HYDROGEN CYANIDE

Classification | Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

1) Hydrogen cyanide may be produced during petroleum refining, electroplating, metallurgy and photographic-developing operations (ACGIH, 1996).

1) Hydrogen cyanide may occur as a by-product of operation of gas works, blast furnaces and coke ovens. It may also be encountered during electroplating, petroleum refining, metallurgic operations and photographic processing (CCOHS, 1988).

1) Catalytic oxidation (platinum catalyst) of an ammonia-methane mixture in air is generally the large-scale production method (Clayton & Clayton, 1994; Budavari, 1996; Lewis, 1997).
2) Hydrogen cyanide can be produced from bituminous coal and ammonia at a temperature of 1250 degrees C (Lewis, 1997). It can also be recovered from coke oven gases (Lewis, 1997).

Specific Substances

1.2.1) MOLECULAR FORMULA
1) C-H-N HCN

Available Forms Sources

1) At room temperature, hydrogen cyanide is a colorless gas. At temperatures below 26.5 degrees C, it exists as a liquid and has been described as colorless or having a bluish-white cast (ACGIH, 1996; (Ashford, 1994; Lewis, 1997).
2) Generally, all grades of hydrogen cyanide contain a stabilizer, often 0.05 percent phosphoric acid. If the compound is not pure or stabilized, it will polymerize with explosive violence (Lewis, 1997).
3) The compound in its commercial form is 96 to 99 percent pure. Technical grades of 96 to 98 percent purity exist as do 2, 5 and 10 percent solutions (Lewis, 1997).

1) Hydrogen cyanide can be produced by treating cyanide salts with dilute sulfuric acid (Clayton & Clayton, 1994). However, it is most often prepared either by catalytically reacting ammonia with natural gas or methane or as a by-product of the synthesis of acrylonitrile from ammonia, propylene and air (Budavari, 1996; Clayton & Clayton, 1994; Lewis, 1997).
2) It can be recovered from coke oven gases and, at 1250 degrees C, from bituminous coal and ammonia (Lewis, 1997).
3) Hydrogen cyanide occurs naturally in bitter almonds (Lewis, 1997).
4) It can be prepared in the laboratory by acidifying sodium cyanide or potassium ferricyanide. Catalytic decomposition of formamide is another production option (Budavari, 1996).
5) Hydrogen cyanide also may be prepared during petroleum refining, electroplating, metallurgy and photographic-developing operations (ACGIH, 1996).
6) Occupational exposure to hydrogen cyanide may occur during the manufacture of resin monomers and during blast furnace, gas works and coke oven operations (Clayton & Clayton, 1994).

1) Hydrogen cyanide is used as a chemical intermediate in the production of synthetic fiber, cyanide salts, plastics and nitriles, and is used to fumigate ships, railroad cars, buildings, orchards, tobacco and certain foods (ACGIH, 1996).
2) It also is used in metallurgy, electroplating, mining and photographic processes and to manufacture cyanuric acid and nylon 66, a hexamethylenediamine-adipic acid polymer. Additionally, hydrogen cyanide is used to manufacture acrylonitrile, acrylates, adiponitrile, dyes, chelates, lactic acid, rodenticides and pesticides (HSDB , 1999; ITI, 1995; Lewis, 1997).
3) Because of hydrogen cyanide's rapid effect on humans after inhalation of high concentrations, the compound has been used in the United States to execute criminals (HSDB , 1999).

Overview

Life Support

Clinical Effects

0.2.1)

A) Coma, tonic-clonic seizures, palpitations, dilated pupils, hyperventilation, hypoventilation, shock, cyanosis, severe metabolic acidosis, initial tachycardia and hypertension followed by bradycardia and hypotension, and respiratory arrest may be seen in serious poisonings. Noncardiogenic pulmonary edema and a wide variety of cardiac conduction defects and arrhythmias may develop. Nausea and vomiting may be noted.
B) Percutaneous absorption may occur, but is usually seen only with total-body liquid exposure or immersion. Dermal absorption of significant amounts of hydrogen cyanide gas has not been reported in humans.

0.2.4)

A) Dilated pupils are common in severe poisoning. Retinal arteries and veins that appear equally red on funduscopic examination suggest the diagnosis. Corneal edema may be seen. A burning sensation in the mouth and throat may occur.

0.2.5)

A) Tachycardia and hypertension may be seen in the initial phases of cyanide poisoning. Bradycardia and hypotension are seen in the late phases of cyanide poisoning. EKG changes and ST-T segment elevation or depression may also be seen.

0.2.6)

A) Respiratory tract irritation, hyperpnea, tachypnea, hypoventilation, apnea, noncardiogenic pulmonary edema and cyanosis may develop at various times after exposure.

0.2.7)

A) Headache may be an early sign of cyanide poisoning. CNS stimulation with varied presentations may be seen in the early stages of cyanide poisoning. Coma and seizures are common in severe cyanide poisoning. In one case paralysis occurred, and parkinsonian syndromes have been observed. Rare cases of neurological sequelae have been reported.

0.2.8)

A) Nausea, vomiting and abdominal pain may occur after ingestion of cyanide salts.

0.2.11)

A) Increased anion gap metabolic acidosis and serum lactate levels are common.

0.2.13)

A) Cherry-red venous blood may occur and is due to the inability of tissue to remove oxygen from the blood.

0.2.14)

A) Cyanide has been said to be absorbed through intact skin.

0.2.16)

A) Insulin resistance was noted in a severely cyanide-poisoned patient.

0.2.18)

A) Irrational and violent behavior and manic episodes occurred in a patient after inhalation exposure.

0.2.20)

A) At the time of this review, no reproductive studies were found for hydrogen cyanide in humans.
B) In laboratory animals, related cyanide compounds did cause resorptions, malformations and teratogenic effects in offspring.

0.2.21)

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

Laboratory Monitoring

Treatment Overview

0.4.2)

A) Perform gastric lavage with a large-bore tube after endotracheal intubation.

1) ACTIVATED CHARCOAL: Administer charcoal as a slurry (240 mL water/30 g charcoal). Usual dose: 25 to 100 g in adults/adolescents, 25 to 50 g in children (1 to 12 years), and 1 g/kg in infants less than 1 year old.
2) GASTRIC LAVAGE: Consider after ingestion of a potentially life-threatening amount of poison if it can be performed soon after ingestion (generally within 1 hour). Protect airway by placement in the head down left lateral decubitus position or by endotracheal intubation. Control any seizures first.

a) CONTRAINDICATIONS: Loss of airway protective reflexes or decreased level of consciousness in unintubated patients; following ingestion of corrosives; hydrocarbons (high aspiration potential); patients at risk of hemorrhage or gastrointestinal perforation; and trivial or non-toxic ingestion.

B) Administer 100 percent oxygen - establish secure large-bore IV.
C) A cyanide antidote, either hydroxocobalamin or the sodium nitrite/sodium thiosulfate kit, should be administered to patients with symptomatic poisoning.
D) HYDROXOCOBALAMIN: ADULT DOSE: 5 g (two 2.5 g vials each reconstituted with 100 mL sterile 0.9% saline) administered as an intravenous infusion over 15 minutes. For severe poisoning, a second dose of 5 g may be infused intravenously over 15 minutes to 2 hours, depending on the patient's condition. CHILDREN: Limited experience; a dose of 70 mg/kg has been used in pediatric patients.
E) Prepare the Cyanide Antidote Kit for use in symptomatic patients.

1) SODIUM NITRITE: Adult: 10 mL (300 mg) of a 3% solution IV at a rate of 2.5 to 5 mL/minute; Child (with normal hemoglobin concentration): 0.2 mL/kg (6 mg/kg) of a 3% solution IV at a rate of 2.5 to 5 mL/minute, not to exceed 10 mL (300 mg).
2) Repeat one-half of initial sodium nitrite dose one-half hour later if there is inadequate clinical response. Calculate pediatric doses precisely to avoid potentially life-threatening methemoglobinemia. Use with caution if carbon monoxide poisoning is also suspected. Monitor blood pressure carefully. Reduce nitrite administration rate if hypotension occurs.
3) SODIUM THIOSULFATE: Administer sodium thiosulfate IV immediately following sodium nitrite. DOSE: ADULT: 50 mL (12.5 g) of a 25% solution; CHILD: 1 mL/kg (250 mg/kg) of a 25% solution, not to exceed 50 mL (12.5 g) total dose. A second dose, one-half of the first dose, may be administered if signs of cyanide toxicity reappear.

F) SODIUM BICARBONATE: Administer one mEq/kg IV to acidotic patients.
G) SEIZURES: Administer a benzodiazepine; DIAZEPAM (ADULT: 5 to 10 mg IV initially; repeat every 5 to 20 minutes as needed. CHILD: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed) or LORAZEPAM (ADULT: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist. CHILD: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue).

1) Consider phenobarbital or propofol if seizures recur after diazepam 30 mg (adults) or 10 mg (children greater than 5 years).
2) Monitor for hypotension, dysrhythmias, respiratory depression, and need for endotracheal intubation. Evaluate for hypoglycemia, electrolyte disturbances, and hypoxia.

H) METHEMOGLOBINEMIA

1) Rarely, clinically significant excessive methemoglobinemia has occurred following sodium nitrite therapy. If excessive methemoglobinemia occurs, some authors have suggested that methylene blue should not be used because it could cause the release of cyanide from the cyanmethemoglobin complex. Such authors have suggested that emergency exchange transfusion is the treatment of choice. Hyperbaric oxygen therapy could be used to support the patient while preparations for exchange transfusion are being made.
2) However, methylene or toluidine blue have been used successfully in this setting without worsening the course of the cyanide poisoning. 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.
3) METHEMOGLOBINEMIA: 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.
4) 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.
5) 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.

I) HYPERBARIC OXYGEN may also be useful in severe cases not responsive to other therapy.
J) ACUTE LUNG INJURY: Maintain ventilation and oxygenation and evaluate with frequent arterial blood gases and/or pulse oximetry monitoring. Early use of PEEP and mechanical ventilation may be needed.
K) HYPOTENSION: Infuse 10 to 20 mL/kg isotonic fluid. If hypotension persists, administer dopamine (5 to 20 mcg/kg/min) or norepinephrine (ADULT: begin infusion at 0.5 to 1 mcg/min; CHILD: begin infusion at 0.1 mcg/kg/min); titrate to desired response.
L) HEMODIALYSIS and HEMOPERFUSION do not seem to be indicated or efficacious in most cases of cyanide poisoning.
M) ALTERNATIVE ANTIDOTES: Kelocyanor(R) (dicobalt-EDTA) and 4-DMAP (4-dimethylaminophenol) are alternative cyanide antidotes in clinical use in various countries outside the USA. See TREATMENT SECTION in the main body of this document for more information.

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 percent oxygen - establish secure large-bore IV.
C) A cyanide antidote, either hydroxocobalamin or the sodium nitrite/sodium thiosulfate kit, should be administered to patients with symptomatic poisoning.
D) HYDROXOCOBALAMIN: ADULT DOSE: 5 g (two 2.5 g vials each reconstituted with 100 mL sterile 0.9% saline) administered as an intravenous infusion over 15 minutes. For severe poisoning, a second dose of 5 g may be infused intravenously over 15 minutes to 2 hours, depending on the patient's condition. CHILDREN: Limited experience; a dose of 70 mg/kg has been used in pediatric patients.
E) Prepare the Cyanide Antidote Kit for use in symptomatic patients.

H) METHEMOGLOBINEMIA

I) HYPERBARIC OXYGEN may also be useful in severe cases not responsive to supportive and antidotal therapy.
J) ACUTE LUNG INJURY: Maintain ventilation and oxygenation and evaluate with frequent arterial blood gases and/or pulse oximetry monitoring. Early use of PEEP and mechanical ventilation may be needed.
K) HYPOTENSION: Infuse 10 to 20 mL/kg isotonic fluid. If hypotension persists, administer dopamine (5 to 20 mcg/kg/min) or norepinephrine (ADULT: begin infusion at 0.5 to 1 mcg/min; CHILD: begin infusion at 0.1 mcg/kg/min); titrate to desired response.
L) ALTERNATIVE ANTIDOTES: Kelocyanor(R) (dicobalt-EDTA) and 4-DMAP (4-dimethylaminophenol) are alternative cyanide antidotes in clinical use in various countries outside the US. See TREATMENT SECTION in the main body of this document for more information.

0.4.4)

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) Laboratory animals have developed serious systemic cyanide poisoning after ocular exposure. Human poisoning cases have not been reported due to eye exposure only. If systemic cyanide poisoning is suspected after eye exposure, REFER to TREATMENT RECOMMENDATIONS in the INHALATION EXPOSURE section above.

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) Although 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 after exposure by this route.
3) Treatment should include recommendations listed in the INHALATION EXPOSURE section when appropriate.

Range Of Toxicity

Clinical Effects

Summary Of Exposure

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) ANIMAL STUDY - 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 (Ballantyne, 1983). No cases of human poisoning after only eye exposure have been reported.
D) CORNEAL EDEMA - One case of corneal edema from exposure to hydrocyanic acid vapors has been reported (Grant, 1993).

3.4.6)

A) BURNING SENSATION - A burning sensation in the mouth and throat may occur (Vogel et al, 1981).

Cardiovascular

3.5.1)

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 later 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).
2) EKG changes following intravenous administration of sodium cyanide included a sinus pause, without evidence of auricular activity, which persisted for 0.88 to 4.2 seconds; nodal escape occurred before auricular activity was re-established in some cases. Immediately after the pause, there were slowing of heart rate and marked sinus irregularity for periods ranging from a few seconds to two minutes, followed by a gradual acceleration to rates above control levels (Wexler et al, 1947).

Respiratory

3.6.1)

A) Respiratory tract irritation, hyperpnea, tachypnea, hypoventilation, apnea, noncardiogenic pulmonary edema and cyanosis may develop at various times after exposure.

3.6.2)

A) RESPIRATORY FAILURE

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).

C) ACUTE LUNG INJURY

1) Noncardiogenic pulmonary edema has been reported in cases of acute cyanide poisoning, even after ingestion (Graham et al, 1977).

D) CYANOSIS

1) Cyanosis is a late finding in cyanide poisoning and usually does not occur until the stage of apnea and circulatory collapse (Hall & Rumack, 1986).

Neurologic

3.7.1)

3.7.2)

A) HEADACHE

1) Headache may be an early sign of cyanide poisoning (Vogel et al, 1981).

B) 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).

C) COMA

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

D) SEIZURE

1) Generalized seizures are common in severe cyanide poisoning (Hall & Rumack, 1986).

E) PARALYSIS

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

F) SEQUELA

1) Most victims of acute poisoning either die acutely or fully recover, but rare cases of neurological sequelae such as personality changes, memory deficits and extrapyramidal syndromes have been reported (Jouglard et al, 1971; Jouglard et al, 1974).

G) SECONDARY PERIPHERAL NEUROPATHY

1) Two workers exposed to vapors from heated tar epoxy resin paint containing hydrogen cyanide, benzene, phenol and naphthalene developed peripheral neuropathy (Sakai et al, 1994). Because of the mixed exposure, this effect cannot be attributed to hydrogen cyanide alone.

H) CASE REPORT

1) PARKINSONISM - An 18-year-old patient who ingested between 975 and 1,300 mg of potassium cyanide developed a parkinsonian syndrome with rigidity and akinesis (Uitti et al, 1985).

Gastrointestinal

3.8.1)

A) Nausea, vomiting and abdominal pain may occur after ingestion of cyanide salts.

3.8.2)

A) NAUSEA AND VOMITING

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

Acid-Base

3.11.1)

A) Increased anion gap metabolic acidosis and serum lactate levels are common.

3.11.2)

A) ACIDOSIS

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

Hematologic

3.13.1)

A) Cherry-red venous blood may occur and is due to the inability of tissue to remove oxygen from the blood.

3.13.2)

A) ABNORMAL COLOR

1) CHERRY-RED VENOUS BLOOD may occur, due to the inability of tissue to remove oxygen from the blood (Clayton & Clayton, 1994; Lewis, 1996).

Dermatologic

3.14.1)

A) Cyanide has been said to be absorbed through intact skin.

3.14.2)

A) POISONING

1) Cyanide has been said to be absorbed through intact skin and carries a "skin" designation for workplace exposures (ACGIH, 1996).
2) 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 salts (Bourrelier & Paulet, 1971).

Endocrine

3.16.1)

A) Insulin resistance was noted in a severely cyanide-poisoned patient.

3.16.2)

A) FINDING OF THYROID FUNCTION

1) Subclinical derangements of thyroid function and B12 and folate metabolism were noted in a group of chronically exposed cyanide workers (Blanc et al, 1985).

B) HYPERGLYCEMIA

1) Insulin resistance was noted in a severely cyanide-poisoned patient (Singh et al, 1989).

Reproductive

3.20.1)

3.20.2)

A) SPECIFIC AGENT

1) HYDROGEN CYANIDE - There are no reported cases of human or animal teratogenicity due to hydrogen cyanide itself.
2) RELATED COMPOUNDS - 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.

a) Neural tube defects (exencephaly, encephalocele) were the most common malformations. Hydropericardium and crooked tails were also noted.
b) 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) Pregnant hamsters exposed by inhalation of 5,000 to 8,000 ppm or given 100 to 400 mg/kg oral or intraperitoneal doses of acetonitrile delivered offspring with severe axial skeletal disorders.

a) Injections of sodium thiosulfate antagonized the teratogenic effects. Increased cyanide and thiocyanate levels were found in all tissues studied 2.5 hours after oral or intraperitoneal dosing, indicating that the in vivo liberation of cyanide from acetonitrile was responsible for the observed teratogenic effects (Willhite, 1983).

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

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

5) Rats fed cassava powder (containing high concentrations of a cyanogenic glycoside) as 50 to 80 percent of the diet during the first 5 days of pregnancy had a low incidence of limb defects, open eye defects, microcephaly and fetal growth retardation in fetuses collected on day 20 of pregnancy (Singh, 1981).
6) Intraperitoneal injections of acrylonitrile or propionitrile to hamsters on day eight of gestation resulted in exencephaly, encephaloceles and rib abnormalities in the offspring.

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

7) Chemicals that liberate cyanide are also known to be teratogenic in laboratory animals. This is especially true of the aliphatic nitriles (Willhite et al, 1981) Smith, 1981), including acrylonitrile (Buchter & Peter, 1984) and acetonitrile (Willhite, 1983).
8) CYANIDE has been linked with congenital cretinism (deformities, dwarfism and mental deficiency) due to thyroid deficiency in regions of the world where cyanogenic 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 also been teratogenic or fetotoxic and has affected the fertility of laboratory animals (Schardein, 1993).

Carcinogenicity

3.21.1)

A) IARC Carcinogenicity Ratings for CAS74-90-8 (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 potential carcinogenic activity of hydrogen cyanide in humans.

3.21.3)

A) LACK OF EFFECT

1) There are no reports of carcinogenicity in humans or laboratory animals due to hydrogen cyanide itself.
2) Acrylonitrile has carcinogenic properties in some species of laboratory animals and has been suggested to be associated with a slight increase in deaths from lung cancer and other malignancies in chronically exposed humans (Buchter & Peter, 1984; Geiger et al, 1983).

a) Whether the metabolic release of cyanide after absorption is involved in carcinogenesis is unknown. In isolated cell preparations, the release of cyanide does not seem to be involved in cell death (Geiger et al, 1983).

Genotoxicity

Laboratory Monitoring

Monitoring Parameters Levels

4.1.1)

A) If respiratory tract irritation or respiratory depression is evident, monitor arterial blood gases, chest x-ray, and pulmonary function tests.
B) Determine hemoglobin, arterial blood gases, venous pO2 or measured venous percent oxygen saturation, electrolytes, serum lactate and whole-blood cyanide levels.
C) MRI studies may be useful in identifying the location and extent of brain injury in patients with cyanide-induced parkinsonian syndrome.

4.1.2)

A) BLOOD/SERUM CHEMISTRY

1) Fatal blood cyanide levels after ingestion

a) Ballantyne et al (1974) reported 34 cases:

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

b) Rehlung (1967) reported 32 cases:

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

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

a) No symptoms:

1) less than 0.2 mg/L (mcg/mL); (0.02 mg%); (SI = 7.7 mcmol/L).

b) Flushing and tachycardia:

1) 0.5-1.0 mg/L (mcg/mL); (0.05-0.1 mg%); (SI = 19.2 to 38.5 mcmol/L).

c) Obtundation:

1) 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); (0.25 mg%); (SI = 96.1 mcmol/L).
e) Death:

1) 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:

1) 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)

5) Serum lactate levels may be useful in monitoring the severity of poisoning and the efficacy of treatment (Vogel et al, 1981).
6) Some victims of smoke inhalation from house fires may have low carboxyhemoglobin levels in the presence of significantly increased blood cyanide levels (Yoshida et al, 1991).

B) ACID/BASE

1) Arterial blood gases, serum electrolytes and serum lactate levels are useful in the assessment of increased anion gap lactic acidosis in patients poisoned with cyanide (Hall & Rumack, 1986; Vogel et al, 1981).
2) A REDUCED ARTERIO-CENTRAL VENOUS MEASURED PERCENT OXYGEN SATURATION

a) DIFFERENCE may be seen due to cellular inability to extract oxygen (Graham et al, 1977; Paulet, 1955). Arteriolization of venous blood gases (increased venous pO2 or measured venous percent oxygen saturation) may serve as an early clue in the diagnosis of cyanide poisoning (Hall & Rumack, 1986; Johnson & Mellors, 1988).

C) HEMATOLOGIC

1) Monitor methemoglobin levels during nitrite administration, especially if more than one dose is needed. Maintain methemoglobin levels less than 30 percent (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) Twenty-four-hour urinary cyanide excretion can be measured after chronic exposure to cyanide fumes and cyanide aerosols (Chandra et al, 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) Patients with respiratory distress should have a chest X-ray.

Methods

1) Cyanide can be measured chemically by several methods but most take several hours to complete and initial therapy must be based on clinical evaluation.
2) BIOLOGICAL SPECIMENS - 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 , 1999).

a) Cyanide can also be measured in biological fluids by gas chromatography after conversion to cyanogen chloride by reaction with chloramine-T (HSDB , 1999).
b) An ion-specific electrode method has sometimes been used for measuring cyanide in biological specimens (Bismuth et al, 1984).
c) A fluorometric diffusion method based on detection of fluorescing p-benzoquinone derivatives can be used to determine cyanide in biological fluids (HSDB , 1999).

3) 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 four to five drops of 20 percent NaOH, then boil and cool the solution.
b) Adding eight to ten drops of 10 percent 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).

4) 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 generally available.
5) For measurement of serum cyanide levels, a Flame Thermionic Detector Gas-chromatograph is convenient and can be effected in a short time (Yoshida et al, 1989).

Treatment

Oral Exposure

6.5.2)

A) SUMMARY

1) In symptomatic patients, skip these steps until other major emergency measures including use of cyanide antidotes and other life support measures have been instituted.

B) ACTIVATED CHARCOAL

1) The usefulness of activated charcoal may be questionable.

a) Although 1 gram of activated charcoal may adsorb 35 milligrams of potassium cyanide (Anderson, 1946), 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 with 25 of 26 untreated animals (Lambert et al, 1988).

2) CHARCOAL ADMINISTRATION

a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.

3) CHARCOAL DOSE

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

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

b) ADVERSE EFFECTS/CONTRAINDICATIONS

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

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 percent oxygen to maintain an increased pO2.

a) Oxygen may reverse the cyanide-cytochrome oxidase complex and facilitate the conversion to thiocyanate after thiosulfate administration (Graham et al, 1977).
b) There is fairly good evidence that 100 percent oxygen, combined with traditional nitrite/thiosulfate therapy, is better than nitrite/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 signs and symptoms (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) IV ACCESS: Establish secure large bore IV line.
2) A cyanide antidote, either hydroxocobalamin or the sodium nitrite/sodium thiosulfate kit, should be administered to patients with symptomatic poisoning.
3) HYDROXOCOBALAMIN - CYANOKIT(R)

a) ADULT DOSE: 5 g (two 2.5 g vials each reconstituted with 100 mL sterile 0.9% saline) administered as an intravenous infusion over 15 minutes. For severe poisoning, a second dose of 5 g may be infused intravenously over 15 minutes to 2 hours, depending on the patient's condition (Prod Info CYANOKIT(R) 2.5g IV injection, 2006).
b) PEDIATRIC DOSE: A dose of 70 mg/kg has been used in pediatric patients, based on limited post-marketing experience outside the US (Prod Info CYANOKIT(R) 2.5g IV injection, 2006).
c) INDICATIONS: Known or suspected cyanide poisoning.
d) ADVERSE EFFECTS: Transient hypertension, allergic reactions (including anaphylaxis), nausea, headache, rash. Hydroxocobalamin's deep red color causes red-colored urine in all patients, and erythema of the skin in most (Prod Info CYANOKIT(R) 2.5g IV injection, 2006).
e) LABORATORY INTERFERENCE: Because of its' color, hydroxocobalamin interferes with colorimetric determination of various laboratory parameters. It may artificially increase serum creatinine, bilirubin, triglycerides, cholesterol, total protein, glucose, albumin , alkaline phosphatase and hemoglobin. It may artificially decrease serum ALT and amylase. It may artificially increase urinary pH, glucose, protein, erythrocytes, leukocytes, ketones, bilirubin, urobilinogen, and nitrate (Prod Info CYANOKIT(R) 2.5g IV injection, 2006).
f) HEMODIALYSIS INTERFERENCE: Dialysis machines have a spectrophotometric safety measure that can shut down after detecting blood leaking across the dialysis membrane. Hydroxocobalamin has a deep red color and can permeate the dialysis membrane, coloring the dialysate and causing the hemodialysis machine to shut down erroneously. In one case report, a patient with cyanide poisoning underwent dialysis after receiving 5 g of IV hydroxocobalamin because of refractory acidemia, reduced kidney function and hyperkalemia. A blood leak alarm caused the dialysis machine to shut down erroneously, delaying therapy, and resulting in the death of the patient (Stellpflug et al, 2013).
g) In a study of heavy smokers, a group given hydroxocobalamin alone in a dose of 5 grams intravenously showed a decrease in whole-blood cyanide of 59 percent. A group given 5 grams of hydroxocobalamin followed by 12.5 grams sodium thiosulfate had an 87 percent decrease in whole-blood cyanide (Forsyth et al, 1993).
h) Hydroxocobalamin has been shown to be effective in treating cyanide-poisoned laboratory animals and has the advantage of producing neither methemoglobinemia nor hypotension, as sodium nitrite does (Hall & Rumack, 1987; Forsyth et al, 1993). Because of its low side effects profile, hydroxocobalamin may be the preferred cyanide antidote (Beasley & Glass, 1998)

E) CYANIDE ANTIDOTE

1) A cyanide antidote, either hydroxocobalamin or the sodium nitrite/sodium thiosulfate kit, should be administered to patients with symptomatic poisoning.
2) HYDROXOCOBALAMIN-CYANOKIT(R)

a) ADULT DOSE: 5 g (two 2.5 g vials each reconstituted with 100 mL sterile 0.9% saline) administered as an intravenous infusion over 15 minutes. For severe poisoning, a second dose of 5 g may be infused intravenously over 15 minutes to 2 hours, depending on the patient's condition (Prod Info CYANOKIT(R) 2.5g IV injection, 2006).
b) PEDIATRIC DOSE: A dose of 70 mg/kg has been used in pediatric patients, based on limited post-marketing experience outside the US (Prod Info CYANOKIT(R) 2.5g IV injection, 2006).
c) INDICATIONS: Known or suspected cyanide poisoning.
d) ADVERSE EFFECTS: Transient hypertension, allergic reactions (including anaphylaxis), nausea, headache, rash. Hydroxocobalamin's deep red color causes red-colored urine in all patients, and erythema of the skin in most (Prod Info CYANOKIT(R) 2.5g IV injection, 2006).
e) LABORATORY INTERFERENCE: Because of its' color, hydroxocobalamin interferes with colorimetric determination of various laboratory parameters. It may artificially increase serum creatinine, bilirubin, triglycerides, cholesterol, total protein, glucose, albumin , alkaline phosphatase and hemoglobin. It may artificially decrease serum ALT and amylase. It may artificially increase urinary pH, glucose, protein, erythrocytes, leukocytes, ketones, bilirubin, urobilinogen, and nitrate (Prod Info CYANOKIT(R) 2.5g IV injection, 2006).
f) HEMODIALYSIS INTERFERENCE: Dialysis machines have a spectrophotometric safety measure that can shut down after detecting blood leaking across the dialysis membrane. Hydroxocobalamin has a deep red color and can permeate the dialysis membrane, coloring the dialysate and causing the hemodialysis machine to shut down erroneously. In one case report, a patient with cyanide poisoning underwent dialysis after receiving 5 g of IV hydroxocobalamin because of refractory acidemia, reduced kidney function and hyperkalemia. A blood leak alarm caused the dialysis machine to shut down erroneously, delaying therapy, and resulting in the death of the patient (Stellpflug et al, 2013).
g) 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, 1988a; 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).

F) MONITORING OF PATIENT

1) Obtain blood for arterial blood gases, venous pO2 or measured venous percent oxygen saturation, electrolytes, serum lactate and whole-blood cyanide levels.

G) ACIDOSIS

1) Administer sodium bicarbonate, 1 milliequivalent/kilogram intravenously, to severely acidotic patients (pH less than 7.1). Base further sodium bicarbonate administration on serial arterial blood gas determinations.
2) Acidosis may be difficult to correct before administration of antidotes in serious cyanide poisoning cases (Hall & Rumack, 1986).
3) The following set of laboratory values indicate poisoning with an agent that inhibits oxidative phosphorylation (such as cyanide or hydrogen sulfide) (Hall & Rumack, 1986).

a) Cyanide and hydrogen sulfide poisoning are treated in essentially the same manner (see Hydrogen Sulfide document) with the exception of a lack of efficacy of sodium thiosulfate in hydrogen sulfide poisoning. Administering sodium thiosulfate will most likely do no harm to an hydrogen sulfide poisoned patient.
b) Arterial pO2 is usually normal until the stage of apnea. This usually remains relatively normal until terminal stages of the poisoning if supplemental oxygen and assisted ventilation are provided.
c) Serum electrolytes: The anion gap is increased. Anion gap = (Na)- (Cl + HCO(3)).

1) Normal values have been reported as 12 plus or minus 4 milliequivalents/liter (millimoles/liter), but vary depending on the laboratory used. The range for a normal anion gap reported in some laboratories is seven +/- four milliequivalents/liter (Hoffman, 1994).

d) Serum lactate is increased (normal, 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 Percent Oxygen 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 percent oxygen saturation approach each other, with MEASURED central venous percent oxygen saturation greater than 70 percent.

1) Arteriolization of venous blood gases (increased venous pO2 or measured venous percent oxygen saturation) may serve as an early clue in the diagnosis of cyanide poisoning (Hall & Rumack, 1986; Johnson & Mellors, 1988).

H) SEIZURE

1) SUMMARY

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

2) DIAZEPAM

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

3) NO INTRAVENOUS ACCESS

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

4) LORAZEPAM

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

5) PHENOBARBITAL

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

6) OTHER AGENTS

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

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

I) METHEMOGLOBINEMIA

1) Although clinically significant excessive methemoglobinemia has occurred after 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 the 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.

7) In cyanide-poisoned rats, administration of toluidine blue to prevent the development of methemoglobinemia in rats treated with either sodium nitrite/sodium thiosulfate, or 4-dimethylaminophenol did not affect the ability of these agents to restore cytochrome oxidase activity (Tadic, 1992).

J) DICOBALT EDETATE

1) Kelocyanor(R) (dicobalt-EDTA) is a highly effective cyanide-chelating agent currently used clinically in Europe, Israel and Australia (Davison, 1969; Hillman et al, 1974). It is not available in the United States.
2) PRECAUTIONS

a) Significant toxicity from the antidote (severe hypertension or hypotension, cardiac ischemia or arrhythmias) may be seen in patients incorrectly diagnosed as being poisoned with cyanide and administered this antidote (Pronczuk de Garbino & Bismuth, 1981; Tyrer, 1981). Therefore, KELOCYANOR(R) SHOULD NOT BE USED IN CASES of MILD CYANIDE POISONING or DIAGNOSTIC UNCERTAINTY (Peden et al, 1986; Tyrer, 1981).
b) Severe anaphylactoid reactions with periorbital and massive facial edema and airway compromise may also occur (Dodds & McKnight, 1985; Wright & Vesey, 1986).
c) ADVERSE EFFECTS can include nausea, vomiting, tachycardia, hypotension, hypertension, anaphylactic reactions, facial and neck edema, chest pain, diaphoresis, nervousness, tremulousness, gastrointestinal hemorrhages, seizures, cardiac irregularities and rashes (Prod Info, 1986; Prod Info, 1987; (Davison, 1969; Tyrer, 1981; Hillman et al, 1974).
d) Cobalt edetate has been shown to significantly increase plasma catecholamine levels, which probably accounts for the cardiac effects of this drug. Vasodilator activities seem to be associated with cobalt edetate, and it may induce a metabolic acidosis (Riou et al, 1993).

3) DOSE

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

1) A third 20-milliliter ampule (300 milligrams) can be injected intravenously over about 1 to 5 minutes, 5 minutes after the first one to two ampules if there is not sufficient clinical improvement (Prod Info, 1978; Prod Info, 1986; Prod Info, 1987; (Davison, 1969).
2) Manufacturers recommend following the Kelocyanor(R) injection with intravenous injection of 50 milliliters of 50 percent dextrose in water (Prod Info, 1978; Prod Info, 1986; Prod Info, 1987).
3) Kelocyanor(R) can be used with other standard cyanide antidotes (Prod Info, 1978).

b) CHILDREN: Pediatric doses have not been established by manufacturers. A suggested dose used in Israel for children is 0.5 milliliter per kilogram (not to exceed 20 milliliters) (Personal Communication, Uri Taitelman, MD, 1963).

a) Kelocyanor(R) is supplied in 20-milliliter ampules containing 300 milligrams of dicobalt-EDTA and 4 grams of dextrose in water for injection (Prod Info, 1978; Prod Info, 1986; Prod Info, 1987).

K) 4-DIMETHYLAMINOPHENOL HYDROCHLORIDE

1) 4-DMAP is a methemoglobin-inducing agent used in some European countries for the treatment of acute cyanide poisoning. Excessive methemoglobinemia may be a major complication after the use of this agent (van Dijk et al, 1986). Hemolysis may occur with therapeutic doses (van Heijst et al, 1987).

L) EXPERIMENTAL THERAPY

1) STROMA-FREE METHEMOGLOBIN SOLUTION prepared from outdated human red blood cells by oxidation of the ferrous iron of hemoglobin to the ferric form in vitro has been used in experimental animals as a cyanide antidote (Ten Eyck et al, 1985).

a) By virtue of its in vitro production, stroma-free methemoglobin solution has the advantage of sparing the oxygen-carrying capacity of the blood (Marrs, 1988).
b) It has not been studied in human poisoning cases and is not available for human administration.

2) ALPHA-KETOGLUTARIC ACID is also being tested as a replacement for sodium nitrite in combination with sodium thiosulfate in animal models, in which it has been efficacious in experimental cyanide poisoning (Moore et al, 1986).

a) In vitro and animal studies found that alpha-ketoglutaric acid binds with cyanide and antagonized cyanide-induced inhibition of brain cytochrome oxidase (Norris et al, 1990).
b) Alpha-ketoglutaric acid administered with sodium thiosulfate abolished the cyanide-induced decrease in brain gamma-aminobutyric acid in mice (Yamamoto, 1990).
c) Oral administration of alpha-ketoglutarate was effective as pretreatment only when given between 10 and 30 minutes before cyanide exposure in rats. In combination with N-acetylcysteine, it improved the protective effect but did not alter the time course for protection (Dulaney et al, 1991).
d) It has not been studied in human poisoning cases and is not available for human administration.

3) CHLORPROMAZINE has been studied in various animal models as a possible cyanide antidote. Conflicting reports of efficacy have been published (Pettersen & Cohen, 1985).

a) Experimental 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 alternative cyanide antidotes have tested phenoxybenzamine, centrophenoxine, naloxone hydrochloride, etomidate, para-aminopropiophenone, hydroxylamine and calcium-ion-channel blockers (Amery et al, 1981; Ashton et al, 1980; Bright & Marrs, 1987; Burrows & Way, 1976; Dubinsky et al, 1984; Johnson et al, 1986; Leung et al, 1984; Bright & Marrs, 1987; Marrs, 1988; Rump & Edelwijn, 1968; Vick & Froehlich, 1985; Vick & Froehlich, 1991).

M) HYPOTENSIVE EPISODE

1) SUMMARY

a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.

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).

N) ACUTE LUNG INJURY

1) ONSET: Onset of acute lung injury after toxic exposure may be delayed up to 24 to 72 hours after exposure in some cases.
2) NON-PHARMACOLOGIC TREATMENT: The treatment of acute lung injury is primarily supportive (Cataletto, 2012). Maintain adequate ventilation and oxygenation with frequent monitoring of arterial blood gases and/or pulse oximetry. If a high FIO2 is required to maintain adequate oxygenation, mechanical ventilation and positive-end-expiratory pressure (PEEP) may be required; ventilation with small tidal volumes (6 mL/kg) is preferred if ARDS develops (Haas, 2011; Stolbach & Hoffman, 2011).

a) To minimize barotrauma and other complications, use the lowest amount of PEEP possible while maintaining adequate oxygenation. Use of smaller tidal volumes (6 mL/kg) and lower plateau pressures (30 cm water or less) has been associated with decreased mortality and more rapid weaning from mechanical ventilation in patients with ARDS (Brower et al, 2000). More treatment information may be obtained from ARDS Clinical Network website, NIH NHLBI ARDS Clinical Network Mechanical Ventilation Protocol Summary, http://www.ardsnet.org/node/77791 (NHLBI ARDS Network, 2008)

3) FLUIDS: Crystalloid solutions must be administered judiciously. Pulmonary artery monitoring may help. In general the pulmonary artery wedge pressure should be kept relatively low while still maintaining adequate cardiac output, blood pressure and urine output (Stolbach & Hoffman, 2011).
4) ANTIBIOTICS: Indicated only when there is evidence of infection (Artigas et al, 1998).
5) EXPERIMENTAL THERAPY: Partial liquid ventilation has shown promise in preliminary studies (Kollef & Schuster, 1995).
6) CALFACTANT: In a multicenter, randomized, blinded trial, endotracheal instillation of 2 doses of 80 mL/m(2) calfactant (35 mg/mL of phospholipid suspension in saline) in infants, children, and adolescents with acute lung injury resulted in acute improvement in oxygenation and lower mortality; however, no significant decrease in the course of respiratory failure measured by duration of ventilator therapy, intensive care unit, or hospital stay was noted. Adverse effects (transient hypoxia and hypotension) were more frequent in calfactant patients, but these effects were mild and did not require withdrawal from the study (Wilson et al, 2005).
7) However, in a multicenter, randomized, controlled, and masked trial, endotracheal instillation of up to 3 doses of calfactant (30 mg) in adults only with acute lung injury/ARDS due to direct lung injury was not associated with improved oxygenation and longer term benefits compared to the placebo group. It was also associated with significant increases in hypoxia and hypotension (Willson et al, 2015).

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 a positive-pressure self-contained breathing apparatus (SCBA) to avoid contaminating themselves during rescue attempts (AAR, 1996).

6.7.2)

A) OXYGEN

1) Administer 100 percent oxygen to maintain an increased pO2.

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) Experimental 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 signs and symptoms (coma, seizures) who do not respond to normal supportive and antidotal therapy, and for those patients poisoned by both cyanide and carbon monoxide secondary to smoke inhalation (Hart et al, 1985).

C) FLUID/ELECTROLYTE BALANCE REGULATION

1) Establish secure large-bore IV line.

D) CYANIDE ANTIDOTE

1) A cyanide antidote, either hydroxocobalamin or the sodium nitrite/sodium thiosulfate kit, should be administered to patients with symptomatic poisoning.
2) HYDROXOCOBALAMIN-CYANOKIT(R)

a) ADULT DOSE: 5 g (two 2.5 g vials each reconstituted with 100 mL sterile 0.9% saline) administered as an intravenous infusion over 15 minutes. For severe poisoning, a second dose of 5 g may be infused intravenously over 15 minutes to 2 hours, depending on the patient's condition (Prod Info CYANOKIT(R) 2.5g IV injection, 2006).
b) PEDIATRIC DOSE: A dose of 70 mg/kg has been used in pediatric patients, based on limited post-marketing experience outside the US (Prod Info CYANOKIT(R) 2.5g IV injection, 2006).
c) INDICATIONS: Known or suspected cyanide poisoning.
d) ADVERSE EFFECTS: Transient hypertension, allergic reactions (including anaphylaxis), nausea, headache, rash. Hydroxocobalamin's deep red color causes red-colored urine in all patients, and erythema of the skin in most (Prod Info CYANOKIT(R) 2.5g IV injection, 2006).
e) LABORATORY INTERFERENCE: Because of its' color, hydroxocobalamin interferes with colorimetric determination of various laboratory parameters. It may artificially increase serum creatinine, bilirubin, triglycerides, cholesterol, total protein, glucose, albumin , alkaline phosphatase and hemoglobin. It may artificially decrease serum ALT and amylase. It may artificially increase urinary pH, glucose, protein, erythrocytes, leukocytes, ketones, bilirubin, urobilinogen, and nitrate (Prod Info CYANOKIT(R) 2.5g IV injection, 2006).
f) HEMODIALYSIS INTERFERENCE: Dialysis machines have a spectrophotometric safety measure that can shut down after detecting blood leaking across the dialysis membrane. Hydroxocobalamin has a deep red color and can permeate the dialysis membrane, coloring the dialysate and causing the hemodialysis machine to shut down erroneously. In one case report, a patient with cyanide poisoning underwent dialysis after receiving 5 g of IV hydroxocobalamin because of refractory acidemia, reduced kidney function and hyperkalemia. A blood leak alarm caused the dialysis machine to shut down erroneously, delaying therapy, and resulting in the death of the patient (Stellpflug et al, 2013).
g) 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

1) INDICATION

2) ADULT DOSE

3) PEDIATRIC DOSE

d) SODIUM THIOSULFATE

E) MONITORING OF PATIENT

1) Obtain blood for arterial blood gases, venous pO2 or measured venous percent oxygen saturation, electrolytes, serum lactate and whole-blood cyanide levels.

F) ACIDOSIS

1) Administer sodium bicarbonate, 1 milliequivalent/kilogram intravenously to severely acidotic patients (pH less than 7.1). Base further sodium bicarbonate administration on serial arterial blood gas determinations.
2) Acidosis may be difficult to correct before administration of antidotes in serious cyanide poisoning cases (Hall & Rumack, 1986).
3) The following set of laboratory values indicate poisoning with an agent that inhibits oxidative phosphorylation (such as cyanide or hydrogen sulfide) (Hall & Rumack, 1986).

d) Serum lactate is increased (normal, 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 Percent Oxygen 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 percent oxygen saturation approach each other with MEASURED central venous percent oxygen saturation greater than 70 percent.

G) SEIZURE

1) SUMMARY

2) DIAZEPAM

3) NO INTRAVENOUS ACCESS

4) LORAZEPAM

5) PHENOBARBITAL

6) OTHER AGENTS

H) 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)

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 United States.
2) PRECAUTIONS

a) Significant toxicity from the antidote (severe hypertension or hypotension, cardiac ischemia or arrhythmias) may be seen in patients incorrectly diagnosed as being poisoned with cyanide and administered this antidote (Pronczuk de Garbino & Bismuth, 1981; Tyrer, 1981). Therefore, KELOCYANOR(R) SHOULD NOT BE USED IN CASES of MILD CYANIDE POISONING or DIAGNOSTIC UNCERTAINTY (Peden et al, 1986; Tyrer, 1981).
b) Severe anaphylactoid reactions with periorbital and massive facial edema, and airway compromise may also occur (Dodds & McKnight, 1985; Wright & Vesey, 1986).
c) ADVERSE EFFECTS can include nausea, vomiting, tachycardia, hypotension, hypertension, anaphylactic reactions, facial and neck edema, chest pain, diaphoresis, nervousness, tremulousness, gastrointestinal hemorrhages, seizures, cardiac irregularities and rashes (Prod Info, 1986; Prod Info, 1987; (Davison, 1969; Tyrer, 1981; Hillman et al, 1974).
d) Cobalt edetate has been shown to significantly increase plasma catecholamine levels which probably accounts for the cardiac effects of this drug. Vasodilator activities appear to be associated with cobalt edetate and it may induce a metabolic acidosis (Riou et al, 1993).

3) DOSE

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

a) Kelocyanor(R) is supplied in 20-milliliter ampules containing 300 milligrams of dicobalt-EDTA and 4 grams of dextrose in water for injection (Prod Info, 1978; Prod Info, 1986; Prod Info, 1987).

J) 4-DIMETHYLAMINOPHENOL HYDROCHLORIDE

1) 4-DMAP is a methemoglobin-inducing agent used in some European countries for the treatment of acute cyanide poisoning. Excessive methemoglobinemia may be a major complication following the use of this agent (van Dijk et al, 1986). Hemolysis may occur with therapeutic doses (van Heijst et al, 1987).

K) EXPERIMENTAL THERAPY

3) CHLORPROMAZINE has been studied in various experimental animal models as a possible cyanide antidote. Conflicting reports of efficacy have been published (Pettersen & Cohen, 1985).

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 laboratory animals have followed ocular exposure (Ballantyne, 1983).
2) Patients exposed by this route should be observed in a controlled setting for the possible development of symptoms of systemic cyanide poisoning.

B) GENERAL TREATMENT

1) Treatment should include recommendations listed in the INHALATION EXPOSURE section when appropriate.

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

Dermal Exposure

6.9.1)

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 after severe burns from molten material (Bourrelier & Paulet, 1971) or total immersion in cyanide solutions (Bismuth et al, 1984; Dodds & McKnight, 1985).

B) GENERAL TREATMENT

1) Treatment should include recommendations listed in the INHALATION EXPOSURE section when appropriate.

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

Enhanced Elimination

1) Hemodialysis may theoretically be an effective adjunct by correcting resistant acidemia and by increasing thiocyanate clearance, thereby favoring thiosulfate-cyanide reaction to thiocyanate (Wesson et al, 1985).
2) It has, however, been used in only one reported case, and antidote therapy with sodium nitrite and sodium thiosulfate was also administered (Wesson et al, 1985).
3) Limited laboratory animal studies, using historical controls and only a few animals, have so far shown some potential effectiveness of hemodialysis when combined with thiosulfate infusion (Gonzales & Sabatini, 1989).
4) Hemodialysis cannot be considered standard therapy for cyanide poisoning.

1) CASE REPORT: Charcoal hemoperfusion has been used in one reported case of cyanide poisoning (Kreig & Saxena, 1987).
2) This patient also received supportive measures and sodium nitrite/thiosulfate antidotes.
3) The outcome in this case was no different from that of other patients treated similarly without hemoperfusion.
4) Hemoperfusion cannot be considered standard therapy for cyanide poisoning.

Life Support

Patient Disposition

6.3.1)

6.3.1.1) ADMISSION CRITERIA/ORAL

A) All symptomatic patients with cyanide exposure should be admitted to the hospital. Whenever the cyanide antidote kit or alternative antidotes are used, the patient should be admitted to the intensive care unit.

6.3.1.5) OBSERVATION CRITERIA/ORAL

A) Patients with a history of significant cyanide exposure but who are asymptomatic should be observed closely in the hospital with an IV in place and the antidotes readily available. If patients remain asymptomatic for a period of two hours, they may be released from the hospital.

Monitoring

Abstracts

Range Of Toxicity

Summary

Minimum Lethal Exposure

1) Other studies state that death occurs in 6 to 8 minutes following a 270-ppm exposure (Hathaway, 1996), after 10 minutes following a 181-ppm exposure and after 30 minutes following a 135-ppm exposure (Clayton & Clayton, 1994) Hathaway, 1996). Between 0.5 and 1 hour or more, exposure to 110 to 135 ppm of hydrogen cyanide gas is dangerous to life or is fatal (Clayton & Clayton, 1994).

Maximum Tolerated Exposure

1) Time to incapacitation was shortened in rats exposed to hydrogen cyanide (HCN) and carbon monoxide, compared with the individual gases. Blood CN levels were a function of both HCN concentration and exposure time in rats exposed to HCN, carbon monoxide and their mixtures. Neither gas affected the uptake of the other to any great extent. Blood CN levels did not correlate directly with incapacitation times (t(i)) (Chaturvedi et al, 1995) -

(HCN) (ppm)	(CO) (ppm)	t(i) (min)	Blood (CN) (mcg/mL)
64	-	35	4.2
-	1902	35	-
64	1902	11.1	1.1
184	-	5	2.3
-	5706	5	-
184	5706	2.6	1.1

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 up to 2.3 micrograms/milliliter (88.5 micromoles/liter) (Vogel et al, 1981).
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 signs and symptoms of poisoning generally occur with whole-blood cyanide levels of 1.0 micrograms/milliliter (38.5 micromoles/liter) or greater (Hall & Rumack, 1986).

2) CASE REPORT: A 48-year-old man was found dead in his car after ingesting potassium cyanide salts and contemporaneous inhalation of hydrogen cyanide. Cyanide concentrations were: stomach content: 0.2 mg/L; brain tissue: 0.96 mg/kg; lungs: 2.79 mg/kg; femoral blood: 5.3 mg/L. It was believed that yellow crystals of potassium ferrocyanide were heated on a camping stove inside his car, which produced a white toxic powder of potassium cyanide. He probably ingested this powder, as white powder was found around his mouth. In addition, he added acid to the powder which converted the salt into the highly toxic gas hydrogen cyanide. During autopsy, hemorrhages and erosions of the mucosa of the respiratory tract, esophagus, and stomach were observed (Musshoff et al, 2011).

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; hydrogen cyanide

a) TLV:

1) TLV-TWA:
2) TLV-STEL:
3) TLV-Ceiling: 4.7 ppm

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: 27.03

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 CAS74-90-8 (National Institute for Occupational Safety and Health, 2007):

1) Listed as: Hydrogen cyanide
2) REL:

a) TWA:
b) STEL: 4.7 ppm (5 mg/m(3))
c) Ceiling:
d) Carcinogen Listing: (Not Listed) Not Listed
e) Skin Designation: [skin]

1) Indicates the potential for dermal absorption; skin exposure should be prevented as necessary through the use of good work practices and gloves, coveralls, goggles, and other appropriate equipment.

f) Note(s):

3) IDLH:

a) IDLH: 50 ppm
b) Note(s): Not Listed

C) Carcinogenicity Ratings for CAS74-90-8 :

1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed ; Listed as: Hydrogen cyanide and cyanide salts, as CN; hydrogen cyanide
2) EPA (U.S. Environmental Protection Agency, 2011): Not Assessed under the IRIS program. ; Listed as: Hydrogen 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: Hydrogen cyanide
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 CAS74-90-8 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):

1) Listed as: Hydrogen cyanide
2) Table Z-1 for Hydrogen cyanide:

a) 8-hour TWA:

1) ppm: 10

a) Parts of vapor or gas per million parts of contaminated air by volume at 25 degrees C and 760 torr.

2) mg/m3: 11

a) Milligrams of substances per cubic meter of air. When entry is in this column only, the value is exact; when listed with a ppm entry, it is approximate.

3) Ceiling Value:
4) Skin Designation: Yes
5) Notation(s): Not Listed

Toxicity Information

7.7.1)

A) References: (ACGIH, 1996; Budavari, 1996 Clayton & Clayton, 1994 (Hathaway, 1996; HSDB, 1999 ITI, 1995 Lewis, 1996 OHM/TADS, 1999 (RTECS, 1999)

1) LD50- (INTRAMUSCULAR)MOUSE:

a) 2700 mcg/kg

2) LD50- (INTRAPERITONEAL)MOUSE:

a) 2990 mcg/kg

3) LD50- (ORAL)MOUSE:

a) 3700 mcg/kg
b) 4 mg/kg

4) LD50- (SUBCUTANEOUS)RAT:

a) 3700 mcg/kg

5) TCLo- (INHALATION)HUMAN:

a) 500 mg/m(3) for 3M continuous

Pharmacology Toxicology

Toxicologic Mechanism

Physicochemical

Physical Characteristics

1) The ability to detect the bitter almond-like odor of cyanide is genetically determined and from 20 to 60 percent of the population are unable to detect its presence (Hall & Rumack, 1986).

Ph

Molecular Weight

Other

1) 1 mg/m(3) (CHRIS, 1999)

Animal Toxicology

References

General Bibliography

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HYDROGEN CYANIDE

Classification | Detailed evidence-based information

Therapeutic Toxic Class

Specific Substances

Available Forms Sources

Life Support

Clinical Effects

Laboratory Monitoring

Treatment Overview

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Summary Of Exposure

Heent

Cardiovascular

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Monitoring Parameters Levels

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Summary

Minimum Lethal Exposure

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Serum Plasma Blood Concentrations

Workplace Standards

Toxicity Information

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Ph

Molecular Weight

Other

General Bibliography