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TOLONIUM

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Tolonium chloride, a phenothiazine dye, is more correctly called toluidine blue O.

Specific Substances

    1) 3-amino-7-dimethylamino-2-methylphenazathionium
    2) chloride
    3) Phenoxazinoxonium, 7-amino-3-(N,N-dimethylamino)
    4) -2-methyl chloride
    5) Bilutene chloride
    6) Toluidine Blue O
    7) Toluidine blue (there are 2 different agents
    8) with this name, see Available Forms section)
    9) Molecular formula C15H16N3SCl
    10) CAS 92-31-9
    11) CI Basic Blue 17
    12) CI 52040

Available Forms Sources

    A) FORMS
    1) NOTE: Tolonium chloride, a phenothiazine dye, is more correctly called toluidine blue O. There is another compound more correctly called toluidine blue. It is m-toluenesulfonic acid, 6,6'-((4,8-dihydroxy-1-5-anthraquinonylene)diimino) Di-, disodium salt (CAS 32090-30-1), which is another blue dye with the color index number of 63340. Toluidine blue is an anthraquinone derivative with a synonym of dimethyl toluthionine chloride and toxicity different from toluidine blue O. Check papers referring to "toluidine blue" for a chemical name to assure proper compound identification.
    2) TRADE NAMES
    a) Oral: Blutene(R), Abbott Laboratories (Winek et al, 1969)
    b) IV: Polybrene (NIOSH, 1985)
    c) Menodin (Italy) (Reynolds, 1989)
    d) Toluidine blue 0 1% solution formulation for staining oral squamous carcinoma (Mashberg, 1980):
    1) Toluidine blue 0 powder 1 gram
    2) Acetic acid 10 mL
    3) Absolute alcohol 4.19 mL
    4) Distilled water approximately 86 mL
    5)
    a) (pH is adjusted to 4.5 or less)
    B) USES
    1) Tolonium chloride, a phenothiazine dye, is more correctly called toluidine blue O. It has been used as a heparin inactivator and as a dye for staining tissues, Helicobacter pylori in gastric biopsy specimens, and Pneumocystis carinii in sputum samples. It is also used to sensitize bacteria in the oral cavity prior to photodynamic therapy in the treatment of chronic periodontal disease (Haley & Stolarsky, 1951; Mashberg, 1980) Yeager & Krementz, 1969; (Cohen & Haffajee, 1990; Wilson, 1993).

Overview

Life Support

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

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) NOTE - There are 2 different agents with this name. Check AVAILABLE FORMS section if you are unclear.
    B) Overdoses have been few, with self-limiting respiratory and gastrointestinal symptoms. Large therapeutic amounts have caused hemolysis, methemoglobinemia, granulocytopenia, and premature atrial and ventricular contractions.
    0.2.5) CARDIOVASCULAR
    A) Animals poisoned by this dye developed bradycardia, atrioventricular block, cardiac failure, and increased blood pressure. Reported effects in humans include T wave depression, flattened T waves, mild hypertension, and premature atrial and ventricular contractions.
    0.2.6) RESPIRATORY
    A) Chest pain and difficulty in breathing were reported in one human case.
    0.2.8) GASTROINTESTINAL
    A) Nausea, vomiting, and tenesmus have been reported.
    0.2.10) GENITOURINARY
    A) Burning on urination and hematuria have been reported. The urine may be colored dark blue to green.
    0.2.13) HEMATOLOGIC
    A) Hemolytic anemia, agranulocytosis, and acute methemoglobinemia have been reported.

Laboratory Monitoring

    A) Blood levels are not indicated.
    B) Urine may be colored dark blue to green depending upon the concentration.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) Treatment is symptomatic and supportive.
    B) ACTIVATED CHARCOAL: Administer charcoal as a slurry (240 mL water/30 g charcoal). Usual dose: 25 to 100 g in adults/adolescents, 25 to 50 g in children (1 to 12 years), and 1 g/kg in infants less than 1 year old.
    C) MONITOR blood pressure, heart rate, fluid and electrolytes (vomiting and diarrhea may be prolonged) and renal function.
    D) HYPERTENSION: Monitor vital signs regularly. For mild/moderate asymptomatic hypertension (no end organ damage), pharmacologic treatment is generally not necessary. Sedation with benzodiazepines may be helpful in agitated patients with hypertension and tachycardia. For severe hypertension sodium nitroprusside is preferred. Labetalol, nitroglycerin, and phentolamine are alternatives. See main treatment section for doses.
    E) ATROPINE: ADULT DOSE: BRADYCARDIA: BOLUS: 0.5 mg IV may repeat every 3 to 5 min. Maximum: 3 mg. PEDIATRIC DOSE: 0.02 mg/kg IV/IO (0.04 to 0.06 mg/kg ET). Repeat once, if needed. Minimum dose: 0.1 mg. Maximum single dose: Child: 0.5 mg; Adolescent: 1 mg. Maximum total dose: Child: 1 mg; Adolescent: 2 mg.
    F) PVCS were noted in two patients receiving 10 mg/kg intravenously. If they do not respond to discontinuing the drug, medical treatment may be necessary.
    1) VENTRICULAR DYSRHYTHMIAS/SUMMARY: Institute continuous cardiac monitoring, obtain an ECG, and administer oxygen. Evaluate for hypoxia, acidosis, and electrolyte disorders. Lidocaine and amiodarone are generally first line agents for stable monomorphic ventricular tachycardia, particularly in patients with underlying impaired cardiac function. Amiodarone should be used with caution if a substance that prolongs the QT interval and/or causes torsades de pointes is involved in the overdose. Unstable rhythms require immediate cardioversion.

Range Of Toxicity

    A) A 10 mg/kg IV dose in an adult decreased bleeding, but caused hemolytic anemia and agranulocytosis. Minor cardiac toxicity occurred at 7 mg/kg IV. More marked symptoms were noted if this dye was administered too quickly or when 10 mg/kg was reached. One case of vomiting, diarrhea, and dyspnea was reported, but the maximum dose available (8.8 g) could not be substantiated as the ingested dose.

Clinical Effects

Summary Of Exposure

    A) NOTE - There are 2 different agents with this name. Check AVAILABLE FORMS section if you are unclear.
    B) Overdoses have been few, with self-limiting respiratory and gastrointestinal symptoms. Large therapeutic amounts have caused hemolysis, methemoglobinemia, granulocytopenia, and premature atrial and ventricular contractions.

Vital Signs

    3.3.3) TEMPERATURE
    A) FEVER - Animals given 7.5 mg/kg IV had increases in body temperature of 0.9 to 1.3 degrees C (Haley & Leitch, 1953).

Heent

    3.4.6) THROAT
    A) VOCAL CORD PARALYSIS - Transient vocal cord paralysis has been reported in 1 patient after intraarterial injection of toluidine blue (Yeager & Krementz, 1969).

Cardiovascular

    3.5.1) SUMMARY
    A) Animals poisoned by this dye developed bradycardia, atrioventricular block, cardiac failure, and increased blood pressure. Reported effects in humans include T wave depression, flattened T waves, mild hypertension, and premature atrial and ventricular contractions.
    3.5.2) CLINICAL EFFECTS
    A) HYPERTENSIVE EPISODE
    1) CASE SERIES - Five of 13 patients who received 7 mg/kg toluidine blue intravenously developed blood pressure increases of 8 to 10 mmHg systolic and 2 to 10 mmHg diastolic. When the dose was increased to 10 mg/kg IV, the blood pressure effects were more pronounced, ranging from 14 to 50 mmHg systolic and 8 to 10 mmHg diastolic (Yeager & Krementz, 1969).
    B) SHORTENED T WAVE
    1) CASE SERIES - Yeager and Krementz (1969) reported on 13 patients where 10 (given 7 mg/kg IV) developed progressive T wave depression and 4 of these had flattened T waves.
    C) CONDUCTION DISORDER OF THE HEART
    1) CASE SERIES - Two patients who received 10 mg/kg of toluidine blue intravenously developed multiple premature atrial and ventricular contractions (Yeager & Krementz, 1969).
    3.5.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) BRADYCARDIA
    a) Animals poisoned by this dye developed bradycardia (30% decrease at 10 mg/kg), atrioventricular block, cardiac failure, and increased blood pressure (Haley & Stolarsky, 1951; Haley & Leitch, 1953). Intra-arterial injection produces vasoconstriction in dogs (Haley & Leitch, 1953).

Respiratory

    3.6.1) SUMMARY
    A) Chest pain and difficulty in breathing were reported in one human case.
    3.6.2) CLINICAL EFFECTS
    A) DYSPNEA
    1) CASE REPORT - Chest pain and difficulty in breathing were reported in one human case (Winek et al, 1969).
    3.6.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) RESPIRATORY DEPRESSION
    a) Animals poisoned with 10 mg/kg showed an initial increase in respiration, then respiratory depression (Haley & Stolarsky, 1951; Haley & Leitch, 1953).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) HEADACHE
    1) CASE REPORT - A 68-year-old woman developed a severe headache on the second day of treatment with toluidine blue 10 mg/kg intravenously for profuse rectal bleeding following hemorrhoidectomy. The headache subsided 4 or 5 days after the discontinuation of toluidine blue infusion (Marquez & Todd, 1959).
    B) PARALYSIS
    1) CASE REPORT - One patient developed transient recurrent laryngeal nerve paralysis following a dose of intra-arterial toluidine blue 0. A cause and effect relationship could not be established (Yeager & Krementz, 1969). It was speculated that this effect may be evidence of neurotoxicity.

Gastrointestinal

    3.8.1) SUMMARY
    A) Nausea, vomiting, and tenesmus have been reported.
    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) Nausea and vomiting may occur (Winek et al, 1969).
    B) TENESMUS
    1) Tenesmus has been reported (Winek et al, 1969).
    C) ABDOMINAL PAIN
    1) CASE REPORT - Abdominal pain was reported in a 16-month-old following an ingestion of an unknown quantity of tablets (Winek et al, 1969).

Genitourinary

    3.10.1) SUMMARY
    A) Burning on urination and hematuria have been reported. The urine may be colored dark blue to green.
    3.10.2) CLINICAL EFFECTS
    A) DYSURIA
    1) Burning on urination has been reported (Marquez & Todd, 1959).
    B) BLOOD IN URINE
    1) Hematuria may develop in patients with hemolysis (Winek et al, 1969; Teunis et al, 1970).
    C) ABNORMAL COLOR
    1) The color of urine may be dark blue to green, depending on the concentration in the urine (Winek et al, 1969).
    D) ACUTE RENAL FAILURE SYNDROME
    1) Acute renal insufficiency may develop in patients with significant hemolysis (Teunis et al, 1970).

Hematologic

    3.13.1) SUMMARY
    A) Hemolytic anemia, agranulocytosis, and acute methemoglobinemia have been reported.
    3.13.2) CLINICAL EFFECTS
    A) HEMOLYTIC ANEMIA
    1) Hemolytic anemia after therapeutic doses has been reported in two patients, one of whom was G6PD deficient (Teunis et al, 1970; Marquez & Todd, 1959).
    B) LEUKOPENIA
    1) CASE REPORT - Granulocytopenia (absolute neutrophil count 361/mm(3)) was reported in one patient who developed hemolytic anemia after receiving 600 mg/day for 4 days followed by 300 mg/day for 2 days (Marquez & Todd, 1959).
    C) METHEMOGLOBINEMIA
    1) CASE REPORT - Methemoglobinemia and hemolysis developed in a G6PD deficient woman who received 7 mg/kg toluidine blue during thyroid surgery (Teunis et al, 1970).
    3.13.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) EMBOLISM - BLOOD CLOT
    a) Dogs receiving intra-arterial infusions of toluidine blue have developed intravascular clotting (Haley & Leitch, 1953).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) DISCOLORATION OF SKIN
    1) A blush tint of the skin has been noted with average or large doses of toluidine blue 0 (Winek et al, 1969).

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS92-31-9 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) Not Listed
    3.21.4) ANIMAL STUDIES
    A) LACK OF EFFECT
    1) The use of toluidine blue O in the hamster cheek pouch failed to establish any evidence of carcinogenicity (Redman et al, 1992).

Genotoxicity

    A) Mutation frequencies were increased in the Ames Salmonella test in vitro, using four bacterial strains, with and without microsomal activation (Dunipace et al, 1992).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Blood levels are not indicated.
    B) Urine may be colored dark blue to green depending upon the concentration.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) BLOOD LEVELS are not indicated.
    4.1.3) URINE
    A) URINALYSIS
    1) URINE may be colored dark blue to green, depending on the concentration in the urine (Winek et al, 1969).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Monitoring

    A) Blood levels are not indicated.
    B) Urine may be colored dark blue to green depending upon the concentration.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) ACTIVATED CHARCOAL
    1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    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) SUPPORT
    1) Treatment is symptomatic and supportive.
    B) MONITORING OF PATIENT
    1) Monitor blood pressure, heart rate, fluid and electrolytes (vomiting and diarrhea may be prolonged), and renal function.
    C) HYPERTENSIVE EPISODE
    1) Monitor vital signs regularly. For mild/moderate hypertension without evidence of end organ damage, pharmacologic intervention is generally not necessary. Sedative agents such as benzodiazepines may be helpful in treating hypertension and tachycardia in agitated patients, especially if a sympathomimetic agent is involved in the poisoning.
    2) For hypertensive emergencies (severe hypertension with evidence of end organ injury (CNS, cardiac, renal), or emergent need to lower mean arterial pressure 20% to 25% within one hour), sodium nitroprusside is preferred. Nitroglycerin and phentolamine are possible alternatives.
    3) SODIUM NITROPRUSSIDE/INDICATIONS
    a) Useful for emergent treatment of severe hypertension secondary to poisonings. Sodium nitroprusside has a rapid onset of action, a short duration of action and a half-life of about 2 minutes (Prod Info NITROPRESS(R) injection for IV infusion, 2007) that can allow accurate titration of blood pressure, as the hypertensive effects of drug overdoses are often short lived.
    4) SODIUM NITROPRUSSIDE/DOSE
    a) ADULT: Begin intravenous infusion at 0.1 microgram/kilogram/minute and titrate to desired effect; up to 10 micrograms/kilogram/minute may be required (American Heart Association, 2005). Frequent hemodynamic monitoring and administration by an infusion pump that ensures a precise flow rate is mandatory (Prod Info NITROPRESS(R) injection for IV infusion, 2007). PEDIATRIC: Initial: 0.5 to 1 microgram/kilogram/minute; titrate to effect up to 8 micrograms/kilogram/minute (Kleinman et al, 2010).
    5) SODIUM NITROPRUSSIDE/SOLUTION PREPARATION
    a) The reconstituted 50 mg solution must be further diluted in 250 to 1000 mL D5W to desired concentration (recommended 50 to 200 mcg/mL) (Prod Info NITROPRESS(R) injection, 2004). Prepare fresh every 24 hours; wrap in aluminum foil. Discard discolored solution (Prod Info NITROPRESS(R) injection for IV infusion, 2007).
    6) SODIUM NITROPRUSSIDE/MAJOR ADVERSE REACTIONS
    a) Severe hypotension; headaches, nausea, vomiting, abdominal cramps; thiocyanate or cyanide toxicity (generally from prolonged, high dose infusion); methemoglobinemia; lactic acidosis; chest pain or dysrhythmias (high doses) (Prod Info NITROPRESS(R) injection for IV infusion, 2007). The addition of 1 gram of sodium thiosulfate to each 100 milligrams of sodium nitroprusside for infusion may help to prevent cyanide toxicity in patients receiving prolonged or high dose infusions (Prod Info NITROPRESS(R) injection for IV infusion, 2007).
    7) SODIUM NITROPRUSSIDE/MONITORING PARAMETERS
    a) Monitor blood pressure every 30 to 60 seconds at onset of infusion; once stabilized, monitor every 5 minutes. Continuous blood pressure monitoring with an intra-arterial catheter is advised (Prod Info NITROPRESS(R) injection for IV infusion, 2007).
    8) NITROGLYCERIN/INDICATIONS
    a) May be used to control hypertension, and is particularly useful in patients with acute coronary syndromes or acute pulmonary edema (Rhoney & Peacock, 2009).
    9) NITROGLYCERIN/ADULT DOSE
    a) Begin infusion at 10 to 20 mcg/min and increase by 5 or 10 mcg/min every 5 to 10 minutes until the desired hemodynamic response is achieved (American Heart Association, 2005). Maximum rate 200 mcg/min (Rhoney & Peacock, 2009).
    10) NITROGLYCERIN/PEDIATRIC DOSE
    a) Usual Dose: 29 days or Older: 1 to 5 mcg/kg/min continuous IV infusion. Maximum 60 mcg/kg/min (Laitinen et al, 1997; Nam et al, 1989; Rasch & Lancaster, 1987; Ilbawi et al, 1985; Friedman & George, 1985).
    D) BRADYCARDIA
    1) ATROPINE/DOSE
    a) ADULT BRADYCARDIA: BOLUS: Give 0.5 milligram IV, repeat every 3 to 5 minutes, if bradycardia persists. Maximum: 3 milligrams (0.04 milligram/kilogram) intravenously is a fully vagolytic dose in most adults. Doses less than 0.5 milligram may cause paradoxical bradycardia in adults (Neumar et al, 2010).
    b) PEDIATRIC DOSE: As premedication for emergency intubation in specific situations (eg, giving succinylchoine to facilitate intubation), give 0.02 milligram/kilogram intravenously or intraosseously (0.04 to 0.06 mg/kg via endotracheal tube followed by several positive pressure breaths) repeat once, if needed (de Caen et al, 2015; Kleinman et al, 2010). MAXIMUM SINGLE DOSE: Children: 0.5 milligram; adolescent: 1 mg.
    1) There is no minimum dose (de Caen et al, 2015).
    2) MAXIMUM TOTAL DOSE: Children: 1 milligram; adolescents: 2 milligrams (Kleinman et al, 2010).
    E) VENTRICULAR ARRHYTHMIA
    1) PVCS were noted in a few patients. If they do not respond to discontinuing the drug, medical treatment may be necessary.
    2) 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.
    3) 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).
    4) 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).
    5) 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).
    6) LIDOCAINE/MONITORING PARAMETERS
    a) Monitor ECG continuously; plasma concentrations as indicated (Prod Info Lidocaine HCl intravenous injection solution, 2006).
    7) PROCAINAMIDE/INDICATIONS
    a) An alternative drug in the treatment of PVCs or recurrent ventricular tachycardia when lidocaine is contraindicated or not effective. It should be avoided when the ingestion involves agents with quinidine-like effects (e.g. tricyclic antidepressants, phenothiazines, chloroquine, antidysrhythmics) and when the ECG reveals QRS widening or QT prolongation suspected to be secondary to overdose(Neumar et al, 2010; Vanden Hoek,TL,et al).
    8) PROCAINAMIDE/ADULT LOADING DOSE
    a) 20 to 50 milligrams/minute IV until dysrhythmia is suppressed or toxicity develops from procainamide (hypotension develops or the QRS is widened by 50%), or a total dose of 17 milligrams/kilogram is given (1.2 grams for a 70 kilogram person) (Neumar et al, 2010).
    b) ALTERNATIVE DOSING: 100 mg every 5 minutes until dysrhythmia is controlled, or toxicity develops from procainamide (hypotension develops or the QRS is widened by 50%) or 17 mg/kg have been given (Neumar et al, 2010).
    c) MAXIMUM DOSE: 17 milligrams/kilogram (Neumar et al, 2010).
    9) PROCAINAMIDE/CONTROLLED INFUSION
    a) In conscious patients, procainamide should be administered as a controlled infusion (20 milligrams/minute) because of the risk of QT prolongation and its hypotensive effects (Link et al, 2015)
    10) PROCAINAMIDE/ADULT MAINTENANCE DOSE
    a) 1 to 4 milligrams/minute via an intravenous infusion (Neumar et al, 2010).
    11) PROCAINAMIDE/PEDIATRIC LOADING DOSE
    a) 15 milligrams/kilogram IV/Intraosseously over 30 to 60 minutes; discontinue if hypotension develops or the QRS widens by 50% (Kleinman et al, 2010).
    12) PROCAINAMIDE/PEDIATRIC MAINTENANCE DOSE
    a) Initiate at 20 mcg/kg/minute and increase in 10 mcg/kg/minute increments every 15 to 30 minutes until desired effect is achieved; up to 80 mcg/kg/minute (Bouhouch et al, 2008; Ratnasamy et al, 2008; Mandapati et al, 2000; Luedtke et al, 1997; Walsh et al, 1997).
    13) PROCAINAMIDE/PEDIATRIC MAXIMUM DOSE
    a) 2 grams/day (Bouhouch et al, 2008; Ratnasamy et al, 2008; Mandapati et al, 2000; Luedtke et al, 1997; Walsh et al, 1997).
    14) MONITORING PARAMETERS
    a) ECG, blood pressure, and blood concentrations (Prod Info procainamide HCl IV, IM injection solution, 2011). Procainamide can produce hypotension and QT prolongation (Link et al, 2015).
    15) AVOID
    a) Avoid in patients with QT prolongation and CHF (Neumar et al, 2010).
    F) METHEMOGLOBINEMIA
    1) This is a rare event and has only been seen with one patient who also had G6PD deficiency. Because tolonium is so similar to methylene blue, and because methylene blue is said to be less effective in G6PD deficient individuals, exchange transfusion or hyperbaric oxygen may need to be considered as alternative treatments.

Range Of Toxicity

Summary

    A) A 10 mg/kg IV dose in an adult decreased bleeding, but caused hemolytic anemia and agranulocytosis. Minor cardiac toxicity occurred at 7 mg/kg IV. More marked symptoms were noted if this dye was administered too quickly or when 10 mg/kg was reached. One case of vomiting, diarrhea, and dyspnea was reported, but the maximum dose available (8.8 g) could not be substantiated as the ingested dose.

Therapeutic Dose

    7.2.1) ADULT
    A) GENERAL
    1) The suggested dose for menorrhagia was 200 to 300 milligrams/day (Winek et al, 1969), 100 to 300 milligrams was recommended for heparin inactivation (4 to 10 milligrams/kilogram intravenously) (Haley & Stolarsky, 1951; Haley & Leitch, 1953).

Maximum Tolerated Exposure

    A) CASE REPORTS
    1) 10 milligrams/kilogram intravenously in an adult decreased bleeding but caused acute hemolytic anemia and agranulocytosis (Marquez & Todd, 1959).
    2) Minor cardiac toxicity occurred at 7 milligrams/kilogram intravenously, more marked symptoms were noted if the dye was administered too quickly or when 10 milligrams/kilogram was reached (Yeager & Krementz, 1969).
    3) One case of vomiting, diarrhea, and dyspnea was reported, but the maximum dose available (8.8 grams) could not be substantiated as the ingested dose (Winek et al, 1969).
    4) Children ingesting small numbers of tablets showed no symptomatology (Winek et al, 1969).

Workplace Standards

    A) ACGIH TLV Values for CAS92-31-9 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    B) NIOSH REL and IDLH Values for CAS92-31-9 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    C) Carcinogenicity Ratings for CAS92-31-9 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    D) OSHA PEL Values for CAS92-31-9 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) LD50- (INTRAPERITONEAL)RAT:
    1) 215 mg/kg (RTECS, 2000)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) The method by which tolonium causes its coagulant action has not been reported. Tolonium sensitizes bacterial cells to the cytotoxic effects of irradiation (Wilson, 1993).

Toxicologic Mechanism

    A) Methemoglobinemia is most likely by oxidation (Teunis et al, 1970).

Physicochemical

Physical Characteristics

    A) Solid: Green crystalline powder with a bronze luster (JEF Reynolds , 2000)
    B) Aqueous Solution: blue-violet (JEF Reynolds , 2000)
    C) Ethanol Solution: blue (Budavari, 1996)

Molecular Weight

    A) 305.8 (JEF Reynolds , 2000)

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