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FORMALDEHYDE CYANOHYDRIN

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Formaldehyde cyanohydrin is a nitrile.

Specific Substances

    A) No Synonyms were found in group or single elements
    1.2.1) MOLECULAR FORMULA
    1) C2-H3-N-O
    2) HOCH2CN

Available Forms Sources

    A) FORMS
    1) It is commercially available as a 70% aqueous solution stabilized with phosphoric acid (ITI, 1988; Lewis, 1993).
    B) USES
    1) Formaldehyde cyanohydrin is utilized as a solvent; barrier resin additive; organic intermediate in the synthesis of bactericides and fungicides, chloroacetonitrile, glycine, hydantoin, alpha-ethylpiperazines, and alpha-aminonitriles; and in pharmaceutical production (Clayton & Clayton, 1994; Lewis, 1993) Sittig, 1991).

Overview

Life Support

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

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) Formaldehyde cyanohydrin may be toxic by eye, skin, inhalation, and oral exposure. It is an irritant and is converted to cyanide in the body.
    B) Death may occur within minutes or may be delayed in onset.
    C) The clinical presentation of the patient depends upon the extent of and time since exposure. Initially the patient may experience flushing, tachycardia, tachypnea, headache, and dizziness. This then may progress to agitation, stupor, coma, apnea, generalized seizures, bradycardia, hypotension, pulmonary edema, and death.
    D) The absence of a rapidly deteriorating course does not exclude the diagnosis of cyanide poisoning. Patients have survived lethal ingestions with only supportive care.
    E) With exposure to nitrile compounds such as formaldehyde cyanohydrin, the onset of cyanide poisoning may be delayed. Cyanide exposure may produce death within minutes. Lesser exposures may produce nausea, vomiting, palpitations, confusion, hyperventilation, anxiety, and vertigo. Severe hypoxic signs in the absence of cyanosis should suggest the diagnosis.
    F) Cyanosis is generally a late finding and does not occur until the stage of circulatory collapse and apnea.
    0.2.3) VITAL SIGNS
    A) Rapid and irregular pulse has been seen. Rapid respirations may be followed by slow, labored breathing.
    0.2.4) HEENT
    A) Formaldehyde cyanohydrin is irritating to the eyes.
    0.2.5) CARDIOVASCULAR
    A) Tachycardia, bradycardia and arrhythmias may be seen.
    0.2.7) NEUROLOGIC
    A) Typical signs of CNS depression, such as headache, dizziness, ataxia, weakness, confusion, and nausea were noted in a dermal exposure incident. Seizures and coma may occur. It is closely related to acetonitrile, for which more toxicologic information is available.
    0.2.8) GASTROINTESTINAL
    A) Nausea, vomiting, and anorexia were seen with dermal exposure.
    0.2.11) ACID-BASE
    A) Lactic acidosis may occur, due to increased rate of glycolysis.
    0.2.14) DERMATOLOGIC
    A) Gives no immediate sensation on the skin, but can be fatal by this route.
    0.2.15) MUSCULOSKELETAL
    A) Weakness has been reported from an acute exposure.
    0.2.17) METABOLISM
    A) Cyanide, a systemic asphyxiant, is formed in the body.
    0.2.18) PSYCHIATRIC
    A) Disorientation and other signs of CNS depression have been seen.
    0.2.20) REPRODUCTIVE
    A) At the time of this review, no reproductive studies were found for formaldehyde cyanohydrin in humans or experimental animals. Acetonitrile, which is structurally similar, is fetotoxic and teratogenic in animals.
    0.2.21) CARCINOGENICITY
    A) At the time of this review, no studies were found on the possible carcinogenic effects of formaldehyde cyanohydrin in humans.
    0.2.22) OTHER
    A) Formaldehyde cyanohydrin may be lethal by any route of exposure. It forms cyanide in the body and may produce an odor of bitter almonds on the breath.

Laboratory Monitoring

    A) Blood cyanide levels may be helpful in confirming exposure, but cyanide formation may be delayed. Treatment of symptomatic patients with cyanide antidote should not be delayed to obtain laboratory confirmation of cyanide poisoning.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) Perform gastric lavage with a large bore tube after endotracheal intubation.
    1) 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.
    B) Administer 100% oxygen, establish secure large bore IV.
    C) A cyanide antidote, either hydroxocobalamin or the sodium nitrite/sodium thiosulfate kit, should be administered to patients with symptomatic poisoning.
    D) HYDROXOCOBALAMIN: ADULT DOSE: 5 g (two 2.5 g vials each reconstituted with 100 mL sterile 0.9% saline) administered as an intravenous infusion over 15 minutes. For severe poisoning, a second dose of 5 g may be infused intravenously over 15 minutes to 2 hours, depending on the patient's condition. CHILDREN: Limited experience; a dose of 70 mg/kg has been used in pediatric patients.
    E) Prepare the Cyanide Antidote Kit for use in symptomatic patients.
    1) SODIUM NITRITE: Adult: 10 mL (300 mg) of a 3% solution IV at a rate of 2.5 to 5 mL/minute; Child (with normal hemoglobin concentration): 0.2 mL/kg (6 mg/kg) of a 3% solution IV at a rate of 2.5 to 5 mL/minute, not to exceed 10 mL (300 mg).
    2) Repeat one-half of initial sodium nitrite dose one-half hour later if there is inadequate clinical response. Calculate pediatric doses precisely to avoid potentially life-threatening methemoglobinemia. Use with caution if carbon monoxide poisoning is also suspected. Monitor blood pressure carefully. Reduce nitrite administration rate if hypotension occurs.
    3) SODIUM THIOSULFATE: Administer sodium thiosulfate IV immediately following sodium nitrite. DOSE: ADULT: 50 mL (12.5 g) of a 25% solution; CHILD: 1 mL/kg (250 mg/kg) of a 25% solution, not to exceed 50 mL (12.5 g) total dose. A second dose, one-half of the first dose, may be administered if signs of cyanide toxicity reappear.
    F) SODIUM BICARBONATE: Administer 1 mEq/kg IV to acidotic patients.
    G) 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.
    H) METHEMOGLOBINEMIA: Methylene or toluidine blue treatment may be considered if excessive methemoglobinemia occurs due to nitrite administration. Consider exchange transfusion for severe methemoglobinemia.
    I) HYPERBARIC OXYGEN AND HEMODIALYSIS may be useful in severe cases not responsive to other therapy.
    J) ACUTE LUNG INJURY: Maintain ventilation and oxygenation and evaluate with frequent arterial blood gases and/or pulse oximetry monitoring. Early use of PEEP and mechanical ventilation may be needed.
    K) ALTERNATE ANTIDOTES -
    1) Kelocyanor(R) (dicobalt-EDTA) and 4-DMAP (4-dimethylaminophenol) are alternate cyanide antidotes in clinical use in various countries outside the US. See TREATMENT SECTION in the main body of this document for more information.
    0.4.3) INHALATION EXPOSURE
    A) Serious exposure cases should be treated as cyanide exposures. Antidote treatment is said not to be as effective in nitrile poisoning as it is with inorganic cyanide cases.
    B) INHALATION: Move patient to fresh air. Monitor for respiratory distress. If cough or difficulty breathing develops, evaluate for respiratory tract irritation, bronchitis, or pneumonitis. Administer oxygen and assist ventilation as required. Treat bronchospasm with an inhaled beta2-adrenergic agonist. Consider systemic corticosteroids in patients with significant bronchospasm.
    C) DECONTAMINATION: Remove contaminated clothing and jewelry and place them in plastic bags. Wash exposed areas with soap and water for 10 to 15 minutes with gentle sponging to avoid skin breakdown. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).
    D) Immediately begin therapy with 100% oxygen. Oxygen may reverse the cyanide-cytochrome oxidase complex.
    E) Obtain, prepare, and administer the cyanide antidote kit: SEE MAIN SECTION FOR DOSES AND CAUTIONS.
    F) 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.
    G) See treatment of inhalation exposure in the main body of this document for complete information.
    0.4.4) EYE EXPOSURE
    A) DECONTAMINATION: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, the patient should be seen in a healthcare facility.
    B) Experimental animals have developed serious systemic cyanide poisoning following ocular exposure. Human poisoning cases have not been reported due to eye exposure only. If systemic cyanide poisoning is suspected following eye exposure, REFER to TREATMENT RECOMMENDATIONS in the INHALATION EXPOSURE section above.
    0.4.5) DERMAL EXPOSURE
    A) OVERVIEW
    1) DECONTAMINATION: Remove contaminated clothing and jewelry and place them in plastic bags. Wash exposed areas with soap and water for 10 to 15 minutes with gentle sponging to avoid skin breakdown. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).
    2) While cyanide can be absorbed through intact skin, most reported cases have involved whole-body immersion in cyanide solutions or large-area burns with molten cyanide solutions. Most nitrile compounds are well absorbed through intact skin, and may cause delayed onset of symptoms following exposure by this route.
    3) Administer 100% oxygen, establish secure large bore IV
    4) A cyanide antidote, either hydroxocobalamin or the sodium nitrite/sodium thiosulfate kit, should be administered to patients with symptomatic poisoning.
    5) HYDROXOCOBALAMIN: ADULT DOSE: 5 g (two 2.5 g vials each reconstituted with 100 mL sterile 0.9% saline) administered as an intravenous infusion over 15 minutes. For severe poisoning, a second dose of 5 g may be infused intravenously over 15 minutes to 2 hours, depending on the patient's condition. CHILDREN: Limited experience; a dose of 70 mg/kg has been used in pediatric patients.
    6) Prepare the Cyanide Antidote Kit for use in symptomatic patients.
    a) SODIUM NITRITE: Adult: 10 mL (300 mg) of a 3% solution IV at a rate of 2.5 to 5 mL/minute; Child (with normal hemoglobin concentration): 0.2 mL/kg (6 mg/kg) of a 3% solution IV at a rate of 2.5 to 5 mL/minute, not to exceed 10 mL (300 mg).
    b) Repeat one-half of initial sodium nitrite dose one-half hour later if there is inadequate clinical response. Calculate pediatric doses precisely to avoid potentially life-threatening methemoglobinemia. Use with caution if carbon monoxide poisoning is also suspected. Monitor blood pressure carefully. Reduce nitrite administration rate if hypotension occurs.
    c) SODIUM THIOSULFATE: Administer sodium thiosulfate IV immediately following sodium nitrite. DOSE: ADULT: 50 mL (12.5 g) of a 25% solution; CHILD: 1 mL/kg (250 mg/kg) of a 25% solution, not to exceed 50 mL (12.5 g) total dose. A second dose, one-half of the first dose, may be administered if signs of cyanide toxicity reappear.
    7) SODIUM BICARBONATE: Administer 1 mEq/kg IV to severely acidotic patients.
    8) 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).
    a) Consider phenobarbital or propofol if seizures recur after diazepam 30 mg (adults) or 10 mg (children greater than 5 years).
    b) Monitor for hypotension, dysrhythmias, respiratory depression, and need for endotracheal intubation. Evaluate for hypoglycemia, electrolyte disturbances, and hypoxia.
    9) METHEMOGLOBINEMIA: Methylene or toluidine blue treatment may be considered if excessive methemoglobinemia occurs due to nitrite administration. Consider exchange transfusion for severe symptoms of excessive methemoglobinemia.
    10) HYPERBARIC OXYGEN AND HEMODIALYSIS may be useful in severe cases not responsive to supportive and antidotal therapy.
    11) ACUTE LUNG INJURY: Maintain ventilation and oxygenation and evaluate with frequent arterial blood gases and/or pulse oximetry monitoring. Early use of PEEP and mechanical ventilation may be needed.
    12) HYPOTENSION: Infuse 10 to 20 mL/kg isotonic fluid. If hypotension persists, administer dopamine (5 to 20 mcg/kg/min) or norepinephrine (ADULT: begin infusion at 0.5 to 1 mcg/min; CHILD: begin infusion at 0.1 mcg/kg/min); titrate to desired response.
    13) ALTERNATE ANTIDOTES: Kelocyanor(R) (dicobalt-EDTA) and 4-DMAP (4-dimethylaminophenol) are alternate cyanide antidotes in clinical use in various countries outside the US. See TREATMENT SECTION in the main body of this document for more information.

Range Of Toxicity

    A) Minimum lethal human exposure is unknown.

Clinical Effects

Summary Of Exposure

    A) Formaldehyde cyanohydrin may be toxic by eye, skin, inhalation, and oral exposure. It is an irritant and is converted to cyanide in the body.
    B) Death may occur within minutes or may be delayed in onset.
    C) The clinical presentation of the patient depends upon the extent of and time since exposure. Initially the patient may experience flushing, tachycardia, tachypnea, headache, and dizziness. This then may progress to agitation, stupor, coma, apnea, generalized seizures, bradycardia, hypotension, pulmonary edema, and death.
    D) The absence of a rapidly deteriorating course does not exclude the diagnosis of cyanide poisoning. Patients have survived lethal ingestions with only supportive care.
    E) With exposure to nitrile compounds such as formaldehyde cyanohydrin, the onset of cyanide poisoning may be delayed. Cyanide exposure may produce death within minutes. Lesser exposures may produce nausea, vomiting, palpitations, confusion, hyperventilation, anxiety, and vertigo. Severe hypoxic signs in the absence of cyanosis should suggest the diagnosis.
    F) Cyanosis is generally a late finding and does not occur until the stage of circulatory collapse and apnea.

Vital Signs

    3.3.1) SUMMARY
    A) Rapid and irregular pulse has been seen. Rapid respirations may be followed by slow, labored breathing.
    3.3.2) RESPIRATIONS
    A) Respirations may initially be rapid, followed by slow and labored breathing (EPA, 1985; Wolfsie, 1960).
    3.3.5) PULSE
    A) Tachycardia and irregular pulse were seen in one case of acute dermal exposure (Clayton & Clayton, 1994; Wolfsie, 1960).

Heent

    3.4.1) SUMMARY
    A) Formaldehyde cyanohydrin is irritating to the eyes.
    3.4.2) HEAD
    A) Headache was seen in a human dermal exposure incident (Clayton & Clayton, 1994; Wolfsie, 1960).
    3.4.3) EYES
    A) LETHAL - Formaldehyde cyanohydrin has been absorbed in fatal amounts by the eye in rabbits; death occurred within 68 minutes (Wolfsie, 1960).
    B) IRRITATION - Formaldehyde cyanohydrin is irritating to the eyes (Lewis, 1996; Wolfsie, 1960).

Cardiovascular

    3.5.1) SUMMARY
    A) Tachycardia, bradycardia and arrhythmias may be seen.
    3.5.2) CLINICAL EFFECTS
    A) TACHYARRHYTHMIA
    1) Tachycardia and irregular pulse were seen in one case of acute dermal exposure (Clayton & Clayton, 1994; Wolfsie, 1960). Tachycardia, bradycardia, and palpitations have been noted in cases of poisoning with closely related acetonitrile (Dequidt et al, 1974; Amdur, 1959).

Neurologic

    3.7.1) SUMMARY
    A) Typical signs of CNS depression, such as headache, dizziness, ataxia, weakness, confusion, and nausea were noted in a dermal exposure incident. Seizures and coma may occur. It is closely related to acetonitrile, for which more toxicologic information is available.
    3.7.2) CLINICAL EFFECTS
    A) CENTRAL NERVOUS SYSTEM DEFICIT
    1) Various signs of CNS depression, due to deprivation of oxygen, have been noted. In one acute human dermal exposure, headache, dizziness, ataxia, weakness, nausea, and confusion were seen (Clayton & Clayton, 1994; Wolfsie, 1960).
    B) SEIZURE
    1) Convulsions may occur along with coma (EPA, 1985).

Gastrointestinal

    3.8.1) SUMMARY
    A) Nausea, vomiting, and anorexia were seen with dermal exposure.
    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) Vomiting and nausea, typical signs of CNS depression, were seen in two dermal exposure incidents (Clayton & Clayton, 1994; Wolfsie, 1960).

Acid-Base

    3.11.1) SUMMARY
    A) Lactic acidosis may occur, due to increased rate of glycolysis.
    3.11.2) CLINICAL EFFECTS
    A) LACTIC ACIDOSIS
    1) There is a possibility of lactic acidosis from nitriles due to increased rates of glycolysis (Dequidt et al, 1974).

Dermatologic

    3.14.1) SUMMARY
    A) Gives no immediate sensation on the skin, but can be fatal by this route.
    3.14.2) CLINICAL EFFECTS
    A) SKIN ABSORPTION
    1) DEATH
    a) Formaldehyde cyanohydrin can be FATAL if allowed to remain on the skin. It gives no immediate sensation (ILO, 1983). Human poisonings have occurred from dermal exposure (Wolfsie, 1960).
    B) SKIN IRRITATION
    1) Mild skin irritation was observed in the rabbit with the Standard Draize Test at a dose of 500 mg/24H (RTECS, 1997).

Musculoskeletal

    3.15.1) SUMMARY
    A) Weakness has been reported from an acute exposure.
    3.15.2) CLINICAL EFFECTS
    A) MUSCLE WEAKNESS
    1) Weakness has been reported from an acute dermal exposure (Clayton & Clayton, 1994; Wolfsie, 1960).

Reproductive

    3.20.1) SUMMARY
    A) At the time of this review, no reproductive studies were found for formaldehyde cyanohydrin in humans or experimental animals. Acetonitrile, which is structurally similar, is fetotoxic and teratogenic in animals.
    3.20.2) TERATOGENICITY
    A) HUMANS
    1) At the time of this review, no data were available to assess the teratogenic potential of formaldehyde cyanohydrin in humans.
    2) Cyanide has been linked with congenital cretinism (deformities, dwarfism, and mental insufficiency) due to thyroid deficiency in regions of the world where cassava is a major part of the diet (Anon, 1972). The critical period is the first trimester, and damage can be prevented with iodine supplements (Anon, 1972).
    B) ANIMAL STUDIES
    1) SKELETAL MALFORMATION
    a) Cyanide has been teratogenic and has affected the fertility of laboratory animals. Chemicals which liberate cyanide are also known to be teratogenic in experimental animals. This is especially true of the aliphatic nitriles (Willhite et al, 1981; Smith, 1981), including acrylonitrile (Buchter & Peter, 1984) and acetonitrile (Willhite, 1983).
    b) Pregnant hamsters exposed by either inhalation of 5,000 or 8,000 ppm or given 100 to 400 mg/kg oral or intraperitoneal doses of the closely related compound acetonitrile delivered offspring with severe axial skeletal disorders (Willhite, 1983). Injections of sodium thiosulfate antagonized the teratogenic effects (Willhite, 1983).
    1) Elevated cyanide and thiocyanate levels were found in all tissue studied 2.5 hours after oral or intraperitoneal dosing, and suggested that the in vivo liberation of cyanide from acetonitrile was responsible for the observed teratogenic effects (Willhite, 1983).
    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 this agent during pregnancy or lactation.

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS107-16-4 (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
    3.21.2) SUMMARY/HUMAN
    A) At the time of this review, no studies were found on the possible carcinogenic effects of formaldehyde cyanohydrin in humans.

Genotoxicity

    A) At the time of this review, no genetic studies were found for formaldehyde cyanohydrin.

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Blood cyanide levels may be helpful in confirming exposure, but cyanide formation may be delayed. Treatment of symptomatic patients with cyanide antidote should not be delayed to obtain laboratory confirmation of cyanide poisoning.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) The level of thiocyanate in the serum of rats fed formaldehyde cyanohydrin was indicative of their intake. Cyanide was generally not present (Wolfsie, 1960).
    2) Patients exposed to 40 to 160 ppm acetonitrile for 4 hours had no elevations in cyanide levels, but did have mildly elevated thiocyanate levels (Pozzani et al, 1959). Thiocyanate levels were inconsistently elevated, however. Because of this data and variability in animal studies on nitriles, no reliance should be placed on cyanide or thiocyanate levels.

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) All patients with cyanide exposure resulting in symptoms should be admitted to the hospital. Whenever the cyanide antidote kit is used, the patient should be admitted to the intensive care unit.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with a history of significant cyanide exposure but who are asymptomatic should be observed closely in the hospital with an IV in place and the drugs drawn up ready at the bedside. If they remain asymptomatic for a period of two hours, they may be released from the hospital.

Monitoring

    A) Blood cyanide levels may be helpful in confirming exposure, but cyanide formation may be delayed. Treatment of symptomatic patients with cyanide antidote should not be delayed to obtain laboratory confirmation of cyanide poisoning.

Oral Exposure

    6.5.2) PREVENTION OF ABSORPTION
    A) SUMMARY
    1) In symptomatic patients, skip these steps until other major emergency measures including use of cyanide antidote kit and other life support measures have been instituted.
    B) GASTRIC LAVAGE
    1) INDICATIONS: Consider gastric lavage with a large-bore orogastric tube (ADULT: 36 to 40 French or 30 English gauge tube {external diameter 12 to 13.3 mm}; CHILD: 24 to 28 French {diameter 7.8 to 9.3 mm}) after a potentially life threatening ingestion if it can be performed soon after ingestion (generally within 60 minutes).
    a) Consider lavage more than 60 minutes after ingestion of sustained-release formulations and substances known to form bezoars or concretions.
    2) PRECAUTIONS:
    a) SEIZURE CONTROL: Is mandatory prior to gastric lavage.
    b) AIRWAY PROTECTION: Place patients in the head down left lateral decubitus position, with suction available. Patients with depressed mental status should be intubated with a cuffed endotracheal tube prior to lavage.
    3) LAVAGE FLUID:
    a) Use small aliquots of liquid. Lavage with 200 to 300 milliliters warm tap water (preferably 38 degrees Celsius) or saline per wash (in older children or adults) and 10 milliliters/kilogram body weight of normal saline in young children(Vale et al, 2004) and repeat until lavage return is clear.
    b) The volume of lavage return should approximate amount of fluid given to avoid fluid-electrolyte imbalance.
    c) CAUTION: Water should be avoided in young children because of the risk of electrolyte imbalance and water intoxication. Warm fluids avoid the risk of hypothermia in very young children and the elderly.
    4) COMPLICATIONS:
    a) Complications of gastric lavage have included: aspiration pneumonia, hypoxia, hypercapnia, mechanical injury to the throat, esophagus, or stomach, fluid and electrolyte imbalance (Vale, 1997). Combative patients may be at greater risk for complications (Caravati et al, 2001).
    b) Gastric lavage can cause significant morbidity; it should NOT be performed routinely in all poisoned patients (Vale, 1997).
    5) CONTRAINDICATIONS:
    a) Loss of airway protective reflexes or decreased level of consciousness if patient is not intubated, following ingestion of corrosive substances, hydrocarbons (high aspiration potential), patients at risk of hemorrhage or gastrointestinal perforation, or trivial or non-toxic ingestion.
    C) ACTIVATED CHARCOAL/CATHARTIC
    1) The usefulness of activated charcoal may be questionable.
    a) 1 gram of activated charcoal may adsorb 35 milligrams of potassium cyanide (Anderson, 1946) but this is a low percentage.
    b) The absorption of cyanide is so rapid that charcoal may be of little use unless administered immediately after ingestion of cyanide.
    c) Immediate administration of a large dose of superactivated charcoal (4 grams/kilogram) to rats given an oral lethal dose of potassium cyanide (35 to 40 milligrams/kilogram) prevented lethality. Eight of 26 treated animals died compared to 25 of 26 untreated animals (Lambert et al, 1988).
    2) 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.
    3) 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) OXYGEN
    1) Administer 100% oxygen to maintain an elevated PO2.
    a) Oxygen may reverse the cyanide-cytochrome oxidase complex and facilitate the conversion to thiocyanate following thiosulfate administration (Graham et al, 1977).
    b) There is fairly good evidence that 100% oxygen, combined with traditional nitrite/thiosulfate therapy is better than thiosulfate alone (Litovitz et al, 1983; Way et al, 1972).
    B) HYPERBARIC OXYGEN THERAPY
    1) Hyperbaric oxygen (HBO) therapy is approved for cyanide poisoning as a category one condition (approved for third party reimbursement and known effective as treatment) by the Undersea Medical Society (Myers & Schnitzer, 1984).
    2) Hyperbaric oxygen has been suggested to improve clinical outcome, especially in those patients with CNS toxicity not responding to more traditional therapy.
    3) Animal studies have both confirmed and refuted this (Skene et al, 1966; Way et al, 1972; Takano et al, 1980).
    4) Case reports suggest that HBO may be of value (Carden, 1970; Trapp, 1970). However, one patient treated with supportive therapy, antidotes, and HBO did not survive a serious poisoning (Litovitz et al, 1983).
    5) Hyperbaric oxygen should be reserved for those patients with significant symptoms (ie, coma, seizures) who do not respond to normal supportive and antidotal therapy, and for those patients poisoned by both cyanide and carbon monoxide secondary to smoke inhalation (Hart et al, 1985).
    C) FLUID/ELECTROLYTE BALANCE REGULATION
    1) Establish secure large bore IV line.
    D) CYANIDE ANTIDOTE
    1) A cyanide antidote, either hydroxocobalamin or the sodium nitrite/sodium thiosulfate kit, should be administered to patients with symptomatic poisoning.
    2) HYDROXOCOBALAMIN - CYANOKIT(R)
    a) ADULT DOSE: 5 g (two 2.5 g vials each reconstituted with 100 mL sterile 0.9% saline) administered as an intravenous infusion over 15 minutes. For severe poisoning, a second dose of 5 g may be infused intravenously over 15 minutes to 2 hours, depending on the patient's condition (Prod Info CYANOKIT(R) 2.5g IV injection, 2006).
    b) PEDIATRIC DOSE: A dose of 70 mg/kg has been used in pediatric patients, based on limited post-marketing experience outside the US (Prod Info CYANOKIT(R) 2.5g IV injection, 2006).
    c) INDICATIONS: Known or suspected cyanide poisoning.
    d) ADVERSE EFFECTS: Transient hypertension, allergic reactions (including anaphylaxis), nausea, headache, rash. Hydroxocobalamin's deep red color causes red-colored urine in all patients, and erythema of the skin in most (Prod Info CYANOKIT(R) 2.5g IV injection, 2006).
    e) LABORATORY INTERFERENCE: Because of its' color, hydroxocobalamin interferes with colorimetric determination of various laboratory parameters. It may artificially increase serum creatinine, bilirubin, triglycerides, cholesterol, total protein, glucose, albumin , alkaline phosphatase and hemoglobin. It may artificially decrease serum ALT and amylase. It may artificially increase urinary pH, glucose, protein, erythrocytes, leukocytes, ketones, bilirubin, urobilinogen, and nitrate (Prod Info CYANOKIT(R) 2.5g IV injection, 2006).
    f) HEMODIALYSIS INTERFERENCE: Dialysis machines have a spectrophotometric safety measure that can shut down after detecting blood leaking across the dialysis membrane. Hydroxocobalamin has a deep red color and can permeate the dialysis membrane, coloring the dialysate and causing the hemodialysis machine to shut down erroneously. In one case report, a patient with cyanide poisoning underwent dialysis after receiving 5 g of IV hydroxocobalamin because of refractory acidemia, reduced kidney function and hyperkalemia. A blood leak alarm caused the dialysis machine to shut down erroneously, delaying therapy, and resulting in the death of the patient (Stellpflug et al, 2013).
    g) In a study of heavy smokers, a group given hydroxocobalamin alone in a dose of 5 grams IV showed a decrease in whole blood cyanide of 59%. A group given 5 grams hydroxocobalamin followed with 12.5 grams sodium thiosulfate showed an 87% decrease in whole blood cyanide (Forsyth et al, 1993).
    h) Hydroxocobalamin has been shown to be effective in treating cyanide poisoned animals and has the advantage of neither producing methemoglobinemia nor hypotension as does sodium nitrite (Forsyth et al, 1993).
    3) CYANIDE ANTIDOTE KIT
    a) OBTAIN AND PREPARE for administration a CYANIDE ANTIDOTE KIT, consisting of sodium nitrite and sodium thiosulfate.
    1) Antidotes should be used only in significantly symptomatic patients (ie, impaired consciousness, convulsions, acidosis, or unstable vital signs).
    2) Even when patients are rendered comatose by the inhalation of hydrogen cyanide gas, antidotes may not be necessary if the exposure is rapidly terminated, the patient has regained consciousness on arrival at the medical facility, and there is no acidosis or abnormality of the vital signs (Peden et al, 1986).
    4) SODIUM NITRITE
    a) INDICATION
    1) Sodium nitrite should be given initially and administered as soon as vascular access is established.
    2) Further administration of sodium nitrite is dictated only by the clinical situation, provided no significant complications (hypotension, excessive methemoglobinemia) are present. Use with caution if carbon monoxide poisoning is also suspected.
    3) The goal of nitrite therapy is to achieve a methemoglobin level of 20% to 30%. This level is not based on clinical data, but represents the tolerated concentration without significant adverse symptoms from methemoglobin in an otherwise healthy individual. Clinical response has been reported to occur with methemoglobin levels in the range of 3.6% to 9.2% (DiNapoli et al, 1989; Johnson et al, 1989; Johnson & Mellors, 1988).
    b) ADULT DOSE
    1) 10 mL of a 3% solution (300 mg) administered intravenously at a rate of 2.5 to 5 mL/minute (Prod Info NITHIODOTE intravenous injection solution, 2011). Frequent blood pressure monitoring must accompany sodium nitrite injection and the rate slowed if hypotension occurs.
    2) If there is inadequate clinical response, an additional dose of sodium nitrite at half the amount of the initial dose may be administered 30 minutes following the first dose (Prod Info NITHIODOTE intravenous injection solution, 2011).
    c) PEDIATRIC DOSE
    1) The recommended pediatric sodium nitrite dose is 0.2 mL/kg of a 3% solution (6 mg/kg) administered intravenously at a rate of 2.5 to 5 mL/minute, not to exceed 10 mL (300 mg) (Prod Info NITHIODOTE intravenous injection solution, 2011).
    2) If there is inadequate clinical response, an additional dose of sodium nitrite at half the amount of the initial dose may be administered 30 minutes following the first dose (Prod Info NITHIODOTE intravenous injection solution, 2011; Berlin, 1970).
    3) PRESENCE OF ANEMIA: If there is a reason to suspect the presence of anemia, the following initial sodium nitrite doses should be given, depending on the child's hemoglobin (sodium nitrite should not exceed the doses listed below; fatal methemoglobinemia may result) (Berlin, 1970):
    a) Hemoglobin: 8 g/dL - Initial 3% sodium nitrite dose: 0.22 mL/kg (6.6 mg/kg)
    b) Hemoglobin: 10 g/dL - Initial 3% sodium nitrite dose: 0.27 mL/kg (8.7 mg/kg)
    c) Hemoglobin: 12 g/dL (average child) - Initial 3% sodium nitrite dose: 0.33 mL/kg (10 mg/kg)
    d) Hemoglobin: 14 g/dL - Initial 3% sodium nitrite dose: 0.39 mL/kg (11.6 mg/kg)
    d) It is highly recommended that total hemoglobin and methemoglobin concentrations be rapidly measured (30 minutes after dose), when possible, before repeating a dose of sodium nitrite to be sure that dangerous methemoglobinemia will not occur, especially in the pediatric patient.
    e) Monitor blood pressure frequently and treat hypotension by slowing infusion rate and giving crystalloids and vasopressors. Consider possible excessive methemoglobin formation if patient deteriorates during therapy.
    f) Excessive methemoglobinemia and hypotension are potential complications of nitrite therapy.
    g) In individuals with G6PD deficiency, therapy with methemoglobin-inducing agents is contraindicated because of the likelihood of serious hemolysis.
    5) SODIUM THIOSULFATE
    a) Sodium thiosulfate is the second component of the cyanide antidote kit. It is supplied as 50 mL of a 25% solution and it is administered intravenously. There are no adverse reactions to thiosulfate itself. The pediatric dose is adjusted for weight and not hemoglobin concentration.
    b) Sodium thiosulfate supplies sulfur for the rhodanese reaction, and is recommended after sodium nitrite, hydroxocobalamin, or 4-DMAP (4-dimethylaminophenol) administration (Marrs, 1988; Hall & Rumack, 1987).
    c) DOSE
    1) Follow sodium nitrite with IV sodium thiosulfate. ADULT: Administer 50 mL (12.5 g) of a 25% solution IV; PEDIATRIC: 1 mL/kg of a 25% solution (250 mg/kg), not to exceed 50 mL (12.5 g) total dose (Prod Info NITHIODOTE intravenous injection solution, 2011).
    2) A second dose, one-half of the first dose, may be administered if signs of cyanide toxicity reappear (Prod Info NITHIODOTE intravenous injection solution, 2011).
    3) Sodium thiosulfate is usually used in combination with sodium nitrite but may be used alone (Prod Info sodium thiosulfate IV injection, 2003).
    4) Sodium thiosulfate can be administered without sodium nitrite in patients at risk to develop further methemoglobinemia (ie excessive methemoglobinemia or hypotension after initial sodium nitrite administration or in the presence of methemoglobinemia or carboxyhemoglobin in patients with smoke inhalation due to fire). Sodium thiosulfate can also be used in combination with hydroxocobalamin to treat cyanide poisoning (Howland, 2011)
    5) CONTINUOUS INFUSION: It has been suggested that a continuous infusion of sodium thiosulfate be given after the initial bolus to maintain high thiosulfate levels. Low sodium intravenous fluids are required to avoid sodium overload. If large amounts of sodium thiosulfate are required, hemodialysis may be necessary to maintain a physiologic serum sodium level (Turchen et al, 1991).
    6) ADVERSE EVENTS: Sodium thiosulfate does not usually produce significant toxicity. Possible adverse events include hypotension, headache, nausea, vomiting, disorientation, and prolonged bleeding time (Prod Info NITHIODOTE intravenous injection solution, 2011).
    E) MONITORING OF PATIENT
    1) Obtain blood for arterial blood gases, venous pO2 or measured venous %O2 saturation, electrolytes, serum lactate, and whole blood cyanide levels.
    F) ACIDOSIS
    1) Administer sodium bicarbonate, 1 milliequivalent/kilogram intravenously to severely acidotic patients (pH <7.1). Base further sodium bicarbonate administration on serial arterial blood gas determinations.
    2) Acidosis may be difficult to correct prior to administration of antidotes in serious cyanide poisoning cases (Hall & Rumack, 1986).
    3) The following set of laboratory values suggest poisoning with an agent that inhibits oxidative phosphorylation (ie, cyanide, hydrogen sulfide) (Hall & Rumack, 1986).
    a) Cyanide and hydrogen sulfide poisoning are treated in essentially the same manner (see Hydrogen Sulfide Management) with the exception of lack of efficacy of sodium thiosulfate in hydrogen sulfide poisoning. Administering sodium thiosulfate will most likely do no harm to a hydrogen sulfide poisoned patient.
    b) Arterial pO2: Usually normal until the stage of apnea. Usually remains normal until terminal stages of the poisoning if supplemental oxygen and assisted ventilation are provided.
    c) Serum electrolytes: Anion gap elevated. Anion gap = (Na - (Cl + HCO(3))).
    1) Normals have been reported as 12 plus or minus 4 milliequivalents/liter, but vary depending on the laboratory used. The range for a normal anion gap reported in some laboratories is 7 plus or minus 4 milliequivalents/liter (Hoffman, 1994).
    d) Serum Lactate: Elevated (normals 0.6 to 1.8 milliequivalents/liter (0.6 to 1.8 millimoles/liter)) due to anaerobic metabolism with excessive production of lactic acid.
    e) Arterio-Central Venous Measured %O2 Saturation Difference: Due to cellular inability to extract and use oxygen, more is present on the venous side. The MEASURED values of arterial and central venous %O2 saturation approach each other with MEASURED central venous %O2 saturation greater than 70 percent.
    1) Arteriolization of venous blood gases (elevated venous pO2 or measured venous %O2 saturation) may serve as an early clue in the diagnosis of cyanide poisoning (Hall & Rumack, 1986; Johnson & Mellors, 1988).
    G) 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).
    H) METHEMOGLOBINEMIA
    1) While clinically significant excessive methemoglobinemia has occurred following sodium nitrite therapy for cyanide poisoning, such instances are rare and usually occur in children receiving excessive nitrite doses.
    a) Inducing a "therapeutic methemoglobin level" of 25 percent is unnecessary to insure satisfactory clinical outcome (Johnson et al, 1989).
    2) If excessive methemoglobinemia occurs, some authors recommend that methylene or toluidine blue should not be used, as they could cause the release of cyanide from the cyanmethemoglobin complex.
    a) In this instance, emergency exchange transfusion has been suggested as the treatment of choice (Berlin, 1970).
    b) Hyperbaric oxygen therapy could be used to support the patient while preparations for exchange transfusion are being made.
    3) However, methylene or toluidine blue have been used successfully in this setting without worsening the course of the cyanide poisoning (van Heijst et al, 1987).
    a) There is some controversy over whether or not the induction of methemoglobinemia is the sodium nitrite mechanism of action in cyanide poisoning.
    1) In cyanide poisoned rats, administration of toluidine blue to prevent the development of methemoglobinemia in rats treated with either sodium nitrite/sodium thiosulfate, or 4-dimethylaminophenol did not affect the ability of these agents to restore cytochrome oxidase activity (Tadic, 1992).
    b) As long as intensive care monitoring and availability of further antidote doses are assured if required, methylene or toluidine blue can most likely be safely administered in this setting.
    I) DICOBALT EDETATE
    1) Kelocyanor(R) (dicobalt-EDTA) is a highly effective cyanide chelating agent currently used clinically in Europe, Israel, and Australia (Davison, 1969; Hillman et al, 1974). It is not available in the US.
    2) PRECAUTIONS
    a) Significant toxicity from the antidote (severe hypertension or hypotension, cardiac ischemia or arrhythmias) may be seen in patients incorrectly diagnosed as being poisoned with cyanide and administered this antidote (Pronczuk de Garbino & Bismuth, 1981; Tyrer, 1981). Therefore, KELOCYANOR(R) SHOULD NOT BE USED IN CASES of MILD CYANIDE POISONING or DIAGNOSTIC UNCERTAINTY (Peden et al, 1986; Tyrer, 1981).
    b) Severe anaphylactoid reactions with periorbital and massive facial edema, and airway compromise may also occur (Dodds & McKnight, 1985; Wright & Vesey, 1986).
    c) ADVERSE EFFECTS: can include nausea, vomiting, tachycardia, hypotension, hypertension, anaphylactic reactions, facial and neck edema, chest pain, diaphoresis, nervousness, tremulousness, gastrointestinal hemorrhages, seizures, cardiac irregularities, and rashes (Prod Info, 1986; Prod Info, 1987; (Davison, 1969; Tyrer, 1981; Hillman et al, 1974).
    d) Cobalt edetate has been shown to significantly increase plasma catecholamine levels which probably accounts for the cardiac effects of this drug. Vasodilator activities appear to be associated with cobalt edetate and it may induce a metabolic acidosis (Riou et al, 1993).
    3) DOSE
    a) ADULTS: One to two 20-milliliter ampules (300 to 600 milligrams) injected intravenously over about 1 to 5 minutes (Prod Info, 1978; Prod Info, 1986; Prod Info, 1987; (Davison, 1969).
    1) A third 20-milliliter ampule (300 milligrams) can be injected intravenously over about 1 to 5 minutes, 5 minutes after the first 1 to 2 ampules if there is not sufficient clinical improvement (Prod Info, 1978; Prod Info, 1986; Prod Info, 1987; (Davison, 1969).
    2) Manufacturers recommend following the Kelocyanor(R) injection with intravenous injection of 50 milliliters of 50 percent dextrose in water (Prod Info, 1978; Prod Info, 1986; Prod Info, 1987).
    3) Kelocyanor(R) can be used with other standard cyanide antidotes (Prod Info, 1978).
    b) CHILDREN: Pediatric doses have not been established by manufacturers. A suggested dose used in Israel for children is 0.5 milliliter per kilogram (not to exceed 20 milliliters) (Personal Communication, Uri Taitelman, MD, 1963).
    a) Kelocyanor(R) is supplied in 20-milliliter ampules containing 300 milligrams of dicobalt-EDTA and 4 grams of dextrose in water for injection (Prod Info, 1978; Prod Info, 1986; Prod Info, 1987).
    J) 4-DIMETHYLAMINOPHENOL HYDROCHLORIDE
    1) 4-DMAP is a methemoglobin-inducing agent used in some European countries for the treatment of acute cyanide poisoning. Excessive methemoglobinemia may be a major complication following the use of this agent (van Dijk et al, 1986). Hemolysis may occur with therapeutic doses (van Heijst et al, 1987).
    K) EXPERIMENTAL THERAPY
    1) STROMA-FREE METHEMOGLOBIN SOLUTION - Stroma-free methemoglobin solution prepared from outdated human red blood cells by oxidation of the ferrous iron of hemoglobin to the ferric form in vitro has been used in experimental animals as a cyanide antidote (Ten Eyck et al, 1985).
    a) By virtue of its in vitro production, stroma-free methemoglobin solution has the advantage of sparing the oxygen-carrying capacity of the blood (Marrs, 1988).
    b) It has not been studied in human poisoning cases and is not available for human administration.
    2) ALPHA-KETOGLUTARIC ACID - Alpha-ketoglutaric acid is also being tested as a replacement for sodium nitrite in combination with sodium thiosulfate in animal models where it has been efficacious in experimental cyanide poisoning (Moore et al, 1986).
    a) In vitro and animal studies show that alpha-ketoglutaric acid binds with cyanide and thereby antagonizes cyanide-induced inhibition of brain cytochrome oxidase (Norris et al, 1990).
    b) Alpha-ketoglutaric acid administered with sodium thiosulfate abolished the cyanide-induced decrease in brain gamma-aminobutyric acid in mice (Yamamoto, 1990).
    c) Oral administration of alpha-ketoglutarate was effective as pretreatment only when given between 10 and 30 minutes prior to cyanide exposure in rats. In combination with N-acetylcysteine, it improved the protective effect but did not alter the time course for protection (Dulaney et al, 1991).
    d) It has not been studied in human poisoning cases and is not available for human administration.
    3) CHLORPROMAZINE - Chlorpromazine has been studied in various animal models as a possible cyanide antidote. Conflicting reports of efficacy have been published (Pettersen & Cohen, 1985).
    a) Animal and in vitro studies show that chlorpromazine can decrease peroxidation of lipid membranes and prevent cyanide-induced calcium influx believed to be responsible for neurotoxicity (Johnson et al, 1986; Maduh et al, 1988).
    b) It has not been studied in human poisoning cases.
    4) OTHER INVESTIGATIONAL ANTIDOTES: Animal studies to identify alternate cyanide antidotes have tested phenoxybenzamine, centrophenoxine, naloxone hydrochloride, etomidate, para-aminopropiophenone, hydroxylamine, and calcium-ion-channel blockers (Amery et al, 1981; Ashton et al, 1980; Bright & Marrs, 1987; Burrows & Way, 1976; Dubinsky et al, 1984; Johnson et al, 1986; Leung et al, 1984; Bright & Marrs, 1987; Marrs, 1988; Rump & Edelwijn, 1968; Vick & Froehlich, 1985; Vick & Froehlich, 1991).
    L) HYPOTENSIVE EPISODE
    1) SUMMARY
    a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.
    2) DOPAMINE
    a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    3) NOREPINEPHRINE
    a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
    b) DOSE
    1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
    2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
    3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).
    M) ACUTE LUNG INJURY
    1) ONSET: Onset of acute lung injury after toxic exposure may be delayed up to 24 to 72 hours after exposure in some cases.
    2) NON-PHARMACOLOGIC TREATMENT: The treatment of acute lung injury is primarily supportive (Cataletto, 2012). Maintain adequate ventilation and oxygenation with frequent monitoring of arterial blood gases and/or pulse oximetry. If a high FIO2 is required to maintain adequate oxygenation, mechanical ventilation and positive-end-expiratory pressure (PEEP) may be required; ventilation with small tidal volumes (6 mL/kg) is preferred if ARDS develops (Haas, 2011; Stolbach & Hoffman, 2011).
    a) To minimize barotrauma and other complications, use the lowest amount of PEEP possible while maintaining adequate oxygenation. Use of smaller tidal volumes (6 mL/kg) and lower plateau pressures (30 cm water or less) has been associated with decreased mortality and more rapid weaning from mechanical ventilation in patients with ARDS (Brower et al, 2000). More treatment information may be obtained from ARDS Clinical Network website, NIH NHLBI ARDS Clinical Network Mechanical Ventilation Protocol Summary, http://www.ardsnet.org/node/77791 (NHLBI ARDS Network, 2008)
    3) FLUIDS: Crystalloid solutions must be administered judiciously. Pulmonary artery monitoring may help. In general the pulmonary artery wedge pressure should be kept relatively low while still maintaining adequate cardiac output, blood pressure and urine output (Stolbach & Hoffman, 2011).
    4) ANTIBIOTICS: Indicated only when there is evidence of infection (Artigas et al, 1998).
    5) EXPERIMENTAL THERAPY: Partial liquid ventilation has shown promise in preliminary studies (Kollef & Schuster, 1995).
    6) CALFACTANT: In a multicenter, randomized, blinded trial, endotracheal instillation of 2 doses of 80 mL/m(2) calfactant (35 mg/mL of phospholipid suspension in saline) in infants, children, and adolescents with acute lung injury resulted in acute improvement in oxygenation and lower mortality; however, no significant decrease in the course of respiratory failure measured by duration of ventilator therapy, intensive care unit, or hospital stay was noted. Adverse effects (transient hypoxia and hypotension) were more frequent in calfactant patients, but these effects were mild and did not require withdrawal from the study (Wilson et al, 2005).
    7) However, in a multicenter, randomized, controlled, and masked trial, endotracheal instillation of up to 3 doses of calfactant (30 mg) in adults only with acute lung injury/ARDS due to direct lung injury was not associated with improved oxygenation and longer term benefits compared to the placebo group. It was also associated with significant increases in hypoxia and hypotension (Willson et al, 2015).

Inhalation Exposure

    6.7.1) DECONTAMINATION
    A) Move patient from the toxic environment to fresh air. Monitor for respiratory distress. If cough or difficulty in breathing develops, evaluate for hypoxia, respiratory tract irritation, bronchitis, or pneumonitis.
    B) OBSERVATION: Carefully observe patients with inhalation exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.
    C) INITIAL TREATMENT: Administer 100% humidified supplemental oxygen, perform endotracheal intubation and provide assisted ventilation as required. Administer inhaled beta-2 adrenergic agonists, if bronchospasm develops. Consider systemic corticosteroids in patients with significant bronchospasm (National Heart,Lung,and Blood Institute, 2007). Exposed skin and eyes should be flushed with copious amounts of water.
    D) DECONTAMINATION: Remove contaminated clothing and jewelry and place them in plastic bags. Wash exposed areas with soap and water for 10 to 15 minutes with gentle sponging to avoid skin breakdown. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).
    6.7.2) TREATMENT
    A) SUPPORT
    1) All exposures of formaldehyde cyanohydrin should be referred to a health care facility for evaluation and observation. Signs and/or symptoms of toxicity may be delayed in onset (Wolfsie, 1960).
    B) OXYGEN
    1) Immediately begin therapy with 100% oxygen. Be prepared for endotracheal intubation if necessary (Graham et al, 1977). Administer 100% oxygen to maintain an elevated PO2. Oxygen may reverse the binding of cyanide to the cytochrome oxidase complex and facilitate the conversion of thiocyanate following thiosulfate administration (Graham et al, 1977).
    2) There is fairly good evidence that 100% oxygen, combined with traditional thiosulfate-nitrite therapy is better than thiosulfate alone (Litovitz et al, 1983).
    C) CYANIDE ANTIDOTE
    1) A cyanide antidote, either hydroxocobalamin or the sodium nitrite/sodium thiosulfate kit, should be administered to patients with symptomatic poisoning.
    2) HYDROXOCOBALAMIN - CYANOKIT(R)
    a) ADULT DOSE: 5 g (two 2.5 g vials each reconstituted with 100 mL sterile 0.9% saline) administered as an intravenous infusion over 15 minutes. For severe poisoning, a second dose of 5 g may be infused intravenously over 15 minutes to 2 hours, depending on the patient's condition (Prod Info CYANOKIT(R) 2.5g IV injection, 2006).
    b) PEDIATRIC DOSE: A dose of 70 mg/kg has been used in pediatric patients, based on limited post-marketing experience outside the US (Prod Info CYANOKIT(R) 2.5g IV injection, 2006).
    c) INDICATIONS: Known or suspected cyanide poisoning.
    d) ADVERSE EFFECTS: Transient hypertension, allergic reactions (including anaphylaxis), nausea, headache, rash. Hydroxocobalamin's deep red color causes red-colored urine in all patients, and erythema of the skin in most (Prod Info CYANOKIT(R) 2.5g IV injection, 2006).
    e) LABORATORY INTERFERENCE: Because of its' color, hydroxocobalamin interferes with colorimetric determination of various laboratory parameters. It may artificially increase serum creatinine, bilirubin, triglycerides, cholesterol, total protein, glucose, albumin , alkaline phosphatase and hemoglobin. It may artificially decrease serum ALT and amylase. It may artificially increase urinary pH, glucose, protein, erythrocytes, leukocytes, ketones, bilirubin, urobilinogen, and nitrate (Prod Info CYANOKIT(R) 2.5g IV injection, 2006).
    f) HEMODIALYSIS INTERFERENCE: Dialysis machines have a spectrophotometric safety measure that can shut down after detecting blood leaking across the dialysis membrane. Hydroxocobalamin has a deep red color and can permeate the dialysis membrane, coloring the dialysate and causing the hemodialysis machine to shut down erroneously. In one case report, a patient with cyanide poisoning underwent dialysis after receiving 5 g of IV hydroxocobalamin because of refractory acidemia, reduced kidney function and hyperkalemia. A blood leak alarm caused the dialysis machine to shut down erroneously, delaying therapy, and resulting in the death of the patient (Stellpflug et al, 2013).
    3) CYANIDE ANTIDOTE KIT
    a) OBTAIN AND PREPARE for administration a CYANIDE ANTIDOTE KIT, consisting of sodium nitrite and sodium thiosulfate.
    1) Antidotes should be used only in significantly symptomatic patients (ie, impaired consciousness, convulsions, acidosis, or unstable vital signs).
    2) Even when patients are rendered comatose by the inhalation of hydrogen cyanide gas, antidotes may not be necessary if the exposure is rapidly terminated, the patient has regained consciousness on arrival at the medical facility, and there is no acidosis or abnormality of the vital signs (Peden et al, 1986).
    4) SODIUM NITRITE
    a) INDICATION
    1) Sodium nitrite should be given initially and administered as soon as vascular access is established.
    2) Further administration of sodium nitrite is dictated only by the clinical situation, provided no significant complications (hypotension, excessive methemoglobinemia) are present. Use with caution if carbon monoxide poisoning is also suspected.
    3) The goal of nitrite therapy is to achieve a methemoglobin level of 20% to 30%. This level is not based on clinical data, but represents the tolerated concentration without significant adverse symptoms from methemoglobin in an otherwise healthy individual. Clinical response has been reported to occur with methemoglobin levels in the range of 3.6% to 9.2% (DiNapoli et al, 1989; Johnson et al, 1989; Johnson & Mellors, 1988).
    b) ADULT DOSE
    1) 10 mL of a 3% solution (300 mg) administered intravenously at a rate of 2.5 to 5 mL/minute (Prod Info NITHIODOTE intravenous injection solution, 2011). Frequent blood pressure monitoring must accompany sodium nitrite injection and the rate slowed if hypotension occurs.
    2) If there is inadequate clinical response, an additional dose of sodium nitrite at half the amount of the initial dose may be administered 30 minutes following the first dose (Prod Info NITHIODOTE intravenous injection solution, 2011).
    c) PEDIATRIC DOSE
    1) The recommended pediatric sodium nitrite dose is 0.2 mL/kg of a 3% solution (6 mg/kg) administered intravenously at a rate of 2.5 to 5 mL/minute, not to exceed 10 mL (300 mg) (Prod Info NITHIODOTE intravenous injection solution, 2011).
    2) If there is inadequate clinical response, an additional dose of sodium nitrite at half the amount of the initial dose may be administered 30 minutes following the first dose (Prod Info NITHIODOTE intravenous injection solution, 2011; Berlin, 1970).
    3) PRESENCE OF ANEMIA: If there is a reason to suspect the presence of anemia, the following initial sodium nitrite doses should be given, depending on the child's hemoglobin (sodium nitrite should not exceed the doses listed below; fatal methemoglobinemia may result) (Berlin, 1970):
    a) Hemoglobin: 8 g/dL - Initial 3% sodium nitrite dose: 0.22 mL/kg (6.6 mg/kg)
    b) Hemoglobin: 10 g/dL - Initial 3% sodium nitrite dose: 0.27 mL/kg (8.7 mg/kg)
    c) Hemoglobin: 12 g/dL (average child) - Initial 3% sodium nitrite dose: 0.33 mL/kg (10 mg/kg)
    d) Hemoglobin: 14 g/dL - Initial 3% sodium nitrite dose: 0.39 mL/kg (11.6 mg/kg)
    d) It is highly recommended that total hemoglobin and methemoglobin concentrations be rapidly measured (30 minutes after dose), when possible, before repeating a dose of sodium nitrite to be sure that dangerous methemoglobinemia will not occur, especially in the pediatric patient.
    e) Monitor blood pressure frequently and treat hypotension by slowing infusion rate and giving crystalloids and vasopressors. Consider possible excessive methemoglobin formation if patient deteriorates during therapy.
    f) Excessive methemoglobinemia and hypotension are potential complications of nitrite therapy.
    g) In individuals with G6PD deficiency, therapy with methemoglobin-inducing agents is contraindicated because of the likelihood of serious hemolysis.
    5) SODIUM THIOSULFATE
    a) Sodium thiosulfate is the second component of the cyanide antidote kit. It is supplied as 50 mL of a 25% solution and it is administered intravenously. There are no adverse reactions to thiosulfate itself. The pediatric dose is adjusted for weight and not hemoglobin concentration.
    b) Sodium thiosulfate supplies sulfur for the rhodanese reaction, and is recommended after sodium nitrite, hydroxocobalamin, or 4-DMAP (4-dimethylaminophenol) administration (Marrs, 1988; Hall & Rumack, 1987).
    c) DOSE
    1) Follow sodium nitrite with IV sodium thiosulfate. ADULT: Administer 50 mL (12.5 g) of a 25% solution IV; PEDIATRIC: 1 mL/kg of a 25% solution (250 mg/kg), not to exceed 50 mL (12.5 g) total dose (Prod Info NITHIODOTE intravenous injection solution, 2011).
    2) A second dose, one-half of the first dose, may be administered if signs of cyanide toxicity reappear (Prod Info NITHIODOTE intravenous injection solution, 2011).
    3) Sodium thiosulfate is usually used in combination with sodium nitrite but may be used alone (Prod Info sodium thiosulfate IV injection, 2003).
    4) Sodium thiosulfate can be administered without sodium nitrite in patients at risk to develop further methemoglobinemia (ie excessive methemoglobinemia or hypotension after initial sodium nitrite administration or in the presence of methemoglobinemia or carboxyhemoglobin in patients with smoke inhalation due to fire). Sodium thiosulfate can also be used in combination with hydroxocobalamin to treat cyanide poisoning (Howland, 2011)
    5) CONTINUOUS INFUSION: It has been suggested that a continuous infusion of sodium thiosulfate be given after the initial bolus to maintain high thiosulfate levels. Low sodium intravenous fluids are required to avoid sodium overload. If large amounts of sodium thiosulfate are required, hemodialysis may be necessary to maintain a physiologic serum sodium level (Turchen et al, 1991).
    6) ADVERSE EVENTS: Sodium thiosulfate does not usually produce significant toxicity. Possible adverse events include hypotension, headache, nausea, vomiting, disorientation, and prolonged bleeding time (Prod Info NITHIODOTE intravenous injection solution, 2011).
    D) MONITORING OF PATIENT
    1) Obtain blood for arterial blood gases with calculated and measured percent oxygen saturation, peripheral venous pO2, electrolytes, and serum lactate.
    E) DICOBALT EDETATE
    1) Kelocyanor(R) appears to be a highly effective antidote and an alternative to the Cyanide Antidote Kit(R). It is currently not available in the United States.
    F) HYPERBARIC OXYGEN THERAPY
    1) Hyperbaric oxygen is approved for cyanide poisoning as a category I condition (approved for third party reimbursement and known effective as treatment) by the Undersea Medical Society (Myers & Schnitzer, 1984). Hyperbaric oxygen has been suggested to improve clinical outcome, especially in those patients with CNS toxicity not responding to more traditional therapy. Animal studies have both confirmed and refuted this.
    2) Hyperbaric oxygen should be reserved for those patients with significant symptoms (ie, coma, seizures) which do not respond to normal supportive and antidotal therapies.
    G) 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).
    H) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Eye Exposure

    6.8.1) DECONTAMINATION
    A) EYE IRRIGATION, ROUTINE: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, an ophthalmologic examination should be performed (Peate, 2007; Naradzay & Barish, 2006).
    6.8.2) TREATMENT
    A) OCULAR ABSORPTION
    1) There are no reports of systemic poisoning in humans exposed to cyanide by the ocular route; however, deaths in experimental animals have followed ocular exposure (Ballantyne, 1983).
    2) Patients exposed by this route should be observed for several hours in a controlled setting for the possible development of symptoms of systemic cyanide poisoning.
    B) GENERAL TREATMENT
    1) Treatment should include recommendations listed in the INHALATION EXPOSURE section when appropriate.
    C) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Dermal Exposure

    6.9.1) DECONTAMINATION
    A) DECONTAMINATION: Remove contaminated clothing and wash exposed area thoroughly with soap and water for 10 to 15 minutes. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).
    6.9.2) TREATMENT
    A) SKIN ABSORPTION
    1) Cyanide can be absorbed and cause systemic cyanide poisoning by the dermal route, usually only following severe burns from molten material (Bourrelier & Paulet, 1971) or total immersion in cyanide solution (Bismuth et al, 1984; Dodds & McKnight, 1985).
    B) OXYGEN
    1) Administer 100% oxygen to maintain an elevated PO2.
    a) Oxygen may reverse the cyanide-cytochrome oxidase complex and facilitate the conversion to thiocyanate following thiosulfate administration (Graham et al, 1977).
    b) There is fairly good evidence that 100% oxygen, combined with traditional nitrite/thiosulfate therapy is better than thiosulfate alone (Litovitz et al, 1983; Way et al, 1972).
    C) HYPERBARIC OXYGEN THERAPY
    1) Hyperbaric oxygen (HBO) therapy is approved for cyanide poisoning as a category one condition (approved for third party reimbursement and known effective as treatment) by the Undersea Medical Society (Myers & Schnitzer, 1984).
    2) Hyperbaric oxygen has been suggested to improve clinical outcome, especially in those patients with CNS toxicity not responding to more traditional therapy.
    3) Animal studies have both confirmed and refuted this (Skene et al, 1966; Way et al, 1972) Takano et al, 1980).
    4) Case reports suggest that HBO may be of value (Carden, 1970; Trapp, 1970). However, one patient treated with supportive therapy, antidotes, and HBO did not survive a serious poisoning (Litovitz et al, 1983).
    5) Hyperbaric oxygen should be reserved for those patients with significant symptoms (ie, coma, seizures) who do not respond to normal supportive and antidotal therapy, and for those patients poisoned by both cyanide and carbon monoxide secondary to smoke inhalation (Hart et al, 1985).
    D) FLUID/ELECTROLYTE BALANCE REGULATION
    1) Establish secure large bore IV line.
    E) CYANIDE ANTIDOTE
    1) A cyanide antidote, either hydroxocobalamin or the sodium nitrite/sodium thiosulfate kit, should be administered to patients with symptomatic poisoning.
    2) HYDROXOCOBALAMIN - CYANOKIT(R)
    a) ADULT DOSE: 5 g (two 2.5 g vials each reconstituted with 100 mL sterile 0.9% saline) administered as an intravenous infusion over 15 minutes. For severe poisoning, a second dose of 5 g may be infused intravenously over 15 minutes to 2 hours, depending on the patient's condition (Prod Info CYANOKIT(R) 2.5g IV injection, 2006).
    b) PEDIATRIC DOSE: A dose of 70 mg/kg has been used in pediatric patients, based on limited post-marketing experience outside the US (Prod Info CYANOKIT(R) 2.5g IV injection, 2006).
    c) INDICATIONS: Known or suspected cyanide poisoning.
    d) ADVERSE EFFECTS: Transient hypertension, allergic reactions (including anaphylaxis), nausea, headache, rash. Hydroxocobalamin's deep red color causes red-colored urine in all patients, and erythema of the skin in most (Prod Info CYANOKIT(R) 2.5g IV injection, 2006).
    e) LABORATORY INTERFERENCE: Because of its' color, hydroxocobalamin interferes with colorimetric determination of various laboratory parameters. It may artificially increase serum creatinine, bilirubin, triglycerides, cholesterol, total protein, glucose, albumin , alkaline phosphatase and hemoglobin. It may artificially decrease serum ALT and amylase. It may artificially increase urinary pH, glucose, protein, erythrocytes, leukocytes, ketones, bilirubin, urobilinogen, and nitrate (Prod Info CYANOKIT(R) 2.5g IV injection, 2006).
    f) HEMODIALYSIS INTERFERENCE: Dialysis machines have a spectrophotometric safety measure that can shut down after detecting blood leaking across the dialysis membrane. Hydroxocobalamin has a deep red color and can permeate the dialysis membrane, coloring the dialysate and causing the hemodialysis machine to shut down erroneously. In one case report, a patient with cyanide poisoning underwent dialysis after receiving 5 g of IV hydroxocobalamin because of refractory acidemia, reduced kidney function and hyperkalemia. A blood leak alarm caused the dialysis machine to shut down erroneously, delaying therapy, and resulting in the death of the patient (Stellpflug et al, 2013).
    g) In a controlled pilot study of male smokers, administration of 5 grams of intravenous 5% hydroxocobalamin significantly decreased whole blood cyanide levels (Forsyth et al, 1992).
    3) CYANIDE ANTIDOTE KIT
    a) OBTAIN AND PREPARE for administration a CYANIDE ANTIDOTE KIT, consisting of sodium nitrite and sodium thiosulfate.
    1) Antidotes should be used only in significantly symptomatic patients (ie, impaired consciousness, convulsions, acidosis, or unstable vital signs).
    2) Even when patients are rendered comatose by the inhalation of hydrogen cyanide gas, antidotes may not be necessary if the exposure is rapidly terminated, the patient has regained consciousness on arrival at the medical facility, and there is no acidosis or abnormality of the vital signs (Peden et al, 1986).
    4) SODIUM NITRITE
    a) INDICATION
    1) Sodium nitrite should be given initially and administered as soon as vascular access is established.
    2) Further administration of sodium nitrite is dictated only by the clinical situation, provided no significant complications (hypotension, excessive methemoglobinemia) are present. Use with caution if carbon monoxide poisoning is also suspected.
    3) The goal of nitrite therapy is to achieve a methemoglobin level of 20% to 30%. This level is not based on clinical data, but represents the tolerated concentration without significant adverse symptoms from methemoglobin in an otherwise healthy individual. Clinical response has been reported to occur with methemoglobin levels in the range of 3.6% to 9.2% (DiNapoli et al, 1989; Johnson et al, 1989; Johnson & Mellors, 1988).
    b) ADULT DOSE
    1) 10 mL of a 3% solution (300 mg) administered intravenously at a rate of 2.5 to 5 mL/minute (Prod Info NITHIODOTE intravenous injection solution, 2011). Frequent blood pressure monitoring must accompany sodium nitrite injection and the rate slowed if hypotension occurs.
    2) If there is inadequate clinical response, an additional dose of sodium nitrite at half the amount of the initial dose may be administered 30 minutes following the first dose (Prod Info NITHIODOTE intravenous injection solution, 2011).
    c) PEDIATRIC DOSE
    1) The recommended pediatric sodium nitrite dose is 0.2 mL/kg of a 3% solution (6 mg/kg) administered intravenously at a rate of 2.5 to 5 mL/minute, not to exceed 10 mL (300 mg) (Prod Info NITHIODOTE intravenous injection solution, 2011).
    2) If there is inadequate clinical response, an additional dose of sodium nitrite at half the amount of the initial dose may be administered 30 minutes following the first dose (Prod Info NITHIODOTE intravenous injection solution, 2011; Berlin, 1970).
    3) PRESENCE OF ANEMIA: If there is a reason to suspect the presence of anemia, the following initial sodium nitrite doses should be given, depending on the child's hemoglobin (sodium nitrite should not exceed the doses listed below; fatal methemoglobinemia may result) (Berlin, 1970):
    a) Hemoglobin: 8 g/dL - Initial 3% sodium nitrite dose: 0.22 mL/kg (6.6 mg/kg)
    b) Hemoglobin: 10 g/dL - Initial 3% sodium nitrite dose: 0.27 mL/kg (8.7 mg/kg)
    c) Hemoglobin: 12 g/dL (average child) - Initial 3% sodium nitrite dose: 0.33 mL/kg (10 mg/kg)
    d) Hemoglobin: 14 g/dL - Initial 3% sodium nitrite dose: 0.39 mL/kg (11.6 mg/kg)
    d) It is highly recommended that total hemoglobin and methemoglobin concentrations be rapidly measured (30 minutes after dose), when possible, before repeating a dose of sodium nitrite to be sure that dangerous methemoglobinemia will not occur, especially in the pediatric patient.
    e) Monitor blood pressure frequently and treat hypotension by slowing infusion rate and giving crystalloids and vasopressors. Consider possible excessive methemoglobin formation if patient deteriorates during therapy.
    f) Excessive methemoglobinemia and hypotension are potential complications of nitrite therapy.
    g) In individuals with G6PD deficiency, therapy with methemoglobin-inducing agents is contraindicated because of the likelihood of serious hemolysis.
    5) SODIUM THIOSULFATE
    a) Sodium thiosulfate is the second component of the cyanide antidote kit. It is supplied as 50 mL of a 25% solution and it is administered intravenously. There are no adverse reactions to thiosulfate itself. The pediatric dose is adjusted for weight and not hemoglobin concentration.
    b) Sodium thiosulfate supplies sulfur for the rhodanese reaction, and is recommended after sodium nitrite, hydroxocobalamin, or 4-DMAP (4-dimethylaminophenol) administration (Marrs, 1988; Hall & Rumack, 1987).
    c) DOSE
    1) Follow sodium nitrite with IV sodium thiosulfate. ADULT: Administer 50 mL (12.5 g) of a 25% solution IV; PEDIATRIC: 1 mL/kg of a 25% solution (250 mg/kg), not to exceed 50 mL (12.5 g) total dose (Prod Info NITHIODOTE intravenous injection solution, 2011).
    2) A second dose, one-half of the first dose, may be administered if signs of cyanide toxicity reappear (Prod Info NITHIODOTE intravenous injection solution, 2011).
    3) Sodium thiosulfate is usually used in combination with sodium nitrite but may be used alone (Prod Info sodium thiosulfate IV injection, 2003).
    4) Sodium thiosulfate can be administered without sodium nitrite in patients at risk to develop further methemoglobinemia (ie excessive methemoglobinemia or hypotension after initial sodium nitrite administration or in the presence of methemoglobinemia or carboxyhemoglobin in patients with smoke inhalation due to fire). Sodium thiosulfate can also be used in combination with hydroxocobalamin to treat cyanide poisoning (Howland, 2011)
    5) CONTINUOUS INFUSION: It has been suggested that a continuous infusion of sodium thiosulfate be given after the initial bolus to maintain high thiosulfate levels. Low sodium intravenous fluids are required to avoid sodium overload. If large amounts of sodium thiosulfate are required, hemodialysis may be necessary to maintain a physiologic serum sodium level (Turchen et al, 1991).
    6) ADVERSE EVENTS: Sodium thiosulfate does not usually produce significant toxicity. Possible adverse events include hypotension, headache, nausea, vomiting, disorientation, and prolonged bleeding time (Prod Info NITHIODOTE intravenous injection solution, 2011).
    F) MONITORING OF PATIENT
    1) Obtain blood for arterial blood gases with venous pO2 or measured venous %O2 saturation, electrolytes, serum lactate, and whole blood cyanide levels.
    2) The following set of laboratory values suggest poisoning with an agent that inhibits oxidative phosphorylation (ie, cyanide, hydrogen sulfide) (Hall & Rumack, 1986).
    a) Cyanide and hydrogen sulfide poisoning are treated in essentially the same manner, (See Hydrogen Sulfide Management) with the exception of lack of efficacy of sodium thiosulfate in hydrogen sulfide poisoning. Administering sodium thiosulfate will most likely do no harm to a hydrogen sulfide poisoned patient.
    b) Arterial pO2: Usually normal until the stage of apnea. Usually remains normal until terminal stages of the poisoning if supplemental oxygen and assisted ventilation are provided.
    c) Serum electrolytes: Elevated anion gap (Na - (C1 + CO2)) (normals 12 to 16 milliequivalents/liter (12 to 16 millimoles/liter) or less) is present from the presence of unmeasured organic anions (usually lactate).
    d) Serum Lactate: Elevated (normals 0.6 to 1.8 milliequivalents/liter) (0.6 to 1.8 millimoles/liter) due to anaerobic metabolism with excessive production of lactic acid.
    e) Arterio-Central Venous Measured %O2 Saturation Difference: Due to cellular inability to extract and use oxygen, more is present on the venous side. The MEASURED values of arterial and central venous %O2 saturation approach each other with MEASURED central venous %O2 saturation greater than 70%.
    1) Arteriolization of venous blood gases (elevated venous pO2 or measured venous %O2 saturation) may serve as an early clue in the diagnosis of cyanide poisoning (Hall & Rumack, 1986; Johnson & Mellors, 1988).
    G) ACIDOSIS
    1) Administer sodium bicarbonate, 1 milliequivalent/kilogram intravenously to severely (pH <7.1) acidotic patients. Base further sodium bicarbonate administration on serial arterial blood gas determinations.
    H) 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).
    I) METHEMOGLOBINEMIA
    1) While clinically significant excessive methemoglobinemia has occurred following sodium nitrite therapy for cyanide poisoning, such instances are rare and usually occur in children receiving excessive nitrite doses.
    a) Inducing a "therapeutic methemoglobin level" of 25% is unnecessary to insure satisfactory clinical outcome (Johnson et al, 1989).
    2) If excessive methemoglobinemia occurs, some authors recommend that methylene or toluidine blue not be used, as they could cause the release of cyanide from the cyanmethemoglobin complex.
    a) In this instance, emergency exchange transfusion has been suggested as the treatment of choice (Berlin, 1970).
    b) Hyperbaric oxygen therapy could be used to support the patient while preparations for exchange transfusion are being made.
    3) However, methylene or toluidine blue have been used successfully in this setting without worsening the course of the cyanide poisoning (van Heijst et al, 1987).
    a) There is some controversy over whether or not the induction of methemoglobinemia is the sodium nitrite mechanism of action in cyanide poisoning.
    b) As long as intensive care monitoring and availability of further antidote doses are assured if required, methylene or toluidine blue can most likely be safely administered in this setting.
    J) DICOBALT EDETATE
    1) Kelocyanor(R) (dicobalt-EDTA) is a highly effective cyanide chelating agent currently used clinically in Europe, Israel, and Australia (Davison, 1969; Hillman et al, 1974). It is not available in the US.
    2) PRECAUTIONS
    a) Significant toxicity from the antidote (severe hypertension or hypotension, cardiac ischemia or arrhythmias) may be seen in patients incorrectly diagnosed as being poisoned with cyanide and administered this antidote (Pronczuk de Garbino & Bismuth, 1981; Tyrer, 1981). Therefore, KELOCYANOR(R) SHOULD NOT BE USED in CASES of MILD CYANIDE POISONING or DIAGNOSTIC UNCERTAINTY (Peden et al, 1986; Tyrer, 1981).
    b) Severe anaphylactoid reactions with periorbital and massive facial edema and airway compromise may also occur (Dodds & McKnight, 1985; Wright & Vesey, 1986).
    c) ADVERSE EFFECTS can include nausea, vomiting, tachycardia, hypotension, hypertension, anaphylactic reactions, facial and neck edema, chest pain, diaphoresis, nervousness, tremulousness, gastrointestinal hemorrhages, convulsions, cardiac irregularities, and rashes (Prod Info, 1986; Prod Info, 1987; (Davison, 1969; Tyrer, 1981; Hillman et al, 1974).
    3) DOSE
    a) ADULTS: One to two 20 milliliter ampules (300 to 600 milligrams) injected intravenously over about 1 to 5 minutes (Prod Info, 1978; Prod Info, 1986; Prod Info, 1987; (Davison, 1969).
    1) A third 20 milliliter ampule (300 milligrams) can be injected intravenously over about 1 to 5 minutes, 5 minutes after the first 1 to 2 ampules if there is not sufficient clinical improvement (Prod Info, 1978; Prod Info, 1986; Prod Info, 1987; (Davison, 1969).
    2) Manufacturers recommend following the Kelocyanor(R) injection with intravenous injection of 50 milliliters of 50% dextrose in water (Prod Info, 1978; Prod Info, 1986; Prod Info, 1987).
    3) Kelocyanor(R) can be used with other standard cyanide antidotes (Prod Info, 1978).
    b) CHILDREN: Pediatric doses have not been established by manufacturers. A suggested dose used in Israel for children is 0.5 milliliter per kilogram (not to exceed 20 milliliters) (Personal Communication, Uri Taitelman, MD, 1963).
    4) Kelocyanor(R) is supplied in 20 milliliter ampules containing 300 milligrams of dicobalt-EDTA and 4 grams of dextrose in water for injection (Prod Info, 1978; Prod Info, 1986; Prod Info, 1987).
    K) 4-DIMETHYLAMINOPHENOL HYDROCHLORIDE
    1) 4-DMAP is a methemoglobin inducing agent used in some European countries for the treatment of acute cyanide poisoning. Excessive methemoglobinemia may be a major complication following the use of this agent (van Dijk et al, 1986).
    L) EXPERIMENTAL THERAPY
    1) STROMA-FREE METHEMOGLOBIN SOLUTION - Stroma-free methemoglobin solution prepared from outdated human red blood cells by oxidation of the ferrous iron of hemoglobin to the ferric form in vitro has been studied in experimental animals and shows promise as a cyanide antidote (Ten Eyck et al, 1985).
    a) By virtue of its in vitro production, stroma-free methemoglobin solution has the advantage of sparing the oxygen-carrying capacity of the blood (Marrs, 1988).
    b) It has not been studied in human poisoning cases and is not available for human administration.
    2) ALPHA-KETOGLUTARIC ACID -
    a) Alpha-ketoglutaric acid is also being tested as a replacement for sodium nitrite in combination with sodium thiosulfate in animal models where it has been efficacious in experimental cyanide poisoning (Moore et al, 1986).
    b) In vitro and animal studies show that alpha-ketoglutaric acid binds with cyanide and thereby antagonizes cyanide-induced inhibition of brain cytochrome oxidase (Norris et al, 1990).
    c) Alpha-ketoglutaric acid administered with sodium thiosulfate abolished the cyanide-induced decrease in brain gamma-aminobutyric acid in mice (Yamamoto, 1990).
    d) It has not been studied in human poisoning cases and is not available for human administration.
    3) CHLORPROMAZINE -
    a) Chlorpromazine has been studied in various animal models as a possible cyanide antidote. Conflicting reports of efficacy have been published (Pettersen & Cohen, 1986).
    b) Animal and in vitro studies show that chlorpromazine can decrease peroxidation of lipid membranes and prevent cyanide-induced calcium influx believed to be responsible for neurotoxicity (Johnson et al, 1986; Maduh et al, 1988).
    c) It has not been studied in human poisoning cases.
    4) OTHER INVESTIGATIONAL ANTIDOTES -
    a) Animal studies to identify alternate cyanide antidotes have tested phenoxybenzamine, centrophenoxine, naloxone hydrochloride, etomidate, para-aminopropiophenone, and calcium-ion-channel blockers, (Amery et al, 1981; Ashton et al, 1980; Bright & Marrs, 1987; Burrows & Way, 1976; Dubinsky et al, 1984; Johnson et al, 1986; Leung et al, 1984; Bright & Marrs, 1987; Marrs, 1988) Rump & Edelwijn, 1986; (Vick & Froehlich, 1985).
    M) HYPOTENSIVE EPISODE
    1) SUMMARY
    a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.
    N) ACUTE LUNG INJURY
    1) ONSET: Onset of acute lung injury after toxic exposure may be delayed up to 24 to 72 hours after exposure in some cases.
    2) NON-PHARMACOLOGIC TREATMENT: The treatment of acute lung injury is primarily supportive (Cataletto, 2012). Maintain adequate ventilation and oxygenation with frequent monitoring of arterial blood gases and/or pulse oximetry. If a high FIO2 is required to maintain adequate oxygenation, mechanical ventilation and positive-end-expiratory pressure (PEEP) may be required; ventilation with small tidal volumes (6 mL/kg) is preferred if ARDS develops (Haas, 2011; Stolbach & Hoffman, 2011).
    a) To minimize barotrauma and other complications, use the lowest amount of PEEP possible while maintaining adequate oxygenation. Use of smaller tidal volumes (6 mL/kg) and lower plateau pressures (30 cm water or less) has been associated with decreased mortality and more rapid weaning from mechanical ventilation in patients with ARDS (Brower et al, 2000). More treatment information may be obtained from ARDS Clinical Network website, NIH NHLBI ARDS Clinical Network Mechanical Ventilation Protocol Summary, http://www.ardsnet.org/node/77791 (NHLBI ARDS Network, 2008)
    3) FLUIDS: Crystalloid solutions must be administered judiciously. Pulmonary artery monitoring may help. In general the pulmonary artery wedge pressure should be kept relatively low while still maintaining adequate cardiac output, blood pressure and urine output (Stolbach & Hoffman, 2011).
    4) ANTIBIOTICS: Indicated only when there is evidence of infection (Artigas et al, 1998).
    5) EXPERIMENTAL THERAPY: Partial liquid ventilation has shown promise in preliminary studies (Kollef & Schuster, 1995).
    6) CALFACTANT: In a multicenter, randomized, blinded trial, endotracheal instillation of 2 doses of 80 mL/m(2) calfactant (35 mg/mL of phospholipid suspension in saline) in infants, children, and adolescents with acute lung injury resulted in acute improvement in oxygenation and lower mortality; however, no significant decrease in the course of respiratory failure measured by duration of ventilator therapy, intensive care unit, or hospital stay was noted. Adverse effects (transient hypoxia and hypotension) were more frequent in calfactant patients, but these effects were mild and did not require withdrawal from the study (Wilson et al, 2005).
    7) However, in a multicenter, randomized, controlled, and masked trial, endotracheal instillation of up to 3 doses of calfactant (30 mg) in adults only with acute lung injury/ARDS due to direct lung injury was not associated with improved oxygenation and longer term benefits compared to the placebo group. It was also associated with significant increases in hypoxia and hypotension (Willson et al, 2015).
    O) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Enhanced Elimination

    A) HEMODIALYSIS
    1) Hemodialysis may be an effective adjunct by correcting resistant acidemia and by increasing thiocyanate clearance, thereby favoring thiosulfate-cyanide reaction to thiocyanate (Wesson et al, 1985).
    2) It has, however, been used in only one reported case, and antidote therapy with sodium nitrite and sodium thiosulfate was also administered (Wesson et al, 1985).
    3) Limited animal studies, using historical controls and only a few animals, have so far shown some potential effectiveness of hemodialysis when combined with thiosulfate infusion (Gonzales & Sabatini, 1989).
    4) Hemodialysis cannot be considered standard therapy for cyanide poisoning at this time.
    B) HEMOPERFUSION
    1) CASE REPORT: Charcoal hemoperfusion has also been used in one reported case of cyanide poisoning (Kreig & Saxena, 1987).
    2) This patient also received supportive measures and sodium nitrite/thiosulfate antidotes.
    3) The outcome in this case was no different from that of other patients treated similarly without hemoperfusion.
    4) Hemoperfusion cannot be considered standard therapy for cyanide poisoning at this time.

Range Of Toxicity

Summary

    A) Minimum lethal human exposure is unknown.

Minimum Lethal Exposure

    A) GENERAL/SUMMARY
    1) The minimum lethal human dose to this agent has not been delineated.

Maximum Tolerated Exposure

    A) GENERAL/SUMMARY
    1) The maximum tolerated human exposure to this agent has not been delineated.
    B) ROUTE OF EXPOSURE
    1) A worker with skin exposure to 70% formaldehyde cyanohydrin (possibly accompanied by an inhalation exposure) developed headache, dizziness, "rubbery legs," and an unsteady gait. The worker vomited several times, was pale, and became first bewildered and then unresponsive. The pulse was rapid and irregular. Following cyanide antidotal treatment, the condition improved. Following return to work the next day, the patient complained of weakness and nausea for 5 additional days, as well as pharyngeal mucosal congestion for longer (Clayton & Clayton, 1994).
    2) Dermal exposure to an undefined dose produced headache, dizziness, ataxia, weakness, vomiting, confusion, tachycardia and cardiac arrhythmia. The patient recovered (Wolfsie, 1960).
    C) ANIMAL DATA
    1) No apparent effects were seen in male rats ingesting up to 62 mg/kg/day, or in female rats fed up to 92 mg/kg/day for 13 weeks (Clayton & Clayton, 1994).
    2) Death occurred in 6 of 7 mice, 2 of 7 rats, and 0 of 7 guinea pigs during an 8 hour inhalation exposure to 27 ppm. The surviving mouse and 4 of the surviving rats died within the next 18 hours, with no lethality resulting in guinea pigs.

Workplace Standards

    A) ACGIH TLV Values for CAS107-16-4 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    B) NIOSH REL and IDLH Values for CAS107-16-4 (National Institute for Occupational Safety and Health, 2007):
    1) Listed as: Glycolonitrile
    2) REL:
    a) TWA:
    b) STEL:
    c) Ceiling: 2 ppm (5 mg/m(3)) [15-minute]
    d) Carcinogen Listing: (Not Listed) Not Listed
    e) Skin Designation: Not Listed
    f) Note(s):
    3) IDLH: Not Listed

    C) Carcinogenicity Ratings for CAS107-16-4 :
    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 ; Listed as: Glycolonitrile
    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 CAS107-16-4 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) References: Clayton & Clayton, 1994 RTECS, 1997; Lewis, 1996 Note: All entries are from RTECS unless otherwise noted.
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 3 mg/kg
    b) 10 mg/kg (Lewis, 1996)
    2) LD50- (ORAL)MOUSE:
    a) 10 mg/kg
    3) LD50- (ORAL)RAT:
    a) 8 mg/kg
    b) 16 mg/kg (Clayton & Clayton, 1994; Lewis, 1996)

Physicochemical

Physical Characteristics

    A) Formaldehyde cyanohydrin exists as an odorless, colorless to white, mobile, oily liquid. It possesses a sweetish taste (HSDB, 2005; Clayton & Clayton, 1994; Lewis, 1993) NIOSH, 1997).

Molecular Weight

    A) 57.05

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