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PLANTS-CONIINE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Coniine is a piperidine alkaloid, (based on the piperidine structure), from the family Apiaceae. Several species of hemlock are relatively common in the wild. These include Poison Hemlock and Water Hemlock (Cicuta virosa).

Specific Substances

    A) CONSTITUENTS OF THE GROUP
    1) Conium maculatum (Poison hemlock) (plant)
    2) Aethusa cynapium (Fool's parsley) (plant)
    3) S-2-propylpiperidine (compound)
    4) Cicutine (compound)
    5) Conicine (compound)
    6) N-methylconine (compound)
    7) Lambda-coniceine (compound)
    8) Conhydrine (compound)
    9) Pseudoconhydrine (compound)
    10) CONIINE, PLANTS

Overview

Life Support

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

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) WITH POISONING/EXPOSURE
    1) Coniine containing plants have actions similar to nicotine. Clinical effects will depend on the dose of coniine or coniine-like alkaloid ingested. The nicotinic effects are biphasic, with stimulation followed by CNS depression and paralysis of respiratory muscles.
    2) Initial symptoms may be vomiting, confusion, respiratory depression, and muscle paralysis. Death, when it occurs, is usually rapid and due to respiratory paralysis.
    0.2.3) VITAL SIGNS
    A) WITH POISONING/EXPOSURE
    1) Tachycardia followed by bradycardia may occur after exposure.
    0.2.4) HEENT
    A) WITH POISONING/EXPOSURE
    1) Profuse salivation, thirst, mydriasis, diplopia and amblyopia have been reported.
    0.2.5) CARDIOVASCULAR
    A) WITH POISONING/EXPOSURE
    1) An initial rapid pulse during a short excitation phase is followed by a bradycardia and pulse that becomes weak and thready.
    0.2.6) RESPIRATORY
    A) WITH POISONING/EXPOSURE
    1) Respiratory depression may lead to asphyxiation.
    0.2.7) NEUROLOGIC
    A) WITH POISONING/EXPOSURE
    1) Seizures may occur. CNS depression has been reported.
    0.2.8) GASTROINTESTINAL
    A) WITH POISONING/EXPOSURE
    1) Nausea and vomiting, and a burning sensation of the mouth, throat, and abdomen may occur.
    0.2.9) HEPATIC
    A) WITH POISONING/EXPOSURE
    1) Transient elevations in liver function tests may occur.
    0.2.10) GENITOURINARY
    A) WITH POISONING/EXPOSURE
    1) Renal failure due to rhabdomyolysis may occur.
    0.2.14) DERMATOLOGIC
    A) WITH POISONING/EXPOSURE
    1) Some species have caused dermatitis.
    0.2.15) MUSCULOSKELETAL
    A) WITH POISONING/EXPOSURE
    1) Paralysis of the skeletal muscles, intense, diffuse muscle pain, swelling and stiffness of muscles, and rhabdomyolysis can occur.
    0.2.20) REPRODUCTIVE
    A) Both coniine and gamma coniceine are considered teratogenic in various animals.

Laboratory Monitoring

    A) Although coniine can be isolated in the blood and urine, no therapeutic/toxic levels are published.
    B) Monitor fluid and electrolytes in patients that develop significant vomiting.
    C) Monitor CPK, renal function studies, LDH, AST, and ALT in patients exhibiting mild to moderate symptoms.
    D) Monitor neuro status following a significant ingestion.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) SUMMARY - Gastric lavage may not effectively remove large pieces of plant material. Consider activated charcoal after large ingestions.
    B) EMESIS: Ipecac-induced emesis is not recommended because of the potential for CNS depression and seizures.
    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) WHOLE GUT LAVAGE - May be of use to assist in expelling large quantities of undigested plant material from the GI tract.
    E) 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.
    F) HYPOTENSION: Infuse 10 to 20 mL/kg isotonic fluid. If hypotension persists, administer dopamine (5 to 20 mcg/kg/min) or norepinephrine (ADULT: begin infusion at 0.5 to 1 mcg/min; CHILD: begin infusion at 0.1 mcg/kg/min); titrate to desired response.
    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.
    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).

Range Of Toxicity

    A) TOXICITY: A toxic dose is difficult to determine due to differing concentrations of at least 5 alkaloids in each plant. A serious toxic dose is estimated to be 60 mg and a lethal dose is estimated to be 100 to 300 mg. A woman developed respiratory arrest about 2 hours after ingesting poison hemlock mistaken for wild celery. She recovered without sequelae following supportive care.

Clinical Effects

Summary Of Exposure

    A) WITH POISONING/EXPOSURE
    1) Coniine containing plants have actions similar to nicotine. Clinical effects will depend on the dose of coniine or coniine-like alkaloid ingested. The nicotinic effects are biphasic, with stimulation followed by CNS depression and paralysis of respiratory muscles.
    2) Initial symptoms may be vomiting, confusion, respiratory depression, and muscle paralysis. Death, when it occurs, is usually rapid and due to respiratory paralysis.

Vital Signs

    3.3.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Tachycardia followed by bradycardia may occur after exposure.
    3.3.2) RESPIRATIONS
    A) WITH POISONING/EXPOSURE
    1) Respiratory depression requiring mechanical ventilation may occur (Rizzi et al, 1989).
    3.3.5) PULSE
    A) WITH POISONING/EXPOSURE
    1) Tachycardia occurs early after exposure followed by bradycardia.

Heent

    3.4.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Profuse salivation, thirst, mydriasis, diplopia and amblyopia have been reported.
    3.4.3) EYES
    A) WITH POISONING/EXPOSURE
    1) MYDRIASIS has been reported (Ober, 1977; HSDB , 2000).
    2) DIPLOPIA has been reported (Ober, 1977).
    3) AMBLYOPIA has been reported (Ober, 1977).
    3.4.6) THROAT
    A) WITH POISONING/EXPOSURE
    1) A burning sensation in the throat has been reported following ingestion.

Cardiovascular

    3.5.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) An initial rapid pulse during a short excitation phase is followed by a bradycardia and pulse that becomes weak and thready.
    3.5.2) CLINICAL EFFECTS
    A) BRADYCARDIA
    1) WITH POISONING/EXPOSURE
    a) The pulse may be initially rapid during a brief excitation phase, followed by a bradycardia and a pulse that becomes weak and thready, along with vasoconstriction (de Boer, 1950).

Respiratory

    3.6.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Respiratory depression may lead to asphyxiation.
    3.6.2) CLINICAL EFFECTS
    A) ACUTE RESPIRATORY INSUFFICIENCY
    1) WITH POISONING/EXPOSURE
    a) The primary effect of coniine is to cause respiratory depression leading to asphyxia and death (de Boer, 1950; Rizzi et al, 1989). Death is due to respiratory arrest from paralysis of the respiratory muscles (HSDB , 2000).
    b) CASE REPORT: Two adults ate "wild celery" (confirmed to be poison hemlock) from a local park and began to feel ill a short time later. Upon arrival they both complained of nausea, dizziness, blurred vision and limb weakness. Neither patient developed significant acetylcholine receptor stimulating symptoms. Initially, laboratory studies and physical exam were within normal limits in both patients. The male patient was given a dose of activated charcoal and his symptoms resolved within 8 hours. However, the female patient became somnolent and developed respiratory arrest about 2 hours after ingestion. She was intubated and ventilated and successfully extubated on day 2 and was discharged to home on day 3 without any permanent effects. The male patient had a positive coniine and gamma-coniceine blood concentration (collected on day 1); however, a blood sample from the female patient obtained on day 2 was negative. The authors suggested that the possible short half-life of coniine and gamma-coniceine may have produced the negative result (Chen et al, 2015).

Neurologic

    3.7.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Seizures may occur. CNS depression has been reported.
    3.7.2) CLINICAL EFFECTS
    A) SEIZURE
    1) WITH POISONING/EXPOSURE
    a) Seizures may occur. They may be tonic-clonic seizures or due to hypoxic effects (de Boer, 1950; Bruneton, 1999).
    B) CENTRAL NERVOUS SYSTEM DEFICIT
    1) WITH POISONING/EXPOSURE
    a) Headache, dizziness, lethargy, confusion, and coma have also been reported. Victims may not lose consciousness (Bruneton, 1999).
    b) CASE REPORT: A 4-year-old boy ingested some leaves of a hemlock plant (presumed to be "wild carrot" tops) and became sleepy within 30 minutes of ingestion, followed by a 2 hour nap (unusual for child) in which the child was difficult to arouse. The child had vomited green-colored emesis at home. An adequate gag reflex was maintained. Decontamination included gastric lavage and activated charcoal, and within 4 hours the child became more alert and was responding appropriately. No permanent sequelae was reported (Frank et al, 1995).

Gastrointestinal

    3.8.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Nausea and vomiting, and a burning sensation of the mouth, throat, and abdomen may occur.
    3.8.2) CLINICAL EFFECTS
    A) VOMITING
    1) WITH POISONING/EXPOSURE
    a) Ingestion of plants containing coniine may produce burning of the mouth, throat, and abdomen (Bruneton, 1999). Nausea and vomiting are frequently observed (Ober, 1977; HSDB , 2000).
    B) EXCESSIVE SALIVATION
    1) WITH POISONING/EXPOSURE
    a) Salivation and thirst have been reported (Ober, 1977; Bruneton, 1999).

Hepatic

    3.9.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Transient elevations in liver function tests may occur.
    3.9.2) CLINICAL EFFECTS
    A) LIVER ENZYMES ABNORMAL
    1) WITH POISONING/EXPOSURE
    a) Significant increases in LDH, AST, and ALT were reported in a series of 11 patients (Rizzi et al, 1989). Fulminant hepatic failure was not a complication in this series.

Genitourinary

    3.10.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Renal failure due to rhabdomyolysis may occur.
    3.10.2) CLINICAL EFFECTS
    A) RENAL FAILURE SYNDROME
    1) WITH POISONING/EXPOSURE
    a) Renal failure has been reported in patients with rhabdomyolysis. Severe tubular epithelium degeneration and dilated tubules filled with cellular debris has been reported. Patients may require peritoneal or hemodialysis as treatment (Rizzi et al, 1989). There can be tubular obstruction due to the precipitation of myoglobin casts (Di Maggio et al, 1990).
    B) MYOGLOBINURIA
    1) WITH POISONING/EXPOSURE
    a) Myoglobinuria was seen in patients who ingested birds containing coniine (De Giacomo et al, 1993).

Dermatologic

    3.14.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Some species have caused dermatitis.
    3.14.2) CLINICAL EFFECTS
    A) ANESTHESIA OF SKIN
    1) WITH POISONING/EXPOSURE
    a) Rubbing Conium maculatum on the skin may produce a burning sensation followed by numbness (Mitchell & Rook, 1979).
    B) DERMATITIS
    1) WITH POISONING/EXPOSURE
    a) Conium maculatum and Aethusa cynapium have produced dermatitis (Mitchell & Rock, 1979).

Musculoskeletal

    3.15.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Paralysis of the skeletal muscles, intense, diffuse muscle pain, swelling and stiffness of muscles, and rhabdomyolysis can occur.
    3.15.2) CLINICAL EFFECTS
    A) PARALYSIS
    1) WITH POISONING/EXPOSURE
    a) Paralysis of the skeletal muscles has been reported (Ober, 1977), and can occur gradually over time (Bruneton, 1999).
    B) MUSCLE PAIN
    1) WITH POISONING/EXPOSURE
    a) Diffuse and intense muscle pain has been reported by patients (Rizzi et al, 1989).
    b) Myalgia and arthralgia were seen after ingestion of small birds containing coniine (De Giacomo et al, 1993).
    C) RHABDOMYOLYSIS
    1) WITH POISONING/EXPOSURE
    a) Muscles have developed rapid swelling and stiffening. Muscle enzymes increased and the urine became red-brown (myoglobin). Muscle tissue showed coarse vacuolization of myocyte sarcoplasm and multifocal necrosis of myocytes (Rizzi et al, 1989).
    b) De Giacomo et al (1993) reported 27 cases of rhabdomyolysis over a 10 year period (De Giacomo et al, 1993).
    c) In a series of patients poisoned by eating contaminated birds, CPK values ranged from 1000 to 28,000 mU/mL (De Giacomo et al, 1993).

Reproductive

    3.20.1) SUMMARY
    A) Both coniine and gamma coniceine are considered teratogenic in various animals.
    3.20.2) TERATOGENICITY
    A) CONGENITAL ANOMALY
    1) Both coniine and gamma coniceine (found in poison hemlock) are considered teratogenic in various animals (Panter et al, 1988).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Although coniine can be isolated in the blood and urine, no therapeutic/toxic levels are published.
    B) Monitor fluid and electrolytes in patients that develop significant vomiting.
    C) Monitor CPK, renal function studies, LDH, AST, and ALT in patients exhibiting mild to moderate symptoms.
    D) Monitor neuro status following a significant ingestion.
    4.1.2) SERUM/BLOOD
    A) TOXICITY
    1) Although coniine can be isolated in the blood and urine, no therapeutic/toxic levels are published.
    B) BLOOD/SERUM CHEMISTRY
    1) Monitor CPK, renal function studies, LDH, AST, and ALT in patients exhibiting mild to moderate symptoms.
    4.1.3) URINE
    A) URINALYSIS
    1) Obtain urinalysis (for myoglobin) in symptomatic patients.

Methods

    A) GAS CHROMATOGRAPHY-MASS SPECTROMETRY
    1) SUMMARY: Bruneton (1999) suggested that gas chromatography and gas chromatography-mass spectrometry are commonly used to analyze both the plant and biological specimens (Bruneton, 1999).
    2) CASE REPORTS: Two adults ate "wild celery" (confirmed to be poison hemlock) from a local park and began to feel ill a short time later. Liquid chromatography time-of-flight mass spectrometry was used to detect coniine and gamma-coniceine in blood specimens (Chen et al, 2015).
    3) Drummer et al (1995) described the use of gas chromatography-mass spectrometry (Hewlett Packard MSD model 5970) to analyze postmortem blood, urine and gastric contents, as well as, plant material found at the scene in 2 separate poisonings with conium maculatum.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Monitoring

    A) Although coniine can be isolated in the blood and urine, no therapeutic/toxic levels are published.
    B) Monitor fluid and electrolytes in patients that develop significant vomiting.
    C) Monitor CPK, renal function studies, LDH, AST, and ALT in patients exhibiting mild to moderate symptoms.
    D) Monitor neuro status following a significant ingestion.

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 and seizures.
    B) 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).
    6.5.2) PREVENTION OF ABSORPTION
    A) EMESIS/NOT RECOMMENDED
    1) EMESIS: Ipecac-induced emesis is not recommended because of the potential for CNS depression and seizures.
    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) WHOLE BOWEL IRRIGATION (WBI)
    1) Whole gut lavage may be of value to assist in the evacuation of large quantities of plant material from the GI tract.
    2) CONTRAINDICATIONS - This procedure should not be used in patients who are currently or are at risk for rapidly becoming obtunded, comatose, or seizing until the airway is secured by endotracheal intubation. Whole bowel irrigation should not be used in patients with bowel obstruction, bowel perforation, megacolon, or toxic colitis.
    3) DOSE - Polyethylene glycol solution (eg Golytely(R)) is taken orally or infused by nasogastric tube at a rate of 20 milliliters/kilogram/hour in children or 2 liters/hour in adults or adolescents until the rectal effluent is clear and there is no radiographic evidence of toxin remaining in the gastrointestinal tract.
    4) ADVERSE EFFECTS - Include nausea, vomiting, abdominal cramping and bloating. Fluid and electrolyte status should be monitored, although significant fluid and electrolyte abnormalities have not been reported. Prolonged periods of irrigation may produce a mild metabolic acidosis.
    6.5.3) TREATMENT
    A) 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).
    B) 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).
    C) RENAL FAILURE SYNDROME
    1) Has been treated with peritoneal dialysis and hemodialysis (Rizzi et al, 1989).
    D) SUPPORT
    1) Hepatic dysfunction should resolve following appropriate supportive care (Rizzi et al, 1989).

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) IRRITATION SYMPTOM
    1) Symptoms are unlikely but since C. maculatum has caused dermatitis, eye irritation is possible (not reported).
    B) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Dermal Exposure

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

Range Of Toxicity

Summary

    A) TOXICITY: A toxic dose is difficult to determine due to differing concentrations of at least 5 alkaloids in each plant. A serious toxic dose is estimated to be 60 mg and a lethal dose is estimated to be 100 to 300 mg. A woman developed respiratory arrest about 2 hours after ingesting poison hemlock mistaken for wild celery. She recovered without sequelae following supportive care.

Minimum Lethal Exposure

    A) SPECIFIC SUBSTANCE
    1) CONIINE: It is estimated in man to be lethal at approximately 100 to 300 mg (Rizzi et al, 1989).
    B) ADULT
    1) CASE REPORTS: Two young adults in semirural Victoria died from hemlock poisoning after ingesting the boiled leaf material and consuming a large quantity of alcohol. Postmortem exam was positive for alcohol and carboxy-tetrahydrocannabinol in the blood and gamma-coniceine in both the blood and urine (Drummer et al, 1995).
    C) PEDIATRIC
    1) CASE REPORT: A 3-year-old boy died after consuming some leaf material (not quantified) thought to be "carrot weed" and died within 2 hours of ingestion; attempts to resuscitate the child were unsuccessful (Drummer et al, 1995).

Maximum Tolerated Exposure

    A) ACUTE
    1) CASE REPORTS: Two adults ate "wild celery" (confirmed to be poison hemlock) from a local park and began to feel ill a short time later. Upon arrival they both complained of nausea, dizziness, blurred vision and limb weakness. Neither patient developed significant acetylcholine receptor stimulating symptoms. Initially, laboratory studies and physical exam were within normal limits in both patients. The male patient was given a dose of activated charcoal and his symptoms resolved within 8 hours. However, the female patient became somnolent and developed respiratory arrest about 2 hours after ingestion. She was intubated and ventilated and successfully extubated on day 2 and was discharged to home on day 3 without any permanent effects. The male patient had a positive coniine and gamma-coniceine blood concentration (collected on day 1); however, a blood sample from the female patient obtained on day 2 was negative. The authors suggested that the possible short half-life of coniine and gamma-coniceine may have produced the negative result (Chen et al, 2015).
    2) Toxic dose: 60 mg (estimate), (Ober, 1977)
    3) Lehal dose: 100 to 300 mg (estimate), (Rizzi et al, 1989)

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) CONIINE
    1) LD50- (ORAL)MOUSE:
    a) 100 mg/kg (RTECS, 2000)
    2) LD50- (SUBCUTANEOUS)MOUSE:
    a) 80 mg/kg (RTECS, 2000)
    B) LAMDA CONICEINE
    1) LD50- (ORAL)MOUSE:
    a) 12 mg/kg (Bowman & Sanghvi, 1963)
    2) LD50- (SUBCUTANEOUS)MOUSE:
    a) 12 mg/kg (Bowman & Sanghvi, 1963)
    C) N-METHYLCONIINE
    1) LD50- (ORAL)MOUSE:
    a) 204.5 (Bowman & Sanghvi, 1963)
    2) LD50- (SUBCUTANEOUS)MOUSE:
    a) 150.5 mg/kg (Bowman & Sanghvi, 1963)

Pharmacology Toxicology

Toxicologic Mechanism

    A) Coniine is a piperidine alkaloid (Fairbairin & Challen, 1958). The two predominant toxins in hemlock are coniine and gamma-coniceine which have caused toxicity in animals and humans (Frank et al, 1995).
    1) The common precursor is a tetra-acetate: transamination between alanine and 5-keto-octanal yields gamma-coniceine and other alkaloids. The total concentration of total alkaloids is variable, and depends on the season, the geographic location, temperature fluctuations, and nycterohemeral cycle. In general, gamma-coniceine is the predominant alkaloid found in the vegetative organ, while coniine is the prominent alkaloid in the ripe fruit (Bruneton, 1999).
    B) It is an initial stimulant and secondary depressant on the autonomic ganglia. Large doses stimulate skeletal muscles and cause neuromuscular block (Bowman & Sanghvi, 1963).
    1) The actions of coniine are similar to nicotine, but produce greater CNS and skeletal muscle nerve ending paralysis (Sollman, 1957). The actions of coniine have also been said to resemble strychnine. There is little, if any, cerebral action (de Boer, 1950).

Physicochemical

Physical Characteristics

    A) Coniine is a colorless liquid with a mousy odor, and a reportedly bitter taste (Frank et al, 1995; HSDB , 2000).

Ph

    A) CONIINE - Alkaline (HSDB , 2000)

Molecular Weight

    A) CONIINE - 127.22

Animal Toxicology

Clinical Effects

    11.1.1) AVIAN/BIRD
    A) Certain small bird (skylarks, chaffinches, robins) are not susceptible to coniine poisoning. Humans may become poisoned by eating muscle tissue and internal organs from these birds (De Giacomo et al, 1993).
    B) Death has been reported in chickens following ingestion of poison hemlock seeds (Short & Edwards, 1989). Turkeys displayed ruffled feathers, paralysis of legs and wings, and marked salivation after coniine ingestion. Hepatic congestion and enteritis was found upon necropsy (Frank & Reed, 1987).
    11.1.2) BOVINE/CATTLE
    A) Muscle tremors, salivation, dyspnea, frequent urination, forceful regurgitation, and right sided recumbency were reported in cattle (Burrows et al, 1982). The onset of signs was 1.5 to 2 hours with a duration of signs 6 to 7 hours.
    B) Ingestion of Conium maculatum during gestation has induced skeletal malformations in cattle (Keeler, 1974; Keeler & Balls, 1978; Keeler et al, 1980).
    11.1.4) CAPRINE/GOAT
    A) Clinical toxicity in goats includes symptoms of muscular weakness, ataxia, incoordination, prostration, and death (Panter et al, 1990; Panter et al, 1990a). Diarrhea, excess salivation, coldness of ears and extremities, trembling, dilated pupils, rapid and shallow respirations, grunting, and screaming have also been described (Short & Edwards, 1989).
    B) Goats gavaged with conium seed had reduced fetal movement, cleft palate, torticollis, scoliosis, lordosis, arthrogryposis, rib cage abnormalities, and flexure and rigidity of the joints. Fresh seeds produced fewer abnormalities and less reduction of fetal movement than did seeds that had been stored for some time (Panter et al, 1990; Panter et al, 1990a).
    11.1.5) EQUINE/HORSE
    A) Trembling in the hindquarters, stumbling and falling down, whole body quivering, and increased respirations have been described. The onset of signs in pregnant mares was 30 to 40 minutes and lasted 4 to 5 hours (Short & Edwards, 1989).
    B) No teratogenic effects were observed following the administration of a commercial preparation of coniine to pregnant mares on days 45 to 75 gestation.
    11.1.9) OVINE/SHEEP
    A) Pregnant ewes given Connium maculatum developed muscle weakness, trembling, ataxia, frequent urination and defecation, excessive salivation, and some died. Effects were seen within 10 minutes of dosing (Panter et al, 1985). In another study, pregnant ewes fed a commercial Conium maculatum preparation developed signs of toxicity within 1.5 to 2 hours, lasting 6 to 7 hours. Signs included: nervousness, tremors, ataxia, and excessive salivation (Keeler et al, 1980).
    B) Lambs born to ewes fed Coniine maculatum at days 30 to 60 of gestation had excessive carpal pint flexure with lateral deviation in the front limbs and kinked tails. All these effects appeared normal by 8 weeks post birth (Panter et al, 1988). Lambs born to ewes fed a commercial preparation of C. maculatum exhibited no teratogenic effects (Keeler et al, 1980).
    11.1.10) PORCINE/SWINE
    A) Gilts fed seeds or plants experienced ataxia, trembling, muscular weakness, polyuria, mydriasis, frequent defecation, and a rapid heart rate which later slowed and became shallow. They then entered a deep sleep which lasted 2 to 3 hours. All had recovered 3 to 5 hours postexposure (Short & Edwards, 1989).
    B) Cleft palate was seen in newborn pigs whose mothers had been fed Conium maculatum during days 30 to 45 of gestation. Limb formation (but not cleft palate) was seen if the hemlock was ingested at days 43 to 53 (Panter et al, 1985; Panter et al, 1985a).
    11.1.13) OTHER
    A) OTHER
    1) Tule elk exhibited toxicity within 1 hour of ingesting fresh poison hemlock. Signs included: depression, lateral recumbency, groaning vocalization, teeth grinding, slowed respiratory and heart rates, and death. Young elks were affected more than adult elk solely on a dose per body weight basis (Jessup et al, 1986).
    2) Of 4 rabbits accidently fed a "large amount" of Conium maculatum, two died. Of the surviving animals one exhibited no symptoms. The other appeared weak and ataxic. He could hop normally but his hindquarters would tremble and his breathing was shallow and slow (Short & Edwards, 1989).

Range Of Toxicity

    11.3.2) MINIMAL TOXIC DOSE
    A) CATTLE
    1) 3.3 mg/kg (Keeler et al, 1980)
    B) HORSE
    1) MARES - 15.5 mg/kg (Keeler et al, 1980)
    C) SHEEP
    1) EWES - 44 mg/kg (Keeler et al, 1980)

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