPAM DOSE
    a) ADULT: 5 to 10 mg IV initially, repeat every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) CHILD: 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).
    4) LORAZEPAM DOSE
    a) ADULT: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed (Manno, 2003).
    b) CHILD: 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 (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    5) Extremely large doses of benzodiazepines may be required in patients with severe intoxication in order to obtain adequate sedation. Titrate dose to clinical response and monitor for hypotension, CNS and respiratory depression, and the need for endotracheal intubation.
    6) Phenothiazines should be avoided due to possible hypotension.
    C) PHYSOSTIGMINE
    1) A diagnostic trial with physostigmine (see physostigmine dosing below) may be initiated. Physostigmine has been reported to be relatively ineffective if given during the first 4 to 6 hours following the onset of BZ effects. Peak impairment following aerosol BZ exposure occurs at 6 to 10 hours. If treatment with physostigmine is not maintained once begun, recovery from BZ poisoning may be slightly prolonged (Ketchum & Sidell, 1997).
    2) PHYSOSTIGMINE/INDICATIONS
    a) Physostigmine is indicated to reverse the CNS effects caused by clinical or toxic dosages of agents capable of producing anticholinergic syndrome; however, long lasting reversal of anticholinergic signs and symptoms is generally not achieved because of the relatively short duration of action of physostigmine (45 to 60 minutes) (Prod Info physostigmine salicylate intravenous injection, intramuscular injection, 2008). It is most often used diagnostically to distinguish anticholinergic delirium from other causes of altered mental status (Frascogna, 2007; Shannon, 1998).
    b) Physostigmine should not be used in patients with suspected tricyclic antidepressant overdose, or an ECG suggestive of tricyclic antidepressant overdose (eg, QRS widening). In the setting of tricyclic antidepressant overdose, use of physostigmine has precipitated seizures and intractable cardiac arrest (Stewart, 1979; Newton, 1975; Pentel & Peterson, 1980; Frascogna, 2007).
    3) DOSE
    a) ADULT: BOLUS: 2 mg IV at slow controlled rate, no more than 1 mg/min. May repeat doses at intervals of 10 to 30 min, if severe symptoms recur (Prod Info physostigmine salicylate intravenous injection, intramuscular injection, 2008). INFUSION: For patients with prolonged anticholinergic delirium, a continuous infusion of physostigmine may be considered. Starting dose is 2 mg/hr, titrate to effect (Eyer et al, 2008)
    b) CHILD: 0.02 mg/kg by slow IV injection, at a rate no more than 0.5 mg/minute. Repeat dosage at 5 to 10 minute intervals as long as the toxic effect persists and there is no sign of cholinergic effects. MAXIMUM DOSAGE: 2 mg total (Prod Info physostigmine salicylate intravenous injection, intramuscular injection, 2008).
    c) AVAILABILITY: Physostigmine salicylate is available in 2 mL ampules, each mL containing 1 mg of physostigmine salicylate in a vehicle containing sodium metabisulfite 0.1%, benzyl alcohol 2%, and water (Prod Info physostigmine salicylate intravenous injection, intramuscular injection, 2008).
    4) CAUTIONS
    a) Relative contraindications to the use of physostigmine are asthma, gangrene, diabetes, cardiovascular disease, intestinal or urogenital tract mechanical obstruction, peripheral vascular disease, cardiac conduction defects, atrioventricular block, and in patients receiving choline esters and depolarizing neuromuscular blocking agents (decamethonium, succinylcholine). It may cause anaphylactic symptoms and life-threatening or less severe asthmatic episodes in patients with sulfite sensitivity (Prod Info physostigmine salicylate intravenous injection, intramuscular injection, 2008).
    b) Too rapid IV administration of physostigmine has resulted in bradycardia, hypersalivation leading to respiratory difficulties, and possible seizures (Prod Info physostigmine salicylate intravenous injection, intramuscular injection, 2008).
    5) ATROPINE FOR PHYSOSTIGMINE TOXICITY
    a) Atropine should be available to reverse life-threatening physostigmine-induced, toxic cholinergic effects (Prod Info physostigmine salicylate intravenous injection, intramuscular injection, 2008; Frascogna, 2007). Atropine may be given at half the dose of previously given physostigmine dose (Daunderer, 1980).
    D) AIRWAY MANAGEMENT
    1) Maintain airway patency and oxygenation; endotracheal intubation and mechanical ventilation may be required.
    E) TACHYARRHYTHMIA
    1) Sinus tachydysrhythmias do not need to be routinely treated unless the patient demonstrates signs/symptoms of hemodynamic instability. Tachyarrhythmias may respond to physostigmine or IV propranolol.
    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/DOSE
    a) 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.
    1) 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).
    b) 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).
    3) LIDOCAINE/MAJOR ADVERSE REACTIONS
    a) 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).
    4) LIDOCAINE/MONITORING PARAMETERS
    a) Monitor ECG continuously; plasma concentrations as indicated (Prod Info Lidocaine HCl intravenous injection solution, 2006).
    5) AMIODARONE/INDICATIONS
    a) 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).
    6) AMIODARONE/ADULT DOSE
    a) 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).
    7) AMIODARONE/PEDIATRIC DOSE
    a) 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).
    8) ADVERSE EFFECTS
    a) Hypotension and bradycardia are the most common adverse effects (Neumar et al, 2010).
    9) Severe dysrhythmias may respond to physostigmine.
    G) BETHANECHOL
    1) Bethanechol has been described as an adjunctive agent for treatment of peripheral anticholinergic side effects of drugs. It is an agonist at muscarinic receptors and does not cross the blood-brain barrier. Bethanechol 5 to 10 milligrams orally three times daily may be given.
    H) SEIZURE
    1) 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).
    2) 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 .
    3) 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).
    4) 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).
    5) 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).
    6) 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).
    I) BODY TEMPERATURE ABOVE REFERENCE RANGE
    1) Place patient in a cool room.
    2) Minimize physical activity and sedate with benzodiazepines (large doses may be necessary). Give ice bath. Sponge patient with tepid to cool water and use fans to maximize evaporative heat loss.
    3) Place patient on a hypothermia blanket.
    4) Other cooling methods for severe hyperthermia include convection evaporation, intubation and cool air ventilation, and gastric lavage with iced saline.
    J) MONITORING OF PATIENT
    1) MONITOR RENAL FUNCTION tests in symptomatic patients.
    K) RHABDOMYOLYSIS
    1) SUMMARY: Early aggressive fluid replacement is the mainstay of therapy and may help prevent renal insufficiency. Diuretics such as mannitol or furosemide may be added if necessary to maintain urine output but only after volume status has been restored as hypovolemia will increase renal tubular damage. Urinary alkalinization is NOT routinely recommended.
    2) Initial treatment should be directed towards controlling acute metabolic disturbances such as hyperkalemia, hyperthermia, and hypovolemia. Control seizures, agitation, and muscle contractions (Erdman & Dart, 2004).
    3) FLUID REPLACEMENT: Early and aggressive fluid replacement is the mainstay of therapy to prevent renal failure. Vigorous fluid replacement with 0.9% saline (10 to 15 mL/kg/hour) is necessary even if there is no evidence of dehydration. Several liters of fluid may be needed within the first 24 hours (Walter & Catenacci, 2008; Camp, 2009; Huerta-Alardin et al, 2005; Criddle, 2003; Polderman, 2004). Hypovolemia, increased insensible losses, and third spacing of fluid commonly increase fluid requirements. Strive to maintain a urine output of at least 1 to 2 mL/kg/hour (or greater than 150 to 300 mL/hour) (Walter & Catenacci, 2008; Camp, 2009; Erdman & Dart, 2004; Criddle, 2003). To maintain a urine output this high, 500 to 1000 mL of fluid per hour may be required (Criddle, 2003). Monitor fluid input and urine output, plus insensible losses. Monitor for evidence of fluid overload and compartment syndrome; monitor serum electrolytes, CK, and renal function tests.
    4) DIURETICS: Diuretics (eg, mannitol or furosemide) may be needed to ensure adequate urine output and to prevent acute renal failure when used in combination with aggressive fluid therapy. Loop diuretics increase tubular flow and decrease deposition of myoglobin. These agents should be used only after volume status has been restored, as hypovolemia will increase renal tubular damage. If the patient is maintaining adequate urine output, loop diuretics are not necessary (Vanholder et al, 2000).
    5) URINARY ALKALINIZATION: Alkalinization of the urine is not routinely recommended, as it has never been documented to reduce nephrotoxicity, and may cause complications such as hypocalcemia and hypokalemia (Walter & Catenacci, 2008; Huerta-Alardin et al, 2005; Brown et al, 2004; Polderman, 2004). Retrospective studies have failed to demonstrate any clinical benefit from the use of urinary alkalinization (Brown et al, 2004; Polderman, 2004; Homsi et al, 1997).
    L) DETERMINATION OF PROGNOSIS
    1) Generally the prognosis is good for exposed patients if they do not develop a secondary injury such as rhabdomyolysis. Following removal from the exposure, and once the BZ is metabolized, patients become more lucid. Full recovery is expected within 4 days. No long-term sequelae are expected from BZ itself ((Holstege, 2001)).
    M) INFORMING OF INCIDENT
    1) In the case of exposures due to terrorist acts against civilians, the local health department, poison center, and law enforcement agency should be contacted immediately. Also, the U.S. Federal Bureau of Investigations (FBI) should be contacted.
    N) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

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) GENERAL TREATMENT
    1) Treatment should include recommendations listed in the INHALATION EXPOSURE section when appropriate.
    B) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Dermal Exposure

    6.9.1) DECONTAMINATION
    A) CLOTHING
    1) "Off-gassing" may occur following an aerosol exposure. Medical personnel involved in decontamination of the patient should wear protective masks and eye goggles.
    2) DECONTAMINATION: Remove contaminated clothing and jewelry and place them in plastic bags. Wash exposed areas with soap and water for 10 to 15 minutes with gentle sponging to avoid skin breakdown. Rescue personnel and bystanders should avoid direct contact with contaminated skin, clothing, or other objects (Burgess et al, 1999). Since contaminated leather items cannot be decontaminated, they should be discarded (Simpson & Schuman, 2002).
    6.9.2) TREATMENT
    A) GENERAL TREATMENT
    1) Treatment should include recommendations listed in the INHALATIONAL EXPOSURE section when appropriate.
    B) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Enhanced Elimination

    A) EXTRACORPOREAL ELIMINATION
    1) Peritoneal dialysis and hemodialysis are not useful for anticholinergic poisoning.

Range Of Toxicity

Summary

    A) The ID50 (dose that incapacitates 50% of adults) of BZ is about 6.2 mcg/kg.
    B) The range of toxicity is variable and unpredictable. Clinical judgment is more important than attempting to determine the amount inhaled.
    C) An absorbed dose of less than 1 mg produces delirium that lasts 2 to 3 days.

Minimum Lethal Exposure

    A) GENERAL/SUMMARY
    1) The reported LCt50 (concentration in air needed to incapacitate 50% of exposed unprotected individuals via inhalation during a set time) of BZ is approximately 200,000 milligrams/minute/cubic meter ((Holstege, 2001)).

Maximum Tolerated Exposure

    A) GENERAL/SUMMARY
    1) POTENCY - BZ is approximately 25-fold more potent centrally than atropine, but only 3-fold more potent than scopolamine. Its effectiveness following oral administration is about 80% that of the intravenous or intramuscular routes (which are the same). When disseminated at an optimal particle size (diameter about 1.0 micrometer) for the inhalation route, it is approximately 40% to 50% as effective as it is parenterally. When applied dermally in a propylene glycol vehicle, apparent absorption is only 5% to 10%, with effects delayed by about 24 hours (Ketchum & Sidell, 1997).
    a) The ID50 (dose that incapacitates 50% of adults) reported for atropine (free base) is about 140 micrograms/kilogram (8 to 14 mg per person) whereas the ID50 reported for BZ is about 6.2 micrograms/kilogram (about 0.5 milligrams per person).
    2) DOSAGE EFFECTS - At a MED50 dose (2.5 micrograms/kilogram), delirium occurs in a mild form (drowsiness, lapses of attention, slight difficulty at following complex instructions); following doses of 4 micrograms/kilogram, moderate delirium develops (somnolence, mild stupor, slurred speech, poor coordination, slowing in thought process, confusion); doses at or higher than the ID50 (6.2 micrograms/kilogram) result in a full syndrome of delirium (hallucinations, bizarre behaviors, paranoia) (Ketchum & Sidell, 1997).
    3) ICt50 - The ICt50 (concentration in air of BZ necessary to incapacitate 50% of exposed persons via inhalation over a set time) is reported to be 100 milligrams/minute/cubic meter ((Holstege, 2001)).
    4) An absorbed BZ dose of less than 1 milligram can produce an acute brain syndrome (toxic delirium, hallucinations) that lasts 2 to 3 days (Ketchum & Sidell, 1997).
    5) A maximum no-effect BZ dose in humans is estimated to be 0.5 to 1.0 micrograms per kilogram (Byrd et al, 1992).

Workplace Standards

    A) ACGIH TLV Values for CAS6581-06-2 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    B) NIOSH REL and IDLH Values for CAS6581-06-2 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    C) Carcinogenicity Ratings for CAS6581-06-2 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    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

    D) OSHA PEL Values for CAS6581-06-2 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) ANIMAL DATA
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 103 mg/kg (RTECS, 2001)

Pharmacology Toxicology

Toxicologic Mechanism

    A) Quinuclidinyl benzilate (BZ) is a synthetic anticholinergic glycolate, which acts by competitively inhibiting muscarinic receptors (parasympathetic nervous system). It affects both peripheral and central nervous systems and is one of the most potent anticholinergic psychomimetics known, with only very small doses needed to produce incapacitation. BZ crosses the blood-brain barrier and blocks central muscarinic cholinergic receptors by competitive inhibition with acetylcholine. In the peripheral cholinergic nervous system, BZ produces parasympathetic blockade, resulting in tachycardia, hyperthermia, increased blood pressure, decreased salivation and reduced gastric motility and urinary tract functions ((Holstege, 2001); Ketchum & Sidell, 1997).
    1) BZ is approximately 25-fold more potent centrally than atropine and 3-fold more potent than scopolamine.
    2) BZ has been demonstrated to have high affinity for both the muscarinic m1- and m2-acetylcholine receptors (Sawada et al, 1990; Gibson et al, 1984). Boulay et al (1996) and Gitler et al (1994) have shown that BZ exhibits substantial m2 selectivity in in vivo studies. It has been suggested that BZ be used as an m2 selective radioligand for positron emission tomographic study of the loss of m2 receptors in cortical and hippocampal regions of the human brain in Alzheimer's disease (Boulay et al, 1996; Gitler et al, 1994; Holman et al, 1985).
    3) Following intravenous injections in rats, Sawada et al (1990) reported that uptake of radioiodinated BZ in cortex and caudate is established within 1 to 5 minutes, and binding to high-affinity m-AChRs is essentially irreversible for the first 360 minutes.
    4) Hiramatsu et al (1994) demonstrated low m3 binding of radioiodinated BZ in in vitro rat studies using the parotid gland, which is normally rich in mAChR subtype m3.
    B) In a mouse study analyzing the N-methyl-D-aspartate (NMDA) antagonistic properties of anticholinergic drugs for potential use to terminate nerve agent-induced seizures and modulate the neuropathologic consequences of agent exposure, BZ was shown to have no NMDA antagonist properties (McDonough & Shih, 1995).

Physicochemical

Physical Characteristics

    A) Quinuclidinyl benzilate (BZ) is a stable and environmentally persistent, odorless, white, crystalline solid. It is thus suitable for dissemination by heat producing (thermal) munitions ((Anon, 1998); Ketchum & Sidell, 1997).
    1) BZ is slightly soluble in water; soluble in dilute acids, trichloroethylene, and most organic solvents, such as alcohol and chloroform; insoluble in aqueous alkali ((Anon, 1998)).

Ph

    A) pH of maximum stability in water at 25 degrees, containing little or no basic anions, is 3.64 (Hull et al, 1979).

Molecular Weight

    A) 337.45 (RTECS , 2001)

References

General Bibliography

    1) 40 CFR 372.28: Environmental Protection Agency - Toxic Chemical Release Reporting, Community Right-To-Know, Lower thresholds for chemicals of special concern. National Archives and Records Administration (NARA) and the Government Printing Office (GPO). Washington, DC. Final rules current as of Apr 3, 2006.
    2) 40 CFR 372.65: Environmental Protection Agency - Toxic Chemical Release Reporting, Community Right-To-Know, Chemicals and Chemical Categories to which this part applies. National Archives and Records Association (NARA) and the Government Printing Office (GPO), Washington, DC. Final rules current as of Apr 3, 2006.
    3) 49 CFR 172.101 - App. B: Department of Transportation - Table of Hazardous Materials, Appendix B: List of Marine Pollutants. National Archives and Records Administration (NARA) and the Government Printing Office (GPO), Washington, DC. Final rules current as of Aug 29, 2005.
    4) 62 FR 58840: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 1997.
    5) 65 FR 14186: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2000.
    6) 65 FR 39264: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2000.
    7) 65 FR 77866: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2000.
    8) 66 FR 21940: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2001.
    9) 67 FR 7164: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2002.
    10) 68 FR 42710: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2003.
    11) 69 FR 54144: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2004.
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