Therapeutic Toxic Class

A)

Specific Substances

1) Cyanoethane
2) Ether Cyanatus
3) Ethyl Cyanide
4) Ethylkyanid (Czech)
5) Hydrocyanic Ether
6) Propanenitrile
7) Propannitril (Czech)
8) Propionic Nitrile
9) Propiononitrile
10) Propylnitrile

1.2.1) MOLECULAR FORMULA
1) C3-H5-N

Available Forms Sources

A)

1) Propionitrile is used as a solvent, a setting agent for resins, and a raw material for the manufacture of medicines (Lewis, 1992; ITI, 1985).

Life Support

A)

Clinical Effects

0.2.1)

A) In one reported human case of propionitrile poisoning, rapid loss of consciousness and metabolic acidosis were noted.
B) Most of the toxicity of propionitrile results from metabolic release of CYANIDE after systemic absorption. Onset of symptoms may therefore be delayed.

1) Expected effects of released CYANIDE include central nervous system and respiratory stimulation followed by depression, giddiness, headache, dyspnea, palpitations, vomiting, bradycardia, hypotension, coma, seizures, cardiac dysrhythmias, and metabolic acidosis. Cyanosis is generally a late sign, seen only at the stage of circulatory collapse and apnea.

C) Propionitrile ingestion causes perforating duodenal ulceration in animals. It is an eye irritant.

0.2.3)

A) Part of the initial presentation of cyanide poisoning may be hyperpnea and tachypnea. Hypoventilation progressing to apnea may be seen in the later phases of cyanide poisoning and is a major cause of death.
B) 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.
C) Tachycardia may occur.

0.2.4)

A) Eye irritation may be seen.

0.2.5)

A) Tachycardia and hypertension are early findings. Bradycardia and hypotension are late findings.

0.2.6)

A) Tachypnea, dyspnea, and hyperpnea may occur early.
B) Hypoventilation leading to apnea and cyanosis is seen late in the course.

0.2.7)

A) Agitation, headache, anxiety, coma and convulsions may be seen.

0.2.8)

A) Nausea, vomiting and abdominal pain may occur. In rats, duodenal ulceration has been reported.

0.2.11)

A) Metabolic acidosis may be noted.

0.2.12)

A) An elevated anion gap metabolic acidosis is seen in cyanide poisoning, largely from excess production of lactic acid.

0.2.16)

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

0.2.20)

A) Some animal studies showed evidence of teratogenicity and maternal toxicity.
B) Sodium cyanide, acetonitrile, acrylonitrile, propionitrile, and laetrile caused resorptions or malformations in the offspring of hamsters.

Laboratory Monitoring

A)

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

1) 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.

C) 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.
D) ADMINISTER 100% OXYGEN.
E) HYPERBARIC OXYGEN: may be useful in severe cases not responsive to supportive and antidotal therapy.
F) Establish secure large bore IV.
G) A cyanide antidote, either hydroxocobalamin OR the sodium nitrite/sodium thiosulfate kit, should be administered to patients with symptomatic poisoning.
H) 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.
I) 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.

J) SODIUM BICARBONATE: Administer 1 mEq/kg IV to acidotic patients. Monitor arterial blood gases to guide further bicarbonate therapy.
K) 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.

L) METHEMOGLOBINEMIA

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

M) 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.
N) 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.
O) HEMODIALYSIS AND HEMOPERFUSION do not seem to be indicated or efficacious in most cases of cyanide poisoning.
P) Observe patients with ingestion carefully for the possible development of esophageal or gastrointestinal tract irritation or burns. If signs or symptoms of esophageal irritation or burns are present, consider endoscopy to determine the extent of injury.

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) Respiratory tract irritation, if severe, can progress to pulmonary edema which may be delayed in onset up to 24 to 72 hours after exposure in some cases.
C) If respiratory tract irritation or respiratory depression is evident, monitor arterial blood gases, chest x-ray, and pulmonary function tests.
D) 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.
E) If bronchospasm and wheezing occur, consider treatment with inhaled sympathomimetic agents.
F) All patients with significant inhalation exposure should be carefully observed for signs of SYSTEMIC CYANIDE POISONING. The following recommendations should be followed if significant cyanide poisoning is present.
G) SYSTEMIC CYANIDE POISONING

1) All patients with significant inhalation exposure should be carefully observed for signs of systemic cyanide poisoning. The following recommendations should be followed if significant cyanide poisoning is present.

H) ADMINISTER 100% OXYGEN.
I) HYPERBARIC OXYGEN: may be useful in severe cases not responsive to supportive and antidotal therapy.
J) Establish secure large bore IV.
K) A cyanide antidote, either hydroxocobalamin OR the sodium nitrite/sodium thiosulfate kit, should be administered to patients with symptomatic poisoning.
L) 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.
M) 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.

N) SODIUM BICARBONATE: Administer 1 mEq/kg IV to acidotic patients. Monitor arterial blood gases to guide further bicarbonate therapy.
O) 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.

P) METHEMOGLOBINEMIA

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

Q) 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.
R) HEMODIALYSIS AND HEMOPERFUSION do not seem to be indicated or efficacious in most cases of cyanide poisoning.

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) SYSTEMIC CYANIDE POISONING

1) ADMINISTER 100% OXYGEN.
2) HYPERBARIC OXYGEN: may be useful in severe cases not responsive to supportive and antidotal therapy.
3) Establish secure large bore IV.
4) A cyanide antidote, either hydroxocobalamin OR the sodium nitrite/sodium thiosulfate kit, should be administered to patients with symptomatic poisoning.
5) HYDROXOCOBALAMIN: ADULT DOSE: 5 g (two 2.5 g vials each reconstituted with 100 mL sterile 0.9% saline) administered as an intravenous infusion over 15 minutes. For severe poisoning, a second dose of 5 g may be infused intravenously over 15 minutes to 2 hours, depending on the patient's condition. CHILDREN: Limited experience; a dose of 70 mg/kg has been used in pediatric patients.
6) 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.

C) SODIUM BICARBONATE: Administer 1 mEq/kg IV to acidotic patients. Monitor arterial blood gases to guide further bicarbonate therapy.

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) SYSTEMIC CYANIDE POISONING

a) It is possible that systemic cyanide poisoning may occur following significant dermal exposure. The following recommendations should be followed if significant cyanide poisoning is present.

3) ADMINISTER 100% OXYGEN.
4) HYPERBARIC OXYGEN: may be useful in severe cases not responsive to supportive and antidotal therapy.
5) Establish secure large bore IV.
6) A cyanide antidote, either hydroxocobalamin OR the sodium nitrite/sodium thiosulfate kit, should be administered to patients with symptomatic poisoning.
7) 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.
8) 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.

9) SODIUM BICARBONATE: Administer 1 mEq/kg IV to acidotic patients. Monitor arterial blood gases to guide further bicarbonate therapy.
10) 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.

11) METHEMOGLOBINEMIA

a) If excessive methemoglobinemia occurs, some authors have suggested that methylene blue should not be used because it could cause release of cyanide from the cyanmethemoglobin complex. Such authors have suggested that emergency exchange transfusion is the treatment of choice. Hyperbaric oxygen therapy could be used to support the patient while preparations for exchange transfusion are being made.
b) However, methylene blue or toluidine blue have been used successfully in this setting without worsening the course of 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.
c) 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.
d) 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.
e) 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.

12) HYPOTENSION: Infuse 10 to 20 mL/kg isotonic fluid. If hypotension persists, administer dopamine (5 to 20 mcg/kg/min) or norepinephrine (ADULT: begin infusion at 0.5 to 1 mcg/min; CHILD: begin infusion at 0.1 mcg/kg/min); titrate to desired response.
13) 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.
14) HEMODIALYSIS AND HEMOPERFUSION do not seem to be indicated or efficacious in most cases of cyanide poisoning.
15) Treat dermal irritation or burns with standard topical therapy. Patients developing dermal hypersensitivity reactions may require treatment with systemic or topical corticosteroids or antihistamines.

Range Of Toxicity

A)

Clinical Effects

Summary Of Exposure

A)

B)

1) Expected effects of released CYANIDE include central nervous system and respiratory stimulation followed by depression, giddiness, headache, dyspnea, palpitations, vomiting, bradycardia, hypotension, coma, seizures, cardiac dysrhythmias, and metabolic acidosis. Cyanosis is generally a late sign, seen only at the stage of circulatory collapse and apnea.

C)

Vital Signs

3.3.1)

A) Part of the initial presentation of cyanide poisoning may be hyperpnea and tachypnea. Hypoventilation progressing to apnea may be seen in the later phases of cyanide poisoning and is a major cause of death.
B) 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.
C) Tachycardia may occur.

3.3.2)

A) Hyperpnea, tachypnea, and dyspnea may be early findings (Hall & Rumack, 1986).
B) Hypoventilation and apnea are late manifestations (Hall & Rumack, 1986).

3.3.4)

A) Severe hypotension may be seen (Hall & Rumack, 1986).

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

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

3.3.5)

A) Tachycardia may be an early finding (Hall & Rumack, 1986).

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

B) Symptomatic bradycardia is a common late finding in severe poisoning (Hall & Rumack, 1986).

Heent

3.4.1)

A) Eye irritation may be seen.

3.4.3)

A) EQUALLY RED RETINAL VEINS AND ARTERIES - A sign suggestive of the diagnosis of cyanide poisoning may be retinal veins and arteries that appear almost equally red on funduscopic examination (Buchanan et al, 1976).
B) SYSTEMIC POISONING - Direct eye contact could result in absorption and possible systemic symptoms (Ballantyne, 1983).
C) CONJUNCTIVITIS - Propionitrile can produce eye irritation (Grant, 1986).
D) Dilated pupils are common in severe cyanide poisoning (Vogel et al, 1981).
E) Propionitrile induced moderate eye irritation in the rabbit in the Standard Draize Test (RTECS , 1991).

Cardiovascular

3.5.1)

A) Tachycardia and hypertension are early findings. Bradycardia and hypotension are late findings.

3.5.2)

A) TACHYARRHYTHMIA

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

B) BRADYCARDIA

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

C) ELECTROCARDIOGRAM ABNORMAL

1) Erratic atrial and ventricular cardiac rhythms with varying degrees of atrioventricular block followed by asystole may be seen in severe cyanide poisoning (Hall & Rumack, 1986).

Respiratory

3.6.1)

A) Tachypnea, dyspnea, and hyperpnea may occur early.
B) Hypoventilation leading to apnea and cyanosis is seen late in the course.

3.6.2)

A) HYPERVENTILATION

1) Part of the initial presentation of cyanide poisoning may be hyperpnea, tachypnea, and dyspnea (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) CYANOSIS

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

D) ACUTE LUNG INJURY

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

Neurologic

3.7.1)

A) Agitation, headache, anxiety, coma and convulsions may be seen.

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 has occurred with dermal and inhalation exposure to propionitrile (Bismuth et al, 1987).

D) SEIZURE

1) Convulsions have not been reported with propionitrile poisoning, but are common in cyanide poisoning (Hall & Rumack, 1986).

E) PARALYSIS

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

F) SEQUELA

1) CASE REPORT - 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).
2) Parkinsonism developed progressively over 3 weeks after acute ingestion of 1,500 mg of potassium cyanide. Slowed gait, masked facies, hypophonia, mild rigidity, and minimal tremor were noted. Damage was permanent, and although not evident on CT or MRI scan at 6 months, was noted on MRI at 12 months postingestion. There was no improvement with levodopa therapy (Rosenberg et al, 1989).
3) Progressive parkinsonism was reported after acute cyanide poisoning over a five-year period in a 46-year-old woman. Drooling and dysphagia increased over this time, and marked tongue and mouth dystonia developed. Apraxia of eyelid opening was also marked (Carella et al, 1988). Some improvement was noted with trihexyphenidyl treatment.
4) 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).

Gastrointestinal

3.8.1)

A) Nausea, vomiting and abdominal pain may occur. In rats, duodenal ulceration has been reported.

3.8.2)

A) VOMITING

1) Vomiting has been reported after dermal and inhalation propionitrile exposure (Bismuth et al, 1987). No odor of bitter almonds was noted in the vomitus.

B) DUODENAL ULCER DISEASE

1) Rats fed propionitrile orally have developed duodenal ulceration with perforation into the pancreas and liver (Szabo et al, 1977; Szabo et al, 1979; Szabo et al, 1982). Possible mechanisms for ulcerogenesis include vagal stimulation (Szabo et al, 1979), gastroduodenal motility alterations (Pihan et al, 1985), stimulation of serum gastrin levels (Lichtenberger et al, 1977), and changes in the rise of duodenal mucosal alkaline secretion in response to acids (Briden et al, 1985). Stimulation of gastric secretion does not appear to be an ulcerogenic mechanism is rats fed propionitrile (Robert et al, 1975).

Acid-Base

3.11.1)

A) Metabolic acidosis may be noted.

3.11.2)

A) ACIDOSIS

1) Metabolic acidosis with elevated serum lactate levels has been reported in propionitrile poisoning (Bismuth et al, 1987).

Dermatologic

3.14.2)

A) SKIN ABSORPTION

1) Propionitrile may be absorbed through intact skin (Bismuth et al, 1987).

B) SKIN IRRITATION

1) Propionitrile induced mild skin irritation in rabbits in the Standard Draize Test (RTECS , 1991).

Endocrine

3.16.1)

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

3.16.2)

A) HYPERGLYCEMIA

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

Reproductive

3.20.1)

A) Some animal studies showed evidence of teratogenicity and maternal toxicity.
B) Sodium cyanide, acetonitrile, acrylonitrile, propionitrile, and laetrile caused resorptions or malformations in the offspring of hamsters.

3.20.2)

A) ANIMAL STUDIES

1) CONGENITAL ANOMALY

a) Hamsters injected intraperitoneally with propionitrile on day 8 of gestation had a high incidence of exencephaly, encephaloceles, and rib malformations in the offspring (Willhite et al, 1981). Intraperitoneal injection of sodium thiosulfate to hamster dams prevented maternal toxicity from the propionitrile and, at lower propionitrile doses, teratogenic effects in the offspring (Willhite et al, 1981). At higher propionitrile doses, sodium thiosulfate injections to the dams did not prevent teratogenic effects in the offspring (Willhite et al, 1981).

2) LACK OF EFFECT

a) A study of rats administered orally 0 to 80 mg/kg/day of propionitrile from days 6 through 19 of gestation did not show evidence of teratogenicity (Johannsen et al, 1986).

3) FETOTOXICITY

a) In rat studies, fetotoxicity and a change in litter size were observed. In hamster studies, fetotoxicity, cytological changes (including somatic cell genetic material), extra embryonic structures and specific developmental abnormalities of the central nervous system and musculoskeletal system were detected (RTECS , 1991).

3.20.3)

A) HUMANS

1) LACK OF INFORMATION

a) Post-implantation mortality was observed in hamster studies (RTECS , 1991). The only reported case of acute human propionitrile poisoning was a 55 year old smoker who coincidentally had a bilateral bronchogenic carcinoma. No evidence is available to otherwise assess the possible carcinogenicity of this agent.

B) ANIMAL STUDIES

1) MATERNAL TOXICITY - Hamster dams injected intraperitoneally with propionitrile of day 8 of gestation developed symptoms of toxicity (Willhite et al, 1981). This maternal toxicity could be prevented with injection of sodium thiosulfate (Willhite et al, 1981).
2) In rats administered 0, 20, 40 and 80 mg/kg of propionitrile daily by gavage from days 6 through 19 of gestation, one maternal death and some evidence of reduced mean maternal body weight and increased early and late resorptions were observed in the 80 mg/kg/day group (Johannsen et al, 1986).

a) In the 80 mg/kg/day group, there were significant decreases in mean fetal body weight, an increase in unossified stephebrae, and an increase in the incidence of post implantation loss in the highest dosing schedules (Johannsen et al, 1986).
b) The authors of this study felt that observed embryotoxicity was secondary to maternal toxicity, that there was no evidence of teratogenicity in this animal model, and that propionitrile is "not likely to be a threat to the offspring of pregnant individuals even in the industrial setting."

Carcinogenicity

3.21.1)

A) IARC Carcinogenicity Ratings for CAS107-12-0 (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) HUMANS

1) PULMONARY CARCINOMA

a) CASE REPORT - The only reported case of acute human propionitrile poisoning was a 55 year old male smoker who coincidentally had a bilateral bronchogenic carcinoma (Bismuth et al, 1987). No evidence is available to otherwise assess the possible carcinogenicity of this agent. Sex chromosome loss/nondisjunction was observed in S. cerevisiae.

Laboratory Monitoring

Monitoring Parameters Levels

4.1.1)

A) Monitor arterial blood gases, venous pO2 or measured venous %O2 saturation, serum electrolytes and lactate, and whole blood cyanide levels.

4.1.2)

A) BLOOD/SERUM CHEMISTRY

1) Arterial blood gases and serum electrolytes are useful in the assessment of potential elevated anion gap metabolic acidosis (Bismuth et al, 1987; 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 evolved 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).
4) Serum lactate levels may be useful in monitoring the severity of poisoning and the efficacy of treatment (Bismuth et al, 1987).
5) Monitor methemoglobin levels during nitrite administration, especially if more than one dose is needed. Maintain methemoglobin levels below 30% (Hall & Rumack, 1986).
6) Monitor arterial blood gases and/or pulse oximetry, pulmonary function tests, and chest x-ray in patients with significant exposure.
7) A number of chemicals produce abnormalities of the hematopoietic system, liver, and kidneys. Monitoring complete blood count, urinalysis, and liver and kidney function tests is suggested for patients with significant exposure.
8) Whole blood cyanide levels are useful to confirm the diagnosis but cannot be obtained quickly enough to be used to determine the need for specific therapy (Hall & Rumack, 1986). Thiocyanate plasma levels may also be useful to confirm the diagnosis (Bismuth et al, 1987) but may be a late finding in some patients and could be falsely elevated in smokers. For more details on the interpretation of blood cyanide levels, SEE CYANIDE MANAGEMENT.
9) Conversion of whole blood cyanide values expressed in traditional units (mcg/mL) to Standard International (SI) units (mcmol/L):

a) mcg/mL = mcmol/L x 0.026
b) mcmol/L = mcg/mL/0.026

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. Urine cyanide and thiocyanate levels are of little or no value in assessing acutely ill patients.

Radiographic Studies

A)

B)

C)

Treatment

Patient Disposition

6.3.1)

6.3.1.1) ADMISSION CRITERIA/ORAL

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

6.3.1.2) HOME CRITERIA/ORAL

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

6.3.1.3) CONSULT CRITERIA/ORAL

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

6.3.1.5) OBSERVATION CRITERIA/ORAL

A) Several hours of observation in a controlled setting are advisable in all cases of significant exposure whether or not symptoms are initially present, as it may take some time for release of cyanide from absorbed propionitrile.
B) Asymptomatic patients with a history of significant cyanide exposure but who are asymptomatic should be observed closely in the hospital. Vascular access should be established, laboratory evaluations performed, and the cyanide antidote kit or hydroxocobalamin ready at the bedside. If laboratory evaluations are normal and the patient remains asymptomatic for at least 8 hours, they may be discharged from the hospital with appropriate follow-up instructions.

6.3.4)

6.3.4.1) ADMISSION CRITERIA/EYE

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

6.3.4.2) HOME CRITERIA/EYE

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

6.3.4.3) CONSULT CRITERIA/EYE

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

6.3.4.5) OBSERVATION CRITERIA/EYE

A) As systemic poisoning could possibly occur after direct ocular exposure, patients require several hours of observation in a controlled setting.
B) Asymptomatic patients with a history of significant cyanide exposure but who are asymptomatic should be observed closely in the hospital. Vascular access should be established, laboratory evaluations performed, and the cyanide antidote kit or hydroxocobalamin ready at the bedside. If laboratory evaluations are normal and the patient remains asymptomatic for at least 8 hours, they may be discharged from the hospital with appropriate follow-up instructions.

6.3.5)

6.3.5.1) ADMISSION CRITERIA/DERMAL

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

6.3.5.2) HOME CRITERIA/DERMAL

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

6.3.5.3) CONSULT CRITERIA/DERMAL

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

6.3.5.5) OBSERVATION CRITERIA/DERMAL

A) Patients with dermal exposure require several hours of observation in a controlled setting, as it may take some time for cyanide to be absorbed and released from propionitrile.
B) Asymptomatic patients with a history of significant cyanide exposure but who are asymptomatic should be observed closely in the hospital. Vascular access should be established, laboratory evaluations performed, and the cyanide antidote kit or hydroxocobalamin ready at the bedside. If laboratory evaluations are normal and the patient remains asymptomatic for at least 8 hours, they may be discharged from the hospital with appropriate follow-up instructions.

Monitoring

A)

Oral Exposure

6.5.2)

A) MEDICAL FACILITY MANAGEMENT

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

B) DILUTION

1) DILUTION: If no respiratory compromise is present, administer milk or water as soon as possible after ingestion. Dilution may only be helpful if performed in the first seconds to minutes after ingestion. The ideal amount is unknown; no more than 8 ounces (240 mL) in adults and 4 ounces (120 mL) in children is recommended to minimize the risk of vomiting (Caravati, 2004).

C) GASTRIC LAVAGE/PRECAUTIONS

1) Significant esophageal or gastrointestinal tract irritation or burns may occur following ingestion. The possible benefit of early removal of some ingested material by cautious gastric lavage must be weighed against potential complications of bleeding or perforation.

D) 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.

E) ACTIVATED CHARCOAL

1) The usefulness of activated charcoal is questionable in cyanide ingestion. One gram of activated charcoal may bind only 35 mg of potassium cyanide (Anderson, 1946). However, because propionitrile is a larger molecule and activated charcoal would theoretically have the potential for greater adsorption, it should probably be administered.

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 mg/kg) 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).

6.5.3)

A) DILUTION

1) DILUTION: If no respiratory compromise is present, administer milk or water as soon as possible after ingestion. Dilution may only be helpful if performed in the first seconds to minutes after ingestion. The ideal amount is unknown; no more than 8 ounces (240 mL) in adults and 4 ounces (120 mL) in children is recommended to minimize the risk of vomiting (Caravati, 2004).

B) 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 nitrite/thiosulfate alone (Way et al, 1972).

C) HYPERBARIC OXYGEN THERAPY

1) Hyperbaric oxygen (HBO) therapy is approved for cyanide poisoning as a Category One condition (approved for third party reimbursement and known to be 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 traditional therapy (Hall & Rumack, 1986). Animal studies have both confirmed and refuted this (Skene et al, 1966; Takano et al, 1980; Way et al, 1972).
3) There have been 2 reported cases of patients treated with both the nitrite/thiosulfate antidote combination and hyperbaric oxygen. One survived (Trapp, 1970) and one died despite both therapies (Litovitz et al, 1983).
4) CONCLUSION: Hyperbaric oxygen therapy should at present be reserved for those patients with significant symptomatology not responding to supportive and antidote therapy and for patients with both cyanide and carbon monoxide poisoning secondary to smoke inhalation (Hall & Rumack, 1986).

D) CYANIDE ANTIDOTE

1) INTRAVENOUS ACCESS: Establish a secure large bore intravenous 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) Hydroxocobalamin, 5 to 20 grams administered IV, 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).

4) 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).

b) SODIUM NITRITE

1) 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.
2) 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.
3) Excessive methemoglobinemia and hypotension are potential complications of nitrite therapy.
4) In individuals with G6PD deficiency, therapy with methemoglobin-inducing agents is contraindicated because of the likelihood of serious hemolysis.
5) 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).

6) 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).

7) 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)

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).

E) ACIDOSIS

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

F) MONITORING OF PATIENT

1) LABORATORY: ARTERIAL BLOOD GASES: Obtain blood for arterial blood gases, a simultaneous central venous %O2 saturation if a central venous line is needed for other monitoring purposes, serum electrolytes and lactate, and cyanide and thiocyanate levels.
2) A number of chemicals produce abnormalities of the hematopoietic system, liver, and kidneys. Monitoring complete blood count, urinalysis, and liver and kidney function tests is suggested for patients with significant exposure.
3) INTERPRETATION OF LABORATORY VALUES

a) Arterial pO2: Usually normal until the stage of apnea. Usually remains normal until terminal stages of the poisoning if supplemental oxygen and assisted ventilation are provided.
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 >70% when supplemental oxygen is not being administered. The effect of administration of supplemental oxygen on these findings is presently unknown.

4) ABDOMINAL EXAMINATION: A careful abdominal examination should be done in cases of propionitrile ingestion. Abdominal pain or tenderness, fever, hematemesis, or hematochezia should prompt an evaluation for gastrointestinal irritation, ulceration or perforation, although to date these effects have only been seen in experimental animals (Szabo et al, 1977).

G) SEIZURE

1) SUMMARY

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

2) DIAZEPAM

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

3) NO INTRAVENOUS ACCESS

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

4) LORAZEPAM

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

5) PHENOBARBITAL

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

6) OTHER AGENTS

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

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

H) METHEMOGLOBINEMIA

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

a) Inducing a "therapeutic methemoglobin level" of 25% 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.

I) ANTIDOTE

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.

J) 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).

K) 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.

6.7.2)

A) OXYGEN

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

B) 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) 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: 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.

Life Support

A)

Abstracts

Case Reports

A)

1) INHALATION: A 55 year old French male chemical worker reported by Bismuth et al (1987) was exposed to propionitrile by the inhalation and dermal routes while attempting to repair a leaking pump without sufficient personal protective equipment.

a) He rapidly became comatose. Neither hypotension, bradycardia, nor apnea were noted 25 minutes later in the company infirmary.
b) The patient was administered supplemental oxygen by nasal cannula and transported to the Clinique Toxicologique in Paris, where skin decontamination with soap and water was done. Mild metabolic acidosis and elevated serum lactate levels were seen on laboratory evaluation.
c) The patient received 4 grams of hydroxycobalamin and 8 grams of sodium thiosulfate and rapidly recovered.
d) A bilateral bronchogenic carcinoma was coincidently diagnosed, but no relationship to propionitrile exposure could be ascertained.
e) Whole blood cyanide level was 5.71 mcg/mL (220 mcmol/L) before antidote treatment, and decreased to 0.93 mcg/mL (36 mcmol/L) after completion of the hydroxycobalamin/sodium thiosulfate infusion 30 minutes later.
f) Plasma thiocyanate was undetectable prior to antidote infusion, and increased to 21.1 mcg/mL (0.36 mmol/L) after infusion completion.

Range Of Toxicity

Summary

A)

Minimum Lethal Exposure

A)

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

B)

1) Air concentrations of HYDROGEN CYANIDE GAS greater than 100 ppm (120 mg/m(3)) are dangerous to life or fatal within 1/2 to 1 hour or more, while concentrations of 270 ppm (300 mg/m(3)) may produce almost instant fatality (Hall & Rumack, 1986).

Maximum Tolerated Exposure

A)

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

B)

1) Air concentrations of HYDROGEN CYANIDE GAS from 18 to 36 ppm (20 to 40 mg/m(3)) are associated with mild symptoms after several hours exposure, while concentrations of 45 to 54 ppm (50 to 60 mg/m(3)) produce no immediate or late effects with exposures from 20 minutes to 1 hour (Hall & Rumack, 1986).

Serum Plasma Blood Concentrations

7.5.2)

A) TOXIC CONCENTRATION LEVELS

1) CASE REPORTS

a) In the one reported case of human propionitrile poisoning, the initial whole blood cyanide level was 5.71 micrograms/milliliter (220 micromoles/liter) (Bismuth et al, 1987).
b) WHOLE BLOOD CYANIDE LEVELS AND ASSOCIATED SYMPTOMS in untreated patients (Hall & Rumack, 1986) -

Whole Blood Cyanide		Symptoms
(mcg/mL)	(mcmol/L)
0.2 to 0.5	8 to 20	None
0.5 to 1.0	20 to 38	Tachycardia, Flushing
1.0 to 2.5	48 to 95	Depressed level of consciousness
2.5 to 3.0	95 to 114	Coma
> 3.0	> 114	Death

c) Patients administered supportive treatment have survived cyanide poisoning with whole blood cyanide levels up to about 3 micrograms/milliliter (114 micromoles/liter) (Hall & Rumack, 1986). Patients treated with specific antidotes have survived cyanide poisoning with whole blood cyanide levels up to 16.3 micrograms/milliliter (627 micromoles/liter) (Hall et al, 1986a).

Workplace Standards

A)

1) Not Listed

B)

1) Listed as: Propionitrile
2) REL:

a) TWA: 6 ppm (14 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: Propionitrile
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: HSDB, 1994 Lewis, 1992 RTECS, 1994

1) LD50- (INTRAPERITONEAL)MOUSE:

a) 28 mg/kg

2) LD50- (ORAL)MOUSE:

a) 35,797 mcg/kg

3) LD50- (INTRAPERITONEAL)RAT:

a) 25 mg/kg

4) LD50- (ORAL)RAT:

a) 39 mg/kg

Pharmacology Toxicology

Toxicologic Mechanism

A)

1) This binding inhibits oxidative phosphorylation, with resultant cellular inability to utilize oxygen, anaerobic metabolism, lactic acid production, and severely decreased ATP production (Bismuth et al, 1987; Hall & Rumack, 1986).

B)

Physicochemical

Physical Characteristics

A)

Molecular Weight

A)

Animal Toxicology

References

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FeedBack

PROPIONITRILE

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

Acid-Base

Dermatologic

Endocrine

Reproductive

Carcinogenicity

Monitoring Parameters Levels

Radiographic Studies

Patient Disposition

Monitoring

Oral Exposure

Inhalation Exposure

Eye Exposure

Dermal Exposure

Enhanced Elimination

Life Support

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