Substances Included Synonyms

Therapeutic Toxic Class

A)

B)

Specific Substances

A)

1.2.1) MOLECULAR FORMULA
1) C4-H7-N

Available Forms Sources

A)

1) Isobutyronitrile is a nitrile compound (general formula R-CN).

B)

1) It is used as a chemical intermediate for the production of insecticides, in organic synthesis, in the production of plastics and synthetic fibers, and as a gasoline additive (Sax & Lewis, 1987; Clayton & Clayton, 1982; EPA, 1985; Thiess & Hey, 1969).

Overview

Life Support

A)

Clinical Effects

0.2.1)

A) Isobutyronitrile produces its systemic toxicity by metabolically releasing CYANIDE after absorption. It is also a primary irritant of the eyes, skin, and respiratory tract.

1) Coma, seizures, retrograde amnesia, dilated pupils, hypoventilation, shock, cyanosis, initial tachycardia and hypertension, and hypotension may be seen.
2) Nausea, vomiting, hepatotoxicity, and metabolic acidosis may be noted. Percutaneous absorption occurs.

0.2.3)

A) Hypoventilation, hypertension, hypotension, and tachycardia may occur.

0.2.4)

A) Conjunctivitis, mydriasis, equally red rectinal veins and arteries upon funduscopic examination, nasal irritation, and throat irritation may occur.

0.2.5)

A) Tachycardia, hypertension, hypotension, and a variety of EKG changes may occur.

0.2.6)

A) Hypoventilation, respiratory tract irritation, or pulmonary edema may develop.

0.2.7)

A) Coma, seizures, amnesia, headache, tremors, CNS stimulation, paralysis, Parkinsonism and additional sequelae may occur.

0.2.8)

A) Nausea and vomiting may occur.

0.2.9)

A) Hepatotoxicity has been observed in animal studies.

0.2.11)

A) Metbolic acidosis may occur.

0.2.14)

A) Dermal irritation and percutaneous absorption may occur.

0.2.18)

A) Amnesia may occur.

0.2.20)

A) At the time of this review, no human data on the potential teratogenicity of isobutyronitrile were available.
B) At the time of this review, no data were available to assess the potential effects of exposure to this agent during pregnancy or lactation.

Laboratory Monitoring

A)

B)

Treatment Overview

0.4.2)

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

1) Perform gastric lavage with a large bore tube after endotracheal intubation.
2) 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.
3) 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) The following treatments are those FOR POISONING BY ALL ROUTES OF EXPOSURE:
C) ADMINISTER 100% OXYGEN. Establish secure large bore IV.
D) A cyanide antidote, either hydroxocobalamin or the sodium nitrite/sodium thiosulfate kit, should be administered to patients with symptomatic poisoning.
E) 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.
F) The Cyanide Antidote Kit is administered as follows:

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.

G) SODIUM BICARBONATE: Administer 1 mEq/kg IV to acidotic patients.
H) 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.

I) 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.

J) HYPERBARIC OXYGEN may be useful in severe cases not responsive to supportive and antidotal therapy.

0.4.3)

A) ADMINISTER 100% OXYGEN. Establish secure large bore IV.
B) A cyanide antidote, either hydroxocobalamin or the sodium nitrite/sodium thiosulfate kit, should be administered to patients with symptomatic poisoning.
C) 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.
D) The Cyanide Antidote Kit is administered as follows:

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.

E) SODIUM BICARBONATE: Administer 1 mEq/kg IV to acidotic patients.
F) 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.

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) HYPERBARIC OXYGEN may be useful in severe cases not responsive to supportive and antidotal therapy.

0.4.4)

A) ADMINISTER 100% OXYGEN. Establish secure large bore IV.
B) A cyanide antidote, either hydroxocobalamin or the sodium nitrite/sodium thiosulfate kit, should be administered to patients with symptomatic poisoning.
C) 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.
D) The Cyanide Antidote Kit is administered as follows:

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.

E) SODIUM BICARBONATE: Administer 1 mEq/kg IV to acidotic patients.
F) SEIZURES: Administer a benzodiazepine; DIAZEPAM (ADULT: 5 to 10 mg IV initially; repeat every 5 to 20 minutes as needed. CHILD: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed) or LORAZEPAM (ADULT: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist. CHILD: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue).

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

G) HYPERBARIC OXYGEN may be useful in severe cases not responsive to supportive and antidotal therapy.

0.4.5)

A) OVERVIEW

1) ADMINISTER 100% OXYGEN. Establish secure large bore IV.
2) A cyanide antidote, either hydroxocobalamin or the sodium nitrite/sodium thiosulfate kit, should be administered to patients with symptomatic poisoning.
3) 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.
4) The Cyanide Antidote Kit is administered as follows:

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

5) SODIUM BICARBONATE: Administer 1 mEq/kg IV to acidotic patients.
6) SEIZURES: Administer a benzodiazepine; DIAZEPAM (ADULT: 5 to 10 mg IV initially; repeat every 5 to 20 minutes as needed. CHILD: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed) or LORAZEPAM (ADULT: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist. CHILD: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue).

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

7) HYPERBARIC OXYGEN may be useful in severe cases not responsive to supportive and antidotal therapy.

Range Of Toxicity

A)

Clinical Effects

Summary Of Exposure

A)

1) Coma, seizures, retrograde amnesia, dilated pupils, hypoventilation, shock, cyanosis, initial tachycardia and hypertension, and hypotension may be seen.
2) Nausea, vomiting, hepatotoxicity, and metabolic acidosis may be noted. Percutaneous absorption occurs.

Vital Signs

3.3.1)

A) Hypoventilation, hypertension, hypotension, and tachycardia may occur.

3.3.2)

A) Hypoventilation and cyanosis were noted in one human isobutyronitrile poisoning (Thiess & Hey, 1969).

3.3.4)

A) Initial hypertension was noted in one human isobutyronitrile poisoning (Thiess & Hey, 1969).
B) Initial hypertension may be followed by hypotension (Thiess & Hey, 1969).

3.3.5)

A) Tachycardia with a weak, thready pulse may be seen (Thiess & Hey, 1969).

Heent

3.4.1)

A) Conjunctivitis, mydriasis, equally red rectinal veins and arteries upon funduscopic examination, nasal irritation, and throat irritation may occur.

3.4.3)

A) CONJUNCTIVITIS - The primary irritant effects of isobutyronitrile may cause conjunctivitis (Clayton & Clayton, 1982).
B) MYDRIASIS - Dilated, reactive pupils have been noted during isobutyronitrile intoxication (O'Donoghue, 1985; Thiess & Hey, 1969).
C) FUNDUSCOPIC EXAMINATION - Retinal arteries and veins that appear equally red on funduscopic examination suggest the diagnosis (Buchanan et al, 1976).

3.4.5)

A) IRRITATION - The primary irritant effects of isobutyronitrile may cause mucous membrane irritation of the nose and throat (Clayton & Clayton, 1982).

3.4.6)

A) IRRITATION - The primary irritant effects of isobutyronitrile may cause mucous membrane irritation of the nose and throat (Clayton & Clayton, 1982).

Cardiovascular

3.5.1)

A) Tachycardia, hypertension, hypotension, and a variety of EKG changes may occur.

3.5.2)

A) HYPERTENSIVE EPISODE

1) Initial hypertension was noted in one human isobutyronitrile poisoning (Thiess & Hey, 1969).

B) HYPOTENSIVE EPISODE

1) The initial hypertension may be followed by hypotension (Thiess & Hey, 1969).

C) TACHYARRHYTHMIA

1) Tachycardia with a weak, thready pulse may be seen (Thiess & Hey, 1969).

D) VASODILATATION

1) Fatally poisoned rats and mice developed vasodilatation (Clayton & Clayton, 1982).

E) 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).

Respiratory

3.6.1)

A) Hypoventilation, respiratory tract irritation, or pulmonary edema may develop.

3.6.2)

A) HYPOVENTILATION

1) Hypoventilation and cyanosis were noted in one human isobutyronitrile poisoning (Thiess & Hey, 1969).

B) HYPERVENTILATION

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

C) 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).

D) ACUTE LUNG INJURY

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

E) CYANOSIS

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

Neurologic

3.7.1)

A) Coma, seizures, amnesia, headache, tremors, CNS stimulation, paralysis, Parkinsonism and additional sequelae may occur.

3.7.2)

A) COMA

1) Coma may develop in significant isobutyronitrile poisoning (Thiess & Hey, 1969).

B) SEIZURE

1) Tonic-clonic convulsions may be seen in significant isobutyronitrile poisoning (Thiess & Hey, 1969).

C) AMNESIA

1) Retrograde amnesia for the incident may be seen in significant isobutyronitrile poisoning (Thiess & Hey, 1969).

D) HEADACHE

1) A persistent headache may follow serious poisoning with isobutyronitrile (Thiess & Hey, 1969).

E) TREMOR

1) Fatally poisoned rats and mice developed symptoms of weakness, tremors, and convulsions (Clayton & Clayton, 1982).

F) 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).

G) PARALYSIS

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

H) SEQUELA

1) Most victims of acute cyanide 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).
2) PARKINSONISM - An 18-year-old patient who ingested between 975 and 1300 mg of potassium cyanide developed a Parkinsonian syndrome with rigidity and akinesis as a late sequelae (Uitti et al, 1985).

Gastrointestinal

3.8.1)

A) Nausea and vomiting may occur.

3.8.2)

A) NAUSEA AND VOMITING

1) Nausea and vomiting may occur after exposure by any route (CHRIS , 1990).

Hepatic

3.9.1)

A) Hepatotoxicity has been observed in animal studies.

3.9.2)

A) HEPATIC NECROSIS

1) Intraperitoneal injection of 38.6 mg/kg for 14 days caused liver injury in rats (Clayton & Clayton, 1982). This effect has not been reported in exposed humans.

Acid-Base

3.11.1)

A) Metbolic acidosis may occur.

3.11.2)

A) ACIDOSIS

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

Dermatologic

3.14.1)

A) Dermal irritation and percutaneous absorption may occur.

3.14.2)

A) SKIN IRRITATION

1) ANIMAL STUDIES - Isobutyronitrile induced mild skin irritation in the rabbit in the Open Draize Test (RTECS , 1991).
2) Dermal irritation may occur from the primary irritant effects of isobutyronitrile (Clayton & Clayton, 1982).

B) SKIN ABSORPTION

1) Percutaneous absorption occurs and can cause systemic poisoning (Clayton & Clayton, 1982).

Reproductive

3.20.1)

A) At the time of this review, no human data on the potential teratogenicity of isobutyronitrile were available.
B) At the time of this review, no data were available to assess the potential effects of exposure to this agent during pregnancy or lactation.

3.20.2)

A) LACK OF INFORMATION

1) At the time of this review, no human data on the potential teratogenicity of isobutyronitrile were available.

B) ANIMAL STUDIES

1) RELATED COMPOUNDS

a) Pregnant hamsters exposed by either 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 (Willhite, 1983).

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

b) Rats fed cassava powder (containing high concentrations of a cyanogenic glycoside) as 50 to 80% of their diet during the first 5 days of pregnancy showed a low incidence of limb defects, open eye defects, microcephaly, and fetal growth retardation in fetuses collected on day 20 of pregnancy (Singh, 1981).
c) Intraperitoneal injections of acrylonitrile or propionitrile to hamsters on day 8 of gestation resulted in exencephaly, encephaloceles, and rib abnormalities in the offspring (Willhite et al, 1981).

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

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

1) Neural tube defects (exencephaly, encephalocele) were the most common malformations. Hydropericardium and crooked tails were also noted (Doherty et al, 1982).
2) Concomitant infusion of sodium thiosulfate prevented both maternal signs of toxicity and the teratogenic effects of the sodium cyanide infusion (Doherty et al, 1982).

3.20.3)

A) LACK OF INFORMATION

1) At the time of this review, no data were available to assess the potential effects of exposure to this agent during pregnancy or lactation.

Carcinogenicity

3.21.1)

A) IARC Carcinogenicity Ratings for CAS78-82-0 (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

3.21.3)

A) LACK OF INFORMATION

1) At the time of this review, no data on the potential carcinogenicity of isobutyronitrile were available.

B) RELATED COMPOUNDS

1) Acrylonitrile has carcinogenic properties in some species of experimental animals and has been suggested to be associated with a slight increase in deaths from lung cancer and other malignancies in humans (Buchter & Peter, 1984; Geiger et al, 1983). Whether the metabolic release of cyanide after absorption plays any role in carcinogenesis is unknown. In isolated cell preparations, the release of cyanide does not appear to play a role in cell death (Geiger et al, 1983).

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) Whole blood cyanide levels may be obtained to document the poisoning and response to treatment.

4.1.2)

A) BLOOD/SERUM CHEMISTRY

1) A number of chemicals produce abnormalities of the hematopoietic system, liver, and kidneys. Monitoring complete blood count and liver and kidney function tests is suggested for patients with significant exposure.
2) BLOOD CYANIDE LEVELS - Fatal blood cyanide levels after oral ingestion

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

AVERAGE LEVEL	RANGE
12.4 mg/L (mcg/mL)	1.1 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)	0.4 to 230 mg/L (mcg/mL)
(3.7 mg%)	(0.04 to 23 mg%)
(SI = 1403.8 mcmol/L)	(SI = 15.4 to 8846 mcmol/L)

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

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

1) (0.02 mg%)
2) (SI = 7.7 mcmol/L)

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

1) (0.05-0.1 mg%)
2) (SI = 19.2 to 38.5 mcmol/L)

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

1) (0.1-0.25 mg%)
2) (SI = 38.5 to 96.1 mcmol/L)

d) Coma and respiratory depression: greater than

1) 2.5 mg/L (mcg/mL)
2) (0.25 mg%)
3) (SI = 96.1 mcmol/L)

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

1) 0.3 mg%
2) (SI = 115.4 mcmol/L)

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

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

1) (SI = 19.2 mcmol/L)

5) 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)

6) Serum lactate levels may be useful in monitoring the severity of poisoning and the efficacy of treatment (Vogel et al, 1981).

B) ACID/BASE

1) Arterial blood gases and serum electrolytes are useful in the assessment of potential elevated anion gap metabolic acidosis in patients poisoned with cyanide (Hall & Rumack, 1986; Vogel et al, 1981).
2) A "% O2 SATURATION GAP" may exist with decreased MEASURED and normal CALCULATED arterial %O2 saturation values due to the propensity for some cyanide to form cyanhemoglobin which will not bind or transport oxygen (Hall & Rumack, 1986).
3) A REDUCED ARTERIO-CENTRAL VENOUS MEASURED %O2 SATURATION DIFFERENCE may be seen due to cellular inability to extract oxygen (Graham et al, 1977; Paulet, 1955).

C) HEMATOLOGIC

1) Monitor methemoglobin levels during nitrite administration, especially if more than one dose is needed. Maintain methemoglobin levels below 30% (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.

4.1.4)

A) OTHER

1) MONITORING

a) If respiratory tract irritation is present, monitor arterial blood gases and chest x-ray.

Radiographic Studies

A)

1) Patients with respiratory distress should have a chest x-ray.

Methods

A)

1) Cyanide can be measured chemically by several methods but there is no time to perform this procedure; initial therapy should be based on clinical examination.
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 spectroscoppy (HSDB , 1990).
3) Cyanide can also be measured in biological fluids by gas chromatography following conversion to cyanogen chloride by reaction with chloramine-T (HSDB , 1990).
4) An ion-specific electrode method has sometimes been used for measuring cyanide in biological specimens (Bismuth et al, 1984).
5) A fluorometric diffusion method based on detection of fluorescing p-benzoquinone derivatives can be used to determine cyanide in biological fluids (HSDB , 1990).
6) An automated microdistillation assay technique has been developed that can provide whole blood and plasma cyanide levels in less than one-half hour (Groff et al, 1985) but is not yet generally available.

Treatment

Life Support

A)

Patient Disposition

6.3.1)

6.3.1.1) ADMISSION CRITERIA/ORAL

A) All patients with isobutyronitrile exposure resulting in symptoms should be admitted to the hospital. Whenever the cyanide antidote kit is used, the patient should be admitted to the intensive care unit.

6.3.1.5) OBSERVATION CRITERIA/ORAL

A) Patients with a history of significant isobutyronitrile exposure but who are asymptomatic should be observed closely in the hospital with an IV in place and the drugs drawn up ready at the bedside.

1) Exposure to some nitrile compounds has resulted in delayed onset of toxicity (from 1 or 2 hours to greater than 12 hours in some cases) (Amdur, 1959; Dequidt et al, 1974). Patients exposed to isobutyronitrile should most likely be observed in a controlled setting for at least 12 hours.

Monitoring

A)

B)

Oral Exposure

6.5.2)

A) MEDICAL FACILITY MANAGEMENT

1) EMERGENCY MEASURES: In symptomatic patients, skip these steps until other major emergency measures including oxygen administration, use of the cyanide antidote kit, and other life support measures have been instituted.

B) ACTIVATED CHARCOAL

1) The usefulness of activated charcoal is questionable. One gram of activated charcoal can adsorb 35 mg of potassium cyanide (Anderson, 1946) but this may be only a small percentage of the ingested dose. The absorption of cyanide is so rapid that charcoal may be of little use unless administered immediately after ingestion of cyanide.

a) 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; 8 of 26 charcoal treated animals died compared to 25 of 26 untreated animals (Lambert et al, 1988).

2) CHARCOAL ADMINISTRATION

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

3) CHARCOAL DOSE

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

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

b) ADVERSE EFFECTS/CONTRAINDICATIONS

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

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% oxygen to maintain an elevated pO2. Oxygen may reverse the cyanide-cytochrome oxidase complex and facilitate the conversion to thiocyanate following thiosulfate administration (Graham et al, 1977). There is fairly good evidence that 100% oxygen, combined with traditional nitrite/thiosulfate therapy is better than thiosulfate alone (Litovitz et al, 1983; Way et al, 1972).
2) 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 Hyperbaric and Undersea Medical Society (Myers & Schnitzer, 1984). Hyperbaric oxygen has been suggested to improve clinical outcome, especially in those patients with CNS toxicity not responding to more traditional therapy. Animal studies have both confirmed and refuted this (Skene et al, 1966; Way et al, 1972; Takano et al, 1980).

a) 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). Hyperbaric oxygen should be reserved for those patients with significant symptoms (i.e., coma, seizures, unstable vital signs) who do not respond to normal supportive and antidotal therapy, and for those poisoned with both cyanide and carbon monoxide secondary to smoke inhalation (Hart et al, 1985).

B) TOXIC EFFECT OF CYANIDE

1) IV ACCESS: Establish secure large bore IV line.
2) Antidotes should be administered in patients who are clinically symptomatic (i.e., unstable vital signs, acidosis, impaired consciousness, seizures, or coma).
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).

4) CYANIDE ANTIDOTE KIT

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

1) INDICATION

a) Sodium nitrite should be given initially and administered as soon as vascular access is established.
b) Further administration of sodium nitrite is dictated only by the clinical situation, provided no significant complications (hypotension, excessive methemoglobinemia) are present. Use with caution if carbon monoxide poisoning is also suspected.
c) The goal of nitrite therapy is to achieve a methemoglobin level of 20% to 30%. This level is not based on clinical data, but represents the tolerated concentration without significant adverse symptoms from methemoglobin in an otherwise healthy individual. Clinical response has been reported to occur with methemoglobin levels in the range of 3.6% to 9.2% (DiNapoli et al, 1989; Johnson et al, 1989; Johnson & Mellors, 1988).

2) ADULT DOSE

a) 10 mL of a 3% solution (300 mg) administered intravenously at a rate of 2.5 to 5 mL/minute (Prod Info NITHIODOTE intravenous injection solution, 2011). Frequent blood pressure monitoring must accompany sodium nitrite injection and the rate slowed if hypotension occurs.
b) If there is inadequate clinical response, an additional dose of sodium nitrite at half the amount of the initial dose may be administered 30 minutes following the first dose (Prod Info NITHIODOTE intravenous injection solution, 2011).

3) PEDIATRIC DOSE

a) The recommended pediatric sodium nitrite dose is 0.2 mL/kg of a 3% solution (6 mg/kg) administered intravenously at a rate of 2.5 to 5 mL/minute, not to exceed 10 mL (300 mg) (Prod Info NITHIODOTE intravenous injection solution, 2011).
b) If there is inadequate clinical response, an additional dose of sodium nitrite at half the amount of the initial dose may be administered 30 minutes following the first dose (Prod Info NITHIODOTE intravenous injection solution, 2011; Berlin, 1970a).
c) PRESENCE OF ANEMIA: If there is a reason to suspect the presence of anemia, the following initial sodium nitrite doses should be given, depending on the child's hemoglobin (sodium nitrite should not exceed the doses listed below; fatal methemoglobinemia may result) (Berlin, 1970a):

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

4) It is highly recommended that total hemoglobin and methemoglobin concentrations be rapidly measured (30 minutes after dose), when possible, before repeating a dose of sodium nitrite to be sure that dangerous methemoglobinemia will not occur, especially in the pediatric patient.
5) Monitor blood pressure frequently and treat hypotension by slowing infusion rate and giving crystalloids and vasopressors. Consider possible excessive methemoglobin formation if patient deteriorates during therapy.
6) Excessive methemoglobinemia and hypotension are potential complications of nitrite therapy.
7) In individuals with G6PD deficiency, therapy with methemoglobin-inducing agents is contraindicated because of the likelihood of serious hemolysis.

d) SODIUM THIOSULFATE

1) Sodium thiosulfate is the second component of the cyanide antidote kit. It is supplied as 50 mL of a 25% solution and it is administered intravenously. There are no adverse reactions to thiosulfate itself. The pediatric dose is adjusted for weight and not hemoglobin concentration.
2) Sodium thiosulfate supplies sulfur for the rhodanese reaction, and is recommended after sodium nitrite, hydroxocobalamin, or 4-DMAP (4-dimethylaminophenol) administration (Marrs, 1988; Hall & Rumack, 1987).
3) DOSE

a) Follow sodium nitrite with IV sodium thiosulfate. ADULT: Administer 50 mL (12.5 g) of a 25% solution IV; PEDIATRIC: 1 mL/kg of a 25% solution (250 mg/kg), not to exceed 50 mL (12.5 g) total dose (Prod Info NITHIODOTE intravenous injection solution, 2011).
b) A second dose, one-half of the first dose, may be administered if signs of cyanide toxicity reappear (Prod Info NITHIODOTE intravenous injection solution, 2011).
c) Sodium thiosulfate is usually used in combination with sodium nitrite but may be used alone (Prod Info sodium thiosulfate IV injection, 2003).
d) Sodium thiosulfate can be administered without sodium nitrite in patients at risk to develop further methemoglobinemia (ie excessive methemoglobinemia or hypotension after initial sodium nitrite administration or in the presence of methemoglobinemia or carboxyhemoglobin in patients with smoke inhalation due to fire). Sodium thiosulfate can also be used in combination with hydroxocobalamin to treat cyanide poisoning (Howland, 2011)
e) CONTINUOUS INFUSION: It has been suggested that a continuous infusion of sodium thiosulfate be given after the initial bolus to maintain high thiosulfate levels. Low sodium intravenous fluids are required to avoid sodium overload. If large amounts of sodium thiosulfate are required, hemodialysis may be necessary to maintain a physiologic serum sodium level (Turchen et al, 1991).
f) ADVERSE EVENTS: Sodium thiosulfate does not usually produce significant toxicity. Possible adverse events include hypotension, headache, nausea, vomiting, disorientation, and prolonged bleeding time (Prod Info NITHIODOTE intravenous injection solution, 2011).

C) ACIDOSIS

1) Administer sodium bicarbonate, 1 milliequivalent/kilogram intravenously to acidotic patients. Base further sodium bicarbonate administration on serial arterial blood gas determinations.
2) Acidosis may be difficult to correct prior to administration of antidotes in serious cyanide poisoning cases (Hall & Rumack, 1986).

D) MONITORING OF PATIENT

1) LABORATORY: Obtain blood for arterial blood gases, serum electrolytes, serum lactate, and whole blood cyanide.
2) INTERPRETATION OF LABORATORY VALUES

a) Arterial pO2 - Usually normal until the stage of hypoventilation or apnea. Usually remains normal until terminal stages of the poisoning if supplemental oxygen and assisted ventilation are provided.
b) SERUM ELECTROLYTES: Elevated anion gap (Na - (Cl + CO2)) (normals 12 to 16 milliequivalents/liter (12 to 16 millimoles/liter) or less) is present from the presence of unmeasured organic anions (usually lactate).
c) SERUM LACTATE: Elevated (normals 0.6 to 1.8 milliequivalents/liter) (0.6 to 1.8 millimoles/liter) due to anaerobic metabolism with excessive production of lactic acid.
d) Arterio-Central Venous Measured %O2 Saturation Difference - Due to cellular inability to extract and use oxygen, more is present on the venous side. The MEASURED values of arterial and central venous %O2 saturation approach each other with MEASURED central venous %O2 saturation greater than 70%.

E) SEIZURE

1) SUMMARY

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

2) DIAZEPAM

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

3) NO INTRAVENOUS ACCESS

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

4) LORAZEPAM

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

5) PHENOBARBITAL

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

6) OTHER AGENTS

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

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

F) METHEMOGLOBINEMIA

1) While clinically significant excessive methemoglobinemia has occurred following sodium nitrite therapy for cyanide poisoning, such instances are rare and usually occur in children receiving excessive nitrite doses.
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.

G) GENERAL TREATMENT

1) ALTERNATE ANTIDOTES

a) DICOBALT-EDTA (KELOCYANOR(R))

1) Dicobalt-EDTA (Kelocyanor(R)) is a highly effective cyanide chelating agent currently used in Europe and Australia. Significant toxicity from the antidote (severe hypertension or hypotension, cardiac ischemia or arrhythmias) may be seen in patients incorrectly diagnosed as being poisoned by cyanide and administered this antidote (Pronczuk de Garbino & Bismuth, 1981). Severe anaphylactoid reactions with airway compromise may also occur (Dodds & McKnight, 1985). Dicobalt-EDTA is not available in America.

b) 4-DIMETHYLAMINOPHENOL (4-DMAP)

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).

c) STROMA-FREE METHEMOGLOBIN SOLUTION

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 studied in experimental animals and shows promise as a cyanide antidote (Ten Eyck et al, 1985). It has not been studied in human poisoning cases and is not available for human administration.

d) ALPHA-KETOGLUTARIC ACID

1) Alpha-ketoglutaric acid is also being tested as a replacement for sodium nitrite in combination with sodium thiosulfate in animal models where it has been efficacious in experimental cyanide poisoning (Moore et al, 1986). It has not been studied in human poisoning cases and is not available for human administration.

e) CHLORPROMAZINE

1) Chlorpromazine has been studied in various animal models as a possible cyanide antidote. Conflicting reports of efficacy have been published (Pettersen & Cohen, 1986). It has not been studied in human poisoning cases.

H) 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).

I) 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).

J) HOSPITAL ADMISSION

1) All patients with cyanide exposure resulting in symptoms should be admitted to the hospital. Whenever the cyanide antidote kit is used, the patient should be admitted to the intensive care unit.

K) OBSERVATION REGIMES

1) Patients with a history of significant cyanide exposure but who are asymptomatic should be observed closely in the hospital with an IV in place and the drugs drawn up ready at the bedside. If they remain asymptomatic for a period of two hours, they may be released from the hospital.

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.

6.7.2)

A) OXYGEN

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

B) 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, as well as cyanide poisoning following smoke inhalation (Borron et al, 2007; Borron et al, 2007a).
h) In a controlled pilot study of male smokers, administration of 5 grams of intravenous 5% hydroxocobalamin significantly decreased whole blood cyanide levels (Forsyth et al, 1992).

3) CYANIDE ANTIDOTE KIT

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

1) Antidotes should be used only in significantly symptomatic patients (ie, impaired consciousness, convulsions, acidosis, or unstable vital signs).
2) Even when patients are rendered comatose by the inhalation of hydrogen cyanide gas, antidotes may not be necessary if the exposure is rapidly terminated, the patient has regained consciousness on arrival at the medical facility, and there is no acidosis or abnormality of the vital signs (Peden et al, 1986).

b) SODIUM NITRITE

1) INDICATION

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.

c) SODIUM THIOSULFATE

1) Sodium thiosulfate is the second component of the cyanide antidote kit. It is supplied as 50 mL of a 25% solution and it is administered intravenously. There are no adverse reactions to thiosulfate itself. The pediatric dose is adjusted for weight and not hemoglobin concentration.
2) Sodium thiosulfate supplies sulfur for the rhodanese reaction, and is recommended after sodium nitrite, hydroxocobalamin, or 4-DMAP (4-dimethylaminophenol) administration (Marrs, 1988; Hall & Rumack, 1987).
3) DOSE

a) Follow sodium nitrite with IV sodium thiosulfate. ADULT: Administer 50 mL (12.5 g) of a 25% solution IV; PEDIATRIC: 1 mL/kg of a 25% solution (250 mg/kg), not to exceed 50 mL (12.5 g) total dose (Prod Info NITHIODOTE intravenous injection solution, 2011).
b) A second dose, one-half of the first dose, may be administered if signs of cyanide toxicity reappear (Prod Info NITHIODOTE intravenous injection solution, 2011).
c) Sodium thiosulfate is usually used in combination with sodium nitrite but may be used alone (Prod Info sodium thiosulfate IV injection, 2003).
d) Sodium thiosulfate can be administered without sodium nitrite in patients at risk to develop further methemoglobinemia (ie excessive methemoglobinemia or hypotension after initial sodium nitrite administration or in the presence of methemoglobinemia or carboxyhemoglobin in patients with smoke inhalation due to fire). Sodium thiosulfate can also be used in combination with hydroxocobalamin to treat cyanide poisoning (Howland, 2011)
e) CONTINUOUS INFUSION: It has been suggested that a continuous infusion of sodium thiosulfate be given after the initial bolus to maintain high thiosulfate levels. Low sodium intravenous fluids are required to avoid sodium overload. If large amounts of sodium thiosulfate are required, hemodialysis may be necessary to maintain a physiologic serum sodium level (Turchen et al, 1991).
f) ADVERSE EVENTS: Sodium thiosulfate does not usually produce significant toxicity. Possible adverse events include hypotension, headache, nausea, vomiting, disorientation, and prolonged bleeding time (Prod Info NITHIODOTE intravenous injection solution, 2011).

C) 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).

Dermal Exposure

6.9.1)

A) DERMAL DECONTAMINATION

1) 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) Some chemicals can produce systemic poisoning by absorption through intact skin. Carefully observe patients with dermal exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.

B) SUPPORT

1) Patients exposed dermally should be evaluated immediately to determine the extent of the exposure. If a severe exposure is suspected, observation and treatment as described in the ORAL EXPOSURE section should be followed.

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

Enhanced Elimination

A)

1) HEMODIALYSIS may be an effective adjunct by correcting resistant acidemia and by increasing thiocyanate clearance, thereby favoring thiosulfate-cyanide reaction to thiocyanate (Wesson et al, 1985).

a) 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).
b) Limited animal studies, using historical controls and only a few animals, have so far shown some potential effectiveness when combined with thiosulfate infusion (Gonzales & Sabatini, 1989).
c) Hemodialysis cannot be considered standard therapy for cyanide poisoning at this time.

B)

1) Charcoal hemoperfusion has also been used in one reported case of cyanide poisoning (Krieg & Saxena, 1987)

a) This patient also received supportive measures and sodium nitrite/thiosulfate antidotes.
b) The outcome in this case was no different than that of other patients treated similarly without hemoperfusion.
c) Hemoperfusion cannot be considered standard therapy for cyanide poisoning at this time.

Abstracts

Case Reports

A)

1) INHALATION: In the only reported human poisoning case, a worker developed coma, tonic-clonic seizures, dilated pupils, hypoventilation, shock, and cyanosis following vapor inhalation exposure during a tank-filling operation.

a) Initial tachycardia and hypertension were seen. Hypotension later developed.
b) Treatment with cyanide antidotes (amyl nitrite, sodium nitrite, sodium nitrite, sodium thiosulfate) caused rapid recovery, but the patient had retrograde amnesia for the accident and a persistent headache (Thiess & Hey, 1969).

Range Of Toxicity

Summary

A)

Minimum Lethal Exposure

A)

1) The minimum lethal human dose to this agent has not been delineated.

B)

1) Inhalation of 5500 ppm of isobutyronitrile vapors for about 1 hour killed all exposed rats. The symptoms noted were similar to those seen after oral exposure (Clayton & Clayton, 1982).

Maximum Tolerated Exposure

A)

1) The maximum tolerated human exposure to this agent has not been delineated.

B)

1) At oral LD50 doses of 50 to 100 mg/kg (rats) and 5 to 10 mg/kg (mice), symptoms of weakness, vasodilatation, tremors, and convulsions were noted (Clayton & Clayton, 1982).
2) Only slight skin irritation was noted in guinea pigs receiving an LD50 dose of 5 mL/kg (Clayton & Clayton, 1982).
3) Feeding rats 200 mg/kg for 14 days produced depressed body weights and decreased organ weights (Clayton & Clayton, 1982). Intraperitoneal injection of 38.6 mg/kg for 14 days caused liver injury in rats (Clayton & Clayton, 1982).

Serum Plasma Blood Concentrations

7.5.2)

A) TOXIC CONCENTRATION LEVELS

1) GENERAL

a) Thiocyanate has been found in the urine of experimental animals poisoned with isobutyronitrile (Clayton & Clayton, 1982).

Workplace Standards

A)

1) Not Listed

B)

1) Listed as: Isobutyronitrile
2) REL:

a) TWA: 8 ppm (22 mg/m(3))
b) STEL:
c) Ceiling:
d) Carcinogen Listing: (Not Listed) Not Listed
e) Skin Designation: Not Listed
f) Note(s):

3) IDLH: Not Listed

C)

1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed ; Listed as: Isobutyronitrile
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)

1) Not Listed

Toxicity Information

7.7.1)

A) References: EPA, 1985 RTECS, 1988

1) LD50- (ORAL)MOUSE:

a) 25 mg/kg

2) LD50- (ORAL)RAT:

a) 50 mg/kg

Pharmacology Toxicology

Toxicologic Mechanism

A)

B)

1) A postulated mechanism for cyanide release is by hydroxylation to cyanohydrin, which in an alkaline medium can spontaneously degrade forming hydrogen cyanide and a corresponding carbonyl compound (Tanii & Hashimoto, 1986).

Physicochemical

Physical Characteristics

A)

Molecular Weight

A)

Animal Toxicology

References

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ISOBUTYRONITRILE

Classification | Detailed evidence-based information

Therapeutic Toxic Class

Specific Substances

Available Forms Sources

Life Support

Clinical Effects

Laboratory Monitoring

Treatment Overview

Range Of Toxicity

Summary Of Exposure

Vital Signs

Heent

Cardiovascular

Respiratory

Neurologic

Gastrointestinal

Hepatic

Acid-Base

Dermatologic

Reproductive

Carcinogenicity

Monitoring Parameters Levels

Radiographic Studies

Methods

Life Support

Patient Disposition

Monitoring

Oral Exposure

Inhalation Exposure

Eye Exposure

Dermal Exposure

Enhanced Elimination

Case Reports

Summary

Minimum Lethal Exposure

Maximum Tolerated Exposure

Serum Plasma Blood Concentrations

Workplace Standards

Toxicity Information

Toxicologic Mechanism

Physical Characteristics

Molecular Weight

General Bibliography