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PLANTS-NICOTINIC

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) The nicotinic plants include various plants from the Nicotiana genus and the Solanaceae family and are native to Central and South America. Nicotiana species are also found in Australia, Europe and the Middle East (Sims et al, 1999; Webb & Dalzell, 1997; Mizrachi et al, 2000).

Specific Substances

    A) CONSTITUENTS OF THE GROUP
    1) Nicotiana attenuata (Wild tobacco)
    2) Nicotiana glauca (Tree tobacco)
    3) Nicotiana longiflora (Cultivated ornamental)
    4) Nicotiana rustica
    5) Nicotiana tabacum (Commercial tobacco)
    6) Nicotiana trigonphylla (Desert tobacco)
    7) Nicotinic plants

Available Forms Sources

    A) SOURCES
    1) Nicotiana tabacum (smoking tobacco) contains nicotine. Nicotiana glauca (tree tobacco), most commonly encountered in intoxications in the Southwest US, contains anabasine, a nicotine-like alkaloid. It is native to South America and Mexico. Intoxication can occur following ingestion.
    a) In one case, an infant developed toxicity following cutaneous absorption of anabasine after the nicotiana glauca leaves were applied to the abdomen as a home remedy to relieve abdominal pain (Murphy et al, 2006).
    2) Included in this management are the alkaloids nicotine, nicotyrine, nornicotine, anabasine, nicotelline, and myosmine (Keeler, 1979).
    3) Nicotiana glauca (family Solanaceae) is a perennial shrub 3 to 6 m tall with smooth green hairless branches and bluish leaves. Flowers are tubular and yellow. Anabasine is more potent than nicotine in humans (Sims et al, 1999a).
    4) Nicotiana glauca (tree tobacco) is a native of Argentina, Uruguay, Paraguay, and Bolivia, but has been naturalized and is a weed in parts of Arizona, Texas, Mexico, California, and the Hawaiian islands (Castorena et al, 1987). Anabasine concentration in this plant is about 0.2%.
    5) In one study, anabasine (the toxic alkaloid of Nicotiana glauca) was found in both the leaves and the flowers of samples collected from 3 different Nicotiana glauca trees(Steenkamp et al, 2002).
    B) USES
    1) Nicotiana glauca has been used as a 'folk remedy' to relieve abdominal pain by applying the leaves directly to the skin (Murphy et al, 2006).

Overview

Life Support

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

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) SOURCES: Nicotinic plants include various plants from the Nicotiana genus that belong to the Solanaceae family, and are native to Central and South America. Nicotiana species are also found in Australia, Europe and the Middle East. Nicotiana glauca has been naturalized in the southwestern United States. Nicotiana tabacum is cultivated for smoking tobacco.
    B) PHARMACOLOGY: Binds to nicotinic acetylcholine receptors that are found throughout the body, most notably in the autonomic nervous system (preganglionic sympathetic synapses and pre- and postganglionic parasympathetic synapses).
    C) TOXICOLOGY: The entire plant is poisonous. The primary toxic alkaloids found in these species are nicotine (N. tabacum) and anabasine (N. glauca), which is closely related to nicotine. Toxic effects are dose related and result from overstimulation of nicotinic receptors often causing inhibition of receptor action following initial stimulatory effects.
    D) EPIDEMIOLOGY: Children may inadvertently ingest parts of the plant, which can rarely result in significant morbidity and death. Systemic toxicity may occur from ongoing dermal exposure during the harvesting of tobacco plants.
    E) WITH THERAPEUTIC USE
    1) ADVERSE EFFECTS: DERMAL EXPOSURE: Symptoms of acute mild nicotine toxicity have been reported among workers harvesting tobacco. Risk factors include alterations in skin integrity and continually wearing wet clothing and shoes. Contact dermatitis has also been reported following dermal exposure to tobacco leaves.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Ingestion may cause: mucous membrane irritation, GI upset, nausea, vomiting, dizziness, headache, tremor, hypertension, tachycardia, CNS stimulation, diaphoresis, and pallor. ONSET: Symptoms usually begin within 15 minutes to 1 hour and can persist for 3 to 12 hours.
    2) SEVERE TOXICITY: Symptoms may include: seizures, confusion, weakness, bradycardia, hypotension and respiratory muscle paralysis.
    0.2.5) CARDIOVASCULAR
    A) WITH POISONING/EXPOSURE
    1) Hypertension and tachycardia occur initially and may be followed by slow, irregular pulse and hypotension.
    0.2.6) RESPIRATORY
    A) WITH POISONING/EXPOSURE
    1) Initially hyperpnea is common, respiratory muscle failure resulting in death may develop.
    0.2.7) NEUROLOGIC
    A) WITH POISONING/EXPOSURE
    1) Brief stimulation may develop followed by depression as well as tremors and seizures. Headache occurs frequently. Confusion, fainting, and hallucinations have all been reported. Paralysis, weakness, and coma usually follow massive ingestion.
    0.2.8) GASTROINTESTINAL
    A) WITH POISONING/EXPOSURE
    1) Initial symptoms may be irritation of the mucous membranes in the mouth, followed by vomiting which may be bloody and violent. Diarrhea and abdominal pain are uncommon occurrences.

Laboratory Monitoring

    A) No testing is required in patients with mild or no symptoms.
    B) Few laboratories can detect these alkaloids in the urine and are generally not useful to guide clinical therapy.
    C) Serum chemistries, creatine kinase, lactate, urinalysis should be performed in patients with severe poisonings.
    D) Obtain an ECG and institute cardiac monitoring in all symptomatic patients.
    E) Urine cotinine levels can be used to follow occupational exposure in tobacco harvesters.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MILD TO MODERATE TOXICITY
    1) Treatment is primarily supportive and symptomatic. Vomiting is common, which tends to limit absorption. Intravenous fluids can be administered. Persistent vital sign abnormalities, altered mental status, muscle weakness, and seizures indicate a more severe poisoning.
    B) SEVERE TOXICITY
    1) Treatment is primarily symptomatic and supportive. Patients may need airway support and mechanical ventilation for altered mental status, respiratory distress, secretions or respiratory paralysis. Atropine can be given for bradycardia or significant muscarinic signs (ie, bronchorrhea), if present. Hypotension should be treated with intravenous fluids and then a vasopressor as needed. Benzodiazepines should be used to treat seizures or severe agitation. Death is primarily from respiratory failure.
    C) DECONTAMINATION
    1) PREHOSPITAL: Prehospital decontamination is unlikely to be of benefit as nicotine is rapidly absorbed and most patients with more than mild toxicity will have significant vomiting.
    2) HOSPITAL: Gastric decontamination is often not necessary, because patients often present with large amounts of vomiting. If the patient is not already vomiting, consider using activated charcoal.
    D) AIRWAY MANAGEMENT
    1) Patients with an altered mental status or respiratory muscle weakness may need mechanical respiratory support and orotracheal intubation.
    E) ANTIDOTE
    1) There is no specific antidote.
    F) ENHANCED ELIMINATION
    1) Enhanced elimination is rarely necessary as life threatening toxicity is rare. Multiple dose activated charcoal may be theoretically be beneficial in improving elimination by interrupting enterohepatic circulation, but it is rarely indicated, it unlikely to be tolerated, and its use in this setting has not been described. Hemodialysis and hemoperfusion should be effective as nicotine has a small volume of distribution and low protein binding, but they are rarely if ever indicated and their use has not been described. The vast majority of patients do well with supportive care.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: Anyone with an intentional ingestion, symptoms other than vomiting, or children who have ingested more than a "taste" amount of nicotine plant material should be evaluated in a healthcare facility.
    2) OBSERVATION CRITERIA: Patients who are asymptomatic after 4 to 6 hours following an oral ingestion of plant material can be discharged.
    3) ADMISSION CRITERIA: Patients with persistent vital sign abnormalities, seizures, altered mental status, or muscle weakness should be admitted.
    4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing severe poisonings or following a significant nicotine plant ingestion by a child.
    H) PITFALLS
    1) Urine acidification (while theoretically helpful in enhancing elimination) is not recommended. Avoid using a H2 blocker or proton pump inhibitor initially because nicotine will be absorbed more easily in an alkaline environment.
    I) TOXICOKINETICS
    1) Symptoms typically develop within 30 minutes to 2 hours after an oral exposure. All parts of the plant are poisonous. Cutaneous absorption in tobacco harvesters, known as "green tobacco sickness", may produce systemic toxicity as well as contact dermatitis.
    J) DIFFERENTIAL DIAGNOSIS
    1) Poisoning by cholinergic agents such as organophosphates and carbamate pesticides may produce a similar presentation.
    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: Toxicity may vary depending on the species. The entire plant is considered poisonous. Nicotine is the primary toxic alkaloid found in Nicotiana tabacum and anabasine is the primary alkaloid found in N. glauca. The toxic dose will vary depending on whether the patient is habituated to the effects of nicotine. Approximately 2 to 5 mg of nicotine may produce nausea and the estimated lethal dose is 0.6 to 1 mg/kg.

Clinical Effects

Summary Of Exposure

    A) SOURCES: Nicotinic plants include various plants from the Nicotiana genus that belong to the Solanaceae family, and are native to Central and South America. Nicotiana species are also found in Australia, Europe and the Middle East. Nicotiana glauca has been naturalized in the southwestern United States. Nicotiana tabacum is cultivated for smoking tobacco.
    B) PHARMACOLOGY: Binds to nicotinic acetylcholine receptors that are found throughout the body, most notably in the autonomic nervous system (preganglionic sympathetic synapses and pre- and postganglionic parasympathetic synapses).
    C) TOXICOLOGY: The entire plant is poisonous. The primary toxic alkaloids found in these species are nicotine (N. tabacum) and anabasine (N. glauca), which is closely related to nicotine. Toxic effects are dose related and result from overstimulation of nicotinic receptors often causing inhibition of receptor action following initial stimulatory effects.
    D) EPIDEMIOLOGY: Children may inadvertently ingest parts of the plant, which can rarely result in significant morbidity and death. Systemic toxicity may occur from ongoing dermal exposure during the harvesting of tobacco plants.
    E) WITH THERAPEUTIC USE
    1) ADVERSE EFFECTS: DERMAL EXPOSURE: Symptoms of acute mild nicotine toxicity have been reported among workers harvesting tobacco. Risk factors include alterations in skin integrity and continually wearing wet clothing and shoes. Contact dermatitis has also been reported following dermal exposure to tobacco leaves.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Ingestion may cause: mucous membrane irritation, GI upset, nausea, vomiting, dizziness, headache, tremor, hypertension, tachycardia, CNS stimulation, diaphoresis, and pallor. ONSET: Symptoms usually begin within 15 minutes to 1 hour and can persist for 3 to 12 hours.
    2) SEVERE TOXICITY: Symptoms may include: seizures, confusion, weakness, bradycardia, hypotension and respiratory muscle paralysis.

Vital Signs

    3.3.3) TEMPERATURE
    A) WITH POISONING/EXPOSURE
    1) DIAPHORESIS: Excessive thirst and hyperthermia are frequently present (Mellick et al, 1999; Mizrachi et al, 2000).

Heent

    3.4.3) EYES
    A) NYSTAGMUS: A primary position upbeat nystagmus is seen following cigarette smoking, chewing of nicotine gum, and ingestion of nicotiana glauca leaves, and has been shown to be caused by nicotine (Sibony et al, 1990; Webb & Dalzell, 1997).
    B) PHOTOPHOBIA: Photophobia and disturbed vision have been reported in patients following the ingestion of plant material containing anabasine (the toxic alkaloid of Nicotiana glauca) (Steenkamp et al, 2002).
    3.4.4) EARS
    A) WITH POISONING/EXPOSURE
    1) DISTURBED HEARING: Disturbed hearing has been reported in patients following the ingestion of plant material containing anabasine (the toxic alkaloid of Nicotiana glauca) (Steenkamp et al, 2002).

Cardiovascular

    3.5.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Hypertension and tachycardia occur initially and may be followed by slow, irregular pulse and hypotension.
    3.5.2) CLINICAL EFFECTS
    A) HYPERTENSIVE EPISODE
    1) WITH POISONING/EXPOSURE
    a) Hypertension and tachycardia occur initially followed by the development of a slow and irregular pulse (Webb & Dalzell, 1997; Mellick et al, 1999).
    B) HYPOTENSIVE EPISODE
    1) WITH POISONING/EXPOSURE
    a) Hypotension may occur late in the course.
    C) CARDIAC ARREST
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 46-year-old man developed headache, hypersalivation, nausea and vomiting, hyperthermia, hypertension, and tachycardia approximately 2 hours after ingesting an unknown amount of Nicotiana glauca leaves. The patient subsequently collapsed and developed cardiac arrest. Despite resuscitative measures, the patient died 6 days postingestion (Mizrachi et al, 2000).

Respiratory

    3.6.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Initially hyperpnea is common, respiratory muscle failure resulting in death may develop.
    3.6.2) CLINICAL EFFECTS
    A) HYPERVENTILATION
    1) WITH POISONING/EXPOSURE
    a) Initial hyperpnea is common.
    B) RESPIRATORY FAILURE
    1) WITH POISONING/EXPOSURE
    a) RESPIRATORY MUSCLE FAILURE: Unrecognized, this may result in severe anoxic injury or death(Manoguerra & Freeman, 1982-1983) . Respiratory failure is the most common cause of death in animals poisoned by anabasine (Haag, 1933).
    b) Respiratory insufficiency was reported in three patients who ingested leaves from the tree tobacco plant (Nicotiana glauca) (Mellick et al, 1999).
    c) Respiratory depression may occur in patients following the ingestion of plant material containing anabasine (the toxic alkaloid of Nicotiana glauca) (Steenkamp et al, 2002).
    d) CASE REPORT/CUTANEOUS EXPOSURE: A 3-month-old presented with a 30 minute history of respiratory failure. Upon admission, intubation was required. Earlier in the day nicotiana glauca {producing anabasine toxicity; urine anabasine level was 30,693 ng/mL) was applied to the infant's abdomen for abdominal pain due to presumed constipation. The infant had a Glasgow coma score of 3. Twenty-four hours after exposure the patient neurologically improved and was successfully extubated at 36 hours. At 6 months the infant's neurologic status was normal, with the exception of a mild decrease in truncal tone (Murphy et al, 2006).

Neurologic

    3.7.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Brief stimulation may develop followed by depression as well as tremors and seizures. Headache occurs frequently. Confusion, fainting, and hallucinations have all been reported. Paralysis, weakness, and coma usually follow massive ingestion.
    3.7.2) CLINICAL EFFECTS
    A) SEIZURE
    1) WITH POISONING/EXPOSURE
    a) Brief stimulation may develop followed by depression, as well as tremors and seizures (Keeler, 1979; Webb & Dalzell, 1997).
    B) HEADACHE
    1) WITH POISONING/EXPOSURE
    a) Headache occurs frequently, especially in harvesters (Ghosh et al, 1991; Mizrachi et al, 2000).
    b) INCIDENCE: In a study of 304 tobacco farmworkers, more than half (54.3%) of the workers reported headache during the growing season (Arcury et al, 2008).
    C) HALLUCINATIONS
    1) WITH POISONING/EXPOSURE
    a) Confusion, delirium, dizziness, altered hearing and vision, fainting, hallucinations, have all been reported (Manoguerra & Freeman, 1982-1983).
    D) COMA
    1) WITH POISONING/EXPOSURE
    a) GENERAL: Coma or lethargy usually follow a massive ingestion.
    b) CASE REPORT/CUTANEOUS EXPOSURE: A 3-month-old presented with a 30 minute history of respiratory failure. Upon admission, intubation was required. Earlier in the day nicotiana glauca {producing anabasine toxicity; urine anabasine level was 30,693 ng/mL) was applied to the infant's abdomen for abdominal pain due to presumed constipation. The infant had a Glasgow coma score of 3 with physical findings of pinpoint pupils, flaccid paralysis, absent gag reflex and negative doll's eye maneuver and negative cold caloric response. A head CT showed mild brain atrophy, and an EEG revealed slow activity and poor reactivity. Twenty-four hours after exposure the patient neurologically improved and was successfully extubated at 36 hours. At 6 months the infant's neurologic status was normal, with the exception of a mild decrease in truncal tone (Murphy et al, 2006).
    E) PARALYSIS
    1) WITH POISONING/EXPOSURE
    a) Severe muscle weakness resulting in motor paresis was reported in 3 patients following ingestion of leaves from the tree tobacco plant. All 3 patients recovered with supportive care (Mellick et al, 1999).
    F) ATAXIA
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 50-year-old woman developed ataxia and paresthesia of her feet 5 hours after ingesting nicotiana glauca leaves. The symptoms spontaneously resolved approximately 24 hours postingestion (Webb & Dalzell, 1997).
    G) VERTIGO
    1) WITH POISONING/EXPOSURE
    a) Vertigo and confusion may occur in patients following the ingestion of plant material containing anabasine (the toxic alkaloid of Nicotiana glauca) (Steenkamp et al, 2002).
    b) INCIDENCE: In a study of 304 tobacco farmworkers, 27% developed dizziness at least once during the growing season (Arcury et al, 2008).
    H) NEUROMUSCULAR BLOCKADE FINDING
    1) WITH POISONING/EXPOSURE
    a) Neuromuscular blockage may occur in patients following the ingestion of plant material containing anabasine (the toxic alkaloid of Nicotiana glauca) (Steenkamp et al, 2002).

Gastrointestinal

    3.8.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Initial symptoms may be irritation of the mucous membranes in the mouth, followed by vomiting which may be bloody and violent. Diarrhea and abdominal pain are uncommon occurrences.
    3.8.2) CLINICAL EFFECTS
    A) VOMITING
    1) WITH POISONING/EXPOSURE
    a) Initial symptoms may be irritation of the mucous membranes of the mouth, followed by nausea and vomiting. The vomiting may be bloody and violent. Nausea and vomiting may be seen in tobacco harvesters (Ghosh et al, 1991; Mellick et al, 1999; Mizrachi et al, 2000).
    b) Nausea and vomiting have been reported in patients following the ingestion of plant material containing anabasine (the toxic alkaloid of Nicotiana glauca) (Steenkamp et al, 2002).
    B) DIARRHEA
    1) WITH POISONING/EXPOSURE
    a) Diarrhea and abdominal pain are uncommon occurrences (Webb & Dalzell, 1997; Mellick et al, 1999).
    b) Diarrhea has been reported in patients following the ingestion of plant material containing anabasine (the toxic alkaloid of Nicotiana glauca) (Steenkamp et al, 2002).
    C) GASTRITIS
    1) WITH POISONING/EXPOSURE
    a) "GREEN TOBACCO SICKNESS": A mild form of nicotine poisoning has been reported in young, nonsmoking tobacco pickers who handle wet, uncured tobacco leaves (Gehlbach et al, 1975).
    1) Symptoms include nausea and vomiting and can be treated with antiemetics. Prevention can be accomplished using protective clothing.
    2) INCIDENCE: In a study of 304 tobacco farmworkers, nausea (22%) and vomiting (9.9%) were reported at least once among workers during a growing season (Arcury et al, 2008).
    D) EXCESSIVE SALIVATION
    1) WITH POISONING/EXPOSURE
    a) Increased salivation has been reported in patients following the ingestion of plant material containing anabasine (the toxic alkaloid of Nicotiana glauca) (Steenkamp et al, 2002).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) CONTACT DERMATITIS
    1) WITH POISONING/EXPOSURE
    a) Contact dermatitis has been reported following skin contact with tobacco leaves. It is characterized by erythema, itching, and papular eruptions at points of skin contact with tobacco leaves. The allergen has not been identified (Nakamura, 1984).
    b) Allergic contact dermatitis has occasionally been reported from green tobacco leaves (Gonacalo et al, 1990).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) PARALYSIS
    1) WITH POISONING/EXPOSURE
    a) Skeletal muscle paralysis may be seen with large ingestions (Manoguerra & Freeman, 1982-1983).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) ACUTE ALLERGIC REACTION
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 21-year-old man experienced allergy symptoms (rhinoconjunctivitis and urticaria) following occupational exposure to an aqueous solution (fumigation product) of cut tobacco. The patient's past medical history was significant for seasonal allergic rhinoconjunctivitis to mugwort pollen. Skin prick tests and conjunctival challenge tests with green tobacco and cured tobacco leaf extracts were positive, as well as serum-specific IgE tests for the tobacco leaf. CAP inhibition experiments also showed that tobacco and mugwort pollen inhibited the binding of the patient's serum to solid-phase tobacco leaf, indicating a cross reactivity of tobacco with mugwort pollen (Ortega et al, 1999).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) No testing is required in patients with mild or no symptoms.
    B) Few laboratories can detect these alkaloids in the urine and are generally not useful to guide clinical therapy.
    C) Serum chemistries, creatine kinase, lactate, urinalysis should be performed in patients with severe poisonings.
    D) Obtain an ECG and institute cardiac monitoring in all symptomatic patients.
    E) Urine cotinine levels can be used to follow occupational exposure in tobacco harvesters.
    4.1.2) SERUM/BLOOD
    A) TOXICITY
    1) No toxic concentration has yet been established. Following the smoking of 7 cigarettes at the rate of 1 per hour, peak plasma nicotine concentrations range from 0.035 to 0.054 mg/L (Armitage et al, 1975).
    2) Plasma half-life averages 40 minutes with a range of 24 to 84 minutes (Russell et al, 1976).
    4.1.4) OTHER
    A) OTHER
    1) MONITORING
    a) Cotinine concentrations in plasma, saliva, and urine correlate with passive exposure to smoke.
    b) Urine cotinine levels can be used to follow occupational exposure in tobacco harvesters (4(6)).

Methods

    A) OTHER
    1) Few laboratories can detect these alkaloids in the urine.
    B) CHROMATOGRAPHY
    1) High pressure liquid chromatography (HPLC) methodology is available (Kyerematen et al, 1982).
    2) Gas chromatography/mass spectrometry (GC/MS) and capillary gas chromatography were used for postmortem identification of anabasine, a major alkaloid of nicotiana glauca, in human blood and urine following ingestion of nicotiana glauca leaves (Sims et al, 1999; Mizrachi et al, 2000).
    3) High performance liquid chromatography/photodiode array/mass spectrometry (HPLC/PDA/MS) has been used to detect and quantify anabasine, the toxic alkaloid of Nicotiana glauca. Anabasine was detected in the two viscera samples (obtained from an elderly woman and her son who died after ingesting Nicotiana glauca) and a flower exhibit (collected from 3 different Nicotiana glauca trees). Anabasine was found in both the leaves and the flowers (Steenkamp et al, 2002).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients with persistent vital sign abnormalities, seizures, altered mental status, or muscle weakness should be admitted.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Anyone with an intentional ingestion, symptoms other than vomiting, or children who have ingested more than a "taste" amount of nicotine plant material should be evaluated in a healthcare facility.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a poison center or medical toxicologist for assistance in managing severe poisonings or following a significant nicotine plant ingestion by a child.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients who are asymptomatic after 4 to 6 hours following an oral ingestion of plant material can be discharged.

Monitoring

    A) No testing is required in patients with mild or no symptoms.
    B) Few laboratories can detect these alkaloids in the urine and are generally not useful to guide clinical therapy.
    C) Serum chemistries, creatine kinase, lactate, urinalysis should be performed in patients with severe poisonings.
    D) Obtain an ECG and institute cardiac monitoring in all symptomatic patients.
    E) Urine cotinine levels can be used to follow occupational exposure in tobacco harvesters.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) ORAL EXPOSURE
    1) Onset of symptoms may be rapid. Emesis is usually spontaneous. Because seizures or CNS depression may occur, DO NOT induce emesis or administer activated charcoal in the prehospital setting.
    6.5.2) PREVENTION OF ABSORPTION
    A) EMESIS/NOT RECOMMENDED
    1) Nicotine has been known to cause seizures in high doses. Since seizures or lethargy may occur within 15 minutes, IPECAC-INDUCED EMESIS IS NOT RECOMMENDED.
    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).
    3) It has been suggested that multiple dose activated charcoal may enhance the elimination of nicotine, although there are no data to confirm this hypothesis (Ivey & Triggs, 1978) (4(6)). Routine use is NOT recommended.
    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) ATROPINE
    1) Atropine may be used for control of signs of excess parasympathetic stimulation.
    2) ATROPINE/DOSE
    a) ADULT BRADYCARDIA: BOLUS: Give 0.5 milligram IV, repeat every 3 to 5 minutes, if bradycardia persists. Maximum: 3 milligrams (0.04 milligram/kilogram) intravenously is a fully vagolytic dose in most adults. Doses less than 0.5 milligram may cause paradoxical bradycardia in adults (Neumar et al, 2010).
    b) PEDIATRIC DOSE: As premedication for emergency intubation in specific situations (eg, giving succinylchoine to facilitate intubation), give 0.02 milligram/kilogram intravenously or intraosseously (0.04 to 0.06 mg/kg via endotracheal tube followed by several positive pressure breaths) repeat once, if needed (de Caen et al, 2015; Kleinman et al, 2010). MAXIMUM SINGLE DOSE: Children: 0.5 milligram; adolescent: 1 mg.
    1) There is no minimum dose (de Caen et al, 2015).
    2) MAXIMUM TOTAL DOSE: Children: 1 milligram; adolescents: 2 milligrams (Kleinman et al, 2010).
    C) 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).
    D) MONITORING OF PATIENT
    1) No testing is required in patients with mild or no symptoms.
    2) Serum chemistries, creatine kinase, lactate, urinalysis should be performed in a patient with severe poisoning.
    3) Obtain ECG and institute continuous cardiac monitoring in symptomatic patients.
    4) Serum levels are not readily available or useful to guide therapy.
    5) Urine cotinine levels can be used to follow occupational exposure in tobacco harvesters.
    E) ANTACID
    1) Antacids are contraindicated because nicotine is better absorbed in an alkaline media (Ivey & Trigg, 1978).
    F) 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).

Enhanced Elimination

    A) SUMMARY
    1) Enhanced elimination is rarely necessary as life threatening toxicity is rare. Multiple dose activated charcoal may theoretically be beneficial in improving elimination by interrupting enterohepatic circulation, but it is rarely indicated and its use in this setting has not been described. Hemodialysis and hemoperfusion should be effective as nicotine has a small volume of distribution and low protein binding, but they are rarely if ever indicated and their use has not been described. The vast majority of patients do well with supportive care.

Range Of Toxicity

Summary

    A) TOXICITY: Toxicity may vary depending on the species. The entire plant is considered poisonous. Nicotine is the primary toxic alkaloid found in Nicotiana tabacum and anabasine is the primary alkaloid found in N. glauca. The toxic dose will vary depending on whether the patient is habituated to the effects of nicotine. Approximately 2 to 5 mg of nicotine may produce nausea and the estimated lethal dose is 0.6 to 1 mg/kg.

Minimum Lethal Exposure

    A) ACUTE
    1) A fatal dose in a 50 kg human is estimated at 40 mg of nicotine orally (0.8 mg/kg) (Keeler, 1979).

Maximum Tolerated Exposure

    A) SUMMARY
    1) Toxicity may vary depending on the species. The entire plant is considered poisonous. Nicotine is the primary toxic alkaloid found in Nicotiana tabacum and anabasine is the primary alkaloid found in N. glauca. These alkaloids are chemically related (Nelson et al, 2007).
    2) NICOTINE
    a) A toxic dose may vary considerably depending on the extent and success of spontaneous and induced emesis.
    b) Nicotine is highly toxic. About 2 to 5 mg can cause nausea. The lethal oral dose for adults is estimated to be 40 to 60 mg (Malizia et al, 1983). Survival has been reported after ingestion of 1 to 4 g (Franke & Thomas, 1936).
    B) ANIMAL DATA
    1) TOXIC DOSE: Sheep: 40 mg/kg. Cows: 60 mg/kg.

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) CONCENTRATION LEVEL
    a) The toxic blood concentration found in a fatally poisoned child was 1.15 milligrams/liter of anabasine (Castorena et al, 1987).
    b) URINE COTININE LEVELS - Were evaluated in 20 infants who ingested cigarettes. The mean values in nanograms per milliliter for cotinine in the urine was 248 at 3 hours. Some cases were as high as 464 and 653 nanograms/milliliter (Vlachos et al, 1992).
    c) The post-mortem blood anabasine concentration was 2.2 milligrams/liter in a 43-year-old male who died after an apparent ingestion of nicotiana glauca water extract (Sims et al, 1999).

Pharmacology Toxicology

Toxicologic Mechanism

    A) NICOTINE - Nicotine acts at ganglionic sites, motor endplates, and smooth muscle. These alkaloids initially stimulate the ganglia of the sympathetic and parasympathetic nervous systems by direct acetylcholine-like action on the ganglion.
    1) Prolonged ganglionic blockage and persistent depolarization may quickly follow. The neuromuscular junction develops a curare-like blockade (Manoguerra, 1982-83).
    B) ANABASINE - Anabasine was greater than 3 times more lethal than nicotine. The cause of death was respiratory paralysis (Haag, 1933). In animals, anabasine was less potent than nicotine in nicotinic effects such as spinal reflex blockage (Clark et al, 1965).

Animal Toxicology

Clinical Effects

    11.1.13) OTHER
    A) OTHER
    1) Initial hyperexcitability, hyperpnea, salivation, vomiting, diarrhea, then depression, incoordination, and paralysis.

Treatment

    11.2.1) SUMMARY
    A) GENERAL TREATMENT
    1) Begin treatment immediately.
    2) Keep animal warm.
    3) Sample vomitus, blood, urine, and feces for analysis.
    4) If skin exposure has occurred, wash animal thoroughly with a mild detergent and flush with copious amounts of water. Remember to protect oneself from contamination during cleansing procedure.
    11.2.4) DECONTAMINATION
    A) GASTRIC DECONTAMINATION
    1) SMALL ANIMALS
    a) Emesis may be dangerous due to rapid onset of symptoms. Multiple-dose activated charcoal may be of use. Symptomatic care for hypotension or hypertension and for seizures should be given.
    b) Gastric lavage may be performed using tap water or normal saline.
    c) Administer activated charcoal, 5 to 50 grams, orally, as a slurry in water.
    d) Then administer Milk of Magnesia 1 to 15 milliliters orally, mineral oil 2 to 15 milliliters orally, sodium sulfate 20%, 2 to 25 grams orally or magnesium sulfate 20%, 2 to 25 grams orally, for catharsis.
    2) LARGE ANIMALS
    a) Emesis may be dangerous due to rapid onset of symptoms. Multiple-dose activated charcoal may be of use. Symptomatic care for hypotension or hypertension and for seizures should be given.
    b) Give 250 to 500 grams of activated charcoal in a water slurry, orally, to adsorb the toxic agent.
    c) Administer an oral cathartic: mineral oil (1 to 3 liters), 20% sodium sulfate (25 to 10,000 grams), 20% magnesium sulfate (25 to 1,000 grams), or Milk of Magnesia (20 to 30 milliliters).

Continuing Care

    11.4.1) SUMMARY
    11.4.1.2) DECONTAMINATION/TREATMENT
    A) GENERAL TREATMENT
    1) Begin treatment immediately.
    2) Keep animal warm.
    3) Sample vomitus, blood, urine, and feces for analysis.
    4) If skin exposure has occurred, wash animal thoroughly with a mild detergent and flush with copious amounts of water. Remember to protect oneself from contamination during cleansing procedure.
    11.4.2) DECONTAMINATION
    11.4.2.2) GASTRIC DECONTAMINATION
    A) GASTRIC DECONTAMINATION
    1) SMALL ANIMALS
    a) Emesis may be dangerous due to rapid onset of symptoms. Multiple-dose activated charcoal may be of use. Symptomatic care for hypotension or hypertension and for seizures should be given.
    b) Gastric lavage may be performed using tap water or normal saline.
    c) Administer activated charcoal, 5 to 50 grams, orally, as a slurry in water.
    d) Then administer Milk of Magnesia 1 to 15 milliliters orally, mineral oil 2 to 15 milliliters orally, sodium sulfate 20%, 2 to 25 grams orally or magnesium sulfate 20%, 2 to 25 grams orally, for catharsis.
    2) LARGE ANIMALS
    a) Emesis may be dangerous due to rapid onset of symptoms. Multiple-dose activated charcoal may be of use. Symptomatic care for hypotension or hypertension and for seizures should be given.
    b) Give 250 to 500 grams of activated charcoal in a water slurry, orally, to adsorb the toxic agent.
    c) Administer an oral cathartic: mineral oil (1 to 3 liters), 20% sodium sulfate (25 to 10,000 grams), 20% magnesium sulfate (25 to 1,000 grams), or Milk of Magnesia (20 to 30 milliliters).

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