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DYPHYLLINE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Dyphylline is a xanthine derivative with similar structure and pharmacologic activity as theophylline. Dyphylline is NOT converted to theophylline in vivo.

Specific Substances

    1) (1,2-Dihydroxy-3-propyl)theophyllin
    2) 1,3-dimethyl-7-(2,3-dihydroxypropyl)xanthine
    3) Dihydroxypropyl theophylline
    4) Diphyllin
    5) Diprofillin
    6) Diprophylline
    7) Glyphyllinum
    8) Propyphylline
    9) Protheophylline
    10) Hyphylline
    11) CAS 479-18-5
    1.2.1) MOLECULAR FORMULA
    1) C10H14N4O4

Available Forms Sources

    A) FORMS
    1) Dyphylline is available as 200 mg and 400 mg tablets (Prod Info Lufyllin(R) oral tablets, 2009).
    B) USES
    1) Dyphylline is used for the relief of acute bronchial asthma and for reversible bronchospasm associated with chronic bronchitis and emphysema (Prod Info Lufyllin(R) oral tablets, 2009).

Overview

Life Support

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

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Dyphylline is used for the relief of acute bronchial asthma and for reversible bronchospasm associated with chronic bronchitis and emphysema.
    B) PHARMACOLOGY: Dyphylline is a xanthine derivative with similar structure and pharmacologic activity as theophylline. Its primary action is bronchodilation, and it also exhibits peripheral vasodilatory and other smooth muscle relaxant activity through competitive inhibition of phosphodiesterase resulting in an increase in cyclic AMP, producing relaxation of bronchial smooth muscle. Dyphylline is NOT converted to theophylline in vivo.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) ADVERSE EFFECTS: COMMON: Headache, nervousness, tachycardia, hypotension, and nausea. LESS COMMON: Seizures, tachypnea, albuminuria, hyperglycemia, and circulatory failure.
    E) WITH POISONING/EXPOSURE
    1) Symptoms similar to those seen with theophylline products are expected, including headache, nervousness, tachycardia, hypotension, nausea, seizures, and circulatory failure.
    2) The early and less severe signs of toxicity may not always precede the more serious signs.
    0.2.5) CARDIOVASCULAR
    A) WITH POISONING/EXPOSURE
    1) Various tachyarrhythmias, including ventricular tachycardia, have been noted with overdose with other xanthines, primarily theophylline. Hypotension may be noted following severe intoxication.
    0.2.7) NEUROLOGIC
    A) WITH POISONING/EXPOSURE
    1) Restlessness, irritability, headache, and nervousness may be noted. Seizures occur following severe intoxication.
    0.2.8) GASTROINTESTINAL
    A) WITH POISONING/EXPOSURE
    1) Nausea, vomiting, and abdominal pain may be noted.
    0.2.12) FLUID-ELECTROLYTE
    A) WITH POISONING/EXPOSURE
    1) Dehydration from excessive severe vomiting and diarrhea may occur.
    0.2.20) REPRODUCTIVE
    A) Dyphylline is classified as FDA pregnancy category C. Xanthines are regarded as relatively safe for use during pregnancy and the general consensus view is that asthma management in pregnant patients should be the same as that of nonpregnant patients. Dyphylline is excreted in breast milk at a concentration that is approximately twice that of the maternal plasma concentration.
    0.2.21) CARCINOGENICITY
    A) At the time of this review, the manufacturer does not report any carcinogenic potential for dyphylline in humans or animals.

Laboratory Monitoring

    A) Monitor serum electrolytes, vital signs and mental status.
    B) Monitor CPK levels and renal function in patients with seizures.
    C) Institute continuous cardiac monitoring and obtain an ECG.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Establish IV access and place the patient on a cardiac monitor. Treat nausea with antiemetic and administer IV fluids. Monitor electrolytes.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) The primary effect of dyphylline is increased sympathomimetic effects; therefore, sympathomimetic agents should be avoid in treatment of severe toxicity. Sedation should be induced with benzodiazepines or barbiturates; high doses may be required. Hemodynamically significant tachycardia should be treated with esmolol, which can paradoxically improve blood pressure in severely tachycardic patients. Hypotension should be treated with IV fluids. Adrenergic vasopressors can theoretically make tachycardia worse, but there are numerous reports of successful treatment of severe theophylline toxicity with these agents. Vasopressin is of theoretical value and has been used effectively in a case of caffeine poisoning. Lidocaine administration has been associated with successful treatment of ventricular fibrillation. Hemodialysis should be performed in patients with severe toxicity Hyperthermia should be managed with external cooling and benzodiazepines to control agitation.
    C) DECONTAMINATION
    1) PREHOSPITAL: Avoid GI decontamination as patients are at high risk to vomit and suffer abrupt deterioration.
    2) HOSPITAL: Activated charcoal should be administered to patients who have a significant acute ingestion. As dyphylline can cause seizures and vomiting, most patients should be intubated prior to charcoal administration.
    D) AIRWAY MANAGEMENT
    1) Perform early in patients with severe intoxication.
    E) ANTIDOTE
    1) None.
    F) ENHANCED ELIMINATION PROCEDURE
    1) Dyphylline is dialyzable and hemodialysis may be of some benefit with severe intoxication, although it is not recommend as a routine procedure in overdose management. Hemodialysis should be reserved for cases where there is no response to general supportive care and symptomatic treatment.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: Patients who are not chronically taking dyphylline and who unintentionally ingest 10 mg/kg/dose or less of the regular release formulation can be managed at home.
    2) OBSERVATION CRITERIA: Patients with an acute ingestion of immediate-release preparations who have only mild clinical effects (ie, mild tachycardia, nausea, vomiting, tremor) can be observed in the ED with activated charcoal therapy, cardiac monitoring and serial dyphylline levels. Patients with worsening signs and symptoms, ingestion of a sustained-release product or rising levels should be admitted to a monitored setting.
    3) ADMISSION CRITERIA: Admit all patients with chronic intoxication or those with acute ingestions in whom serum dyphylline levels are not falling. Patients with symptoms beyond mild tachycardia, nausea, vomiting and tremor and those whose symptoms do not resolve should be admitted. Because of the potential for severe toxicity, most patients should be admitted to an intensive care setting.
    4) TRANSFER CRITERIA: Patients who are at risk for developing life-threatening toxicity should be transferred to a facility where emergent hemodialysis is available.
    5) CONSULT CRITERIA: Consult a medical toxicologist or poison center for any patient with severe toxicity or in whom the diagnosis is unclear. Consult a nephrologist early in any patient with severe toxicity or rapidly rising dyphylline concentrations.
    H) PITFALLS
    1) The control of nausea and vomiting with an antiemetic and the early administration of activated charcoal is crucial in order to prevent further absorption and enhance elimination of dyphylline. Patients who have ingested sustained-release formulations may not develop peak serum concentrations for 24 hours. Patients toxicity may develop severe clinical effects abruptly.
    I) PHARMACOKINETICS
    1) Reaches a peak plasma concentration of 17.1 mcg/ml in approximately 45 minutes following a single oral dose of 1000 mg; peak levels occur within 3 hours after administration of the sustained release product. Dyphylline is not metabolized by the liver. Approximately 88% of a single oral dose of dyphylline is excreted unchanged in the urine. Renal clearance would be expected to be reduced in individuals with renal dysfunction; The half-life after IV or PO administration is approximately 2 hours.
    J) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that may cause tachycardia, hypotension, seizures, and agitation (eg, theophylline, caffeine, cocaine, amphetamines, CNS stimulants).

Range Of Toxicity

    A) TOXICITY: A specific toxic dose has not been established. The minimum lethal or toxic dose is not well established in the literature. Doses greater than the therapeutic recommendations of 10 mg/kg/dose of the regular tablets or liquid or 40 mg/kg/dose of the sustained released product may cause toxic symptoms.
    B) THERAPEUTIC DOSE: The recommended dose of dyphylline is up to 15 mg/kg every six hours.

Clinical Effects

Summary Of Exposure

    A) USES: Dyphylline is used for the relief of acute bronchial asthma and for reversible bronchospasm associated with chronic bronchitis and emphysema.
    B) PHARMACOLOGY: Dyphylline is a xanthine derivative with similar structure and pharmacologic activity as theophylline. Its primary action is bronchodilation, and it also exhibits peripheral vasodilatory and other smooth muscle relaxant activity through competitive inhibition of phosphodiesterase resulting in an increase in cyclic AMP, producing relaxation of bronchial smooth muscle. Dyphylline is NOT converted to theophylline in vivo.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) ADVERSE EFFECTS: COMMON: Headache, nervousness, tachycardia, hypotension, and nausea. LESS COMMON: Seizures, tachypnea, albuminuria, hyperglycemia, and circulatory failure.
    E) WITH POISONING/EXPOSURE
    1) Symptoms similar to those seen with theophylline products are expected, including headache, nervousness, tachycardia, hypotension, nausea, seizures, and circulatory failure.
    2) The early and less severe signs of toxicity may not always precede the more serious signs.

Vital Signs

    3.3.3) TEMPERATURE
    A) WITH POISONING/EXPOSURE
    1) HYPERTHERMIA and diaphoresis may occur following severe overdose with overdose with other xanthines, primarily theophylline (Prod Info Lufyllin(R)-400 oral tablets, 2009).

Heent

    3.4.4) EARS
    A) WITH POISONING/EXPOSURE
    1) TINNITUS may occur following an overdose of dyphylline (Prod Info Lufyllin(R)-400 oral tablets, 2009).

Cardiovascular

    3.5.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Various tachyarrhythmias, including ventricular tachycardia, have been noted with overdose with other xanthines, primarily theophylline. Hypotension may be noted following severe intoxication.
    3.5.2) CLINICAL EFFECTS
    A) VENTRICULAR TACHYCARDIA
    1) WITH POISONING/EXPOSURE
    a) Ventricular tachycardia and atrial arrhythmias (including fibrillation) have been seen in severe poisonings with overdose with other xanthines, primarily theophylline. Adverse reactions of xanthines also include palpitations and extrasystoles (Prod Info Lufyllin(R)-400 oral tablets, 2009).
    B) HYPOTENSIVE EPISODE
    1) WITH POISONING/EXPOSURE
    a) Cardiovascular collapse has occurred in some fatalities following massive overdosage with overdose with other xanthines, primarily theophylline(Prod Info Lufyllin(R)-400 oral tablets, 2009).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) HYPERVENTILATION
    1) WITH THERAPEUTIC USE
    a) Tachypnea may occur with therapeutic use (Prod Info Lufyllin(R)-400 oral tablets, 2009).

Neurologic

    3.7.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Restlessness, irritability, headache, and nervousness may be noted. Seizures occur following severe intoxication.
    3.7.2) CLINICAL EFFECTS
    A) SEIZURE
    1) WITH POISONING/EXPOSURE
    a) Generalized tonic-clonic seizures or grand mal seizures may occur during severe toxicity with overdose with other xanthines, primarily theophylline, and frequently respond poorly to conventional anticonvulsant therapy. Often, no premonitory symptoms of toxicity are present prior to seizures (Prod Info Lufyllin(R)-400 oral tablets, 2009)
    B) FEELING NERVOUS
    1) WITH POISONING/EXPOSURE
    a) Agitation, nervousness, restlessness, irritability, and headaches are signs of moderate toxicity with overdose with other xanthines, primarily theophylline (Prod Info Lufyllin(R)-400 oral tablets, 2009).

Gastrointestinal

    3.8.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Nausea, vomiting, and abdominal pain may be noted.
    3.8.2) CLINICAL EFFECTS
    A) GASTROENTERITIS
    1) WITH THERAPEUTIC USE
    a) Therapeutically, dyphylline is generally well-tolerated and produces fewer gastrointestinal side effects than other xanthines when dosed orally (Prod Info Lufyllin(R)-400 oral tablets, 2009).
    2) WITH POISONING/EXPOSURE
    a) Nausea and vomiting plus occasional abdominal cramps and diarrhea occur frequently in both oral and parenteral overdoses with overdose with other xanthines, primarily theophylline. Severe vomiting may occur in large overdoses resulting in hypovolemia and dehydration (Prod Info Lufyllin(R)-400 oral tablets, 2009).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) ALBUMINURIA
    1) WITH POISONING/EXPOSURE
    a) Albuminuria and gross and microscopic hematuria and diuresis are adverse reactions associated with xanthines (Prod Info Lufyllin(R)-400 oral tablets, 2009).

Reproductive

    3.20.1) SUMMARY
    A) Dyphylline is classified as FDA pregnancy category C. Xanthines are regarded as relatively safe for use during pregnancy and the general consensus view is that asthma management in pregnant patients should be the same as that of nonpregnant patients. Dyphylline is excreted in breast milk at a concentration that is approximately twice that of the maternal plasma concentration.
    3.20.2) TERATOGENICITY
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the teratogenic potential of dyphylline (Prod Info LUFYLLIN(R) oral tablets, 2009; Prod Info LUFYLLIN(R)-400 oral tablets, 2009).
    3.20.3) EFFECTS IN PREGNANCY
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the potential effects of exposure to dyphylline during pregnancy in humans (Prod Info LUFYLLIN(R) oral tablets, 2009; Prod Info LUFYLLIN(R)-400 oral tablets, 2009).
    B) PREGNANCY CATEGORY
    1) The manufacturer has classified dyphylline as FDA pregnancy category C (Prod Info LUFYLLIN(R) oral tablets, 2009; Prod Info LUFYLLIN(R)-400 oral tablets, 2009).
    C) LACK OF EFFECT
    1) Xanthines are regarded as relatively safe for use during pregnancy. Although there have been no epidemiological studies or case reports on the use of dyphylline in pregnant women, poor oxygenation due to uncontrolled asthma represents a greater danger to the fetus than any potential harm associated with the drugs used to treat the disease. The general consensus view is that the management of asthma in pregnant patients should be the same as that of nonpregnant patients (Weinberger & Weiss, 1995)(Cunningham et al, 1993).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) Dyphylline is excreted in breast milk at a concentration that is approximately twice that of the maternal plasma concentration (Prod Info LUFYLLIN(R) oral tablets, 2009; Prod Info LUFYLLIN(R)-400 oral tablets, 2009). In a study of 20 lactating women who received a single dyphylline dose of 5 mg/kg, the ratio of dyphylline concentrations in breast milk was 2 times the maternal serum concentration. A single 160-mL feeding in a 5-kg infant was calculated to deliver 2.4 mg, resulting in a peak serum level of 4.6 mcg/mL (Jarboe et al, 1981).
    3.20.5) FERTILITY
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the potential effects on fertility from exposure to dyphylline in humans or animals (Prod Info LUFYLLIN(R) oral tablets, 2009; Prod Info LUFYLLIN(R)-400 oral tablets, 2009).

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) At the time of this review, the manufacturer does not report any carcinogenic potential for dyphylline in humans or animals.
    3.21.4) ANIMAL STUDIES
    A) LACK OF INFORMATION
    1) At the time of this review, the manufacturer does not report any carcinogenic potential for dyphylline in animals (Prod Info LUFYLLIN(R) oral tablets, 2009; Prod Info LUFYLLIN(R)-400 oral tablets, 2009).

Genotoxicity

    A) At the time of this review, the manufacturer does not report any mutagenic potential for dyphylline in humans or animals (Prod Info LUFYLLIN(R) oral tablets, 2009; Prod Info LUFYLLIN(R)-400 oral tablets, 2009).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor serum electrolytes, vital signs and mental status.
    B) Monitor CPK levels and renal function in patients with seizures.
    C) Institute continuous cardiac monitoring and obtain an ECG.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Monitor dyphylline serum levels, if available.
    2) Monitor serum electrolytes.
    3) Dyphylline plasma levels are generally not rapidly available in most institutions. A level of 30 mcg/ml was well tolerated in one patient following chronic ingestion of therapeutic doses.

Methods

    A) CHROMATOGRAPHY
    1) GAS CHROMATOGRAPHY - Flame-ionization gas chromatography is one method to assay dyphylline (Shihabi & Dave, 1977).
    2) LIQUID CHROMATOGRAPHY - (HPLC) has been used to assay dyphylline (Valia et al, 1980).
    B) OTHER
    1) Although dyphylline is 70% theophylline by molecular weight ratio, it is NOT converted to theophylline in vivo.
    a) The use of theophylline serum levels to monitor dyphylline therapy has resulted in serious dosing errors (Personal Communication, 1981).
    b) Dyphylline does not interfere with the EMIT theophylline assay (Bussey, 1981).
    2) XANTHINE-CONTAINING BEVERAGES - Such as coffee and colas do not falsely elevate serum dyphylline concentrations (USP, 1991).

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) Admit all patients with chronic intoxication or those with acute ingestions in whom serum dyphylline levels are not falling. Patients with symptoms beyond mild tachycardia, nausea, vomiting and tremor and those whose symptoms do not resolve should be admitted. Because of the potential for severe toxicity, most patients should be admitted to an intensive care setting.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Patients who are not chronically taking dyphylline and who unintentionally ingest 10 mg/kg/dose or less of the regular release formulation can be managed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a medical toxicologist or poison center for any patient with severe toxicity or in whom the diagnosis is unclear. Consult a nephrologist early in any patient with severe toxicity or rapidly rising dyphylline concentrations.
    6.3.1.4) PATIENT TRANSFER/ORAL
    A) Patients who are at risk for developing life-threatening toxicity should be transferred to a facility where emergent hemodialysis is available.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with an acute ingestion of immediate-release preparations who have only mild clinical effects (ie, mild tachycardia, nausea, vomiting, tremor) can be observed in the ED with activated charcoal therapy, cardiac monitoring and serial dyphylline levels. Patients with worsening signs and symptoms, ingestion of a sustained-release product or rising levels should be admitted to a monitored setting.

Monitoring

    A) Monitor serum electrolytes, vital signs and mental status.
    B) Monitor CPK levels and renal function in patients with seizures.
    C) Institute continuous cardiac monitoring and obtain an ECG.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Prehospital GI decontamination is generally not recommended because of the risk of abrupt onset seizures and the potential for aspiration.
    6.5.2) PREVENTION OF ABSORPTION
    A) 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) MONITORING OF PATIENT
    1) Monitor serum electrolytes, vital signs and mental status. Monitor CPK levels and renal function in patients with seizures. Institute continuous cardiac monitoring and obtain an ECG. Monitor dyphylline serum levels, if available.
    B) 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).
    7) RECURRING SEIZURES
    a) If seizures are not controlled by the above measures, patients will require endotracheal intubation, mechanical ventilation, continuous EEG monitoring, a continuous infusion of an anticonvulsant, and may require neuromuscular paralysis and vasopressor support. Consider continuous infusions of the following agents:
    1) MIDAZOLAM: ADULT DOSE: An initial dose of 0.2 mg/kg slow bolus, at an infusion rate of 2 mg/minute; maintenance doses of 0.05 to 2 mg/kg/hour continuous infusion dosing, titrated to EEG (Brophy et al, 2012). PEDIATRIC DOSE: 0.1 to 0.3 mg/kg followed by a continuous infusion starting at 1 mcg/kg/minute, titrated upwards every 5 minutes as needed (Loddenkemper & Goodkin, 2011).
    2) PROPOFOL: ADULT DOSE: Start at 20 mcg/kg/min with 1 to 2 mg/kg loading dose; maintenance doses of 30 to 200 mcg/kg/minute continuous infusion dosing, titrated to EEG; caution with high doses greater than 80 mcg/kg/minute in adults for extended periods of time (ie, longer than 48 hours) (Brophy et al, 2012); PEDIATRIC DOSE: IV loading dose of up to 2 mg/kg; maintenance doses of 2 to 5 mg/kg/hour may be used in older adolescents; avoid doses of 5 mg/kg/hour over prolonged periods because of propofol infusion syndrome (Loddenkemper & Goodkin, 2011); caution with high doses greater than 65 mcg/kg/min in children for extended periods of time; contraindicated in small children (Brophy et al, 2012).
    3) PENTOBARBITAL: ADULT DOSE: A loading dose of 5 to 15 mg/kg at an infusion rate of 50 mg/minute or lower; may administer additional 5 to 10 mg/kg. Maintenance dose of 0.5 to 5 mg/kg/hour continuous infusion dosing, titrated to EEG (Brophy et al, 2012). PEDIATRIC DOSE: A loading dose of 3 to 15 mg/kg followed by a maintenance dose of 1 to 5 mg/kg/hour (Loddenkemper & Goodkin, 2011).
    4) THIOPENTAL: ADULT DOSE: 2 to 7 mg/kg, at an infusion rate of 50 mg/minute or lower. Maintenance dose of 0.5 to 5 mg/kg/hour continuous infusing dosing, titrated to EEG (Brophy et al, 2012)
    b) Endotracheal intubation, mechanical ventilation, and vasopressors will be required (Brophy et al, 2012) and consultation with a neurologist is strongly advised.
    c) Neuromuscular paralysis (eg, rocuronium bromide, a short-acting nondepolarizing agent) may be required to avoid hyperthermia, severe acidosis, and rhabdomyolysis. If rhabdomyolysis is possible, avoid succinylcholine chloride, because of the risk of hyperkalemic-induced cardiac dysrhythmias. Continuous EEG monitoring is mandatory if neuromuscular paralysis is used (Manno, 2003).
    C) 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
    a) LIDOCAINE/INDICATIONS
    1) Ventricular tachycardia or ventricular fibrillation (Prod Info Lidocaine HCl intravenous injection solution, 2006; Neumar et al, 2010; Vanden Hoek et al, 2010).
    b) LIDOCAINE/DOSE
    1) ADULT: 1 to 1.5 milligrams/kilogram via intravenous push. For refractory VT/VF an additional bolus of 0.5 to 0.75 milligram/kilogram can be given at 5 to 10 minute intervals to a maximum dose of 3 milligrams/kilogram (Neumar et al, 2010). Only bolus therapy is recommended during cardiac arrest.
    a) Once circulation has been restored begin a maintenance infusion of 1 to 4 milligrams per minute. If dysrhythmias recur during infusion repeat 0.5 milligram/kilogram bolus and increase the infusion rate incrementally (maximal infusion rate is 4 milligrams/minute) (Neumar et al, 2010).
    2) CHILD: 1 milligram/kilogram initial bolus IV/IO; followed by a continuous infusion of 20 to 50 micrograms/kilogram/minute (de Caen et al, 2015).
    c) LIDOCAINE/MAJOR ADVERSE REACTIONS
    1) Paresthesias; muscle twitching; confusion; slurred speech; seizures; respiratory depression or arrest; bradycardia; coma. May cause significant AV block or worsen pre-existing block. Prophylactic pacemaker may be required in the face of bifascicular, second degree, or third degree heart block (Prod Info Lidocaine HCl intravenous injection solution, 2006; Neumar et al, 2010).
    d) LIDOCAINE/MONITORING PARAMETERS
    1) Monitor ECG continuously; plasma concentrations as indicated (Prod Info Lidocaine HCl intravenous injection solution, 2006).
    3) AMIODARONE
    a) AMIODARONE/INDICATIONS
    1) Effective for the control of hemodynamically stable monomorphic ventricular tachycardia. Also recommended for pulseless ventricular tachycardia or ventricular fibrillation in cardiac arrest unresponsive to CPR, defibrillation and vasopressor therapy (Link et al, 2015; Neumar et al, 2010). It should be used with caution when the ingestion involves agents known to cause QTc prolongation, such as fluoroquinolones, macrolide antibiotics or azoles, and when ECG reveals QT prolongation suspected to be secondary to overdose (Prod Info Cordarone(R) oral tablets, 2015).
    b) AMIODARONE/ADULT DOSE
    1) For ventricular fibrillation or pulseless VT unresponsive to CPR, defibrillation, and a vasopressor therapy give an initial dose of 300 mg IV followed by 1 dose of 150 mg IV. For stable ventricular tachycardias: Infuse 150 milligrams over 10 minutes, and repeat if necessary. Follow by a 1 milligram/minute infusion for 6 hours, then a 0.5 milligram/minute. Maximum total dose over 24 hours is 2.2 grams (Neumar et al, 2010).
    c) AMIODARONE/PEDIATRIC DOSE
    1) Infuse 5 milligrams/kilogram as a bolus for pulseless ventricular tachycardia or ventricular fibrillation; may repeat twice up to 15 mg/kg. Infuse 5 milligrams/kilogram over 20 to 60 minutes for perfusing tachycardias. Maximum single dose is 300 mg. Routine use with other drugs that prolong the QT interval is NOT recommended (Kleinman et al, 2010).
    d) ADVERSE EFFECTS
    1) Hypotension and bradycardia are the most common adverse effects (Neumar et al, 2010).
    D) TACHYARRHYTHMIA
    1) 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).
    E) HYPOTENSIVE EPISODE
    1) Shock, if it occurs, should be treated with fluids and body position; vasopressors should be avoided.
    2) 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.
    3) 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).
    4) NOREPINEPHRINE
    a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
    b) DOSE
    1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
    2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
    3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).
    F) BODY TEMPERATURE ABOVE REFERENCE RANGE
    1) Place patient in a cool room.
    2) Minimize physical activity with aggressive use of benzodiazepines. Sponge patient with tepid to cool water, and use fans to maximize evaporative heat loss.
    3) Place patient on a hypothermia blanket.
    4) Other methods include convection evaporation, intubation and cool air ventilation, and gastric lavage with iced saline (Bauwens et al, 1989).

Enhanced Elimination

    A) HEMODIALYSIS
    1) Hemodialysis is expected to remove dyphylline and may be warranted in the face of extremely high blood levels or clinically severe toxicity. However, the half-life of dyphylline is very short, and hemodialysis is not likely to be necessary.

Abstracts

Case Reports

    A) ACUTE EFFECTS
    1) PEDIATRIC
    a) A commercially available form of dyphylline, theophylline, and proxyphylline (D, T, P) in Germany was given in accidental overdose to a 3-year-old child who manifested refractory seizures and tachycardia.
    1) Following rectal administration of 600 mg D, 400 mg T, and 600 mg P, hemoperfusion through an exchange resin was required to alleviate the symptoms.
    2) Serum level of dyphylline was below the therapeutic range of 90 to 150 mg/L before hemoperfusion, so it may not have caused clinical signs.
    3) However, this multiple ingredient preparation should be used with caution, especially in infants and children (Gordjani et al, 1990).

Range Of Toxicity

Maximum Tolerated Exposure

    A) GENERAL/SUMMARY
    1) Single doses of 27 milligrams/kilogram have been tolerated without adverse effect. A single dose of 28 milligrams/kilogram resulted in severe headache (Simons & Simons, 1979).

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) GENERAL
    a) THERAPEUTIC SERUM LEVELS -
    1) An oral dose of 10 mg/kg produced a peak serum level of 14.3 mcg/ml at one hour (Simons et al, 1975a).
    2) An oral dose of 15 mg/kg produced a peak level of 12.1 mcg/ml at 0.6 hour (Simon et al, 1975b).
    b) TOXIC SERUM LEVELS -
    1) The relationship between plasma levels of dyphylline and appearance of toxicity is unknown (Prod Info Lufyllin(R)-400 oral tablets, 2009).
    2) A serum level of 36.4 mcg/ml was associated with severe headache in one patient (Simons & Simons, 1979).
    3) Peak serum levels of 19 to 30 mcg/ml have been tolerated (Baselt, 1982; Simons et al, 1977).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) References: RTECS, 2000
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 195 mg/kg
    2) LD50- (ORAL)MOUSE:
    a) 1954 mg/kg
    3) LD50- (SUBCUTANEOUS)MOUSE:
    a) 1052 mg/kg
    4) LD50- (SUBCUTANEOUS)RAT:
    a) 1253 mg/kg

Summary

    A) TOXICITY: A specific toxic dose has not been established. The minimum lethal or toxic dose is not well established in the literature. Doses greater than the therapeutic recommendations of 10 mg/kg/dose of the regular tablets or liquid or 40 mg/kg/dose of the sustained released product may cause toxic symptoms.
    B) THERAPEUTIC DOSE: The recommended dose of dyphylline is up to 15 mg/kg every six hours.

Therapeutic Dose

    7.2.1) ADULT
    A) DYPHYLLINE
    1) The usual oral dose is up to 15 mg/kg every 6 hours. Dose should be titrated based on clinical severity and patient response (Prod Info LUFYLLIN(R) oral tablets, 2009; Prod Info LUFYLLIN(R)-400 oral tablets, 2009).
    B) DYPHYLLINE/GUAIFENESIN
    1) The usual oral dose is 30 mL (dyphylline 200 mg/guaifenesin 200 mg) 4 times per day. Dose should be titrated based on clinical severity and patient response. This formulation contains 17% alcohol per tablespoon (15 mL)(Prod Info LUFYLLIN(R) oral solution, 2009).
    7.2.2) PEDIATRIC
    A) DYPHYLLINE
    1) Safety and effectiveness have not been established in pediatric patients (Prod Info LUFYLLIN(R) oral tablets, 2009; Prod Info LUFYLLIN(R)-400 oral tablets, 2009).
    B) DYPHYLLINE/GUAIFENESIN
    1) CHILDREN 6 YEARS OF AGE AND OLDER: The usual oral dose is 15 mL to 30 mL (dyphylline 100 mg/guaifenesin 100 mg per 15 mL) 3 or 4 times per day. Dose should be titrated based on clinical severity and patient response This formulation contains 17% alcohol per tablespoon (15 mL)(Prod Info LUFYLLIN(R) oral solution, 2009).
    2) CHILDREN YOUNGER THAN 6 YEARS OF AGE: Safety and effectiveness have not been established in pediatric patients under 6 years of age; use is not recommended (Prod Info LUFYLLIN(R) oral solution, 2009).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Dyphylline is a xanthine derivative which primarily exhibits bronchodilation, and to a lesser extent, peripheral vasodilation and other smooth muscle relaxation. Effect is mediated through competitive inhibition of phosphodiesterase with a resulting increase in cyclic AMP production and relaxation of bronchial smooth muscle. Dyphylline is thought to work similarly to theophylline and other members of the xanthine class (Prod Info Lufyllin(R)-400 oral tablets, 2009).

Physicochemical

Physical Characteristics

    A) Dyphylline is a white, odorless, extremely bitter, crystalline powder that is freely soluble in water and soluble in alcohol to the extent of 2 g/100 mL (Prod Info LUFYLLIN(R) oral tablets, 2009; Prod Info LUFYLLIN(R)-400 oral tablets, 2009).

Molecular Weight

    A) 254.25 (Prod Info LUFYLLIN(R) oral tablets, 2009; Prod Info LUFYLLIN(R)-400 oral tablets, 2009)

Animal Toxicology

Clinical Effects

    11.1.13) OTHER
    A) OTHER
    1) In general, small animals exposed to xanthines may exhibit vomiting, diarrhea, diuresis, restlessness, hyperactivity, tachycardia, PVCs, tachypnea, ataxia, tremors, seizures, weakness, coma, cyanosis and hypertension.
    a) They may be dehydrated or hyperthermic. Hypokalemia commonly develops; death results from cardiac arrhythmias or respiratory failure.

Treatment

    11.2.1) SUMMARY
    A) GENERAL TREATMENT
    1) Goals are to maintain basic life support; prevent absorption of xanthine; and supportively treat seizures, arrhythmias, and respiratory difficulties.
    2) Begin treatment immediately; keep animal warm; sample vomitus, blood, and urine.
    3) 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) SMALL ANIMALS
    a) EMESIS -
    1) If within 2 hours of exposure, induce emesis with 1 to 2 milliliters/kilogram syrup of ipecac per os. Dogs can have syrup of ipecac or one tablet (6 milligrams) apomorphine diluted in 3 to 5 milliliters water and instilled into the conjunctival sac or per os.
    a) Do not use an emetic if the animal is hypoxic. In the absence of a gag reflex or if vomiting cannot be induced, place a cuffed endotracheal tube and begin gastric lavage.
    b) Pass large bore stomach tube and instill 5 to 10 milliliters/kilogram water or lavage solution, then aspirate. Repeat 10 times (Kirk, 1986).
    b) CHARCOAL -
    1) Administer repeated doses of activated charcoal at 0.5 gram/kilogram per os or via stomach tube every three hours for up to 72 hours.
    a) Give the course of activated charcoal even if exposure occurred several hours before; this has been proven to shorten the half-life of methylxanthines in the body (Kirk, 1986).
    c) CATHARTIC -
    1) Administer a dose of a saline cathartic such as magnesium or sodium sulfate (sodium sulfate dose is 1 gram/kilogram) per os or via stomach tube at 0 and 3 hours to hasten evacuation.
    2) Give the cathartic even if exposure occurred several hours before; this has been proven to shorten the half-life of methylxanthines in the body (Kirk, 1986).
    2) LARGE ANIMALS
    a) EMESIS -
    1) Do not attempt to induce emesis in ruminants (cattle) or equids (horses).
    b) CHARCOAL -
    1) Give 250 to 500 grams activated charcoal in a water slurry per os or via stomach tube. Give the course of activated charcoal even if exposure occurred several hours before; this has been proven to shorten the half-life of methylxanthines in the body (Kirk, 1986).
    c) CATHARTIC -
    1) Administer an oral cathartic:
    2) Mineral oil (small ruminants and swine, 60 to 200 milliliters; equids and cattle, 0.5 to 1 gallon) or
    3) Magnesium sulfate (ruminants and swine, 1 to 2 grams/kilogram; equine, 0.2 to 0.9 gram/kilogram) or
    4) 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).
    5) Give these solutions via stomach tube and monitor for aspiration. Give the cathartic even if exposure occurred several hours before; this has been proven to shorten the half-life of methylxanthines in the body (Kirk, 1986).
    11.2.5) TREATMENT
    A) SMALL ANIMALS
    1) MAINTAIN VITAL FUNCTIONS - as necessary.
    2) SEIZURES - Seizures may be controlled with diazepam or barbiturate anticonvulsants.
    a) Dose of diazepam: 0.5 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 6 milligrams/kilogram 2 to 4 times daily as needed.
    3) EKG -
    a) EKG must be monitored in ill animals. Bradycardias can be treated with atropine at 0.02 milligram/kilogram intravenously.
    1) 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 percent solution at 30 to 50 micrograms/kilogram per minute.
    2) DO NOT USE LIDOCAINE IN CATS. Propranolol or metaprolol, beta blockers, can be used in dogs refractory to lidocaine. Either is dosed in dogs at 0.04 to 0.15 milligram/kilogram intravenously over 1 to 2 minutes three times daily.
    3) 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.
    4) Metaprolol is the preferred beta-blocker, despite difficulty in obtaining it, since propranolol has been shown to reduce clearance of theophylline, another xanthine, in humans.
    b) Catheterize the urinary bladder to prevent absorption of caffeine from urine in the bladder.
    c) Avoid erythromycin and corticosteroids (they interfere with the excretion of methylxanthines) (Beasley et al, 1989).
    B) LARGE ANIMALS
    1) MAINTAIN VITAL FUNCTIONS - Secure airway, supply oxygen if cyanotic, and begin supportive fluid therapy.
    2) SEIZURES - Seizures may be controlled with diazepam or barbiturate anticonvulsants.
    a) Dose of diazepam: 1 milligram/kilogram intravenous bolus; may repeat dose every ten minutes for four total doses. Give slowly over 5 to 10 minutes.
    3) EKG - Monitor if possible. Bradycardias can be treated with atropine at 0.04 milligram/kilogram intravenously. PVCs can be treated with lidocaine (without epinephrine).
    a) HORSES - Dose of 1 to 1.5 milligrams/kilogram lidocaine as an intravenous bolus followed by an intravenous drip of a 0.1 percent solution at 25 to 80 micrograms/kilogram per minute.
    4) Avoid erythromycin and corticosteroids (they interfere with the excretion of methylxanthines) (Beasley et al, 1989).

Continuing Care

    11.4.1) SUMMARY
    11.4.1.2) DECONTAMINATION/TREATMENT
    A) GENERAL TREATMENT
    1) Goals are to maintain basic life support; prevent absorption of xanthine; and supportively treat seizures, arrhythmias, and respiratory difficulties.
    2) Begin treatment immediately; keep animal warm; sample vomitus, blood, and urine.
    3) 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) SMALL ANIMALS
    a) EMESIS -
    1) If within 2 hours of exposure, induce emesis with 1 to 2 milliliters/kilogram syrup of ipecac per os. Dogs can have syrup of ipecac or one tablet (6 milligrams) apomorphine diluted in 3 to 5 milliliters water and instilled into the conjunctival sac or per os.
    a) Do not use an emetic if the animal is hypoxic. In the absence of a gag reflex or if vomiting cannot be induced, place a cuffed endotracheal tube and begin gastric lavage.
    b) Pass large bore stomach tube and instill 5 to 10 milliliters/kilogram water or lavage solution, then aspirate. Repeat 10 times (Kirk, 1986).
    b) CHARCOAL -
    1) Administer repeated doses of activated charcoal at 0.5 gram/kilogram per os or via stomach tube every three hours for up to 72 hours.
    a) Give the course of activated charcoal even if exposure occurred several hours before; this has been proven to shorten the half-life of methylxanthines in the body (Kirk, 1986).
    c) CATHARTIC -
    1) Administer a dose of a saline cathartic such as magnesium or sodium sulfate (sodium sulfate dose is 1 gram/kilogram) per os or via stomach tube at 0 and 3 hours to hasten evacuation.
    2) Give the cathartic even if exposure occurred several hours before; this has been proven to shorten the half-life of methylxanthines in the body (Kirk, 1986).
    2) LARGE ANIMALS
    a) EMESIS -
    1) Do not attempt to induce emesis in ruminants (cattle) or equids (horses).
    b) CHARCOAL -
    1) Give 250 to 500 grams activated charcoal in a water slurry per os or via stomach tube. Give the course of activated charcoal even if exposure occurred several hours before; this has been proven to shorten the half-life of methylxanthines in the body (Kirk, 1986).
    c) CATHARTIC -
    1) Administer an oral cathartic:
    2) Mineral oil (small ruminants and swine, 60 to 200 milliliters; equids and cattle, 0.5 to 1 gallon) or
    3) Magnesium sulfate (ruminants and swine, 1 to 2 grams/kilogram; equine, 0.2 to 0.9 gram/kilogram) or
    4) 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).
    5) Give these solutions via stomach tube and monitor for aspiration. Give the cathartic even if exposure occurred several hours before; this has been proven to shorten the half-life of methylxanthines in the body (Kirk, 1986).
    11.4.3) TREATMENT
    11.4.3.5) SUPPORTIVE CARE
    A) GENERAL
    1) Treatment is symptomatic and supportive.
    11.4.3.6) OTHER
    A) OTHER
    1) GENERAL
    a) LABORATORY -
    1) If samples are submitted, request testing for dyphylline specifically. Methylxanthines and their metabolites are stable in serum or plasma at room temperature for 7 days, in the refrigerator for 14 days, and frozen for 4 months (Kirk, 1986).
    b) HORSE -
    1) ELIMINATION HALF-LIFE - 1.9 to 2.9 hours after an IV dose of 20 mg/kg (Ayres et al, 1985).
    c) Pharmacokinetics are represented by a 2-compartment open model in some animals and a 3-compartment open model in others (Ayres et al, 1985).

Kinetics

    11.5.1) ABSORPTION
    A) SPECIFIC TOXIN
    1) Absorption is rapid after oral or parenteral exposure (Beasley et al, 1989).
    11.5.2) DISTRIBUTION
    A) SPECIFIC TOXIN
    1) Methylxanthines are excreted in the bile and then undergo enterohepatic recirculation (Beasley et al, 1989).
    11.5.4) ELIMINATION
    A) SPECIFIC TOXIN
    1) Xanthines are excreted in the bile, urine, and a trace in the feces.

References

General Bibliography

    1) AMA Department of DrugsAMA Department of Drugs: AMA Evaluations Subscription, American Medical Association, Chicago, IL, 1992.
    2) Ayres JW, Pearson EG, & Riebold TW: Theophylline and dyphylline pharmacokinetics in the horse. Am J Vet Res 1985; 46:2500-2506.
    3) Baselt RC: Disposition of Toxic Drugs and Chemicals in Man, 2nd ed, Biomedical Publications, Davis, CA, 1982, pp 291-293.
    4) Baselt RC: Dyphylline. In: Disposition of Toxic Drugs and Chemicals in Man, 9th ed. Biomedical Publications, Seal Beach, CA, 2011, pp 573-574.
    5) Beasley VR, Dorman DC, & Fikes JD: A Systems Affected Approach to Veterinary Toxicology, University of Illinois, Urbana, IL, 1989.
    6) Brophy GM, Bell R, Claassen J, et al: Guidelines for the evaluation and management of status epilepticus. Neurocrit Care 2012; 17(1):3-23.
    7) Chamberlain JM, Altieri MA, & Futterman C: A prospective, randomized study comparing intramuscular midazolam with intravenous diazepam for the treatment of seizures in children. Ped Emerg Care 1997; 13:92-94.
    8) Chin RF , Neville BG , Peckham C , et al: Treatment of community-onset, childhood convulsive status epilepticus: a prospective, population-based study. Lancet Neurol 2008; 7(8):696-703.
    9) Choonara IA & Rane A: Therapeutic drug monitoring of anticonvulsants state of the art. Clin Pharmacokinet 1990; 18:318-328.
    10) Chyka PA, Seger D, Krenzelok EP, et al: Position paper: Single-dose activated charcoal. Clin Toxicol (Phila) 2005; 43(2):61-87.
    11) Cunningham FG, MacDonald PC, Leveno KF, et alCunningham FG, MacDonald PC, Leveno KF, et al (Eds): Williams Obstetrics, 19th. Appleton & Lange, Norwalk, CT, 1993.
    12) Elliot CG, Colby TV, & Kelly TM: Charcoal lung. Bronchiolitis obliterans after aspiration of activated charcoal. Chest 1989; 96:672-674.
    13) FDA: Poison treatment drug product for over-the-counter human use; tentative final monograph. FDA: Fed Register 1985; 50:2244-2262.
    14) Golej J, Boigner H, Burda G, et al: Severe respiratory failure following charcoal application in a toddler. Resuscitation 2001; 49:315-318.
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