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PLANTS-THEOBROMA CACAO

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Theobroma cacao L. subspecies belongs to the family Sterculiaceaea or Byttneriaceae. The term cacao describes the crude material from the plant, while the term cocoa describes the processed products. Theobromine is the principle alkaloid in cocoa with activity similar to that of caffeine. It produces weak CNS stimulation, but is a more potent diuretic, cardiac stimulant, and coronary dilator than caffeine.

Specific Substances

    A) Theobroma cacao
    1) Chocolate Tree
    2) Cacao
    3) Cacao Beans
    4) Cacao Seeds
    5) Theobroma
    6) Cocoa bean
    Theobromine
    1) 3,7-Dihydro-3,7-dimethyl-1H-purine-2,6-dione
    2) 3,7-Dimethylxanthine
    3) Diurobromine
    4) Santheose
    5) SC 15090
    6) Teobromin
    7) Theosalvose
    8) Theostene
    9) Thesal
    10) Thesodate
    11) Xanthine, 3,7-dimethyl-
    12) Molecular Formula: C7-H8-N4-O2
    13) CAS 83-67-0

Available Forms Sources

    A) FORMS
    1) Cacao seeds/beans contain 35 to 50% fixed oil, 15% starch, 15% protein, 1 to 4% theobromine, 0.07 to 0.36% caffeine.
    2) When cacao seeds are roasted, much of the theobromine passes from the kernel to the shells where it is commercially extracted (Tyler et al, 1976).
    3) THEOBROMINE CONTENT (Stavric, 1977; Zoumas, 1980):
    THEOBROMINE CONTENT (Stavric, 1977; Zoumas, 1980):
    Cocoas1.9%
    Chocolate (various types)0.15 to 0.46%
    Chocolate liquors (various)1.2% (average)
    Hot chocolate65 mg/5 oz serving (average)
    Cocoa beverages0.26% (Craig & Nguyen, 1984)

    B) SOURCES
    1) Cocoa powder, cocoa butter and cocoa extracts are obtained from cacao seeds. After curing and fermentation, the beans are dried and roasted until the desired flavor, color, and aroma are obtained. Theobromine is commercially derived from cocoa husks.
    2) Chocolate used in candy is obtained from the seeds of the theobroma cacao after fermentation and roasting. A 4 ounce Hershey Milk Chocolate Bar contains approximately 240 mg of theobromine (Glauberg & Blumenthal, 1983). Unsweetened chocolate contains 393 mg theobromine/ounce and 47 mg caffeine/ounce. Milk chocolate contains 58 mg theobromine/ounce and 6 mg caffeine/ounce (Note: The exact amounts of methylxanthines (ie, theobromine and caffeine) can vary because of variations of the coca bean and variation within brands) (Gwaltney-Brant, 2001).
    C) USES
    1) Shells from theobroma cacao are used in landscaping and have been a source of theobromine poisoning. Theobromine content of cacao meal varies from 1% to 3%, the shells may have 0.19% to 2.98% depending upon plant variety and amount of fermentation (Blakemore & Shearer, 1943).
    2) Cocoa products are used extensively in the food and pharmaceutical industries. The powder and syrup are widely used as flavorings, while cocoa butter is used extensively as a suppository and ointment base, as an emollient and as an ingredient in various topical cosmetic formulas. Cocoa butter may be a source of natural antioxidants.
    3) Chocolate contains the important components of cocoa powder and butter, which are mixed with chocolate liquor (ground cacao nibs), sugar, milk, and other flavors.

Overview

Life Support

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

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) The plant theobroma cacoa does not grow naturally in the United States. Toxicity from this plant is primarily due to theobromine, although small amounts of caffeine are also present. Theobroma cacoa extracts are present in most forms of chocolate.
    1) Most poisonings have been the result of small animals ingesting large amounts of chocolate. Similar cases have not been reported in humans.
    2) Efffects seen with theobromine poisoning resemble those of caffeine and theophylline, and may include CNS excitation, tachycardia, nausea and vomiting.
    0.2.4) HEENT
    A) Cyanotic mucous membranes were reported in severely poisoned animals.
    0.2.5) CARDIOVASCULAR
    A) Pharmacologic actions of theobromine include cerebral vasoconstriction, peripheral vasodilation and cardiac muscle stimulation. Tachycardia may occur following massive overdoses.
    0.2.7) NEUROLOGIC
    A) Although theobromine has less CNS activity than caffeine, in sufficient doses it can cause seizures and CNS stimulation.
    B) Headache may occur in humans.
    0.2.8) GASTROINTESTINAL
    A) Thirst, diarrhea and vomiting have been seen in poisoned animals.
    0.2.10) GENITOURINARY
    A) Therapeutically, theobromine and caffeine may produce diuresis. Fatally poisoned dogs had hyperemic kidneys. Hyperoxaluria may be seen in humans with as little as 50 g.
    0.2.14) DERMATOLOGIC
    A) Handling the shells of theobroma cacao while processing for theobromine and caffeine removal has occasionally caused dermatitis.
    0.2.15) MUSCULOSKELETAL
    A) Smooth muscle relaxation is reported with use of caffeine and theobromine.
    0.2.20) REPRODUCTIVE
    A) Fetotoxicity, craniofacial deformities and musculoskeletal system developmental abnormalities were reported in mouse studies.

Laboratory Monitoring

    A) A method for theobromine screening is microscale reverse phase high pressure liquid chromatography.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) Significant poisoning rarely develops in humans after acute ingestion. Gastrointestinal decontamination is usually not necessary.
    B) 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.
    C) Urinary output should be monitored carefully, fluids should be replaced as appropriate.
    D) TACHYCARDIA - Rarely requires treatment. If hemodynamic instability or myocardial ischemia develop secondary to tachycardia, a short acting cardioselective agent such as esmolol is preferred.

Range Of Toxicity

    A) Therapeutic dose in humans is 200 mg/m(2).
    B) A serum concentration of 133 mg/L was lethal in a dog. Death in a 12.3 kg dog was caused by 2 pounds of ingested chocolate. Effects are often delayed 1 to 2 days.

Clinical Effects

Summary Of Exposure

    A) The plant theobroma cacoa does not grow naturally in the United States. Toxicity from this plant is primarily due to theobromine, although small amounts of caffeine are also present. Theobroma cacoa extracts are present in most forms of chocolate.
    1) Most poisonings have been the result of small animals ingesting large amounts of chocolate. Similar cases have not been reported in humans.
    2) Efffects seen with theobromine poisoning resemble those of caffeine and theophylline, and may include CNS excitation, tachycardia, nausea and vomiting.

Heent

    3.4.1) SUMMARY
    A) Cyanotic mucous membranes were reported in severely poisoned animals.
    3.4.2) HEAD
    A) Cyanotic mucous membranes were reported in severely poisoned animals (Decker & Meyers, 1972).

Cardiovascular

    3.5.1) SUMMARY
    A) Pharmacologic actions of theobromine include cerebral vasoconstriction, peripheral vasodilation and cardiac muscle stimulation. Tachycardia may occur following massive overdoses.
    3.5.2) CLINICAL EFFECTS
    A) VASCULAR DISORDER
    1) Pharmacologic actions of theobromine include cerebral vasoconstriction, peripheral vasodilatation and cardiac muscle stimulation (Glauberg & Blumenthal, 1983).
    B) TACHYARRHYTHMIA
    1) Paroxysmal atrial tachycardia or supraventricular tachycardias may occur following massive poisoning with theobromine.

Neurologic

    3.7.1) SUMMARY
    A) Although theobromine has less CNS activity than caffeine, in sufficient doses it can cause seizures and CNS stimulation.
    B) Headache may occur in humans.
    3.7.2) CLINICAL EFFECTS
    A) HEADACHE
    1) Frequent headache was noted in one woman after ingestion of 50 grams of cocoa (Czok, 1974).
    B) SEIZURE
    1) Although theobromine has much less CNS activity than caffeine (Czok, 1974), in sufficient doses it can cause seizures and CNS stimulation (Sollmann, 1957). When cocoa (equivalent to 1.5 g daily of methylxanthines) was taken chronically, trembling was noted (Stavric, 1988).
    3.7.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) SEIZURES
    a) Poisonings in animals have resulted in restlessness, excitement, seizures, muscle spasms and coma. Death may occur 12 to 24 hours after the ingestion (Drolet et al, 1984; Decker & Meyers, 1972; Glauberg & Blumenthal, 1983).

Gastrointestinal

    3.8.1) SUMMARY
    A) Thirst, diarrhea and vomiting have been seen in poisoned animals.
    3.8.2) CLINICAL EFFECTS
    A) VOMITING
    1) A massive poisoning with theobromine may result in nausea and vomiting (Reynolds, 2000).
    3.8.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) VOMITING
    a) Vomiting has been seen in animals. Swollen, red mucous membrane surfaces were seen in the stomach and duodenum of a dog fatally poisoned on chocolate (Decker & Meyers, 1972).
    2) ANOREXIA
    a) Nausea and anorexia may be seen after large doses (undefined) (Reynolds, 2000).
    3) THIRST
    a) Thirst may occur.

Hepatic

    3.9.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) HEPATOCELLULAR DAMAGE
    a) DOG - Congestion and hyperemia of the liver were reported in a fatally poisoned dog (Drolet et al, 1984).

Genitourinary

    3.10.1) SUMMARY
    A) Therapeutically, theobromine and caffeine may produce diuresis. Fatally poisoned dogs had hyperemic kidneys. Hyperoxaluria may be seen in humans with as little as 50 g.
    3.10.2) CLINICAL EFFECTS
    A) POLYURIA
    1) Therapeutically, theobromine and caffeine produce diuresis (Glauberg & Blumenthal, 1983). Overdoses are expected to result in polyuria and diuresis.
    B) CRYSTALLURIA
    1) HYPEROXALURIA - Fasting adults given 50 g of chocolate had peak values 235% greater than control levels. With 100 g, the increase was 289%. Peak levels occurred at 2 to 4 hours. (Balcke et al, 1989).
    3.10.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) NEPHRITIS
    a) DOG - Fatally poisoned dogs had hyperemic kidneys with cytoplasmic hyaline droplets, pyknosis and karyorrhexis of the convoluted tubules (Drolet et al, 1984).

Dermatologic

    3.14.1) SUMMARY
    A) Handling the shells of theobroma cacao while processing for theobromine and caffeine removal has occasionally caused dermatitis.
    3.14.2) CLINICAL EFFECTS
    A) DERMATITIS
    1) Handling the shells of theobroma cacao while processing for theobromine and caffeine removal has occasionally caused dermatitis (Mitchell & Rook, 1979).
    B) EXCESSIVE SWEATING
    1) Ingestion of theobromine in cocoa products (equivalent of 1.5 grams methylxanthines) chronically may produce sweating (Stavric, 1988).

Musculoskeletal

    3.15.1) SUMMARY
    A) Smooth muscle relaxation is reported with use of caffeine and theobromine.
    3.15.2) CLINICAL EFFECTS
    A) DECREASED MUSCLE TONE
    1) Smooth muscle relaxation is reported with use of caffeine and theobromine (Glauberg & Blumenthal, 1983).

Reproductive

    3.20.1) SUMMARY
    A) Fetotoxicity, craniofacial deformities and musculoskeletal system developmental abnormalities were reported in mouse studies.
    3.20.2) TERATOGENICITY
    A) FETOTOXICITY
    1) MOUSE - Fetotoxicity, craniofacial deformities and musculoskeletal system developmental abnormalities were reported in mouse studies at doses of 500 mg/kg when given to the dam for 13 days (RTECS , 2000).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) CHOCOLATE - Six mothers ingested 113 g of milk chocolate containing 240 mg of theobromine, mean peak levels of 5.3 mg/L were found in breast milk 2 to 3 hours postingestion. The concentration in milk matched plasma levels closely (concentration radio milk/plasma was 0.82 +/- 0.17). If a mother ate 4 oz of chocolate every 6 hours and the infant fed at peak concentration times, an infant would receive about 10 mg of theobromine per day (Resnan et al, 1977).

Genotoxicity

    A) MUTATIONS - No lethal mutations were seen in rats at doses equivalent to 25 to 225 times those seen in human consumption (Shively et al, 1984).
    B) Sister chromatid exchange was seen in human lymphocytes at doses of 100 mg/L (RTECS , 2000).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) A method for theobromine screening is microscale reverse phase high pressure liquid chromatography.
    4.1.2) SERUM/BLOOD
    A) TOXICITY
    1) The serum concentration of 133 mg/L was lethal in a dog (Glauberg & Blumenthal, 1983).
    4.1.3) URINE
    A) URINARY LEVELS
    1) Urinary oxalic acid levels were greatly (but transiently) increased after ingestion of chocolate (Balcke et al, 1989)

Methods

    A) CHROMATOGRAPHY
    1) Various methods are available including a micro-scale reverse phase high pressure liquid chromatography (Orcutt et al, 1977).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Monitoring

    A) A method for theobromine screening is microscale reverse phase high pressure liquid chromatography.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) SUMMARY -
    1) Significant poisoning rarely develops in humans after acute ingestion. Gastrointestinal decontamination is usually not necessary.
    6.5.2) PREVENTION OF ABSORPTION
    A) SUMMARY -
    1) Significant poisoning rarely develops in humans after acute ingestion. Gastrointestinal decontamination is usually not necessary. Consider activated charcoal after very large ingestions or in symptomatic patients.
    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).
    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) 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/INDICATIONS
    a) Ventricular tachycardia or ventricular fibrillation (Prod Info Lidocaine HCl intravenous injection solution, 2006; Neumar et al, 2010; Vanden Hoek et al, 2010).
    3) 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).
    4) 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).
    5) LIDOCAINE/MONITORING PARAMETERS
    a) Monitor ECG continuously; plasma concentrations as indicated (Prod Info Lidocaine HCl intravenous injection solution, 2006).
    C) TACHYARRHYTHMIA
    1) Tachycadia rarely requires treatment. If hemodynamic instability or myocardial ischemia develop secondary to tachycardia, a short acting cardioselective agent such as esmolol is preferred.
    2) TACHYCARDIA SUMMARY
    a) Evaluate patient to be sure that tachycardia is not a physiologic response to dehydration, anemia, hypotension, fever, sepsis, or hypoxia. Sinus tachycardia does not generally require treatment unless hemodynamic compromise develops.
    b) If therapy is required, a short acting, cardioselective agent such as esmolol is generally preferred (Prod Info BREVIBLOC(TM) intravenous injection, 2012).
    c) ESMOLOL/ADULT LOADING DOSE
    1) Infuse 500 micrograms/kilogram (0.5 mg/kg) IV over 1 minute (Neumar et al, 2010).
    d) ESMOLOL/ADULT MAINTENANCE DOSE
    1) Follow loading dose with infusion of 50 mcg/kg per minute (0.05 mg/kg per minute) (Neumar et al, 2010).
    2) EVALUATION OF RESPONSE: If response is inadequate, infuse second loading bolus of 0.5 mg/kg over 1 minute and increase the maintenance infusion to 100 mcg/kg (0.1 mg/kg) per minute. Reevaluate therapeutic effect, increase in the same manner if required to a maximum infusion rate of 300 mcg/kg (0.3 mg/kg) per minute (Neumar et al, 2010).
    3) The manufacturer recommends that a maximum of 3 loading doses be used (Prod Info BREVIBLOC(TM) intravenous injection, 2012).
    4) END POINT OF THERAPY: As the desired heart rate or blood pressure is approached, omit loading dose and adjust maintenance infusion as required (Prod Info BREVIBLOC(TM) intravenous injection, 2012).
    e) CAUTION
    1) Esmolol is a short acting beta-adrenergic blocking agent with negative inotropic effects. Esmolol should be avoided in patients with asthma, obstructive airway disease, decompensated heart failure and pre-excited atrial fibrillation (wide complex irregular tachycardia) or atrial flutter (Neumar et al, 2010).

Dermal Exposure

    6.9.2) TREATMENT
    A) DERMATITIS
    1) Although dermatitis has been reported from handling theobroma cacao shells, these have not been serious reactions. Dermal exposures to chocolate rarely need any treatment.
    B) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Range Of Toxicity

Summary

    A) Therapeutic dose in humans is 200 mg/m(2).
    B) A serum concentration of 133 mg/L was lethal in a dog. Death in a 12.3 kg dog was caused by 2 pounds of ingested chocolate. Effects are often delayed 1 to 2 days.

Therapeutic Dose

    7.2.1) ADULT
    A) GENERAL
    1) Therapeutic doses of theobromine vary by species.
    a) HUMAN - 200 mg/m(2) as a single therapeutic dose (Glauberg & Blumenthal, 1983).

Minimum Lethal Exposure

    A) ANIMAL DATA
    1) DOG - 100 to 250 milligrams/kilogram may be lethal; one ingestion of 130 milligrams/kilogram was lethal (Decker & Myers, 1972).
    2) RAT - 0.6% of diet or 310 mg/kg/day was a toxic dose (Tarka et al, 1979).
    B) ROUTE OF EXPOSURE
    1) THEOBROMINE CONTENT/OUNCE -
     SUBSTANCEAMOUNT OF THEOBROMINE
    1Milk Chocolate44-60 mg
    2Unsweetened Choc450 mg
    3Cacao Meal300-900 mg
    4Cacao Beans300-1200 mg
    5Hot Chocolate13 mg
    6White Chocolate0.25 mg

Maximum Tolerated Exposure

    A) ANIMAL DATA
    1) Therapeutic doses of theobromine vary by species.
    a) DOG - A therapeutic dose is 20 mg/kg (Decker & Meyers, 1972).

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) ANIMAL DATA
    a) A serum concentration of 133 mg/L was lethal in a dog (Glauberg & Blumenthal, 1983).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) THEOBROMINE
    1) LD50- (ORAL)MOUSE:
    a) 837 mg/kg (RTECS, 2000)
    2) LD50- (ORAL)RAT:
    a) 1265 mg/kg (RTECS, 2000)
    B) THEOPHYLLINE

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Theobromine and caffeine both have activity on the cardiac muscle, CNS, the kidney and muscle tissue. Caffeine is in much lower concentrations in theobroma cacao, but would have a greater CNS activity. Theobromine has greater activity on the muscles (112 times that of caffeine) with intermediate activity on heart and kidney (Sollmann, 1957).

Physicochemical

Physical Characteristics

    A) Theobromine is 3, 7-dimethylxanthine. Caffeine is trimethylxanthine.

Molecular Weight

    A) Theobromine: 180.21

Animal Toxicology

Clinical Effects

    11.1.3) CANINE/DOG
    A) SUMMARY - Dogs will readily eat a toxic dose of chocolate. Signs include vomiting, restlessness, cardiac arrhythmias, diuresis, ataxia, and seizures. Death may occur 18 to 24 hours later.
    1) Patient often presents excited, incontinent, vomiting, and tachycardic. Diagnosis is based upon history or evidence of ingestion. Late in the course, patient may present with bloody emesis, muscular rigidity, and seizures. Respiratory insufficiency may occur.
    2) Death may be delayed for several days, then occur suddenly from cardiac failure (Decker & Myers, 1972). Cardiomyopathy has been reported (Gans et al, 1980). Death may also occur following respiratory failure.
    B) VOMITING occurs (Glauberg & Blumenthal, 1983). Severely irritated gastric mucosal surfaces were reported in one fatally poisoned dog (Decker & Myers, 1972).
    C) NEPHRITIS - Fatally poisoned dogs had hyperemic kidneys with cytoplasmic hyaline droplets, pyknosis, and karyorrhexis of the convoluted tubules (Drolet et al, 1984).
    D) REPRODUCTIVE EFFECTS - Theobroma crosses the placenta and is also excreted in the milk. It may also be teratogenic (Beasley et al, 1990).
    11.1.5) EQUINE/HORSE
    A) Signs include anorexia, diarrhea, and violent excitement which leads to death.
    11.1.12) RODENT
    A) Damage to lymphatic tissues, testicular atrophy, and decreased reproductive parameters (decreased number of pups per litter and fewer litters) have been reported in rodents with chronic exposure to high theobromine concentrations (Friedman et al, 1979; Gans et al, 1980) Tarka et al, 1980; (Gans, 1982; Choudhury et al, 1984).
    11.1.13) OTHER
    A) OTHER
    1) OTHER ANIMALS POISONED include horses, swine, chickens, ducks, and calves (Drolet et al, 1984). Most of the non-companion animals are poisoned by ingesting plant parts (especially hulls) of theobroma cacao.

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) Treatment should always be done on the advice and with the consultation of a veterinarian.
    5) Additional information regarding treatment of poisoned animals may be obtained from a Board Certified (ABVT) Veterinary Toxicologist (check with nearest veterinary school or veterinary diagnostic laboratory) or the National Animal Poison Control Center.
    6) ANIMAL POISON CONTROL CENTERS
    a) ASPCA Animal Poison Control Center, An Allied Agency of the University of Illinois, 1717 S. Philo Rd, Suite 36, Urbana, IL 61802, website www.aspca.org/apcc
    b) It is an emergency telephone service which provides toxicology information to veterinarians, animal owners, universities, extension personnel and poison center staff for a fee. A veterinary toxicologist is available for consultation.
    c) The following 24-hour phone number is available: (888) 426-4435. A fee may apply. Please inquire with the poison center. The agency will make follow-up calls as needed in critical cases at no extra charge.
    11.2.2) LIFE SUPPORT
    A) GENERAL
    1) MAINTAIN VITAL FUNCTIONS: Secure airway, supply oxygen, and begin supportive fluid therapy if necessary.
    11.2.4) DECONTAMINATION
    A) GASTRIC DECONTAMINATION
    1) DOGS/CATS
    a) EMESIS - DO NOT induce emesis if the animal is extremely excited, ataxic, or experiencing tremors or seizures. Emesis and lavage may not be productive if the chocolate has formed a concretion in the stomach.
    b) EMESIS AND LAVAGE - If within 2 hours of exposure, induce emesis with 1 to 2 milliliters/kilogram syrup of ipecac per os. Dogs may vomit more readily with 1 tablet (6 milligrams) apomorphine diluted in 3 to 5 milliliters water and instilled into the conjunctival sac or per os.
    1) Dogs may also be given apomorphine intravenously at 40 micrograms/kilogram, although this route may not be as effective. Do not use an emetic if the animal is hypoxic.
    2) In the absence of a gag reflex or if vomiting cannot be induced, place a cuffed endotracheal tube and begin gastric lavage. Pass large bore stomach tube and instill 5 to 10 milliliters/kilogram water or lavage solution, then aspirate. Repeat 10 times.
    c) ACTIVATED CHARCOAL - Administer repeated doses of activated charcoal at a dose of 0.5 to 1 gram/kilogram per os or via stomach tube every three hours for up to 72 hours. Avoid aspiration by proper restraint, careful technique, and if necessary tracheal intubation.
    d) CATHARTIC - Administer one to two doses of a saline or sorbitol cathartic such as magnesium or sodium sulfate (sodium sulfate dose is 1 gram/kilogram). If access to these agents is limited, give 5 to 15 milliliters magnesium oxide (Milk of Magnesia) per os for dilution.
    2) RUMINANTS/HORSES/SWINE
    a) EMESIS - Do not attempt to induce emesis in ruminants (cattle) or equids (horses).
    b) ACTIVATED CHARCOAL -
    1) Adult horses: administer 0.5 to 1 kilogram of activated charcoal in up to 1 gallon warm water via nasogastric tube.
    2) Neonate horses: administer 250 grams (one-half pound) activated charcoal in up to 2 quarts water.
    3) Adult cattle: administer 2 to 9 grams/kilogram of activated charcoal in a slurry of 1 gram charcoal/3 to 5 milliliters warm water via stomach tube.
    4) Sheep may be given 0.5 kilogram charcoal in slurry.
    c) CATHARTIC - Administer an oral cathartic via stomach tube and monitor for aspiration.
    1) Mineral oil (small ruminants and swine, 60 to 200 milliliters; equids and cattle, 0.5 to 1 gallon) or
    2) Magnesium sulfate (ruminants and swine, 1 to 2 grams/kilogram; equine, 0.2 to 0.9 grams/kilogram) or
    3) Milk of Magnesia (small ruminants, up to 0.25 gram/kilogram in 1 to 3 gallons warm water; adult cattle up to 1 gram/kilogram in 1 to 3 gallons warm water or 2 to 4 boluses MgOH per os).
    11.2.5) TREATMENT
    A) DOGS/CATS
    1) SUMMARY - Treatment includes life support, control of seizures, and supportive care for cardiac arrhythmias and respiratory problems.
    2) MAINTAIN VITAL FUNCTIONS - as necessary.
    3) SEIZURES -
    a) DIAZEPAM - Dose of diazepam for DOGS & CATS is 0.5 to 1 milligram/kilogram intravenous bolus; may repeat dose every ten minutes for four total doses. Give slowly over 1 to 2 minutes.
    b) PHENOBARBITAL may be used as adjunct treatment at 5 to 30 milligrams/kilogram over 5 to 10 minutes intravenously.
    c) REFRACTORY SEIZURES - Consider anaesthesia or heavy sedation. Administer pentobarbital to DOGS & CATS at a dose of 3 to 15 milligrams/kilogram intravenously slowly to effect. The dose may need to be repeated in 4 to 8 hours. Be sure to protect the airway.
    4) EKG must be monitored.
    a) Bradycardias can be treated with atropine at 0.02 milligram/kilogram intravenously.
    b) DOGS - PVCs in dogs can be treated with lidocaine (without epinephrine) at a dose of 1 to 2 milligrams/kilogram as an intravenous bolus followed by an intravenous drip of a 0.1 per cent solution at 30 to 50 micrograms/kilogram per minute. DO NOT USE LIDOCAINE IN CATS.
    1) Metaprolol, a beta blocker, can be used in dogs with ventricular tachycardia or who are refractory to lidocaine. Metaprolol is preferred to propranolol because the latter may slow renal excretion of methylxanthines (Beasley et al, 1990). If metaprolol is not available, use propranolol. Both are dosed in dogs at 0.04 to 0.15 milligrams/kilogram intravenously over 1 to 2 minutes three times daily.
    2) CATS - Use propranolol instead of lidocaine; dose at 0.25 milligram diluted in 1 milliliter saline and give 0.2 milliliter boluses intravenously to effect. Monitor for hypotension and decrease in cardiac output.
    5) RESPIRATORY SUPPORT including positive pressure ventilation should be used if necessary (Glauberg & Blumenthal, 1983).
    6) CATHETERIZE the urinary bladder to prevent reabsorption of theobromine from urine.
    7) CORTICOSTEROIDS ARE NOT RECOMMENDED. They interfere with the excretion of methylxanthines.
    B) RUMINANTS/HORSES/SWINE
    1) SUMMARY - Treatment includes life support, control of seizures, and supportive care for cardiac arrhythmias and respiratory problems.
    2) MAINTAIN VITAL FUNCTIONS - Secure airway, supply oxygen and begin supportive fluid therapy if necessary.
    3) SEIZURES may be controlled with diazepam. Doses of diazepam, given slowly intravenously: 1 milligram/kilogram (HORSES); 0.5 to 1.5 milligrams/kilogram (CATTLE, SHEEP AND SWINE).
    4) RESPIRATORY SUPPORT including positive pressure ventilation should be used if necessary (Glauberg & Blumenthal, 1983).
    5) CATHETERIZE the urinary bladder to prevent reabsorption of theobromine from urine.
    6) CORTICOSTEROIDS ARE NOT RECOMMENDED. They interfere with the excretion of methylxanthines.

Range Of Toxicity

    11.3.1) THERAPEUTIC DOSE
    A) DOG
    1) A "therapeutic" theobromine dose is 20 milligrams/kilogram (Decker & Myers, 1972). It is not currently used therapeutically in veterinary medicine.
    11.3.2) MINIMAL TOXIC DOSE
    A) DOGS/CATS
    1) POTENTIALLY LETHAL DOSE - 100 to 250 milligrams/kilogram caffeine or theobromine. This equals approximately 2 ounces MILK CHOCOLATE per kilogram body weight or two-tenths of an ounce BAKING CHOCOLATE per kilogram body weight (Beasley et al, 1990).
    a) Death in a 12.3-kilogram dog was caused by ingestion of 2 pounds of milk chocolate (estimated 1600 milligrams theobromine, or 130 milligrams/kilogram) (Decker & Myers, 1972).
    2) Lethal serum concentration: 133 milligrams/liter (Glauberg & Blumenthal, 1983).
    B) SWINE
    1) A ration containing 8 percent cocoa meal (at 2.5 percent theobromine) caused death when fed to weanling pigs (Tarka, 1982).
    C) RODENT
    1) Rats fed cocoa as 40% of their diet died within a few days (Weaver, 1974).

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) Treatment should always be done on the advice and with the consultation of a veterinarian.
    5) Additional information regarding treatment of poisoned animals may be obtained from a Board Certified (ABVT) Veterinary Toxicologist (check with nearest veterinary school or veterinary diagnostic laboratory) or the National Animal Poison Control Center.
    6) ANIMAL POISON CONTROL CENTERS
    a) ASPCA Animal Poison Control Center, An Allied Agency of the University of Illinois, 1717 S. Philo Rd, Suite 36, Urbana, IL 61802, website www.aspca.org/apcc
    b) It is an emergency telephone service which provides toxicology information to veterinarians, animal owners, universities, extension personnel and poison center staff for a fee. A veterinary toxicologist is available for consultation.
    c) The following 24-hour phone number is available: (888) 426-4435. A fee may apply. Please inquire with the poison center. The agency will make follow-up calls as needed in critical cases at no extra charge.
    11.4.2) DECONTAMINATION
    11.4.2.2) GASTRIC DECONTAMINATION
    A) GASTRIC DECONTAMINATION
    1) DOGS/CATS
    a) EMESIS - DO NOT induce emesis if the animal is extremely excited, ataxic, or experiencing tremors or seizures. Emesis and lavage may not be productive if the chocolate has formed a concretion in the stomach.
    b) EMESIS AND LAVAGE - If within 2 hours of exposure, induce emesis with 1 to 2 milliliters/kilogram syrup of ipecac per os. Dogs may vomit more readily with 1 tablet (6 milligrams) apomorphine diluted in 3 to 5 milliliters water and instilled into the conjunctival sac or per os.
    1) Dogs may also be given apomorphine intravenously at 40 micrograms/kilogram, although this route may not be as effective. Do not use an emetic if the animal is hypoxic.
    2) In the absence of a gag reflex or if vomiting cannot be induced, place a cuffed endotracheal tube and begin gastric lavage. Pass large bore stomach tube and instill 5 to 10 milliliters/kilogram water or lavage solution, then aspirate. Repeat 10 times.
    c) ACTIVATED CHARCOAL - Administer repeated doses of activated charcoal at a dose of 0.5 to 1 gram/kilogram per os or via stomach tube every three hours for up to 72 hours. Avoid aspiration by proper restraint, careful technique, and if necessary tracheal intubation.
    d) CATHARTIC - Administer one to two doses of a saline or sorbitol cathartic such as magnesium or sodium sulfate (sodium sulfate dose is 1 gram/kilogram). If access to these agents is limited, give 5 to 15 milliliters magnesium oxide (Milk of Magnesia) per os for dilution.
    2) RUMINANTS/HORSES/SWINE
    a) EMESIS - Do not attempt to induce emesis in ruminants (cattle) or equids (horses).
    b) ACTIVATED CHARCOAL -
    1) Adult horses: administer 0.5 to 1 kilogram of activated charcoal in up to 1 gallon warm water via nasogastric tube.
    2) Neonate horses: administer 250 grams (one-half pound) activated charcoal in up to 2 quarts water.
    3) Adult cattle: administer 2 to 9 grams/kilogram of activated charcoal in a slurry of 1 gram charcoal/3 to 5 milliliters warm water via stomach tube.
    4) Sheep may be given 0.5 kilogram charcoal in slurry.
    c) CATHARTIC - Administer an oral cathartic via stomach tube and monitor for aspiration.
    1) Mineral oil (small ruminants and swine, 60 to 200 milliliters; equids and cattle, 0.5 to 1 gallon) or
    2) Magnesium sulfate (ruminants and swine, 1 to 2 grams/kilogram; equine, 0.2 to 0.9 grams/kilogram) or
    3) Milk of Magnesia (small ruminants, up to 0.25 gram/kilogram in 1 to 3 gallons warm water; adult cattle up to 1 gram/kilogram in 1 to 3 gallons warm water or 2 to 4 boluses MgOH per os).
    11.4.3) TREATMENT
    11.4.3.5) SUPPORTIVE CARE
    A) GENERAL
    1) Ongoing treatment is symptomatic and supportive.
    11.4.3.6) OTHER
    A) OTHER
    1) GENERAL
    a) Submit frozen plasma, urine, or stomach contents if methylxanthine analysis is desired.

Kinetics

    11.5.1) ABSORPTION
    A) DOG
    1) Glauberg & Blumenthal (1983) showed that absorption of theobromine from chocolate in dogs is slow (approximately 10 hours) compared to the same amount of theobromine absorbed in humans (approximately 3 hours).
    B) RODENT
    1) The half-life, in rats, of theobromine is about twice that of humans (Bonati et al, 1984).
    11.5.4) ELIMINATION
    A) DOG
    1) The elimination half-life in dogs is 17.5 hours.

Sources

    A) GENERAL
    1) Dogs most frequently ingest chocolate (baking, semi-sweet, and milk) and also can be poisoned by ingesting large amounts of medications containing methylxanthines. Horses and cattle are most often poisoned by ingesting cocoa bean hulls or waste which are used as bedding or feed additives.

References

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