BENZYL CYANIDE

Classification | Detailed evidence-based information

Therapeutic Toxic Class

Specific Substances

1.2.1) MOLECULAR FORMULA
1) C8-H7-N

Life Support

Clinical Effects

0.2.1)

A) USES: Benzyl cyanide is an aromatic nitrile compound made from benzyl chloride and sodium or potassium cyanide. It is found naturally in watercress and certain other plants. Benzyl cyanide is available as a technical grade material and is used as an intermediate in organic synthesis, especially for penicillin precursors, amphetamines, phenobarbital, methyl phenidylacetate, esters for perfumes, and flavoring agents.
B) TOXICOLOGY: The toxicity of benzyl cyanide is presumably by metabolism with release of cyanide after absorption.
C) EPIDEMIOLOGY: To date, no cases of serious human poisoning have been reported.
D) WITH POISONING/EXPOSURE

1) The following are signs and symptoms from cyanide poisoning in general. All of these effects may not be documented for benzyl cyanide, but could potentially occur in individual cases.
2) MILD TO MODERATE TOXICITY: Tachycardia and hypertension may be seen in the initial phases of cyanide poisoning. A burning sensation in the mouth and throat may occur. Part of the initial presentation of cyanide poisoning may be hyperpnea and tachypnea. Headache may be an early sign of cyanide poisoning. CNS stimulation with varied presentations from anxiety to agitation and combative behavior may be seen in the early stages of cyanide poisoning. Nausea, vomiting, and abdominal pain may occur, especially after ingestion of cyanide salts. Elevated anion gap metabolic acidosis and elevated serum lactate levels are frequently found in cyanide poisoning.
3) SEVERE TOXICITY: Mydriasis is common in severe poisoning. Bradycardia and hypotension are seen in the late phases of cyanide poisoning. Erratic atrial and ventricular cardiac rhythms with varying degrees of atrioventricular block followed by asystole may be seen in severe cyanide poisoning. ST-T segment elevation or depression may be noted. Hypoventilation progressing to apnea may be seen in the later phases of cyanide poisoning and is a major cause of death. Noncardiogenic pulmonary edema has been reported in cases of acute cyanide poisoning. Cyanosis is a late finding in cyanide poisoning and does not occur until the stage of apnea and circulatory collapse. Seizures and coma are common in severe cyanide poisoning. Rare cases of neurological sequelae, such as personality changes, memory deficits, and extrapyramidal syndromes, have been reported.

0.2.20)

A) There are no reported cases of human or animal teratogenicity due to benzyl cyanide itself.

0.2.21)

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

0.2.22)

A) Patients with cyanide poisoning characteristically have an odor of bitter almonds in gastric contents or expired breath, although up to 50% of the population cannot detect its presence

Laboratory Monitoring

Treatment Overview

0.4.2)

A) MANAGEMENT OF MILD TO MODERATE TOXICITY

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

B) MANAGEMENT OF SEVERE TOXICITY

1) Elevated lactate, increased anion gap metabolic acidosis, and an elevated venous oxygen saturation all suggest a significant cyanide exposure. Manage airway early. Patients who are comatose or severely ill due to suspected cyanide poisoning should be administered a cyanide antidote kit. In addition, standard ACLS or PALS therapy should be provided to manage symptoms. Administer sodium bicarbonate for severe acidemia. Treat seizures with IV benzodiazepines; barbiturates or propofol may be needed if seizures persist or recur. Treat severe hypotension with IV 0.9% NaCl at 10 to 20 mL/kg. Add dopamine or norepinephrine if unresponsive to fluids.

C) DECONTAMINATION

1) PREHOSPITAL: Prehospital activated charcoal can be considered for large ingestions in which there will be a delay in definitive healthcare; however, a poison center should initially be consulted.
2) HOSPITAL: Activated charcoal binds poorly to cyanide salts; however, the use of activated charcoal should be considered in a patient that presents within one hour of an oral ingestion.

D) AIRWAY MANAGEMENT

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

E) CYANIDE ANTIDOTE

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

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

3) CYANIDE ANTIDOTE KIT

a) An alternative, a sodium nitrite/sodium thiosulfate kit, is administered as follows: SODIUM NITRITE: ADULT: Administer 300 mg (10 mL of 3% solution) IV at a rate of 2.5 to 5 mL/min; PEDIATRIC (with normal hemoglobin concentration): 0.2 mL/kg of a 3% solution (6 mg/kg) IV at a rate of 2.5 to 5 mL/min, not to exceed 10 mL (300 mg). The dose may be lowered if the patient is severely anemic, but administration should not be delayed for laboratory results. Blood methemoglobin levels should be monitored for 30 to 60 minutes following the infusion to prevent severe toxicity. If methemoglobin concentration is greater than 30%, it should likely be reversed with methylene blue. Nitrites may also cause vasodilatory effects which may contribute to hypotension. A second dose, one-half of the first dose, may be administered 30 minutes later if there is inadequate clinical response. Use with caution if carbon monoxide poisoning is also suspected. SODIUM THIOSULFATE: Follow sodium nitrite with IV sodium thiosulfate. ADULT: Administer 50 mL (12.5 g) of a 25% solution IV; PEDIATRIC: 1 mL/kg of a 25% solution (250 mg/kg), not to exceed 50 mL (12.5 g) total dose. A second dose, one-half of the first dose, may be administered if signs of cyanide toxicity reappear. This agent enhances conversion of cyanide to thiocyanate which is eliminated in the urine. Patients with renal failure may need dialysis to eliminate thiocyanate. ALTERNATE ANTIDOTES: Kelocyanor(R) (dicobalt-EDTA) and 4-DMAP (4-dimethylaminophenol) are among the cyanide antidotes in clinical use outside the US.

F) METHEMOGLOBINEMIA

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

G) ENHANCED ELIMINATION

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

H) PATIENT DISPOSITION

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

I) PITFALLS

1) Treatment should not be delayed for laboratory results if a cyanide exposure is strongly suspected. If cyanide toxicity develops concurrent with carbon monoxide poisoning (e.g., closed space fire), hydroxocobalamin is the preferred antidote. If that is not available, sodium thiosulfate may be used alone. Use of amyl nitrite or sodium nitrite will cause methemoglobinemia, further reducing oxygen carrying capacity.

J) TOXICOKINETICS

1) Benzyl cyanide can be absorbed by ingestion, inhalation, and through the skin. The toxicity of benzyl cyanide is presumably by metabolism with release of cyanide after absorption, in a manner similar to that of other nitriles. The released cyanide metabolite can then be complexed with sulfane sulfur by the endogenous enzyme, rhodanese, and excreted in the urine as thiocyanate.

K) DIFFERENTIAL DIAGNOSIS

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

0.4.3)

A) INHALATION: Move patient to fresh air. Monitor for respiratory distress. If cough or difficulty breathing develops, evaluate for respiratory tract irritation, bronchitis, or pneumonitis. Administer oxygen and assist ventilation as required. Treat bronchospasm with an inhaled beta2-adrenergic agonist. Consider systemic corticosteroids in patients with significant bronchospasm.
B) Administer 100% oxygen, establish secure large bore IV.
C) CYANIDE ANTIDOTE SUMMARY

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

D) HYDROXOCOBALAMIN

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

E) CYANIDE ANTIDOTE KIT

1) An alternative, a sodium nitrite/sodium thiosulfate kit, is administered as follows: SODIUM NITRITE: ADULT: Administer 300 mg (10 mL of 3% solution) IV at a rate of 2.5 to 5 mL/min; PEDIATRIC (with normal hemoglobin concentration): 0.2 mL/kg of a 3% solution (6 mg/kg) IV at a rate of 2.5 to 5 mL/min, not to exceed 10 mL (300 mg). The dose may be lowered if the patient is severely anemic, but administration should not be delayed for laboratory results. Blood methemoglobin levels should be monitored for 30 to 60 minutes following the infusion to prevent severe toxicity. If methemoglobin concentration is greater than 30%, it should likely be reversed with methylene blue. Nitrites may also cause vasodilatory effects which may contribute to hypotension. A second dose, one-half of the first dose, may be administered 30 minutes later if there is inadequate clinical response. Use with caution if carbon monoxide poisoning is also suspected. SODIUM THIOSULFATE: Follow sodium nitrite with IV sodium thiosulfate. ADULT: Administer 50 mL (12.5 g) of a 25% solution IV; PEDIATRIC: 1 mL/kg of a 25% solution (250 mg/kg), not to exceed 50 mL (12.5 g) total dose. A second dose, one-half of the first dose, may be administered if signs of cyanide toxicity reappear. This agent enhances conversion of cyanide to thiocyanate which is eliminated in the urine. Patients with renal failure may need dialysis to eliminate thiocyanate. ALTERNATE ANTIDOTES: Kelocyanor(R) (dicobalt-EDTA) and 4-DMAP (4-dimethylaminophenol) are among the cyanide antidotes in clinical use outside the US.

F) METHEMOGLOBINEMIA

0.4.4)

A) DECONTAMINATION: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, the patient should be seen in a healthcare facility.

0.4.5)

A) OVERVIEW

1) DECONTAMINATION: Remove contaminated clothing and jewelry and place them in plastic bags. Wash exposed areas with soap and water for 10 to 15 minutes with gentle sponging to avoid skin breakdown. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).
2) While cyanide can be absorbed through intact skin, most reported cases have involved whole-body immersion in cyanide solutions or large-area burns with molten cyanide solutions. Most nitrile compounds are well absorbed through intact skin, and may cause delayed onset of symptoms following exposure by this route.
3) Administer 100% oxygen, establish secure large bore IV.
4) CYANIDE ANTIDOTE SUMMARY

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

5) HYDROXOCOBALAMIN

6) CYANIDE ANTIDOTE KIT

a) An alternative, a sodium nitrite/sodium thiosulfate kit, is administered as follows: SODIUM NITRITE: ADULT: Administer 300 mg (10 mL of 3% solution) IV at a rate of 2.5 to 5 mL/min; PEDIATRIC (with normal hemoglobin concentration): 0.2 mL/kg of a 3% solution (6 mg/kg) IV at a rate of 2.5 to 5 mL/min, not to exceed 10 mL (300 mg). The dose may be lowered if the patient is severely anemic, but administration should not be delayed for laboratory results. Blood methemoglobin levels should be monitored for 30 to 60 minutes following the infusion to prevent severe toxicity. If methemoglobin concentration is greater than 30%, it should likely be reversed with methylene blue. Nitrites may also cause vasodilatory effects which may contribute to hypotension. A second dose, one-half of the first dose, may be administered 30 minutes later if there is inadequate clinical response. SODIUM THIOSULFATE: Follow sodium nitrite with IV sodium thiosulfate. ADULT: Administer 50 mL (12.5 g) of a 25% solution IV; PEDIATRIC: 1 mL/kg of a 25% solution (250 mg/kg), not to exceed 50 mL (12.5 g) total dose. A second dose, one-half of the first dose, may be administered if signs of cyanide toxicity reappear. This agent enhances conversion of cyanide to thiocyanate which is eliminated in the urine. Patients with renal failure may need dialysis to eliminate thiocyanate. ALTERNATE ANTIDOTES: Kelocyanor(R) (dicobalt-EDTA) and 4-DMAP (4-dimethylaminophenol) are among the cyanide antidotes in clinical use outside the US.

7) METHEMOGLOBINEMIA

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

Range Of Toxicity

Clinical Effects

Summary Of Exposure

Heent

3.4.3)

A) MYDRIASIS: Dilated pupils are common in severe poisoning (Vogel et al, 1981).
B) FUNDUSCOPIC EXAMINATION: Retinal arteries and veins that appear equally red on funduscopic examination suggest the diagnosis (Buchanan et al, 1976).

3.4.6)

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

Cardiovascular

3.5.2)

A) TACHYARRHYTHMIA

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

B) BRADYCARDIA

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

C) ELECTROCARDIOGRAM ABNORMAL

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

Respiratory

3.6.2)

A) HYPERVENTILATION

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

B) APNEA

1) Hypoventilation progressing to apnea may be seen in the later phases of cyanide poisoning and is a major cause of death (Vogel et al, 1981).

C) ACUTE LUNG INJURY

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

D) 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

3.7.2)

A) HEADACHE

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

B) CENTRAL STIMULANT ADVERSE REACTION

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

C) COMA

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

D) SEIZURE

1) Seizures are common in severe 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) 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

3.8.2)

A) NAUSEA AND VOMITING

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

Acid-Base

3.11.2)

A) LACTIC 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

3.14.2)

A) SKIN ABSORPTION

1) Benzyl cyanide can be absorbed through intact skin (Sax, 1984).

B) SKIN IRRITATION

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

Reproductive

3.20.1)

A) There are no reported cases of human or animal teratogenicity due to benzyl cyanide itself.

3.20.2)

A) LACK OF INFORMATION

1) There are no reported cases of human teratogenicity due to benzyl cyanide itself.

B) ANIMAL STUDIES

1) RELATED COMPOUNDS

a) ACETONITRILE - 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). Injections of sodium thiosulfate antagonized the teratogenic effects (Willhite, 1983).

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

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

c) CASSAVA - 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).
d) ACRYLONITRILE/PROPIONITRILE - 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).

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

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

Carcinogenicity

3.21.1)

A) IARC Carcinogenicity Ratings for CAS140-29-4 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):

1) Not Listed

3.21.2)

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

3.21.3)

A) LACK OF INFORMATION

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

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) Monitor serum chemistry and lactate concentrations.
B) Monitor vital signs.
C) Monitor arterial and venous blood gases.
D) Cyanide levels can be measured to confirm the diagnosis, but are usually not available in a timely manner to be clinically useful.
E) Institute continuous cardiac monitoring and obtain an ECG.
F) Methemoglobin should also be monitored frequently in patients receiving intravenous sodium nitrite.
G) Obtain a carboxyhemoglobin level in the setting of a fire.
H) Consider a head CT for comatose patients.

4.1.2)

A) ACID/BASE

1) Obtain blood for arterial blood gases, venous pO2 or measured venous %O2 saturation.

B) BLOOD/SERUM CHEMISTRY

1) Obtain blood for electrolytes, serum lactate, and whole blood cyanide levels.
2) Blood cyanide levels and associated symptoms (Graham et al, 1977):

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

1) No symptoms: Less than 0.2 mg/L (mcg/mL) (0.02 mg%; SI = 7.7 mcmol/L)
2) Flushing and tachycardia: 0.5-1.0 mg/L (mcg/mL) (0.05-0.1 mg%; SI = 19.2 to 38.5 mcmol/L)
3) Obtundation: 1.0-2.5 mg/L (mcg/mL) (0.1-0.25 mg%; SI = 38.5 to 96.1 mcmol/L)
4) Coma and respiratory depression: Greater than 2.5 mg/L (mcg/mL) (0.25 mg%; SI = 96.1 mcmol/L)
5) Death: Greater than 3 mg/L (mcg/mL) (0.3 mg%; SI = 115.4 mcmol/L)

C) LABORATORY INTERFERENCE

1) Based on in vivo studies, hydroxocobalamin (an approved cyanide antidote), due to its red color, may interfere with the following spectrophotometric tests: serum AST, creatinine, bilirubin, magnesium and serum iron (Beckerman et al, 2009; Curry et al, 1992).
2) In vitro studies, involving hydroxocobalamin samples, have reported artificially increased laboratory parameters of serum creatinine, bilirubin, triglycerides, cholesterol, total protein, glucose, albumin, and alkaline phosphatase concentrations. These studies have also reported artificially decreased parameters of serum ALT and amylase concentrations (Beckerman et al, 2009).
3) CARBOXYHEMOGLOBIN: In vitro and in vivo studies, involving rabbits and using a co-oximeter as a measurement tool, have demonstrated hydroxocobalamin interference with carboxyhemoglobin measurements, with a dose-dependent 14.7% increase in carboxyhemoglobin concentration (Beckerman et al, 2009; Lee et al, 2007). It has been suggested that , this interference is not clinically significant, particularly in emergent situations involving suspected cases of cyanide poisoning (Borron et al, 2007). However, it is recommended that a carboxyhemoglobin measurement be obtained prior to hydroxocobalamin administration in order to avoid any possible interference .

D) OTHER

1) SCREENING LABORATORY TESTS: 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).
4) Serum lactate levels may be useful in monitoring the severity of poisoning and the efficacy of treatment (Vogel et al, 1981).
5) Monitor methemoglobin levels during nitrite administration, especially if more than one dose is needed. Maintain methemoglobin levels below 30% (Hall & Rumack, 1986).
6) CYANIDE LEVELS AFTER HYDROXOCOBALAMIN: A 51-year-old man received a hydroxocobalamin infusion as an antidote following an intentional ingestion of an unknown amount of potassium cyanide solution (3 g/L) and, one hour after the hydroxocobalamin infusion, the patient's cyanide plasma level was 42 mcg/dL. His plasma cyanide level before the hydroxocobalamin infusion was 29 mcg/dL. It is believed that hydroxocobalamin was extracting cyanide from the red blood cells (which typically contain a higher concentration of cyanide than in plasma) to form cyanocobalamin (vitamin B12 ) in plasma, which was subsequently detected as cyanide (Weng et al, 2004).

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.

Radiographic Studies

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

Methods

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/SPECTROSCOPY: Cyanide can be liberated from biological specimens by acidification, followed by absorption in alkali and interaction with chromophoric reagents for quantification by absorbance spectroscopy (HSDB , 1990).
3) BIOLOGICAL SPECIMENS/GAS CHROMATOGRAPHY: Cyanide can also be measured in biological fluids by gas chromatography following conversion to cyanogen chloride by reaction with chloramine-T (HSDB , 1990).
4) BIOLOGICAL SPECIMENS/SPECIFIC ELECTRODE: An ion-specific electrode method has sometimes been used for measuring cyanide in biological specimens (Bismuth et al, 1984).
5) BIOLOGICAL SPECIMENS/FLUOROMETRIC DIFFUSION: A fluorometric diffusion method based on detection of fluorescing p-benzoquinone derivatives can be used to determine cyanide in biological fluids (HSDB , 1990).
6) BIOLOGICAL SPECIMENS/MICRODISTILLATION ASSAY: 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

Patient Disposition

6.3.1)

6.3.1.1) ADMISSION CRITERIA/ORAL

A) Any patient with symptomatic poisoning should be admitted to an 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) Any exposure to benzyl cyanide should be referred to a healthcare facility. Patients who remain asymptomatic with normal laboratory studies can be discharged after 6 hours.

Monitoring

Oral Exposure

6.5.1)

A) SUMMARY

1) If the clinical presentation following benzyl cyanide exposure is consistent, the treatment is essentially that of cyanide poisoning.
2) In symptomatic patients, institute emergency measures including basic life support and administration of cyanide antidote kit (if readily available) before performing the following steps:

B) ACTIVATED CHARCOAL

1) Absorption of cyanide is rapid and charcoal may only be beneficial if administered immediately after ingestion.
2) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION

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

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

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).

6.5.2)

A) SUMMARY

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

B) ACTIVATED CHARCOAL

1) The usefulness of activated charcoal may be questionable.

a) 1 gram of activated charcoal may adsorb 35 milligrams of potassium cyanide (Anderson, 1946) but this is a low percentage.
b) The absorption of cyanide is so rapid that charcoal may be of little use unless administered immediately after ingestion of cyanide.
c) Immediate administration of a large dose of superactivated charcoal (4 grams/kilogram) to rats given an oral lethal dose of potassium cyanide (35 to 40 milligrams/kilogram) prevented lethality. Eight of 26 treated animals died compared to 25 of 26 untreated animals (Lambert et al, 1988).

2) CHARCOAL ADMINISTRATION

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

3) CHARCOAL DOSE

b) ADVERSE EFFECTS/CONTRAINDICATIONS

C) GASTRIC LAVAGE

1) INDICATIONS: Consider gastric lavage with a large-bore orogastric tube (ADULT: 36 to 40 French or 30 English gauge tube {external diameter 12 to 13.3 mm}; CHILD: 24 to 28 French {diameter 7.8 to 9.3 mm}) after a potentially life threatening ingestion if it can be performed soon after ingestion (generally within 60 minutes).

a) Consider lavage more than 60 minutes after ingestion of sustained-release formulations and substances known to form bezoars or concretions.

2) PRECAUTIONS:

a) SEIZURE CONTROL: Is mandatory prior to gastric lavage.
b) AIRWAY PROTECTION: Place patients in the head down left lateral decubitus position, with suction available. Patients with depressed mental status should be intubated with a cuffed endotracheal tube prior to lavage.

3) LAVAGE FLUID:

a) Use small aliquots of liquid. Lavage with 200 to 300 milliliters warm tap water (preferably 38 degrees Celsius) or saline per wash (in older children or adults) and 10 milliliters/kilogram body weight of normal saline in young children(Vale et al, 2004) and repeat until lavage return is clear.
b) The volume of lavage return should approximate amount of fluid given to avoid fluid-electrolyte imbalance.
c) CAUTION: Water should be avoided in young children because of the risk of electrolyte imbalance and water intoxication. Warm fluids avoid the risk of hypothermia in very young children and the elderly.

4) COMPLICATIONS:

a) Complications of gastric lavage have included: aspiration pneumonia, hypoxia, hypercapnia, mechanical injury to the throat, esophagus, or stomach, fluid and electrolyte imbalance (Vale, 1997). Combative patients may be at greater risk for complications (Caravati et al, 2001).
b) Gastric lavage can cause significant morbidity; it should NOT be performed routinely in all poisoned patients (Vale, 1997).

5) CONTRAINDICATIONS:

a) Loss of airway protective reflexes or decreased level of consciousness if patient is not intubated, following ingestion of corrosive substances, hydrocarbons (high aspiration potential), patients at risk of hemorrhage or gastrointestinal perforation, or trivial or non-toxic ingestion.

6.5.3)

A) SUPPORT

1) If the clinical presentation is consistent, the treatment of benzyl cyanide poisoning is the same as that for cyanide intoxication.
2) MANAGEMENT OF MILD TO MODERATE TOXICITY

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

3) MANAGEMENT OF SEVERE TOXICITY

a) Elevated lactate, increased anion gap metabolic acidosis, and an elevated venous oxygen saturation all suggest a significant cyanide exposure. Manage airway early. Patients who are comatose or severely ill due to suspected cyanide poisoning should be administered a cyanide antidote kit. In addition, standard ACLS or PALS therapy should be provided to manage symptoms. Administer sodium bicarbonate for severe acidemia. Treat seizures with IV benzodiazepines; barbiturates or propofol may be needed if seizures persist or recur. Treat severe hypotension with IV 0.9% NaCl at 10 to 20 mL/kg. Add dopamine or norepinephrine if unresponsive to fluids.

B) MONITORING OF PATIENT

1) Monitor serum chemistry and lactate concentrations.
2) Monitor vital signs.
3) Monitor arterial and venous blood gases.
4) Cyanide levels can be measured to confirm the diagnosis, but are usually not available in a timely manner to be clinically useful.
5) Institute continuous cardiac monitoring and obtain an ECG.
6) Methemoglobin should also be monitored frequently in patients receiving intravenous sodium nitrite.
7) Obtain a carboxyhemoglobin level in the setting of a fire.
8) Consider a head CT for comatose patients.
9) The following set of laboratory values suggest poisoning with an agent that inhibits oxidative phosphorylation (ie, cyanide, hydrogen sulfide) (Hall & Rumack, 1986).

a) Cyanide and hydrogen sulfide poisoning are treated in essentially the same manner, (See Hydrogen Sulfide Management) with the exception of lack of efficacy of sodium thiosulfate in hydrogen sulfide poisoning. Administering sodium thiosulfate will most likely do no harm to a hydrogen sulfide poisoned patient.
b) Arterial pO2: Usually normal until the stage of apnea. Usually remains normal until terminal stages of the poisoning if supplemental oxygen and assisted ventilation are provided.
c) Serum electrolytes: Elevated anion gap (Na - (C1 + CO2)) (normals 12 to 16 milliequivalents/liter (12 to 16 millimoles/liter) or less) is present from the presence of unmeasured organic anions (usually lactate).
d) Serum Lactate: Elevated (normals 0.6 to 1.8 milliequivalents/liter) (0.6 to 1.8 millimoles/liter) due to anaerobic metabolism with excessive production of lactic acid.
e) Arterio-Central Venous Measured %O2 Saturation Difference: Due to cellular inability to extract and use oxygen, more is present on the venous side. The MEASURED values of arterial and central venous %O2 saturation approach each other with MEASURED central venous %O2 saturation greater than 70%.

1) Arteriolization of venous blood gases (elevated venous pO2 or measured venous %O2 saturation) may serve as an early clue in the diagnosis of cyanide poisoning (Hall & Rumack, 1986; Johnson & Mellors, 1988).

C) OXYGEN

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

a) Oxygen may reverse the cyanide-cytochrome oxidase complex and facilitate the conversion to thiocyanate following thiosulfate administration (Graham et al, 1977).
b) There is fairly good evidence that 100% oxygen, combined with traditional nitrite/thiosulfate therapy is better than thiosulfate alone (Litovitz et al, 1983; Way et al, 1972).

D) FLUID/ELECTROLYTE BALANCE REGULATION

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

E) CYANIDE ANTIDOTE

a) ADULT DOSE: 5 g (two 2.5 g vials each reconstituted with 100 mL sterile 0.9% saline) administered as an intravenous infusion over 15 minutes. For severe poisoning, a second dose of 5 g may be infused intravenously over 15 minutes to 2 hours, depending on the patient's condition (Prod Info CYANOKIT(R) 2.5g IV injection, 2006).
b) PEDIATRIC DOSE: A dose of 70 mg/kg has been used in pediatric patients, based on limited post-marketing experience outside the US (Prod Info CYANOKIT(R) 2.5g IV injection, 2006).
c) INDICATIONS: Known or suspected cyanide poisoning.
d) ADVERSE EFFECTS: Transient hypertension, allergic reactions (including anaphylaxis), nausea, headache, rash. Hydroxocobalamin's deep red color causes red-colored urine in all patients, and erythema of the skin in most (Prod Info CYANOKIT(R) 2.5g IV injection, 2006).
e) LABORATORY INTERFERENCE: Because of its' color, hydroxocobalamin interferes with colorimetric determination of various laboratory parameters. It may artificially increase serum creatinine, bilirubin, triglycerides, cholesterol, total protein, glucose, albumin , alkaline phosphatase and hemoglobin. It may artificially decrease serum ALT and amylase. It may artificially increase urinary pH, glucose, protein, erythrocytes, leukocytes, ketones, bilirubin, urobilinogen, and nitrate (Prod Info CYANOKIT(R) 2.5g IV injection, 2006).
f) HEMODIALYSIS INTERFERENCE: Dialysis machines have a spectrophotometric safety measure that can shut down after detecting blood leaking across the dialysis membrane. Hydroxocobalamin has a deep red color and can permeate the dialysis membrane, coloring the dialysate and causing the hemodialysis machine to shut down erroneously. In one case report, a patient with cyanide poisoning underwent dialysis after receiving 5 g of IV hydroxocobalamin because of refractory acidemia, reduced kidney function and hyperkalemia. A blood leak alarm caused the dialysis machine to shut down erroneously, delaying therapy, and resulting in the death of the patient (Stellpflug et al, 2013).
g) Hydroxocobalamin, 5 to 20 grams administered intravenously, has been shown to be effective, as sole antidotal therapy, for acute cyanide poisoning following cyanide salt ingestion or inhalation (Borron et al, 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).
i) Hydroxocobalamin has been shown to be effective in treating cyanide poisoned animals and has the advantage of neither producing methemoglobinemia nor hypotension as does sodium nitrite (Forsyth et al, 1993).
j) According to antidote stocking guidelines, hydroxocobalamin was preferred over the conventional cyanide antidote kit due to its wider indications, ease of use, and anticipated safety in widespread use. It can safely be used in patients with smoke inhalation (None Listed, 2008).
k) In cases of cyanide ingestion, both the nitrite/thiosulfate combination and hydroxocobalamin seem to be effective antidotes. Hydroxocobalamin offers an improved safety profile for children and pregnant women, as well as patients suffering from cyanide poisoning in conjunction with smoke inhalation (Shepherd & Velez, 2008). Patients who are exposed to cyanide in house fires may have high carbon monoxide levels. Inducing methemoglobinemia with nitrites may further impair oxygen carrying capacity.
l) Some authors advocate combined hydroxocobalamin-thiosulfate therapy because of possible synergy of complementary mechanisms (Kerns et al, 2008).

3) CYANIDE ANTIDOTE KIT

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

1) INDICATION

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

2) ADULT DOSE

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

3) PEDIATRIC DOSE

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

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

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

d) SODIUM THIOSULFATE

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

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

F) 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).

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).

7) PHENYTOIN/FOSPHENYTOIN

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

1) PHENYTOIN INTRAVENOUS PUSH VERSUS INTRAVENOUS INFUSION

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

c) FOSPHENYTOIN

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

8) RECURRING SEIZURES

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

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

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

H) METHEMOGLOBINEMIA

1) CAUSE

a) The goal of nitrite therapy has been to achieve a methemoglobin level of 20% to 30%. This level is not based on clinical data, but represents the tolerated concentration without significant adverse symptoms from methemoglobin in an otherwise healthy individual. Clinical response has been reported to occur with methemoglobin levels in the range of 3.6% to 9.2% (DiNapoli et al, 1989; Johnson et al, 1989; Johnson & Mellors, 1988).
b) Clinically significant excessive methemoglobinemia has rarely occurred following sodium nitrite therapy for cyanide poisoning. It usually occurs in children receiving excessive nitrite doses. Intravenous sodium nitrite administered as a 3% solution over 15 to 20 minutes induces approximately 7% to 14% methemoglobin (Kirk et al, 1993).

2) TREATMENT

a) If excessive methemoglobinemia occurs, some authors have suggested that methylene blue should not be used because it could cause release of cyanide from the cyanmethemoglobin complex. Such authors have suggested that emergency exchange transfusion is the treatment of choice (Berlin, 1970). Hyperbaric oxygen therapy could be used to support the patient while preparations for exchange transfusion are being made.
b) However, methylene or toluidine blue have been used successfully in this setting without worsening the course of the cyanide poisoning (van Heijst et al, 1987). There is some controversy over whether or not the induction of methemoglobinemia is the sodium nitrite mechanism of action in cyanide poisoning. As long as intensive care monitoring and further antidote doses (if required) are available, methylene blue can most likely be safely administered in this setting.
c) SUMMARY

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

d) METHYLENE BLUE

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

e) TOLUIDINE BLUE OR TOLONIUM CHLORIDE (GERMANY)

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

I) 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).

J) 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).

K) DICOBALT EDETATE

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

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

3) DOSE

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

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

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

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

L) 4-DIMETHYLAMINOPHENOL HYDROCHLORIDE

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

M) HYPERBARIC OXYGEN THERAPY

1) Hyperbaric oxygen (HBO) therapy is approved for cyanide poisoning as a category one condition (approved for third party reimbursement and known effective as treatment) by the Undersea Medical Society (Myers & Schnitzer, 1984).
2) Hyperbaric oxygen has been suggested to improve clinical outcome, especially in those patients with CNS toxicity not responding to more traditional therapy.
3) Animal studies have both confirmed and refuted this (Skene et al, 1966; Way et al, 1972; Takano et al, 1980).
4) Case reports suggest that HBO may be of value (Carden, 1970; Trapp, 1970). However, one patient treated with supportive therapy, antidotes, and HBO did not survive a serious poisoning (Litovitz et al, 1983).
5) Hyperbaric oxygen should be reserved for those patients with significant symptoms (ie, coma, seizures) who do not respond to normal supportive and antidotal therapy, and for those patients poisoned by both cyanide and carbon monoxide secondary to smoke inhalation (Hart et al, 1985).

N) EXPERIMENTAL THERAPY

1) STROMA-FREE METHEMOGLOBIN SOLUTION

a) Stroma-free methemoglobin solution prepared from outdated human red blood cells by oxidation of the ferrous iron of hemoglobin to the ferric form in vitro has been used in experimental animals as a cyanide antidote (Ten Eyck et al, 1985).
b) By virtue of its in vitro production, stroma-free methemoglobin solution has the advantage of sparing the oxygen-carrying capacity of the blood (Marrs, 1988).
c) It has not been studied in human poisoning cases and is not available for human administration.

2) ALPHA-KETOGLUTARIC ACID

a) Alpha-ketoglutaric acid is also being tested as a replacement for sodium nitrite in combination with sodium thiosulfate in animal models where it has been efficacious in experimental cyanide poisoning (Moore et al, 1986).
b) In vitro and animal studies show that alpha-ketoglutaric acid binds with cyanide and thereby antagonizes cyanide-induced inhibition of brain cytochrome oxidase (Norris et al, 1990).
c) Alpha-ketoglutaric acid administered with sodium thiosulfate abolished the cyanide-induced decrease in brain gamma-aminobutyric acid in mice (Yamamoto, 1990).
d) Oral administration of alpha-ketoglutarate was effective as pretreatment only when given between 10 and 30 minutes prior to cyanide exposure in rats. In combination with N-acetylcysteine, it improved the protective effect but did not alter the time course for protection (Dulaney et al, 1991).
e) It has not been studied in human poisoning cases and is not available for human administration.

3) CHLORPROMAZINE

a) Chlorpromazine has been studied in various animal models as a possible cyanide antidote. Conflicting reports of efficacy have been published (Pettersen & Cohen, 1985).
b) Animal and in vitro studies show that chlorpromazine can decrease peroxidation of lipid membranes and prevent cyanide-induced calcium influx believed to be responsible for neurotoxicity (Johnson et al, 1986; Maduh et al, 1988).
c) It has not been studied in human poisoning cases.

4) 3-MERCAPTOPYRUVATE PRODRUGS

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

5) OTHER INVESTIGATIONAL ANTIDOTES

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

Inhalation Exposure

6.7.1)

A) Move patient from the toxic environment to fresh air. Monitor for respiratory distress. If cough or difficulty in breathing develops, evaluate for hypoxia, respiratory tract irritation, bronchitis, or pneumonitis.
B) OBSERVATION: Carefully observe patients with inhalation exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.
C) INITIAL TREATMENT: Administer 100% humidified supplemental oxygen, perform endotracheal intubation and provide assisted ventilation as required. Administer inhaled beta-2 adrenergic agonists, if bronchospasm develops. Consider systemic corticosteroids in patients with significant bronchospasm (National Heart,Lung,and Blood Institute, 2007). Exposed skin and eyes should be flushed with copious amounts of water.
D) High concentrations of cyanide gas may cause a rapid loss of consciousness (Peden et al, 1986). Rescuers should wear self-contained positive pressure breathing apparatus to avoid contaminating themselves during rescue attempts (NFPA, 1986).

6.7.2)

A) SUPPORT

1) If the clinical presentation is consistent, the treatment of benzyl cyanide poisoning is the same as that for cyanide intoxication.

B) OXYGEN

1) Administer 100% humidified supplemental oxygen with assisted ventilation as required.
2) Oxygen may reverse the cyanide-cytochrome oxidase complex and facilitate the conversion to thiocyanate following thiosulfate administration (Graham et al, 1977).
3) There is fairly good evidence that 100% oxygen, combined with traditional nitrite/thiosulfate therapy is better than thiosulfate alone (Litovitz et al, 1983; Way et al, 1972).

C) HYPERBARIC OXYGEN THERAPY

D) MONITORING OF PATIENT

E) FLUID/ELECTROLYTE BALANCE REGULATION

1) Establish secure large bore IV line.

F) CYANIDE ANTIDOTE

3) CYANIDE ANTIDOTE KIT

1) INDICATION

2) ADULT DOSE

3) PEDIATRIC DOSE

d) SODIUM THIOSULFATE

G) ACIDOSIS

H) SEIZURE

1) SUMMARY

2) DIAZEPAM

3) NO INTRAVENOUS ACCESS

4) LORAZEPAM

5) PHENOBARBITAL

6) OTHER AGENTS

7) PHENYTOIN/FOSPHENYTOIN

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

1) PHENYTOIN INTRAVENOUS PUSH VERSUS INTRAVENOUS INFUSION

c) FOSPHENYTOIN

8) RECURRING SEIZURES

I) METHEMOGLOBINEMIA

1) CAUSE

a) The goal of nitrite therapy has been to achieve a methemoglobin level of 20% to 30%. This level is not based on clinical data, but represents the tolerated concentration without significant adverse symptoms from methemoglobin in an otherwise healthy individual. Clinical response has been reported to occur with methemoglobin levels in the range of 3.6% to 9.2% (DiNapoli et al, 1989; Johnson et al, 1989; Johnson & Mellors, 1988).
b) Clinically significant excessive methemoglobinemia has rarely occurred following sodium nitrite therapy for cyanide poisoning. It usually occurs in children receiving excessive nitrite doses. Intravenous sodium nitrite administered as a 3% solution over 15-20 minutes induces approximately 7% to 14% methemoglobin (Kirk et al, 1993).

2) TREATMENT

d) METHYLENE BLUE

e) TOLUIDINE BLUE OR TOLONIUM CHLORIDE (GERMANY)

J) HYPOTENSIVE EPISODE

1) SUMMARY

2) DOPAMINE

3) NOREPINEPHRINE

K) ACUTE LUNG INJURY

L) DICOBALT EDETATE

3) DOSE

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

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

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

M) 4-DIMETHYLAMINOPHENOL HYDROCHLORIDE

N) EXPERIMENTAL THERAPY

1) STROMA-FREE METHEMOGLOBIN SOLUTION

2) ALPHA-KETOGLUTARIC ACID

3) CHLORPROMAZINE

4) OTHER INVESTIGATIONAL ANTIDOTES

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

Eye Exposure

6.8.1)

A) EYE IRRIGATION, ROUTINE: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, an ophthalmologic examination should be performed (Peate, 2007; Naradzay & Barish, 2006).

6.8.2)

A) OCULAR ABSORPTION

1) There are no reports of systemic poisoning in humans exposed to cyanide by the ocular route; however, deaths in experimental animals have followed ocular exposure (Ballantyne, 1983).
2) Patients exposed by this route should be observed for several hours in a controlled setting for the possible development of symptoms of systemic cyanide poisoning.

B) SUPPORT

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

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

Dermal Exposure

6.9.1)

A) DECONTAMINATION: Remove contaminated clothing and wash exposed area thoroughly with soap and water for 10 to 15 minutes. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).

6.9.2)

A) SUPPORT

1) If the clinical presentation is consistent, the treatment of benzyl cyanide poisoning is the same as that for cyanide intoxication.

B) SKIN ABSORPTION

1) Cyanide can be absorbed and cause systemic cyanide poisoning by the dermal route, usually only following severe burns from molten material (Bourrelier & Paulet, 1971) or total immersion in cyanide solution (Bismuth et al, 1984; Dodds & McKnight, 1985).

C) OXYGEN

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

D) HYPERBARIC OXYGEN THERAPY

1) Hyperbaric oxygen (HBO) therapy is approved for cyanide poisoning as a category one condition (approved for third party reimbursement and known effective as treatment) by the Undersea Medical Society (Myers & Schnitzer, 1984).
2) Hyperbaric oxygen has been suggested to improve clinical outcome, especially in those patients with CNS toxicity not responding to more traditional therapy.
3) Animal studies have both confirmed and refuted this (Skene et al, 1966a; Way et al, 1972; Takano et al, 1980).
4) Case reports suggest that HBO may be of value (Carden, 1970; Trapp, 1970a). However, one patient treated with supportive therapy, antidotes, and HBO did not survive a serious poisoning (Litovitz et al, 1983).
5) Hyperbaric oxygen should be reserved for those patients with significant symptoms (ie, coma, seizures) who do not respond to normal supportive and antidotal therapy, and for those patients poisoned by both cyanide and carbon monoxide secondary to smoke inhalation (Hart et al, 1985).

E) FLUID/ELECTROLYTE BALANCE REGULATION

1) Establish secure large bore IV line.

F) CYANIDE ANTIDOTE

1) SUMMARY

2) HYDROXOCOBALAMIN

3) CYANIDE ANTIDOTE KIT

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

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

b) SODIUM NITRITE

1) INDICATION

2) ADULT DOSE

3) PEDIATRIC DOSE

c) SODIUM THIOSULFATE

G) MONITORING OF PATIENT

H) ACIDOSIS

I) SEIZURE

1) SUMMARY

2) DIAZEPAM

3) NO INTRAVENOUS ACCESS

4) LORAZEPAM

5) PHENOBARBITAL

6) OTHER AGENTS

J) METHEMOGLOBINEMIA

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

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

2) If excessive methemoglobinemia occurs, some authors have suggested that methylene blue should not be used because it could cause release of cyanide from the cyanmethemoglobin complex. Such authors have suggested that emergency exchange transfusion is the treatment of choice (Berlin, 1970). Hyperbaric oxygen therapy could be used to support the patient while preparations for exchange transfusion are being made.
3) However, methylene or toluidine blue have been used successfully in this setting without worsening the course of the cyanide poisoning (van Heijst et al, 1987). There is some controversy over whether or not the induction of methemoglobinemia is the sodium nitrite mechanism of action in cyanide poisoning. As long as intensive care monitoring and further antidote doses (if required) are available, methylene blue can most likely be safely administered in this setting.
4) SUMMARY

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

5) METHYLENE BLUE

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

6) TOLUIDINE BLUE OR TOLONIUM CHLORIDE (GERMANY)

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

K) DICOBALT EDETATE

a) Significant toxicity from the antidote (severe hypertension or hypotension, cardiac ischemia or arrhythmias) may be seen in patients incorrectly diagnosed as being poisoned with cyanide and administered this antidote (Pronczuk de Garbino & Bismuth, 1981; Tyrer, 1981). Therefore, KELOCYANOR(R) SHOULD NOT BE USED in CASES of MILD CYANIDE POISONING or DIAGNOSTIC UNCERTAINTY (Peden et al, 1986; Tyrer, 1981).
b) Severe anaphylactoid reactions with periorbital and massive facial edema and airway compromise may also occur (Dodds & McKnight, 1985; Wright & Vesey, 1986).
c) ADVERSE EFFECTS can include nausea, vomiting, tachycardia, hypotension, hypertension, anaphylactic reactions, facial and neck edema, chest pain, diaphoresis, nervousness, tremulousness, gastrointestinal hemorrhages, convulsions, cardiac irregularities, and rashes (Prod Info, 1986) (Prod Info, 1987) (Davison, 1969; Tyrer, 1981; Hillman et al, 1974).

3) DOSE

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

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

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

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

L) 4-DIMETHYLAMINOPHENOL HYDROCHLORIDE

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

M) EXPERIMENTAL THERAPY

1) STROMA-FREE METHEMOGLOBIN SOLUTION

a) 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, 1985a).
b) By virtue of its in vitro production, stroma-free methemoglobin solution has the advantage of sparing the oxygen-carrying capacity of the blood (Marrs, 1988).
c) It has not been studied in human poisoning cases and is not available for human administration.

2) ALPHA-KETOGLUTARIC ACID

a) Alpha-ketoglutaric acid is also being tested as a replacement for sodium nitrite in combination with sodium thiosulfate in animal models where it has been efficacious in experimental cyanide poisoning (Bhattacharya & Vijayaraghavan, 2002; Moore et al, 1986a).
b) In vitro and animal studies show that alpha-ketoglutaric acid binds with cyanide and thereby antagonizes cyanide-induced inhibition of brain cytochrome oxidase (Norris et al, 1990).
c) Alpha-ketoglutaric acid administered with sodium thiosulfate abolished the cyanide-induced decrease in brain gamma-aminobutyric acid in mice (Yamamoto, 1990).
d) It has not been studied in human poisoning cases and is not available for human administration.

3) CHLORPROMAZINE

a) Chlorpromazine has been studied in various animal models as a possible cyanide antidote. Conflicting reports of efficacy have been published (Pettersen & Cohen, 1986).
b) Animal and in vitro studies show that chlorpromazine can decrease peroxidation of lipid membranes and prevent cyanide-induced calcium influx believed to be responsible for neurotoxicity (Johnson et al, 1986; Maduh et al, 1988).
c) It has not been studied in human poisoning cases.

4) OTHER INVESTIGATIONAL ANTIDOTES

a) Animal studies to identify alternate cyanide antidotes have tested phenoxybenzamine, centrophenoxine, naloxone hydrochloride, etomidate, para-aminopropiophenone, calcium-ion-channel blockers, and prodrugs of 3-mercaptopyruvate (Amery et al, 1981; Ashton et al, 1980; Bright & Marrs, 1987; Budavari, 1976; Dubinsky et al, 1984; Johnson et al, 1986; Leung et al, 1984; Bright & Marrs, 1987; Marrs, 1988) (Rump & Edelwijn, 1986) (Vick & Froehlich, 1985; Nagasawa et al, 2007).

N) HYPOTENSIVE EPISODE

1) SUMMARY

2) DOPAMINE

3) NOREPINEPHRINE

O) ACUTE LUNG INJURY

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

Enhanced Elimination

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 been suggested that hemodialysis may be helpful in the following ways:

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

2) It has, however, been used in only one reported case, and antidote therapy with sodium nitrite and sodium thiosulfate was also administered (Wesson et al, 1985).
3) Limited animal studies, using historical controls and only a few animals, have so far shown some potential effectiveness of hemodialysis when combined with thiosulfate infusion (Gonzales & Sabatini, 1989).
4) Hemodialysis may be considered after supportive care and pharmacologic therapy have been maximized.
5) 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).

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

Abstracts

Range Of Toxicity

Summary

Minimum Lethal Exposure

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

Maximum Tolerated Exposure

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

Serum Plasma Blood Concentrations

7.5.2)

A) TOXIC CONCENTRATION LEVELS

1) CONCENTRATION LEVELS

a) Fatal blood cyanide levels after oral ingestion

1) 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)

2) Rehling (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)

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

Workplace Standards

1) Not Listed

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
5) MAK (DFG, 2002): Not Listed
6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

1) Not Listed

Toxicity Information

7.7.1)

A) LD50- (INTRAPERITONEAL)MOUSE:

1) 10 mg/kg (RTECS , 1988a)

B) LD50- (ORAL)MOUSE:

1) 45.5 mg/kg (RTECS , 1988a)

C) LD50- (ORAL)RAT:

1) 270 mg/kg (RTECS , 1988a)

D) LD50- (SKIN)RAT:

1) 2000 mg/kg (RTECS , 1988a)

Pharmacology Toxicology

Toxicologic Mechanism

Physicochemical

Physical Characteristics

Molecular Weight

Animal Toxicology

References

General Bibliography

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FeedBack

BENZYL CYANIDE

Classification | Detailed evidence-based information

Therapeutic Toxic Class

Specific Substances

Life Support

Clinical Effects

Laboratory Monitoring

Treatment Overview

Range Of Toxicity

Summary Of Exposure

Heent

Cardiovascular

Respiratory

Neurologic

Gastrointestinal

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

Summary

Minimum Lethal Exposure

Maximum Tolerated Exposure

Serum Plasma Blood Concentrations

Workplace Standards

Toxicity Information

Toxicologic Mechanism

Physical Characteristics

Molecular Weight

General Bibliography