SODIUM CYANIDE

Classification | Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

Specific Substances

1) Caswell No 758
2) Cianuro di sodio (Italian)
3) Cyanide of sodium
4) Cyanobrik
5) Cyanogran
6) Cyanure de sodium (French)
7) Cymag
8) Hydrocyanic acid, sodium salt
9) Kyanid sodny (Czech)
10) M-44 cyanide capsules
11) Molecular Formula: C-N-Na
12) NIOSH/RTECS VZ 7525000
13) RCRA WASTE NUMBER: P106
14) Sodium cyanide
15) Sodium cyanide solid
16) Sodium cyanide solution
17) STCC 4923227 (Solution)
18) STCC 4923228 (Solid)
19) CAS 143-33-9
20) CYANIDE, SODIUM

1.2.1) MOLECULAR FORMULA
1) C-N-Na NaCN

Available Forms Sources

1) AVAILABILITY: Sodium cyanide is available in solutions of 30, 73 to 75, and 96 to 98% purity, and as a reagent or technical grade material in briquette or granular form (Lewis, 1993).
2) OVER-THE-COUNTER (OTC) TAMPERING

a) Episodes of deliberate tampering with OTC capsule medications in 1982, 1986, and 1991 have resulted in 11 deaths from cyanide poisoning (CDC, 1991; Wolnik et al, 1984; Varnell et al, 1987). Since 1982, OTC capsules have been required to have at least 2 tamper-resistant features. Medications with any alteration in these features should not be used, and should be provided to the FDA. Features may include:

1) Sealing of the capsule with a band
2) Blister packs with foil backing
3) Sealing of the package with a safety tab
4) Identification of blister pack and box with identical code numbers

1) Sodium cyanide is used in extracting gold and silver ores; recovery of precious metals from used x-ray and photographic film; electroplating operations (coppering, zincing); for metal heat treating (hardening); in metal cleaning; in the manufacturing of mirrors; as a chelating compound, a copper/zinc plating reagent, and a benzoin condensation catalyst; for ore flotation; and in the manufacture of dyes, pigments, nylon, adiponitrile, hydrocyanic acid, and many other cyanides (ACGIH, 1986; Ashford, 1994; Blanc et al, 1985; Budavari, 1996; Clayton & Clayton, 1994; EPA, 1985; Hathaway et al, 1996) Lewis, 1993).
2) Commercial and household uses of cyanide include fumigation, ore-extraction, electroplating, silver-polishing, synthetic rubber production, and in the manufacture of fertilizers, rodenticides and insecticides. Imported metal cleaning solutions used by Hmong refugees to clean coins may contain cyanide salts (Budavari, 1996; Kreig & Saxena, 1987).
3) It also is used as a poison for coyote, fox, and wild dog found on pastures, range land, and forest land (HSDB , 1998).

Overview

Life Support

Clinical Effects

0.2.1)

A) Sodium cyanide exposure may produce death within minutes. Signs and symptoms following non-lethal, subacute, or chronic exposure may include syncope, weight loss, headache, dizziness, nausea, vomiting, palpitations, confusion, deep inspiratory gasps followed by hyperpnea, hyperventilation, anxiety, and vertigo.
B) Cyanosis is generally a late finding and usually does not occur until circulatory collapse and apnea are evident; particularly at the premorbid stage of cyanide toxicity. Initially the patient may experience flushing, tachycardia, tachypnea, headache, and dizziness. This may progress to agitation, stupor, coma, apnea, seizures, metabolic acidosis, pulmonary edema, bradycardia, hypotension, and death.
C) Sodium cyanide exposure may produce death within minutes. IMMEDIATELY BEGIN ADMINISTERING 100% OXYGEN. OBTAIN THE CYANIDE ANTIDOTE KIT AND PREPARE IT FOR USE. Non-lethal, subacute, or chronic exposure may produce headache, dizziness, nausea, vomiting, palpitations, confusion, deep inspiratory gasps followed by hyperpnea, hyperventilation, anxiety, and vertigo. Severe signs of hypoxia in the absence of cyanosis suggest cyanide poisoning. Patients have reportedly survived potentially lethal ingestions with only supportive care. The absence of a rapidly deteriorating course does not exclude cyanide poisoning.

0.2.3)

A) Tachycardia, deep inspiratory gasps followed by hyperpnea, tachypnea, hypertension may be early findings after acute cyanide poisoning, followed by hypotension, bradycardia, dyspnea, apnea, and asystole.

1) Tachycardia and hypertension may be seen in the initial phases of cyanide poisoning (Vogel et al, 1981).
2) Bradycardia and hypotension are seen in the late phases of cyanide poisoning (Stewart, 1974; Hall & Rumack, 1986).

0.2.4)

A) Dilated pupils are common in severe poisoning; corneal edema, conjunctivitis, and keratitis may occur. Retinal arteries and veins may appear equally red on funduscopic examination.
B) Transient blindness has been reported in rare instances. Damaged optic nerves have been observed in experimental animals. A burning sensation in the nose, mouth, and throat may occur.

0.2.5)

A) Tachycardia, bradycardia, hypertension, hypotension, cardiac dysrhythmias, EKG changes, and asystole may be observed.

0.2.6)

A) Tachypnea, deep inspiratory gasps followed by hyperpnea, apnea, noncardiogenic pulmonary edema may be apparent.

0.2.7)

A) Symptoms following acute cyanide exposure include syncope, headache or CNS stimulation, agitation, dizziness, and vertigo followed by coma, seizures, and death. Sequelae may be paralysis and a Parkinsonian syndrome.

0.2.8)

A) Nausea, vomiting, and abdominal pain may occur.

0.2.11)

A) Anion gap metabolic acidosis and lactic acidosis are evident following cyanide toxicity.

0.2.13)

A) Venous blood may have a bright red color. Anemia has also been reported.

0.2.14)

A) Cyanide has been said to be absorbed through intact skin. Itching, irritation, rash, and dermatitis may occur.
B) Cyanosis may be evident particularly at the premorbid stage of cyanide toxicity.

0.2.16)

A) Enlarged thyroid glands may occur. Thyroid dysfunction has been reported from chronic occupational exposure to cyanide.

0.2.20)

A) ANIMAL STUDIES - Sodium cyanide administered to pregnant rats has produced an increased incidence of resorptions and congenital malformations in the offspring, consisting of neural tube defects including exencephaly and encephalocele (Doherty et al, 1982). Concomitant administration of sodium thiosulfate prevented these teratogenic effects (Doherty et al, 1982). Post-implantation mortality was observed in the hamster.
B) At the time of this review, no data were available to assess the potential effects of exposure to this agent during lactation.
C) No information about possible male reproductive effects was found in available references at the time of this review.

0.2.21)

A) At the time of this review, no studies were found on the possible carcinogenic activity of sodium cyanide in humans.

0.2.22)

A) The odor of bitter almonds in expired breath or gastric contents of patients may not be detected by a significant portion of the population.

Laboratory Monitoring

Treatment Overview

0.4.2)

A) MANAGEMENT OF MILD TO MODERATE TOXICITY

1) Patients with even brief or small exposures should be monitored extremely closely for signs of deterioration. Supplemental oxygen should be administered immediately with continuous monitoring of vital signs. Establish intravenous access immediately. An antidote kit should available at the bedside. Worsening or severe acidosis, hypotension, seizures, dysrhythmias and coma indicate a more severe poisoning.

B) MANAGEMENT OF SEVERE TOXICITY

1) Elevated lactate, increased anion gap metabolic acidosis, and an elevated venous oxygen saturation all suggest a significant cyanide exposure. Manage airway early. Patients who are comatose or severely ill due to suspected cyanide poisoning should be administered a cyanide antidote kit. In addition, standard ACLS or PALS therapy should be provided to manage symptoms. Administer sodium bicarbonate for severe acidemia.

C) DECONTAMINATION

1) PREHOSPITAL: Prehospital activated charcoal can be considered for large ingestions in which there will be a delay in definitive healthcare; however, a poison center should initially be consulted.
2) HOSPITAL: DERMAL EXPOSURE: Remove clothes and wash the skin with water. Healthcare providers should use personal protective equipment if there could be a dermal exposure. Activated charcoal binds poorly to cyanide salts; however, the lethal dose is so small that the use of activated charcoal should be considered in a patient that presents with one hour of an oral ingestion

D) AIRWAY MANAGEMENT

1) Patients who are comatose or with altered mental status need early endotracheal intubation and mechanical ventilation.

E) ANTIDOTE

1) SUMMARY: A cyanide antidote, either hydroxocobalamin OR the sodium nitrite/sodium thiosulfate kit, should be administered to symptomatic patients. If cyanide toxicity develops concurrent with carbon monoxide poisoning (e.g., closed space fire), hydroxocobalamin is the preferred antidote. If that is not available, sodium thiosulfate may be used alone. Use of amyl nitrite or sodium nitrite will cause methemoglobinemia, further reducing oxygen carrying capacity.
2) HYDROXOCOBALAMIN

a) ADULT: Administer 5 g IV over 15 minutes. A second dose may be given (infused over 15 to 120 minutes) in patients with severe toxicity. PEDIATRIC: A dose of 70 mg/kg has been used. Hydroxocobalamin forms cyanocobalamin which is a nontoxic, water soluble metabolite that is eliminated in the urine. It is generally safer and easier to use than other antidotes (i.e., nitrite and thiosulfate kits). Sodium thiosulfate may also be administered with hydroxocobalamin, but it is not part of the kit. ADVERSE EFFECTS: Flushing is common. Hydroxocobalamin is bright red and causes discoloration of the skin, urine, and serum. It can also interfere with many colorimetric based tests.

3) CYANIDE ANTIDOTE KIT

a) An alternative, a sodium nitrite/sodium thiosulfate kit, is administered as follows: SODIUM NITRITE: ADULT: Administer 300 mg (10 mL of 3% solution) IV at a rate of 2.5 to 5 mL/min; PEDIATRIC (with normal hemoglobin concentration): 0.2 mL/kg of a 3% solution (6 mg/kg) IV at a rate of 2.5 to 5 mL/min, not to exceed 10 mL (300 mg). The dose may be lowered if the patient is severely anemic, but administration should not be delayed for laboratory results. Nitrites may also cause vasodilatory effects which may contribute to hypotension. A second dose, one-half of the first dose, may be administered 30 minutes later if there is inadequate clinical response. Use with caution if carbon monoxide poisoning is also suspected. SODIUM THIOSULFATE: 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. A second dose, one-half of the first dose, may be administered if signs of cyanide toxicity reappear. This agent enhances conversion of cyanide to thiocyanate which is eliminated in the urine. Patients with renal failure may need dialysis to eliminate thiocyanate. ALTERNATE ANTIDOTES: Kelocyanor(R) (dicobalt-EDTA) and 4-DMAP (4-dimethylaminophenol) are among the cyanide antidotes in clinical use outside the US.

F) METHEMOGLOBINEMIA

1) Blood methemoglobin levels should be monitored for 30 to 60 minutes following the sodium nitrite infusion to prevent severe toxicity. Initiate oxygen therapy. Treat with methylene blue if patient is symptomatic (usually at methemoglobin concentrations greater than 20% to 30% or at lower concentrations in patients with anemia, underlying pulmonary or cardiovascular disease). METHYLENE BLUE: INITIAL DOSE/ADULT OR CHILD: 1 mg/kg IV over 5 to 30 minutes; a repeat dose of up to 1 mg/kg may be given 1 hour after the first dose if methemoglobin levels remain greater than 30% or if signs and symptoms persist. NOTE: Methylene blue is available as follows: 50 mg/10 mL (5 mg/mL or 0.5% solution) single-dose ampules and 10 mg/1 mL (1% solution) vials. Additional doses may sometimes be required. Improvement is usually noted shortly after administration if diagnosis is correct. Consider other diagnoses or treatment options if no improvement has been observed after several doses. If intravenous access cannot be established, methylene blue may also be given by intraosseous infusion. Methylene blue should not be given by subcutaneous or intrathecal injection. NEONATES: DOSE: 0.3 to 1 mg/kg.

G) ENHANCED ELIMINATION

1) Antidotes increase elimination; however, the role of hemodialysis is uncertain.

H) PATIENT DISPOSITION

1) HOME CRITERIA: There is no role for home management of cyanide exposure.
2) OBSERVATION CRITERIA: Any exposure to cyanide salts or cyanide gas should be referred to a healthcare facility. Patients who remain asymptomatic with normal laboratory studies can be discharged after 6 hours.
3) ADMISSION CRITERIA: Any patient with symptomatic poisoning should be admitted to an intensive care unit.
4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing symptomatic patients.

I) PITFALLS

1) Treatment should not be delayed for laboratory results if a cyanide exposure is strongly suspected.

J) PHARMACOKINETICS

1) The volume of distribution is not completely known, but cyanide is widely distributed to organs and tissues. The half-life for conversion of a nonlethal dose of cyanide to thiocyanate is 20 to 60 minutes, but the elimination half-life is not completely known.

K) TOXICOKINETICS

1) The amount, duration of exposure, route of exposure and premorbid conditions of the patient will affect the time and severity of the poisoning. Symptoms typically begin within 5 minutes of a significant inhalational exposure and within 30 minutes of a significant oral exposure.

L) DIFFERENTIAL DIAGNOSIS

1) Carbon monoxide and hydrogen sulfide gas exposures may cause transient loss consciousness with apnea, coma, and acidosis. The differential of an elevated anion gap acidosis is otherwise extremely broad and consists of toxicologic and non-toxicologic causes.

0.4.3)

A) 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.
B) Administer 100% oxygen, establish secure large bore IV.
C) CYANIDE ANTIDOTE SUMMARY

1) A cyanide antidote, either hydroxocobalamin OR the sodium nitrite/sodium thiosulfate kit, should be administered to patients with symptomatic poisoning. If cyanide toxicity develops concurrent with carbon monoxide poisoning (e.g., closed space fire), hydroxocobalamin is the preferred antidote. If that is not available, sodium thiosulfate may be used alone. Use of amyl nitrite or sodium nitrite will cause methemoglobinemia, further reducing oxygen carrying capacity.

D) HYDROXOCOBALAMIN

1) ADULT: Administer 5 g IV over 15 minutes. A second dose may be given (infused over 15 to 120 minutes) in patients with severe toxicity. PEDIATRIC: A dose of 70 mg/kg has been used. Hydroxocobalamin forms cyanocobalamin which is a nontoxic, water soluble metabolite that is eliminated in the urine. It is generally safer and easier to use than other antidotes (i.e., nitrite and thiosulfate kits). Sodium thiosulfate may also be administered with hydroxocobalamin, but it is not part of the kit. ADVERSE EFFECTS: Flushing is common. Hydroxocobalamin is bright red and causes discoloration of the skin, urine, and serum. It can also interfere with many colorimetric based tests.

E) CYANIDE ANTIDOTE KIT

1) An alternative, a sodium nitrite/sodium thiosulfate kit, is administered as follows: SODIUM NITRITE: ADULT: Administer 300 mg (10 mL of 3% solution) IV at a rate of 2.5 to 5 mL/min; PEDIATRIC (with normal hemoglobin concentration): 0.2 mL/kg of a 3% solution (6 mg/kg) IV at a rate of 2.5 to 5 mL/min, not to exceed 10 mL (300 mg). The dose may be lowered if the patient is severely anemic, but administration should not be delayed for laboratory results. Nitrites may also cause vasodilatory effects which may contribute to hypotension. A second dose, one-half of the first dose, may be administered 30 minutes later if there is inadequate clinical response. Use with caution if carbon monoxide poisoning is also suspected. SODIUM THIOSULFATE: 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. A second dose, one-half of the first dose, may be administered if signs of cyanide toxicity reappear. This agent enhances conversion of cyanide to thiocyanate which is eliminated in the urine. Patients with renal failure may need dialysis to eliminate thiocyanate. ALTERNATE ANTIDOTES: Kelocyanor(R) (dicobalt-EDTA) and 4-DMAP (4-dimethylaminophenol) are among the cyanide antidotes in clinical use outside the US.

F) METHEMOGLOBINEMIA

0.4.4)

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.

0.4.5)

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. If cyanide toxicity develops concurrent with carbon monoxide poisoning (e.g., closed space fire), hydroxocobalamin is the preferred antidote. If that is not available, sodium thiosulfate may be used alone. Use of amyl nitrite or sodium nitrite will cause methemoglobinemia, further reducing oxygen carrying capacity.
5) HYDROXOCOBALAMIN

6) CYANIDE ANTIDOTE KIT

a) An alternative, a sodium nitrite/sodium thiosulfate kit, is administered as follows: SODIUM NITRITE: ADULT: Administer 300 mg (10 mL of 3% solution) IV at a rate of 2.5 to 5 mL/min; PEDIATRIC (with normal hemoglobin concentration): 0.2 mL/kg of a 3% solution (6 mg/kg) IV at a rate of 2.5 to 5 mL/min, not to exceed 10 mL (300 mg). The dose may be lowered if the patient is severely anemic, but administration should not be delayed for laboratory results. Nitrites may also cause vasodilatory effects which may contribute to hypotension. A second dose, one-half of the first dose, may be administered 30 minutes later if there is inadequate clinical response. SODIUM THIOSULFATE: 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. A second dose, one-half of the first dose, may be administered if signs of cyanide toxicity reappear. This agent enhances conversion of cyanide to thiocyanate which is eliminated in the urine. Patients with renal failure may need dialysis to eliminate thiocyanate. ALTERNATE ANTIDOTES: Kelocyanor(R) (dicobalt-EDTA) and 4-DMAP (4-dimethylaminophenol) are among the cyanide antidotes in clinical use outside the US.

7) METHEMOGLOBINEMIA

a) Blood methemoglobin levels should be monitored for 30 to 60 minutes following the sodium nitrite infusion to prevent severe toxicity. Treat with methylene blue if patient is symptomatic (usually at methemoglobin concentrations greater than 20% to 30% or at lower concentrations in patients with anemia, underlying pulmonary or cardiovascular disease). METHYLENE BLUE: INITIAL DOSE/ADULT OR CHILD: 1 mg/kg IV over 5 to 30 minutes; a repeat dose of up to 1 mg/kg may be given 1 hour after the first dose if methemoglobin levels remain greater than 30% or if signs and symptoms persist. NOTE: Methylene blue is available as follows: 50 mg/10 mL (5 mg/mL or 0.5% solution) single-dose ampules and 10 mg/1 mL (1% solution) vials. Additional doses may sometimes be required. Improvement is usually noted shortly after administration if diagnosis is correct. Consider other diagnoses or treatment options if no improvement has been observed after several doses. If intravenous access cannot be established, methylene blue may also be given by intraosseous infusion. Methylene blue should not be given by subcutaneous or intrathecal injection. NEONATES: DOSE: 0.3 to 1 mg/kg.

Range Of Toxicity

Clinical Effects

Genitourinary

3.10.3)

A) ANIMAL STUDIES

1) TESTIS DISORDER

a) TESTICULAR DEGENERATION - Subchronic dosing (12 mg of potassium cyanide injected subcutaneously for 28 doses during 6 weeks) caused degenerative changes in the testes of rats (Haguenoer et al, 1975).

Acid-Base

3.11.1)

A) Anion gap metabolic acidosis and lactic acidosis are evident following cyanide toxicity.

3.11.2)

A) ACIDOSIS

1) Elevated anion gap metabolic acidosis and elevated serum lactate levels are frequently found in cyanide poisoning (Hall & Rumack, 1986; Vogel et al, 1981).

Hematologic

3.13.1)

A) Venous blood may have a bright red color. Anemia has also been reported.

3.13.2)

A) ANEMIA

1) Anemia has also been reported (Gettler & St George, 1934).

B) ABNORMAL COLOR

1) VENOUS BLOOD - In acute cases of cyanide poisoning, the most specific pathologic finding is the bright red color of venous blood, evidence of the inability of tissue cells to utilize oxygen. Venous blood is only about 1 volume percent lower in oxygen content than arterial blood (Clayton & Clayton, 1982; (Proctor et al, 1988).

Dermatologic

3.14.1)

A) Cyanide has been said to be absorbed through intact skin. Itching, irritation, rash, and dermatitis may occur.
B) Cyanosis may be evident particularly at the premorbid stage of cyanide toxicity.

3.14.2)

A) SYSTEMIC DISEASE

1) DERMAL ABSORPTION - Cyanide has been said to be absorbed through intact skin and carries a "skin designation" for workplace exposures (ACGIH, 1986) ACGIH, 1989).

a) However, most cases of toxicity from dermal exposure have been due to industrial accidents with immersion in vats of cyanide solutions (Bismuth et al, 1984; Dodds & McKnight, 1985) or severe, large total body area burns with molten cyanide (Bourrelier & Paulet, 1971).

B) ERUPTION

1) IRRITATION - Dermal contact with sodium cyanide solutions can cause itching and irritation, probably because these solutions are alkaline (Proctor et al, 1988). Dermatoses has been described in chronically exposed workers (Sax & Lewis, 1987; Saia et al, 1970).

C) DISCOLORATION OF SKIN

1) The skin may be a bright pink color due to high concentrations of oxyhemoglobin in the venous return (HSDB , 1991).

D) DERMATITIS

1) CHRONIC EXPOSURE - Dermatitis, itching, scarlet rash and papules have been reported in workers in the electroplating industry (Finkel, 1983; HSDB , 1991).

3.14.3)

A) ANIMAL STUDIES

1) SYSTEMIC EFFECTS

a) RABBITS - In rabbits, cyanide fumigation powders were well absorbed through wet or mildly abraded skin, less so with dry intact skin (Ballantyne, 1988).
b) DOGS AND GUINEA PIGS - Hydrogen cyanide gas was absorbed through the skin of dogs and guinea pigs; the outcome was fatal at high enough concentrations (Walton & Witherspoon, 1926).

Summary Of Exposure

Vital Signs

3.3.1)

3.3.4)

A) HYPERTENSION - In the early stages of cyanide poisoning, increased vasoconstrictor tone results in an increased blood pressure and reflex slowing of the heart rate (HSDB , 1991).

3.3.5)

A) BRADYCARDIA - In the early stages of cyanide poisoning, increased vasoconstrictor tone results in an increased blood pressure and reflex slowing of the heart rate (HSDB , 1991).
B) TACHYCARDIA - Following the initial slowing of the heart rate, the pulse becomes rapid, weak, and sometimes irregular (HSDB , 1991).

Heent

3.4.1)

3.4.3)

A) MYDRIASIS - Dilated pupils are common in severe poisoning (Vogel et al, 1981).
B) FUNDUSCOPIC EXAMINATION - Retinal arteries and veins that appear equally red on funduscopic examination suggest the diagnosis (Buchanan et al, 1976).
C) EYE EXPOSURE - When solid particles or concentrated solutions of NaCN, KCN or HCN were instilled into rabbit eyes, the product was rapidly absorbed producing systemic toxicity and death.

1) Accidental eye contamination with industrial chemicals may produce systemic symptoms (Ballantyne, 1983). One case of corneal edema from exposure to hydrocyanic acid vapors has been reported (Grant & Schuman, 1993).
2) Animals exposed to cyanide fumigation powders experienced marked lacrimation, conjunctival hyperemia, and chemosis which developed into corneal opacification and iritis (Ballantyne, 1988).

D) BLINDNESS - Transient blindness has been reported in rare instances of sublethal cyanide poisoning (Grant & Schuman, 1993).
E) OPTIC NEURITIS - Damaged optic nerves have been observed in experimental animals injected with lethal or near lethal doses of cyanide; however, optic neuropathy has not been reported in chronic industrial exposure (Grant & Schuman, 1993).

1) Optic neuropathy has been ascribed to the high cyanide content of unprocessed cassava (Freeman, 1988).

3.4.4)

A) CHRONIC EXPOSURE - Functional hearing changes were described in a group of workers chronically exposed to cyanide (Saia et al, 1970).

3.4.5)

A) IRRITATION - Irritation of the nose leading to obstruction, bleeding, sloughs, and in some cases perforation of the septum has been reported in workers in the electroplating industry (Finkel, 1983; HSDB , 1991).

3.4.6)

A) BURNING SENSATION - A burning sensation in the mouth and throat may occur (Vogel et al, 1981).
B) HOARSENESS - Occurred with chronic exposure to cyanogen chloride (ACGIH, 1986; Grant, 1986).

Cardiovascular

3.5.1)

A) Tachycardia, bradycardia, hypertension, hypotension, cardiac dysrhythmias, EKG changes, and asystole may be observed.

3.5.2)

A) TACHYARRHYTHMIA

1) Tachycardia and hypertension may be seen in the initial phases of cyanide poisoning (Vogel et al, 1981).

B) BRADYCARDIA

1) Bradycardia and hypotension are seen in the late phases of cyanide poisoning (Hall & Rumack, 1986).

C) ELECTROCARDIOGRAM ABNORMAL

1) Erratic atrial and ventricular cardiac rhythms with varying degrees of atrioventricular block followed by asystole may be seen in severe cyanide poisoning (Hall & Rumack, 1986). ST-T segment elevation or depression may be noted (Cope, 1961).

a) Early EKG changes may include ectopic ventricular beats, atrial fibrillation, and abnormal QRS complex with T wave originating high on the R wave (HSDB , 1991).

D) PALPITATIONS

1) Palpitations have been described in workers chronically exposed to cyanide (Colle, 1972).

Respiratory

3.6.1)

A) Tachypnea, deep inspiratory gasps followed by hyperpnea, apnea, noncardiogenic pulmonary edema may be apparent.

3.6.2)

A) HYPERVENTILATION

1) Part of the initial presentation of cyanide poisoning may be hyperpnea and tachypnea (Hall & Rumack, 1986).

B) APNEA

1) Hypoventilation progressing to apnea may be seen in the later phases of cyanide poisoning and is a major cause of death (Vogel et al, 1981). Massive doses may result in sudden death from respiratory arrest without warning (HSDB , 1991).

C) ACUTE LUNG INJURY

1) Noncardiogenic pulmonary edema has been reported in cases of acute cyanide poisoning (Graham et al, 1977). Pulmonary edema can also occur with chronic cyanogen chloride exposure (Gosselin et al, 1984).

D) CYANOSIS

1) Cyanosis is generally a late finding and usually does not occur until circulatory collapse and apnea are evident; particularly at the premorbid stage of cyanide toxicity (Hall & Rumack, 1986).

E) DISORDER OF RESPIRATORY SYSTEM

1) CHRONIC EXPOSURE - Respiratory tract irritation, chest discomfort, effort dyspnea, and varying degrees of persistent rhinitis, nasal obstruction, and bleeding have been described in workers chronically exposed to cyanide (Proctor et al, 1988; Saia et al, 1970; Colle, 1972; Finkel, 1983).

Musculoskeletal

3.15.2)

A) SEQUELA

1) Permanent motor impairment may occur with chronic exposure (Baselt, 1988; Baselt & Cravey, 1989).

Endocrine

3.16.1)

A) Enlarged thyroid glands may occur. Thyroid dysfunction has been reported from chronic occupational exposure to cyanide.

3.16.2)

A) GOITER

1) Workers exposed to cyanide salts in heat treatment of metals reportedly developed enlarged thyroid glands. It has been suggested that absorption of cyanide dust and hydrogen cyanide, followed by metabolism to thiocyanate and failure to eliminate this caused the goiterogenic effect (HSDB , 1991).
2) Abnormal thyroid function tests have been reported following chronic cyanide exposure in the occupational setting (Blanc et al, 1985; Banerjee et al, 1997).

B) HYPERGLYCEMIA

1) INSULIN RESISTANCE occurred in a severely cyanide poisoned patient (Singh et al, 1989).

Reproductive

3.20.1)

3.20.2)

A) SODIUM CYANIDE

1) ANIMAL STUDIES

a) SODIUM CYANIDE - Sodium cyanide solution delivered by constant infusion to pregnant Golden Hamsters at doses from 0.126 to 0.1295 mmol/kg/hour between days 6 and 9 of gestation caused a high incidence of both resorptions and malformations in the offspring (Doherty et al, 1982).

1) Neural tube defects (exencephaly, encephalocele) were the most common malformations. Hydropericardium and crooked tails were also noted (Doherty et al, 1982).
2) Concomitant infusion of sodium thiosulfate prevented both maternal signs of toxicity and the teratogenic effects of the sodium cyanide infusion (Doherty et al, 1982).
3) Fetotoxicity and specific developmental abnormalities in the musculoskeletal, cardiovascular, and central nervous systems were observed in experimental hamster studies (RTECS , 1991).

B) CYANIDE

1) CYANIDE has been linked with congenital cretinism (deformities, dwarfism, and mental retardation) 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). Cyanide has been teratogenic and has affected the fertility of laboratory animals.
2) Chemicals which liberate cyanide are also known to be teratogenic in animals. This is especially true of the aliphatic nitriles (Willhite et al, 1981; Smith, 1981), including acrylonitrile (Buchter & Peter, 1984) and acetonitrile (Willhite, 1983).

C) ACETONITRILE

1) ANIMAL STUDIES

a) Pregnant hamsters exposed to acetonitrile by either inhalation of 5000 to 8000 ppm or given 100 to 400 milligrams/kilogram orally or intraperitoneally delivered offspring with severe axial skeletal disorders (Willhite, 1983).

1) Injections of sodium thiosulfate antagonized the teratogenic effects (Willhite, 1983). Elevated cyanide and thiocyanate levels were found in all tissues 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).

D) LAETRILE

1) ANIMAL STUDIES

a) Laetrile given orally to pregnant hamsters produced skeletal malformations in the offspring and increased levels of tissue cyanide (Willhite, 1982). Intravenous administration of laetrile produced neither effect (Willhite, 1982).

1) Sodium thiosulfate administration protected the fetus from teratogenic effects (Willhite, 1982). These data suggested that the teratogenic effects were due to cyanide released in vivo from oral laetrile dosing (Willhite, 1982).

E) CASSAVA

1) ANIMAL STUDIES

a) Rats fed cassava powder (containing high concentrations of a cyanogenic glycoside) as 50% to 80% of their diet during the first 5 days of pregnancy showed a low incidence of limb defects, open eye defects, microcephaly, and fetal growth retardation in fetuses collected on day 20 of pregnancy (Singh, 1981).

F) ACRYLONITRILE

1) ANIMAL STUDIES

a) Intraperitoneal injections of acrylonitrile or propionitrile to hamsters on day 8 of gestation resulted in exencephaly, encephaloceles, and rib abnormalities in the offspring (Willhite et al, 1981).

1) Sodium thiosulfate injections protected the fetus from these effects, except at larger nitrile doses where thiosulfate protected the dam against overt poisoning but did not protect the fetus against malformations (Willhite et al, 1981).
2) The teratogenic effects of both nitriles may be related to the metabolic release of cyanide after absorption (Willhite et al, 1981).

3.20.3)

A) STILLBIRTH

1) Post-implantation mortality was observed experimentally in the hamster (RTECS , 1991).

3.20.4)

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 lactation.

Carcinogenicity

3.21.1)

A) IARC Carcinogenicity Ratings for CAS143-33-9 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):

1) Not Listed

3.21.2)

A) At the time of this review, no studies were found on the possible carcinogenic activity of sodium cyanide in humans.

3.21.3)

A) CARCINOMA

1) RELATED COMPOUNDS -

a) Acrylonitrile has carcinogenic properties in some species of experimental animals and has been suggested to be associated with a slight increase in deaths from lung cancer and other malignancies in humans (Buchter & Peter, 1984; Geiger et al, 1983).

1) Whether the metabolic release of cyanide after absorption plays any role in carcinogenesis is unknown. In isolated cell preparations, the release of cyanide does not appear to play a role in cell death (Geiger et al, 1983).

B) LACK OF EFFECT

1) SODIUM CYANIDE -

a) There are no reports of carcinogenicity in humans or experimental animals due to cyanide itself.

3.21.4)

A) CARCINOMA

1) RELATED COMPOUNDS -

Genotoxicity

Neurologic

3.7.1)

3.7.2)

A) NEUROPATHY

1) SUMMARY - Neurologic signs include syncope, headache or CNS stimulation, dizziness, and vertigo. Coma and seizures are common in severe poisoning. Parkinsonian syndrome may be a sequelae.
2) CHRONIC EXPOSURE - Chronic exposure may produce headache, vertigo, tremors, weakness, fatigue, dizziness, confusion, functional changes in hearing, motor aphasia, optic neuropathy, seizures, paresis/hemiparesis, myelopathy, and permanent mental impairment (Blanc et al, 1985; Proctor et al, 1988; Baselt, 1988; Baselt & Cravey, 1989; Sax & Lewis, 1987; Saia et al, 1970).

B) CENTRAL NERVOUS SYSTEM FINDING

1) Headache may be an early sign of cyanide poisoning (Vogel et al, 1981). Frequent headaches, vertigo, fatigue, poor appetite, and sleeping disturbances have been described in workers chronically exposed to cyanide (Saia et al, 1970; Colle, 1972).
2) Optic neuropathy, sensory ataxia, and spastic paraparesis with myelopathy of the corticospinal tracts have been ascribed to the high cyanide content of unprocessed cassava (Casadei et al, 1990; Cliff et al, 1986; Freeman, 1988).
3) Elevated urinary thiocyanate levels occurred among the afflicted children, who were rendered more at risk because of malnutrition and inadequate supply of sulfur-containing amino acids which are essential for cyanide detoxification (Casadei et al, 1990; Freeman, 1988). However, no studies were made to rule out other possible causes, such as consumption of lentyl lathyrus sativa.

C) CENTRAL STIMULANT ADVERSE REACTION

1) CNS stimulation with varied presentations from anxiety to agitation and combative behavior may be seen in the early stages of cyanide poisoning (Vogel et al, 1981).

D) COMA

1) Coma is common in severe poisoning (Hall & Rumack, 1986; Vogel et al, 1981).

E) SEIZURE

1) Seizures are common in severe cyanide poisoning (Hall & Rumack, 1986). The violent seizures are epileptiform or tonic and are usually generalized (Hall & Rumack, 1986; HSDB , 1991).
2) Seizures have been reported from chronic occupational exposure (Finkel, 1983).

F) PARALYSIS

1) CASE REPORT - Opisthotonos, trismus, and paralysis were reported in one case of cyanide poisoning (De Busk & Seidl, 1969).

G) EXTRAPYRAMIDAL DISEASE

1) CASE REPORT - An 18-year-old patient who ingested between 975 and 1,300 mg of potassium cyanide and survived his cyanide overdose developed a Parkinsonian syndrome over the following weeks after his recovery. The patient was treated with anticholinergic drugs. One month later no changes were observed (Uitti et al, 1985).
2) CASE REPORT - A 46-year-old woman developed progressive parkinsonism over a five-year period after acute cyanide poisoning. Drooling and dysphagia increased over this time, and marked tongue and mouth dystonia developed. Apraxia of eyelid opening was also apparent. Some improvement was noted with trihexyphenidyl treatment (Carella et al, 1988).
3) CASE REPORT - Parkinsonism developed progressively over 3 weeks after acute ingestion of 1,500 mg of potassium cyanide. Slowed gait, masked facies, hypophonia, mild rigidity, and minimal tremor were noted. Damage was permanent, was not evident on CT or MRI scan at 6 months, but was evident on MRI at 12 months postingestion. There was no improvement with levodopa (Rosenberg et al, 1989).
4) CASE REPORT - A 39-year-old man who had suffered from long term psychosis attempted suicide by swallowing an unknown amount of sodium cyanide. CT scan of the head was normal on admission. The patient developed a parkinsonian syndrome with severe dystonia. A follow-up CT scan of the head showed mild cortical atrophy and bilateral lucencies in the putamen and external globus pallidus (Grandas et al, 1989).
5) CASE REPORT - A 28-year-old man developed severe parkinsonian symptoms, micrographia, hypersalivation, and bilateral basal ganglia abnormalities on MRI after ingestion of 800 mg of potassium cyanide (Feldman & Feldman, 1990). With intensive medical and psychotherapeutic intervention, he survived, but had persistent deficits.
6) CASE REPORT - A severe dystonia syndrome, with slurred speech, involuntary athetoid movements of the neck, trunk, and limbs, generalized dystonia, hyperextension of the lower limbs and trunk, and occasional opisthotonoid posturing, developed a few days after apparent full recovery from ingestion of 1 gram of potassium cyanide in a 16-year-old man (Valenzuela et al, 1992):

a) He responded to levodopa 3600 mg/day, which was given for 38 days. Follow-up 21 years later showed mild dystonia, athetoid hand movements, and symmetrical putamen hypodensities on CT scan.

H) SEQUELA

1) Most victims of acute poisoning either die acutely or fully recover. However, cases of patients developing neurological sequelae such as personality changes, paranoid psychosis, memory deficits, extrapyramidal syndromes, and Parkinsonian syndrome have been reported (Jouglard et al, 1971; Jouglard et al, 1974; Uitti et al, 1985; Borgohain et al, 1995; Rosenow et al, 1995; Kales et al, 1997).

3.7.3)

A) ANIMAL STUDIES

1) ENCEPHALOPATHY

a) Demyelinating lesions have been described in the brain in exposed experimental animals (Gosselin et al, 1984).

Gastrointestinal

3.8.1)

A) Nausea, vomiting, and abdominal pain may occur.

3.8.2)

A) DRUG-INDUCED GASTROINTESTINAL DISTURBANCE

1) Nausea, vomiting, and abdominal pain may occur, especially after ingestion of cyanide salts (Hall & Rumack, 1986; Vogel et al, 1981).

a) The odor of bitter almonds in expired breath or gastric contents of patients may not be detected by a significant portion of the population (Hall & Rumack, 1986; HSDB , 1991).

2) CHRONIC EXPOSURE - Nausea and occasional vomiting have been described in workers chronically exposed to cyanide (Colle, 1972; Saia et al, 1970).

B) GASTRIC ULCER

1) Ingestion of cyanide salts can cause irritation or corrosion of the esophageal or gastric mucosa (HSDB, 1990; (Jouglard et al, 1974).

Laboratory Monitoring

Monitoring Parameters Levels

4.1.1)

A) Laboratory tests should include CBC, arterial and venous blood gases, serum electrolytes and lactate, assessment of renal function, chest x-ray (following inhalation exposure or if the patient has abnormal respiratory signs and symptoms), and whole blood cyanide levels.
B) If respiratory tract irritation or respiratory depression is evident, monitor arterial blood gases, chest x-ray, and pulmonary function tests.
C) Whole blood cyanide levels may be useful in confirming the diagnosis. However, it is not clinically useful unless the results are available within a reasonable time. Treatment should be initiated based on clinical judgement.

4.1.2)

A) BLOOD/SERUM CHEMISTRY

1) Fatal blood cyanide levels after oral ingestion

a) Ballantyne et al (1974) reported 34 cases

AVERAGE LEVEL	RANGE
12.4 mg/L (mcg/mL) (1.2 mg%) (SI = 476.9 mcmol/L)	1.1 to 53.1 mg/L (mcg/mL) (0.1 to 5.3 mg%) (SI = 42.3 to 2042 mcmol/L)

b) Rehlung (1967) reported 32 cases

AVERAGE LEVEL	RANGE
36.5 mg/L (mcg/mL)	0.4 to 230 mg/L (mcg/mL)
(3.7 mg%)	(0.04 to 23 mg%)
(SI = 1403.8 mcmol/L)	(SI = 15.4 to 8846 mcmol/L)

2) Blood cyanide levels and associated symptoms (Graham et al, 1977):

a) No symptoms: Less than 0.2 mg/L (mcg/mL)

No symptoms:	Less than 0.2 mg/L (mcg/mL)
.	(0.02 mg%)
.	(SI = 7.7 mcmol/L)

b) Flushing and tachycardia: 0.5-1.0 mg/L (mcg/mL)

Flushing and tachycardia:	0.5-1.0 mg/L (mcg/mL)
.	(0.05-0.1 mg%)
.	(SI = 19.2 to 38.5 mcmol/L)

c) Obtundation: 1.0-2.5 mg/L (mcg/mL)

Obtundation:	1.0-2.5 mg/L (mcg/mL)
.	(0.1-0.25 mg%)
.	(SI = 38.5 to 96.1 mcmol/L)

d) Coma and respiratory depression: Greater than 2.5 mg/L (mcg/mL)

Coma and respiratory depression:	Greater than 2.5 mg/L (mcg/mL)
.	(0.25 mg%)
.	(SI = 96.1 mcmol/L)

e) Death: Greater than 3 mg/L (mcg/mL)

Death:	Greater than 3 mg/L (mcg/mL)
.	0.3 mg%
.	(SI = 115.4 mcmol/L)

3) Blood cyanide levels associated with smoking (Clark et al, 1981):

a) Smokers: Up to 0.5 mg/L (mcg/mL)

Smokers:	Up to 0.5 mg/L (mcg/mL)
.	(SI = 19.2 mcmol/L)

4) Blood cyanide levels in smoke inhalation victims

a) (Hart et al, 1985)

Patient 1	3.9 mcg/mL	(expired)
Patient 2	1.8 mcg/mL	(survived)
Patient 3	0.35 mcg/mL	(survived)
Patient 4	0.42 mcg/mL	(survived)
Patient 5	1.65 mcg/mL	(survived)

b) (Jones et al, 1987)

Case 1	1.8 mcg/mL	(expired)
Case 2	2.4 mcg/mL	(expired)
Case 3	1.4 mcg/mL	(expired)
Case 4	1.5 mcg/mL	(expired)

B) ACID/BASE

1) ARTERIAL BLOOD GASES - Monitor oxygenation and acid-base status in patients with severe poisoning.
2) CHERRY RED BLOOD COLORATION - Is not always seen, but has been reported (Espinoza et al, 1992).
3) INTERPRETATION OF LABORATORY VALUES -

a) The following set of laboratory values suggest poisoning with an agent that inhibits oxidative phosphorylation (ie, cyanide, hydrogen sulfide) (Hall & Rumack, 1986).

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).
2) Serum electrolytes: Anion gap metabolic acidosis [Na - (Cl + CO2)] is invariably present in serious cyanide poisoning. The normal anion gap is 12 to 16 milliequivalents/liter.
3) Serum lactate levels may be useful in monitoring the severity of poisoning and the efficacy of treatment (Vogel et al, 1981).

a) Serum Lactate: Lactate concentrations may be elevated. The normal lactate range is 0.6 to 1.8 milliequivalents/liter (0.6 to 1.8 millimoles/liter).

4) Arterial blood gas: Metabolic acidosis and respiratory alkalosis may be evident.
5) Arterial pO2 usually remains normal until the stage of apnea or until the terminal stages of the poisoning if supplemental oxygen and assisted ventilation are provided.
6) Fall in oxygen consumption accompanying cyanide poisoning can allow for increased oxygen content of peripheral and mixed venous blood. The presence of bright red venous blood or retinal venins suggests the possibility of cyanide poisoning.
7) 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.
8) Invasive hemodynamic and metabolic monitoring may reveal changes compatible with sepsis (eg; metabolic acidosis, hypotension, fall in oxygen consumption, rise in mixed venous oxygen content, and a fall in arterial-venous oxygen gradient).
9) RBC or whole blood cyanide levels may be useful to CONFIRM cyanide poisoning.

C) HEMATOLOGIC

1) It is highly recommended that total hemoglobin and methemoglobin concentrations be rapidly measured following the administration of intravenous sodium nitrite (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 patients. Methemoglobin levels should not exceed 30% during treatment with sodium nitrite (Hall & Rumack, 1986).

4.1.3)

A) URINARY LEVELS

1) Cyanide and thiocyanate levels can also be measured in timed urine collections which may yield useful information on cyanide clearance. However, such testing is seldom done clinically; it is more a research tool.
2) URINARY CYANIDE EXCRETION - 24-hour urinary excretion has been measured after chronic exposure to cyanide fumes and cyanide aerosols (Chandra, 1980):

WORKERS (n=23)	Cyanide mcg/100 mL
WORKERS (n=23)	RANGE	MEAN
Smokers (n=8)	0 to 18	6.23
Nonsmokers (n=15)	0 to 14.67	5.4
Controls (n=20)	.
Smokers (n=10)	0 to 8.45	3.2
Nonsmokers (n=10)	0 to 4.36	2.15

Radiographic Studies

1) If respiratory tract irritation is present, monitor chest x-ray.

1) MRI studies may be useful in identifying the location and extent of injury in patients with cyanide-induced parkinsonian syndrome (Feldman & Feldman, 1990; Grandas et al, 1989; Rosenberg et al, 1989; Carella et al, 1988).

Methods

1) Cyanide can be measured chemically by several methods. Blood cyanide levels may be useful in confirming the diagnosis. However, it is not clinically useful unless the results are available within a reasonable time. Treatment should be initiated based on clinical judgement.
2) SPECTROSCOPY - Cyanide can be liberated from biological specimens by acidification, followed by absorption in alkali and interaction with chromophoric reagents for quantification by absorbance spectroscopy (HSDB, 1990).
3) GAS CHROMATOGRAPHY - Cyanide can also be measured in biological fluids by gas chromatography following conversion to cyanogen chloride by reaction with chloramine-T (HSDB, 1990).
4) An ion-specific electrode method has sometimes been used for measuring cyanide in biological specimens (Bismuth et al, 1984).
5) A fluorometric diffusion method based on detection of fluorescing p-benzoquinone derivatives can be used to determine cyanide in biological fluids (HSDB, 1990).
6) An automated microdistillation assay technique has been developed that can provide whole blood and plasma cyanide levels in less than one-half hour (Groff et al, 1985) but is not yet generally available.
7) PAPER STRIP - A semiquantitative paper strip method (CYANTESMO, available from Gallard-Schlesinger, Carle Place, NY) is sensitive to concentrations of 0.2 mg/L of cyanide in whole blood. A 5-hour incubation time is required to rule out false negative results, but concentrations of greater than 1 mg/L require only 30 to 60 minutes to be detected (Fligner et al, 1992).
8) GASTRIC ASPIRATE EXAMINATION - Cyanide presence in gastric aspirate can be detected by adding a few crystals of FeSO4 to 5 to 10 mL of the aspirate.

a) Add 4 to 5 drops of 20% NaOH, then boil and cool the solution.
b) Adding 8 to 10 drops of 10% HCl will result in a greenish-blue precipitate if cyanide is present.
c) Salicylates may interfere with this test, resulting in an initial blue-green color that converts to a purple color (Graham et al, 1977).

9) STABILITY DURING STORAGE - Up to 50% of cyanide was lost within 12 minutes after spiking blood in an unstoppered container. Loss of cyanide from forensic specimens may be minimized, but not eliminated by rapid analysis after death, collection of blood from a closed source (subclavian vein), storage in a fluoride-oxalate tube with minimal dead space and sealed immediately, and storage frozen at minus 20 degrees C (Bright et al, 1990).

Treatment

Life Support

Patient Disposition

6.3.1)

6.3.1.1) ADMISSION CRITERIA/ORAL

A) All symptomatic patients should be admitted to the hospital following a cyanide exposure. Whenever the cyanide antidote kit is used, the patient should be admitted to the intensive care unit.

6.3.1.2) HOME CRITERIA/ORAL

A) There is no role for home management of cyanide exposure.

6.3.1.3) CONSULT CRITERIA/ORAL

A) Consult a poison center or medical toxicologist for assistance in managing symptomatic patients.

6.3.1.5) OBSERVATION CRITERIA/ORAL

A) Asymptomatic patients with a history of significant cyanide exposure but who are asymptomatic should be observed closely in the hospital. Vascular access should be established, laboratory evaluations performed, and the cyanide antidote kit or hydroxocobalamin ready at the bedside. If laboratory evaluations are normal and the patient remains asymptomatic for at least 8 hours, they may be discharged from the hospital with appropriate follow-up instructions.

Monitoring

Oral Exposure

6.5.1)

A) SUMMARY

1) In symptomatic patients, institute emergency measures including basic life support and administration of cyanide antidote kit (if readily available) before performing the following steps.

B) ACTIVATED CHARCOAL

1) Absorption of cyanide is rapid and charcoal may only be beneficial if administered immediately after ingestion.
2) Immediate administration of a large dose of superactivated charcoal (4 g/kg) to rats given an oral lethal dose of potassium cyanide (35 to 40 mg/kg) prevented lethality. Eight of 26 treated animals died compared to 25 of 26 untreated animals.
3) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION

a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).

1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).

4) CHARCOAL DOSE

a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).

1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).

b) ADVERSE EFFECTS/CONTRAINDICATIONS

1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).

6.5.2)

A) SUMMARY

1) In symptomatic patients, institute emergency measures basic life support and administration of cyanide antidote kit (if readily available) before performing the following steps.

B) ACTIVATED CHARCOAL

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

b) ADVERSE EFFECTS/CONTRAINDICATIONS

C) 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.

6.5.3)

A) OXYGEN

1) Administer 100% humidified supplemental with assisted ventilation as required.

a) Oxygen may reverse the cyanide-cytochrome oxidase complex and facilitate the conversion to thiocyanate following thiosulfate administration (Graham et al, 1977).
b) Animal data suggests that supplemental oxygen as adjunct treatment of cyanide poisoning increases the overall antidotal efficacy of sodium nitrite and sodium thiosulfate (Burrows & Way, 1977) (Way et al, 1966)(Sheehy & Way, 1968).

B) FLUID/ELECTROLYTE BALANCE REGULATION

1) Establish secure intravenous access; consider obtaining at least two intravenous lines. Administer crystalloids and vasopressors for hypotension. Administer sodium bicarbonate according to arterial blood gases and serum bicarbonate.

C) CYANIDE ANTIDOTE

1) SUMMARY

a) A cyanide antidote, either hydroxocobalamin OR the sodium nitrite/sodium thiosulfate kit, should be administered to patients with symptomatic poisoning. If cyanide toxicity develops concurrent with carbon monoxide poisoning (e.g., closed space fire), hydroxocobalamin is the preferred antidote. If that is not available, sodium thiosulfate may be used alone. Use of amyl nitrite or sodium nitrite will cause methemoglobinemia, further reducing oxygen carrying capacity.

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) Hydroxocobalamin, 5 to 20 grams administered intravenously, has been shown to be effective, as sole antidotal therapy, for acute cyanide poisoning following cyanide salt ingestion or inhalation (Borron et al, 2007)
h) 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).
i) 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).
j) According to antidote stocking guidelines, hydroxocobalamin was preferred over the conventional cyanide antidote kit due to its wider indications, ease of use, and anticipated safety in widespread use. It can safely be used in patients with smoke inhalation (None Listed, 2008).
k) In cases of cyanide ingestion, both the nitrite/thiosulfate combination and hydroxocobalamin seem to be effective antidotes. Hydroxocobalamin offers an improved safety profile for children and pregnant women, as well as patients suffering from cyanide poisoning in conjunction with smoke inhalation (Shepherd & Velez, 2008). Patients who are exposed to cyanide in house fires may have high carbon monoxide levels. Inducing methemoglobinemia with nitrites may further impair oxygen carrying capacity.
l) Some authors advocate combined hydroxocobalamin-thiosulfate therapy because of possible synergy of complementary mechanisms (Kerns et al, 2008).

3) CYANIDE ANTIDOTE KIT

a) OBTAIN AND PREPARE for administration a CYANIDE ANTIDOTE KIT, consisting of sodium nitrite and sodium thiosulfate.
b) Antidotes should be administered in patients who are clinically symptomatic (i.e., unstable vital signs, acidosis, impaired consciousness, seizures, or coma).
c) SODIUM NITRITE

1) INDICATION

a) Sodium nitrite should be given initially and administered as soon as vascular access is established.
b) 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.
c) 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).

2) ADULT DOSE

a) 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.
b) 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).

3) PEDIATRIC DOSE

a) 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).
b) 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, 1970a).
c) 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, 1970a):

1) Hemoglobin: 8 g/dL - Initial 3% sodium nitrite dose: 0.22 mL/kg (6.6 mg/kg)
2) Hemoglobin: 10 g/dL - Initial 3% sodium nitrite dose: 0.27 mL/kg (8.7 mg/kg)
3) Hemoglobin: 12 g/dL (average child) - Initial 3% sodium nitrite dose: 0.33 mL/kg (10 mg/kg)
4) Hemoglobin: 14 g/dL - Initial 3% sodium nitrite dose: 0.39 mL/kg (11.6 mg/kg)

4) 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.
5) 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.
6) Excessive methemoglobinemia and hypotension are potential complications of nitrite therapy.
7) In individuals with G6PD deficiency, therapy with methemoglobin-inducing agents is contraindicated because of the likelihood of serious hemolysis.

d) SODIUM THIOSULFATE

1) 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.
2) 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).
3) DOSE

a) 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).
b) 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).
c) Sodium thiosulfate is usually used in combination with sodium nitrite but may be used alone (Prod Info sodium thiosulfate IV injection, 2003).
d) 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)
e) 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).
f) 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) ACIDOSIS

1) METABOLIC ACIDOSIS: Treat severe metabolic acidosis (pH less than 7.1) with sodium bicarbonate, 1 to 2 mEq/kg is a reasonable starting dose(Kraut & Madias, 2010). Monitor serum electrolytes and arterial or venous blood gases to guide further therapy.
2) Acidosis may be difficult to correct prior to administration of antidotes in serious cyanide poisoning cases (Hall & Rumack, 1986).

E) SEIZURE

1) SUMMARY

a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).

2) DIAZEPAM

a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .

3) NO INTRAVENOUS ACCESS

a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).

4) LORAZEPAM

a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).

5) PHENOBARBITAL

a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).

6) OTHER AGENTS

a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):

1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).

7) PHENYTOIN/FOSPHENYTOIN

a) Benzodiazepines and/or barbiturates are preferred to phenytoin or fosphenytoin in the treatment of drug or withdrawal induced seizures (Wallace, 2005).
b) PHENYTOIN

1) PHENYTOIN INTRAVENOUS PUSH VERSUS INTRAVENOUS INFUSION

a) Administer phenytoin undiluted, by very slow intravenous push or dilute 50 mg/mL solution in 50 to 100 mL of 0.9% saline.
b) ADULT DOSE: A loading dose of 20 mg/kg IV; may administer an additional 5 to 10 mg/kg dose 10 minutes after loading dose. Rate of administration should not exceed 50 mg/minute (Brophy et al, 2012).
c) PEDIATRIC DOSE: A loading dose of 20 mg/kg, at a rate not exceeding 1 to 3 mg/kg/min or 50 mg/min, whichever is slower (Loddenkemper & Goodkin, 2011; Prod Info Dilantin(R) intravenous injection, intramuscular injection, 2013).
d) CAUTIONS: Administer phenytoin while monitoring ECG. Stop or slow infusion if dysrhythmias or hypotension occur. Be careful not to extravasate. Follow each injection with injection of sterile saline through the same needle (Prod Info Dilantin(R) intravenous injection, intramuscular injection, 2013).
e) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over next 12 to 24 hours for maintenance of therapeutic concentrations. Therapeutic concentrations of 10 to 20 mcg/mL have been reported (Prod Info Dilantin(R) intravenous injection, intramuscular injection, 2013).

c) FOSPHENYTOIN

1) ADULT DOSE: A loading dose of 20 mg phenytoin equivalent/kg IV, at a rate not exceeding 150 mg phenytoin equivalent/minute; may give additional dose of 5 mg/kg 10 minutes after the loading infusion (Brophy et al, 2012).
2) CHILD DOSE: 20 mg phenytoin equivalent/kg IV, at a rate of 3 mg phenytoin equivalent/kg/minute, up to a maximum of 150 mg phenytoin equivalent/minute (Loddenkemper & Goodkin, 2011).
3) CAUTIONS: Perform continuous monitoring of ECG, respiratory function, and blood pressure throughout the period where maximal serum phenytoin concentrations occur (about 10 to 20 minutes after the end of fosphenytoin infusion) (Prod Info CEREBYX(R) intravenous injection, 2014).
4) SERUM CONCENTRATION MONITORING: Monitor serum phenytoin concentrations over the next 12 to 24 hours; therapeutic levels 10 to 20 mcg/mL. Do not obtain serum phenytoin concentrations until at least 2 hours after infusion is complete to allow for conversion of fosphenytoin to phenytoin (Prod Info CEREBYX(R) intravenous injection, 2014).

8) RECURRING SEIZURES

a) If seizures are not controlled by the above measures, patients will require endotracheal intubation, mechanical ventilation, continuous EEG monitoring, a continuous infusion of an anticonvulsant, and may require neuromuscular paralysis and vasopressor support. Consider continuous infusions of the following agents:

1) MIDAZOLAM: ADULT DOSE: An initial dose of 0.2 mg/kg slow bolus, at an infusion rate of 2 mg/minute; maintenance doses of 0.05 to 2 mg/kg/hour continuous infusion dosing, titrated to EEG (Brophy et al, 2012). PEDIATRIC DOSE: 0.1 to 0.3 mg/kg followed by a continuous infusion starting at 1 mcg/kg/minute, titrated upwards every 5 minutes as needed (Loddenkemper & Goodkin, 2011).
2) PROPOFOL: ADULT DOSE: Start at 20 mcg/kg/min with 1 to 2 mg/kg loading dose; maintenance doses of 30 to 200 mcg/kg/minute continuous infusion dosing, titrated to EEG; caution with high doses greater than 80 mcg/kg/minute in adults for extended periods of time (ie, longer than 48 hours) (Brophy et al, 2012); PEDIATRIC DOSE: IV loading dose of up to 2 mg/kg; maintenance doses of 2 to 5 mg/kg/hour may be used in older adolescents; avoid doses of 5 mg/kg/hour over prolonged periods because of propofol infusion syndrome (Loddenkemper & Goodkin, 2011); caution with high doses greater than 65 mcg/kg/min in children for extended periods of time; contraindicated in small children (Brophy et al, 2012).
3) PENTOBARBITAL: ADULT DOSE: A loading dose of 5 to 15 mg/kg at an infusion rate of 50 mg/minute or lower; may administer additional 5 to 10 mg/kg. Maintenance dose of 0.5 to 5 mg/kg/hour continuous infusion dosing, titrated to EEG (Brophy et al, 2012). PEDIATRIC DOSE: A loading dose of 3 to 15 mg/kg followed by a maintenance dose of 1 to 5 mg/kg/hour (Loddenkemper & Goodkin, 2011).
4) THIOPENTAL: ADULT DOSE: 2 to 7 mg/kg, at an infusion rate of 50 mg/minute or lower. Maintenance dose of 0.5 to 5 mg/kg/hour continuous infusing dosing, titrated to EEG (Brophy et al, 2012)

b) Endotracheal intubation, mechanical ventilation, and vasopressors will be required (Brophy et al, 2012) and consultation with a neurologist is strongly advised.
c) Neuromuscular paralysis (eg, rocuronium bromide, a short-acting nondepolarizing agent) may be required to avoid hyperthermia, severe acidosis, and rhabdomyolysis. If rhabdomyolysis is possible, avoid succinylcholine chloride, because of the risk of hyperkalemic-induced cardiac dysrhythmias. Continuous EEG monitoring is mandatory if neuromuscular paralysis is used (Manno, 2003).

F) METHEMOGLOBINEMIA

1) CAUSE

a) The goal of nitrite therapy has been 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) Clinically significant excessive methemoglobinemia has rarely occurred following sodium nitrite therapy for cyanide poisoning. It usually occurs in children receiving excessive nitrite doses. Intravenous sodium nitrite administered as a 3% solution over 15 to 20 minutes induces approximately 7% to 14% methemoglobin (Kirk et al, 1993).

2) TREATMENT

a) If excessive methemoglobinemia occurs, some authors have suggested that methylene blue should not be used because it could cause release of cyanide from the cyanmethemoglobin complex. Such authors have suggested that emergency exchange transfusion is the treatment of choice (Berlin, 1970). Hyperbaric oxygen therapy could be used to support the patient while preparations for exchange transfusion are being made.
b) 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). There is some controversy over whether or not the induction of methemoglobinemia is the sodium nitrite mechanism of action in cyanide poisoning. As long as intensive care monitoring and further antidote doses (if required) are available, methylene blue can most likely be safely administered in this setting.
c) SUMMARY

1) Determine the methemoglobin concentration and evaluate the patient for clinical effects of methemoglobinemia (ie, dyspnea, headache, fatigue, CNS depression, tachycardia, metabolic acidosis). Treat patients with symptomatic methemoglobinemia with methylene blue (this usually occurs at methemoglobin concentrations above 20% to 30%, but may occur at lower methemoglobin concentrations in patients with anemia, or underlying pulmonary or cardiovascular disorders). Administer oxygen while preparing for methylene blue therapy.

d) METHYLENE BLUE

1) INITIAL DOSE/ADULT OR CHILD: 1 mg/kg IV over 5 to 30 minutes; a repeat dose of up to 1 mg/kg may be given 1 hour after the first dose if methemoglobin levels remain greater than 30% or if signs and symptoms persist. NOTE: Methylene blue is available as follows: 50 mg/10 mL (5 mg/mL or 0.5% solution) single-dose ampules (Prod Info PROVAYBLUE(TM) intravenous injection, 2016) and 10 mg/1 mL (1% solution) vials (Prod Info methylene blue 1% intravenous injection, 2011). REPEAT DOSES: Additional doses may be required, especially for substances with prolonged absorption, slow elimination, or those that form metabolites that produce methemoglobin. NOTE: Large doses of methylene blue may cause methemoglobinemia or hemolysis (Howland, 2006). Improvement is usually noted shortly after administration if diagnosis is correct. Consider other diagnoses or treatment options if no improvement has been observed after several doses. If intravenous access cannot be established, methylene blue may also be given by intraosseous infusion. Methylene blue should not be given by subcutaneous or intrathecal injection (Prod Info methylene blue 1% intravenous injection, 2011; Herman et al, 1999). NEONATES: DOSE: 0.3 to 1 mg/kg (Hjelt et al, 1995).
2) CONTRAINDICATIONS: G-6-PD deficiency (methylene blue may cause hemolysis), known hypersensitivity to methylene blue, methemoglobin reductase deficiency (Shepherd & Keyes, 2004)
3) FAILURE: Failure of methylene blue therapy suggests: inadequate dose of methylene blue, inadequate decontamination, NADPH dependent methemoglobin reductase deficiency, hemoglobin M disease, sulfhemoglobinemia, or G-6-PD deficiency. Methylene blue is reduced by methemoglobin reductase and nicotinamide adenosine dinucleotide phosphate (NADPH) to leukomethylene blue. This in turn reduces methemoglobin. Red blood cells of patients with G-6-PD deficiency do not produce enough NADPH to convert methylene blue to leukomethylene blue (do Nascimento et al, 2008).
4) DRUG INTERACTION: Concomitant use of methylene blue with serotonergic drugs, including serotonin reuptake inhibitors (SRIs), selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), norepinephrine-dopamine reuptake inhibitors (NDRIs), triptans, and ergot alkaloids may increase the risk of potentially fatal serotonin syndrome (U.S. Food and Drug Administration, 2011; Stanford et al, 2010; Prod Info methylene blue 1% IV injection, 2011).

e) TOLUIDINE BLUE OR TOLONIUM CHLORIDE (GERMANY)

1) DOSE: 2 to 4 mg/kg intravenously over 5 minutes. Dose may be repeated in 30 minutes (Nemec, 2011; Lindenmann et al, 2006; Kiese et al, 1972).
2) SIDE EFFECTS: Hypotension with rapid intravenous administration. Vomiting, diarrhea, excessive sweating, hypotension, dysrhythmias, hemolysis, agranulocytosis and acute renal insufficiency after overdose (Dunipace et al, 1992; Hix & Wilson, 1987; Winek et al, 1969; Teunis et al, 1970; Marquez & Todd, 1959).
3) CONTRAINDICATIONS: G-6-PD deficiency; may cause hemolysis.

G) 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).

H) 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).

I) DICOBALT EDETATE

1) Dicobalt-EDTA (Kelocyanor(R)) 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 United States.
2) Kelocyanor(R) is supplied in 20 mL ampules containing 300 mg of dicobalt-EDTA and 4 g of dextrose in water for injection (Prod Info Kelocyanor(R), 1987).
3) DOSE

a) ADULT DOSE: One to two 20 mL ampules (300 to 600 mg) IV over about 1 to 5 minutes (Prod Info Kelocyanor(R), 1987) (Davison, 1969).

1) If there is insufficient clinical improvement 5 minutes after giving the first 1 to 2 ampules (300 to 600 mg), an additional 20 milliliter ampule (300 mg) may be administered intravenously over about 1 to 5 minutes (Prod Info Kelocyanor(R), 1987) (Davison, 1969).
2) Manufacturers recommend that the intravenous site where Kelocyanor(R) has been injected be flushed with 50 mL of 50% dextrose in water (Prod Info Kelocyanor(R), 1987).
3) Kelocyanor(R) can be used with other standard cyanide antidotes (Prod Info Kelocyanor(R), 1978).

b) PEDIATRIC DOSE: Pediatric doses have not been established by manufacturers. In Israel the recommended pediatric dose is 0.5 milliliter/kilogram, not to exceed 20 mL (Pers Comm, Uri Taitelman,MD, 1963).

4) ADVERSE EFFECTS

a) Serious adverse effects include hypotension, cardiac dysrhythmias, decrease cerebral blood flow, and angioedema (Dodds & McKnight, 1985; Wright & Vesey, 1986). These adverse reactions are magnified when a patient does not have cyanide intoxication. It may be prudent to reserve the use of Kelocyanor(R) to confirmed cyanide poisonings. The inherent problems in delaying treatment while waiting for confirmation is apparent and relegates this antidote to limited clinical usefulness; unless cyanide poisoning can be confirmed readily (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) ADVERSE EFFECTS may include nausea, vomiting, tachycardia, hypotension, hypertension, anaphylactic reactions, facial and neck edema, chest pain, diaphoresis, nervousness, tremulousness, gastrointestinal hemorrhages, seizures, cardiac arrhythmias, and rashes (Prod Info Kelocyanor(R), 1987 ) (Davison, 1969; Tyrer, 1981; Hillman et al, 1974; Dodds & McKnight, 1985; Wright & Vesey, 1986).

J) 4-DIMETHYLAMINOPHENOL HYDROCHLORIDE

1) 4-DMAP is a methemoglobin-inducing agent used in some European countries for the treatment of acute cyanide poisoning. A more rapid onset of methemoglobin production is observed following administration of 4-DMAP than following sodium nitrite. Methemoglobin peaks at 5 minutes after 4-DMAP versus 30 minutes after sodium nitrite (Kruszyna et al, 1982; Moore et al, 1987; Weger, 1990).
2) The dose of 4-DMAP is 3 mg/kg and is coadministered with thiosulfate.
3) ADVERSE EFFECTS: 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) HYPERBARIC OXYGEN THERAPY

1) The Undersea Medical Society has classified cyanide poisoning as a disorder for which hyperbaric oxygen therapy is mandatory (Category 1: approved for third party reimbursement and known effective as treatment) (Myers & Schnitzer, 1984). Category 1, a category intended for disorders in which the efficacy of hyperbaric oxygen has been established in extensive clinical trials. The placement of cyanide poisoning in Category 1 stands in contrast to the existing literature, which indicates that the role of hyperbaric oxygen as an adjunct to the chemical antidote treatment of the cyanide poisoned patient has not been clearly established.
2) Animal data suggests that hyperbaric oxygen treatment may have direct effects in attenuating cyanide toxicity (Ivanov, 1959; Skene et al, 1966; Takano et al, 1980). However, not all animal studies have shown hyperbaric oxygen to improve outcome (Way et al, 1972).
3) The reported results involving hyperbaric oxygen treatment in clinical cases of isolated cyanide poisonings refractory to standard antidote treatment (sodium nitrite and sodium thiosulfate) have been equivocal (Trapp, 1970; Litovitz et al, 1983; Trapp & Lepawsky, 1983; Hart et al, 1985; Davis & Ewer, 1988; Rosenberg et al, 1989; Feldman & Feldman, 1990; Scolnick et al, 1993; Goodhart, 1994). Further research in hyperbaric oxygen treatment and cyanide poisoning is necessary.
4) The literature seems to indicate that the role of hyperbaric oxygen as an adjunct to the chemical antidote treatment of the cyanide poisoned patient has not been clearly established. Further research in this area is necessary. Because cyanide is among the most lethal poisons, and intoxication is rapid, "standard antidotal therapy" for isolated cyanide poisoning should be of primary importance. Hyperbaric oxygen may be an adjunct to be considered in patients who are not responding to supportive care and antidotal therapy, and for those patients poisoned by both cyanide and carbon monoxide (Hart et al, 1985).

L) EXPERIMENTAL THERAPY

1) STROMA-FREE METHEMOGLOBIN SOLUTION

a) Stroma-free methemoglobin, oxidized hemoglobin to the ferric form in which the cell membrane has been removed, attenuates lethality and prevents hemodynamic changes in animal models (Breen et al, 1996; Ten Eyck et al, 1985) (Ten Eyck et al, 1986). The advantage to this treatment is that it provide exogenous methemoglobin without compromising oxygen-carrying capacity of native hemoglobin. Removal of the cell membrane eliminates the antigenicity problem (Marrs, 1988).
b) AVAILABILITY: 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 (Bhattacharya & Vijayaraghavan, 2002; Moore et al, 1986).
b) In vitro and animal studies show that alpha-ketaglutaric 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) 3-MERCAPTOPYRUVATE PRODRUGS

a) A series of 3 prodrugs of 3-mercaptopyruvate (3-MP) have been developed as possible cyanide antidotes and have been successfully tested in animal models. When given intraperitoneally to mice 5 minutes post-cyanide administration, the protective index (P.I.; a ratio of the righting reflex recovery time of the cyanide-only controls divided by the righting reflex recovery times of the cyanide-plus-antidote-treated animals) ranged from 1.4 to 3.9 as compared with the cyanide-only controls with a P.I. of 1. The prodrugs also appeared to be effective when given to mice prior to cyanide administration. The P.I of the prodrugs ranged from 2.0 to 5.4 when given orally 30 to 60 minutes pre-cyanide administration, suggesting that the prodrugs may be useful as prophylactic agents by first responders; further investigation is warranted (Nagasawa et al, 2007).

Inhalation Exposure

6.7.1)

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) High concentrations of cyanide gas may cause a rapid loss of consciousness (Peden et al, 1986). Rescuers should wear self-contained positive pressure breathing apparatus to avoid contaminating themselves during rescue attempts (AAR, 1987) (NFPA, 1986).

6.7.2)

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) SUMMARY

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) Hydroxocobalamin, 5 to 20 grams administered intravenously, has been shown to be effective, as sole antidotal therapy, for acute cyanide poisoning following cyanide salt ingestion or inhalation, as well as cyanide poisoning following smoke inhalation (Borron et al, 2007a; Borron et al, 2007).
h) 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).

b) SODIUM NITRITE

1) INDICATION

2) ADULT DOSE

3) PEDIATRIC DOSE

c) SODIUM THIOSULFATE

E) 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%.

F) ACIDOSIS

G) SEIZURE

1) SUMMARY

2) DIAZEPAM

3) NO INTRAVENOUS ACCESS

4) LORAZEPAM

5) PHENOBARBITAL

6) OTHER AGENTS

7) PHENYTOIN/FOSPHENYTOIN

a) Benzodiazepines and/or barbiturates are preferred to phenytoin or fosphenytoin in the treatment of drug or withdrawal induced seizures (Wallace, 2005).
b) PHENYTOIN

1) PHENYTOIN INTRAVENOUS PUSH VERSUS INTRAVENOUS INFUSION

c) FOSPHENYTOIN

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% is unnecessary to insure satisfactory clinical outcome (Johnson et al, 1989).

2) If excessive methemoglobinemia occurs, some authors have suggested that methylene blue should not be used because it could cause release of cyanide from the cyanmethemoglobin complex. Such authors have suggested that emergency exchange transfusion is the treatment of choice (Berlin, 1970). 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). There is some controversy over whether or not the induction of methemoglobinemia is the sodium nitrite mechanism of action in cyanide poisoning. As long as intensive care monitoring and further antidote doses (if required) are available, methylene blue can most likely be safely administered in this setting.
4) SUMMARY

a) Determine the methemoglobin concentration and evaluate the patient for clinical effects of methemoglobinemia (ie, dyspnea, headache, fatigue, CNS depression, tachycardia, metabolic acidosis). Treat patients with symptomatic methemoglobinemia with methylene blue (this usually occurs at methemoglobin concentrations above 20% to 30%, but may occur at lower methemoglobin concentrations in patients with anemia, or underlying pulmonary or cardiovascular disorders). Administer oxygen while preparing for methylene blue therapy.

5) METHYLENE BLUE

a) INITIAL DOSE/ADULT OR CHILD: 1 mg/kg IV over 5 to 30 minutes; a repeat dose of up to 1 mg/kg may be given 1 hour after the first dose if methemoglobin levels remain greater than 30% or if signs and symptoms persist. NOTE: Methylene blue is available as follows: 50 mg/10 mL (5 mg/mL or 0.5% solution) single-dose ampules (Prod Info PROVAYBLUE(TM) intravenous injection, 2016) and 10 mg/1 mL (1% solution) vials (Prod Info methylene blue 1% intravenous injection, 2011). REPEAT DOSES: Additional doses may be required, especially for substances with prolonged absorption, slow elimination, or those that form metabolites that produce methemoglobin. NOTE: Large doses of methylene blue may cause methemoglobinemia or hemolysis (Howland, 2006). Improvement is usually noted shortly after administration if diagnosis is correct. Consider other diagnoses or treatment options if no improvement has been observed after several doses. If intravenous access cannot be established, methylene blue may also be given by intraosseous infusion. Methylene blue should not be given by subcutaneous or intrathecal injection (Prod Info methylene blue 1% intravenous injection, 2011; Herman et al, 1999). NEONATES: DOSE: 0.3 to 1 mg/kg (Hjelt et al, 1995).
b) CONTRAINDICATIONS: G-6-PD deficiency (methylene blue may cause hemolysis), known hypersensitivity to methylene blue, methemoglobin reductase deficiency (Shepherd & Keyes, 2004)
c) FAILURE: Failure of methylene blue therapy suggests: inadequate dose of methylene blue, inadequate decontamination, NADPH dependent methemoglobin reductase deficiency, hemoglobin M disease, sulfhemoglobinemia, or G-6-PD deficiency. Methylene blue is reduced by methemoglobin reductase and nicotinamide adenosine dinucleotide phosphate (NADPH) to leukomethylene blue. This in turn reduces methemoglobin. Red blood cells of patients with G-6-PD deficiency do not produce enough NADPH to convert methylene blue to leukomethylene blue (do Nascimento et al, 2008).
d) DRUG INTERACTION: Concomitant use of methylene blue with serotonergic drugs, including serotonin reuptake inhibitors (SRIs), selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), norepinephrine-dopamine reuptake inhibitors (NDRIs), triptans, and ergot alkaloids may increase the risk of potentially fatal serotonin syndrome (U.S. Food and Drug Administration, 2011; Stanford et al, 2010; Prod Info methylene blue 1% IV injection, 2011).

6) TOLUIDINE BLUE OR TOLONIUM CHLORIDE (GERMANY)

a) DOSE: 2 to 4 mg/kg intravenously over 5 minutes. Dose may be repeated in 30 minutes (Nemec, 2011; Lindenmann et al, 2006; Kiese et al, 1972).
b) SIDE EFFECTS: Hypotension with rapid intravenous administration. Vomiting, diarrhea, excessive sweating, hypotension, dysrhythmias, hemolysis, agranulocytosis and acute renal insufficiency after overdose (Dunipace et al, 1992; Hix & Wilson, 1987; Winek et al, 1969; Teunis et al, 1970; Marquez & Todd, 1959).
c) CONTRAINDICATIONS: G-6-PD deficiency; may cause hemolysis.

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, 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).

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).
2) In individuals with G6PD deficiency, therapy with methemoglobin-inducing agents is contraindicated because of the likelihood of serious hemolysis.

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 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: 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 (Bhattacharya & Vijayaraghavan, 2002; 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) 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, 1986).

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, calcium-ion-channel blockers, and prodrugs of 3-mercaptopyruvate(Amery et al, 1981; Ashton et al, 1980; Bright & Marrs, 1987; Budavari, 1976; Dubinsky et al, 1984; Johnson et al, 1986; Leung et al, 1984; Bright & Marrs, 1987; Marrs, 1988) (Rump & Edelwijn, 1986) (Vick & Froehlich, 1985; Nagasawa et al, 2007).

L) HYPOTENSIVE EPISODE

1) SUMMARY

2) DOPAMINE

3) NOREPINEPHRINE

M) ACUTE LUNG INJURY

N) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Eye Exposure

6.8.1)

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)

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 at least several hours in the hospital setting for the possible development of symptoms of systemic cyanide poisoning.

B) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Dermal Exposure

6.9.1)

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)

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, 1984a; Dodds & McKnight, 1985).

B) OXYGEN

1) Administer 100% oxygen to maintain an elevated PO2.

C) HYPERBARIC OXYGEN THERAPY

D) FLUID/ELECTROLYTE BALANCE REGULATION

1) Establish secure large bore IV line.

E) CYANIDE ANTIDOTE

1) SUMMARY

2) HYDROXOCOBALAMIN - CYANOKIT(R)

3) CYANIDE ANTIDOTE KIT

a) OBTAIN AND PREPARE for administration a CYANIDE ANTIDOTE KIT, consisting of sodium nitrite and sodium thiosulfate.

b) SODIUM NITRITE

1) INDICATION

2) ADULT DOSE

3) PEDIATRIC DOSE

c) SODIUM THIOSULFATE

F) MONITORING OF PATIENT

G) ACIDOSIS

H) SEIZURE

1) SUMMARY

2) DIAZEPAM

3) NO INTRAVENOUS ACCESS

4) LORAZEPAM

5) PHENOBARBITAL

6) OTHER AGENTS

I) METHEMOGLOBINEMIA

a) Inducing a "therapeutic methemoglobin level" of 25% is unnecessary to insure satisfactory clinical outcome (Johnson et al, 1989).

5) METHYLENE BLUE

6) TOLUIDINE BLUE OR TOLONIUM CHLORIDE (GERMANY)

J) DICOBALT EDETATE

3) DOSE

a) ADULTS: One to two 20 milliliter ampules (300 to 600 mg) injected IV over about 1 to 5 minutes (Prod Info, 1978; Prod Info, 1986; Prod Info, 1987) (Davison, 1969).

1) A third 20 milliliter ampule (300 mg) can be injected IV 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 mL) (Personal Communication, Uri Taitelman, MD, 1963).

4) Kelocyanor(R) is supplied in 20 mL ampules containing 300 mg 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

L) EXPERIMENTAL THERAPY

2) ALPHA-KETOGLUTARIC ACID

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, calcium-ion-channel blockers, and prodrugs of 3-mercaptopyruvate (Amery et al, 1981; Ashton et al, 1980; Bright & Marrs, 1987; Budavari, 1976; Dubinsky et al, 1984; Johnson et al, 1986; Leung et al, 1984; Bright & Marrs, 1987; Marrs, 1988) (Rump & Edelwijn, 1986) (Vick & Froehlich, 1985; Nagasawa et al, 2007).

M) HYPOTENSIVE EPISODE

1) SUMMARY

N) ACUTE LUNG INJURY

O) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Enhanced Elimination

1) Hemodialysis as adjunct treatment to supportive care, intravenous sodium nitrite, and sodium thiosulfate has been reported in the management of a patient with cyanide toxicity (Wesson et al, 1985).
2) It has been suggested that hemodialysis may be helpful in the following ways:

a) Removal of the small extracellular reservoir of cyanide, particularly if cyanide is still being absorbed from the gastrointestinal tract.
b) Correction of severe metabolic acidosis caused by cyanide poisoning.
c) Removal of thiocyanate which should decrease both tissue and plasma cyanide levels.

3) Limited animal studies have shown some potential effectiveness of hemodialysis when combined with thiosulfate infusion (Wesson et al, 1985; Gonzales & Sabatini, 1989).
4) Hemodialysis may be considered after supportive care and pharmacologic therapy have been maximized.

1) Charcoal hemoperfusion as adjunct treatment to supportive care, intravenous sodium nitrite, and sodium thiosulfate has been reported in the management of a patient with cyanide toxicity (Kreig & Saxena, 1987).
2) The outcome in this case was no different from that of other patients treated similarly without hemoperfusion.
3) Hemoperfusion cannot be considered routine or standard adjunct therapy for cyanide poisoning at this time.

Abstracts

Range Of Toxicity

Summary

Minimum Lethal Exposure

1) LDLo - (ORAL) HUMAN: 2800 mcg/kg (RTECS, 2001)

Maximum Tolerated Exposure

1) TDLo - (ORAL) HUMAN, Male: 714 mcg/kg (RTECS, 2001)

Serum Plasma Blood Concentrations

7.5.2)

A) TOXIC CONCENTRATION LEVELS

1) GENERAL

a) Patients treated with only supportive measures have survived severe poisoning with whole blood cyanide levels of 2.3 to 4.65 micrograms/milliliter (88.5 micromoles/liter) (Vogel et al, 1981 Saincher et al, 1992).
b) Patients treated with specific antidotes have survived severe poisoning with whole blood cyanide levels of 3.85 to 40 micrograms/milliliter (1,538 micromoles/liter) (Litovitz et al, 1983; Hall & Rumack, 1986; Hall & Rumack, 1986; Feihl et al, 1982).
c) Significant symptoms of poisoning generally occur with whole blood cyanide levels of 1 microgram/milliliter (38.5 micromoles/liter) or greater (Hall & Rumack, 1986).

Workplace Standards

1) Editor's Note: The listed values are recommendations or guidelines developed by ACGIH(R) to assist in the control of health hazards. They should only be used, interpreted and applied by individuals trained in industrial hygiene. Before applying these values, it is imperative to read the introduction to each section in the current TLVs(R) and BEI(R) Book and become familiar with the constraints and limitations to their use. Always consult the Documentation of the TLVs(R) and BEIs(R) before applying these recommendations and guidelines.

a) Adopted Value

1) Hydrogen cyanide and cyanide salts, as CN; cyanide salts

a) TLV:

1) TLV-TWA:
2) TLV-STEL:
3) TLV-Ceiling: 5 mg/m(3)

b) Notations and Endnotes:

1) Carcinogenicity Category: Not Listed
2) Codes: Skin
3) Definitions:

a) Skin: This refers to the potential significant contribution to the overall exposure by the cutaneous route, including mucous membranes and the eyes, either by contact with vapors or, of likely greater significance, by direct skin contact with the substance. It should be noted that although some materials are capable of causing irritation, dermatitis, and sensitization in workers, these properties are not considered relevant when assigning a skin notation. Rather, data from acute dermal studies and repeated dose dermal studies in animals or humans, along with the ability of the chemical to be absorbed, are integrated in the decision-making toward assignment of the skin designation. Use of the skin designation provides an alert that air sampling would not be sufficient by itself in quantifying exposure from the substance and that measures to prevent significant cutaneous absorption may be warranted. Please see "Definitions and Notations" (in TLV booklet) for full definition.

c) TLV Basis - Critical Effect(s): URT irr; headache; nausea; thyroid eff
d) Molecular Weight: Varies

1) For gases and vapors, to convert the TLV from ppm to mg/m(3):

a) [(TLV in ppm)(gram molecular weight of substance)]/24.45

2) For gases and vapors, to convert the TLV from mg/m(3) to ppm:

a) [(TLV in mg/m(3))(24.45)]/gram molecular weight of substance

e) Additional information:

B) NIOSH REL and IDLH Values for CAS143-33-9 (National Institute for Occupational Safety and Health, 2007):

1) Listed as: Sodium cyanide (as CN)
2) REL:

a) TWA:
b) STEL:
c) Ceiling: 5 mg/m(3) (4.7 ppm) [10-minute]
d) Carcinogen Listing: (Not Listed) Not Listed
e) Skin Designation: Not Listed
f) Note(s): [*Note: The REL and PEL also applies to other cyanides (as CN) except Hydrogen cyanide.]

3) IDLH: Not Listed

C) Carcinogenicity Ratings for CAS143-33-9 :

1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed ; Listed as: Hydrogen cyanide and cyanide salts, as CN; cyanide salts
2) EPA (U.S. Environmental Protection Agency, 2011): Not Assessed under the IRIS program. ; Listed as: Sodium cyanide
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: Sodium cyanide (as CN)
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 CAS143-33-9 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):

1) Not Listed

Toxicity Information

7.7.1)

A) ANIMAL DATA

1) LD50- (INTRAPERITONEAL)MOUSE:

a) 4900 mcg/kg (RTECS, 2001)
b) 5881 mcg/kg (Lewis, 1996a)

2) LD50- (SUBCUTANEOUS)MOUSE:

a) 3600 mcg/kg (RTECS, 2001)

3) LD50- (INTRAPERITONEAL)RAT:

a) 4300 mcg/kg (RTECS, 2001)

4) LD50- (ORAL)RAT:

a) 6440 mcg/kg (RTECS, 2001)

Pharmacology Toxicology

Toxicologic Mechanism

1) Cytochrome oxidase is an iron containing metalloenzyme essential for oxidative phosphorylation and aerobic energy production. It functions in the electron transport chain within the mitochondria, converting glucose metabolites into ATP. Cyanide induces cellular hypoxia by inhibiting the aa3 component of cytochrome oxidase; blocking efficient ATP production. Lactate production is increased as the result of anaerobic energy production in an attempt to maintain ATP production. Pyruvate can no longer enter the Krebs' cycle from glycolysis and it is converted to lactate. Cyanide also causes direct neurotoxicity by lipid peroxidation with the greatest extent being in the brain.

Physicochemical

Physical Characteristics

Ph

Molecular Weight

Other

1) Currently not available (CHRIS , 2002)

Animal Toxicology

References

General Bibliography

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SODIUM CYANIDE

Classification | Detailed evidence-based information

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General Bibliography