1) Based on a 10-year study conducted in the US, cyanide is a rare form of intentional injury or death and an occupational association has been observed. Occupations that have easy access to cyanide include: chemists, jewelers, individuals involved in pest control, mineral refining, photography, electroplating, dyeing, printing, and salmon poaching. The study also found that males were more likely to use this method of suicide over females. In this study, the 14 of 17 fatal cyanide cases were males, and 8 of the fatalities were from the West Indies/Caribbean Islands or South America (Gill et al, 2004).

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.

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.

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. It 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.

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.

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.

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.

a) EYE EXPOSURE: When solid particles or concentrated solutions of NaCN, KCN or HCN were instilled into rabbit eyes, the product was rapidly absorbed producing systemic toxicity and death (Ballantyne, 1983).

a) Tachycardia and hypertension may be seen in the initial phases of cyanide poisoning (Garlich et al, 2012; Vogel et al, 1981).

a) Bradycardia and hypotension are seen in the late phases of cyanide poisoning (Garlich et al, 2012; Hall & Rumack, 1986; Stewart, 1974) .
b) CASE REPORT: A 17-year-old boy developed severe metabolic acidosis, hypotension, and bradycardia after unintentionally ingesting a beverage containing 1.5 g potassium cyanide. Despite administration of antidote therapy and supportive care, the patient continued to show hemodynamic instability. An MRI revealed complete cerebellar infarction, and the patient was declared brain dead approximately 60 hours post-ingestion (Peddy et al, 2006).

a) 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 occur (Cope, 1961).
b) CASE REPORT: A 24-year-old man presented to the emergency department unresponsive (Glasgow Coma Scale score of 8) and foaming at the mouth approximately 2 hours after reportedly ingesting potassium cyanide. Laboratory data revealed metabolic acidosis (pH 6.9, pCO2 24 mmHg, HCO3 4.8 mmol/L), a serum lactate level of 29 mmol/L, and a blood cyanide concentration of 4.02 mcg/mL. Urine drug screen was positive for acetaminophen and benzodiazepines. An ECG demonstrated atrial fibrillation with a QRS of 116 ms and a QTc of 572 msec, with a heart rate of 116 beats/min. Treatment included administration of IV fluids, IV sodium bicarbonate, and an IV infusion of hydroxocobalamin. Following hydroxocobalamin therapy, the patient's serum lactate normalized to 1.4 mmol/L, his acidosis resolved, and a repeat ECG revealed normal sinus rhythm, with narrowing of his QRS complex (92 msec), a shortening of his QTc interval (406 msec) and a decrease in his heart rate to 71 beats/min. The patient was discharged to an inpatient psychiatric unit within 48 hours of presentation (Johnson et al, 2015).
c) CASE REPORT: First degree atrioventricular block and bradycardia (40 beats/min) were reported in a 33-year-old who ingested potassium cyanide in a suicide attempt (Hsiao et al, 2015).

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

a) CASE REPORT: A 30-year-old woman developed severe hypotension, coma, and severe metabolic acidosis after injecting herself with cyanide subcutaneously (blood cyanide ion level 4.6 mcg/mL) . After 4 hours of hemodialysis and 48 hours of supportive care, she recovered and was discharged without further sequelae (Prieto et al, 2005).
b) CASE REPORT: A 17-year-old boy developed severe metabolic acidosis, hypotension, and bradycardia after unintentionally ingesting a beverage containing 1.5 g potassium cyanide. Despite administration of antidote therapy and supportive care, the patient continued to show hemodynamic instability. An MRI revealed complete cerebellar infarction, and the patient was declared brain dead approximately 60 hours post-ingestion (Peddy et al, 2006).
c) CASE REPORT: A 29-year-old man presented with coma (Glasgow Coma Scale score of 3), tachypnea (35 to 45 breaths/minute), tachycardia (95 beats/minute), and hypotension (80/60 mmHg). Whole blood cyanide concentration was 6.9 mg/L and blood alcohol concentration was 270 mg/dL. Further questioning of the patient determined that he had intentionally ingested approximately 50 grams potassium dicyanoaurate (containing cyanide 25 mg/g; total amount of cyanide ingested 1250 mg [a 5-fold lethal dose of cyanide]). Following antidotal therapy with sodium thiosulfate and supportive care, the patient recovered uneventfully and was discharged to a psychiatric unit 2 days postingestion (Kampe et al, 2000).

a) Part of the initial presentation of cyanide poisoning may be hyperpnea and tachypnea (Kampe et al, 2000; Hall & Rumack, 1986).
b) CASE REPORT: A 29-year-old man presented with coma (Glasgow Coma Scale score of 3), tachypnea (35 to 45 breaths/minute), tachycardia (95 beats/minute), and hypotension (80/60 mmHg). Whole blood cyanide concentration was 6.9 mg/L and blood alcohol concentration 270 mg/dL. Further questioning of the patient determined that he had intentionally ingested approximately 50 grams potassium dicyanoaurate (containing cyanide 25 mg/g; total amount of cyanide ingested 1250 mg [a 5-fold lethal dose of cyanide]). Following antidotal therapy with sodium thiosulfate and supportive care, the patient recovered uneventfully and was discharged to a psychiatric unit 2 days postingestion (Kampe et al, 2000).

a) 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).
b) CASE REPORT: A 17-year-old boy presented with coma, apnea, and seizures. On arrival at the emergency department, his Glasgow Coma Scale score was 3 with nonreactive pupils and absent corneal, gag, and cough reflexes. Venous blood gas analysis showed metabolic acidosis, with elevated anion gap and lactate levels, and evidence of decreased tissue oxygen utilization with an arteriovenous saturation difference of zero. The patient also developed persistent hypotension and bradycardia. Suspecting cyanide poisoning, the patient was given a cyanide antidote kit, consisting of 600 mg of sodium nitrite followed by 25 g of sodium thiosulfate. His bradycardia resolved within minutes and his blood pressure improved; however, over the next several hours, his hypotension recurred. The cyanide antidote kit was readministered four separate times because of fluctuating arteriovenous saturation differences, but the sodium nitrite infusion was discontinued due to a methemoglobin level of 35%. Over the next 48 hours, the patient continued to be hemodynamically unstable. An MRI showed complete cerebellar infarction and severe edema in the brain stem and upper spinal cord. He was declared brain dead approximately 60 hours following presentation. A police investigation reported that the patient had been poisoned with 1.5 grams of potassium cyanide placed in his beverage (Peddy et al, 2006).

a) Noncardiogenic pulmonary edema has been reported in cases of acute cyanide poisoning (Graham et al, 1977). Pulmonary edema can also occur with chronic cyanogen chloride exposure (Gosselin et al, 1984). Pulmonary edema may result from a direct effect on the myocardium leading to left ventricular failure and increased pulmonary venous pressure.

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

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

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

a) Central nervous 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).

a) Coma is common in severe poisoning (Johnson et al, 2015; Lenart et al, 2010; Hall & Rumack, 1986; Vogel et al, 1981).
b) CASE REPORT: A 30-year-old woman developed severe hypotension, coma, and severe metabolic acidosis after injecting herself with cyanide subcutaneously (blood cyanide ion level 4.6 mcg/mL). After 4 hours of hemodialysis and 48 hours of supportive care, she recovered and was discharged without further sequelae (Prieto et al, 2005).
c) CASE REPORT: A 17-year-old boy presented with coma, apnea, and seizures. On arrival at the emergency department, his Glasgow Coma Scale score was 3 with nonreactive pupils and absent corneal, gag, and cough reflexes. Venous blood gas analysis showed metabolic acidosis, with elevated anion gap and lactate levels, and evidence of decreased tissue oxygen utilization with an arteriovenous saturation difference of zero. The patient also developed persistent hypotension and bradycardia. Suspecting cyanide poisoning, the patient was given a cyanide antidote kit, consisting of 600 mg of sodium nitrite followed by 25 g of sodium thiosulfate. His bradycardia resolved within minutes and his blood pressure improved; however, over the next several hours, his hypotension recurred. The cyanide antidote kit was readministered four separate times because of fluctuating arteriovenous saturation differences, but the sodium nitrite infusion was discontinued due to a methemoglobin level of 35%. Over the next 48 hours, the patient continued to be hemodynamically unstable. An MRI showed complete cerebellar infarction and severe edema in the brain stem and upper spinal cord. He was declared brain dead approximately 60 hours following presentation. A police investigation reported that the patient had been poisoned with 1.5 grams of potassium cyanide placed in his beverage (Peddy et al, 2006).
d) CASE REPORT: A 29-year-old man presented with coma (Glasgow Coma Scale score of 3), tachypnea (35 to 45 breaths/minute), tachycardia (95 beats/minute), and hypotension (80/60 mmHg). Whole blood cyanide concentration was 6.9 mg/L and blood alcohol concentration was 270 mg/dL. Further questioning of the patient determined that he had intentionally ingested approximately 50 grams potassium dicyanoaurate (containing cyanide 25 mg/g; total amount of cyanide ingested 1250 mg [a 5-fold lethal dose of cyanide]). Following antidotal therapy with sodium thiosulfate and supportive care, the patient recovered uneventfully and was discharged to a psychiatric unit 2 days postingestion (Kampe et al, 2000).
e) CASE REPORT: A 33-year-old woman presented to the emergency department comatose (Glasgow Coma Scale [GCS] score of E1M1V2). An ECG indicated first-degree atrioventricular block and bradycardia (40 bpm), and arterial blood gas analysis revealed high anion gap metabolic acidosis (pH 6.81, PaCO2 24.7 mmHg, HCO3 3.8 mmol/L, anion gap 36.2). With supportive therapy, including administration of IV sodium bicarbonate and IV fluids, the patient regained consciousness (GCS E4M6Vt) 4 hours post-admission, with gradual improvement of laboratory parameters. Interview of the patient revealed that she had ingested a "small" amount of potassium cyanide (serum cyanide level was 3.5 mg/L) in a suicide attempt. The patient was discharged 7 days later following an uneventful recovery. There was no evidence of neurological sequelae at 6 months follow-up (Hsiao et al, 2015).
f) CASE REPORT: A 58-year-old man intentionally ingested 1200 to 1500 mg of pure potassium cyanide powder and subsequently lost consciousness for 1 to 1.5 minutes and had one episode of generalized seizures. At presentation to the hospital, the patient was severely somnolent with mydriasis and lactic acidosis. The patient required emergent intubation, analgosedation and ventilation. Cyanide antidotal treatment was initiated 1.5 hours post-ingestion with hydroxocobalamin followed by sodium thiosulfate. Following antidotal therapy, the patient's arterial blood gases normalized on the day of admission. On hospital day 3, he was extubated, and the next day was discharged without visual or neurologic sequelae, which continued at his 5-month follow-up appointment (Zakharov et al, 2015).

a) Seizures are common in severe cyanide poisoning (Zakharov et al, 2015; Hall & Rumack, 1986; Peddy et al, 2006).

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

a) An 18-year-old patient who ingested between 975 and 1,300 mg of potassium cyanide developed a parkinsonian syndrome with rigidity and akinesis (Uitti et al, 1985).
b) Parkinsonism developed progressively over 3 weeks after acute ingestion of 1,500 mg of potassium cyanide. Slowed gait, masked facies, hypotonia, mild rigidity, and minimal tremor were noted. Damage was permanent, and although not evident on CT or MRI scan at 6 months, was found on MRI at 12 months postingestion. There was no improvement with levodopa (Rosenberg et al, 1989).
c) A 46-year-old woman developed progressive parkinsonism over a five-year period after acute cyanide poisoning in a 46-year-old woman (Carella et al, 1988). Drooling and dysphagia developed over this time, and marked tongue and mouth dystonia developed. Apraxia of eyelid was also apparent. Some improvement occurred with trihexyphenidyl treatment.
d) A 39-year-old man who had suffered form long term psychosis attempted suicide by swallowing an unknown amount of sodium cyanide. CT scan of the head was normal on admission. The patient developed parkinsonian syndrome with severe dystonia. A follow up CT scan of the head showed mild cortical atrophy and bilateral lucencies in the putamen and external globus pallidus (Grandas et al, 1989).
e) A 28-year-old man developed severe parkinsonian symptoms, micrographia, hypersalivation, and bilateral basal ganglia abnormalities on MRI after ingestion of 800 mg of potassium cyanide (Feldman & Feldman, 1990). With intensive medical and psychotherapeutic intervention, he survived, although with persistent deficits.
f) A severe dystonia syndrome, with slurred speech, involuntary athetoid movements of the neck, truzakharnk, and limbs, generalized dystonia, hyperextension of the lower limbs and trunk, and occasional opisthotonoid posturing, developed a few days after apparent full recovery from ingestion of 1 gram of potassium cyanide in a 16-year-old man (Valenzuela et al, 1992).
g) CASE REPORT: After ingesting potassium cyanide in a suicide attempt, a 35-year-old woman survived following antidote therapy and supportive care. On day 5, she developed agitation, choreoathetotic involuntary stereotypical movements of the upper and lower extremities and the trunk for several days. It was followed by akinetic mutism and buccofacial and ideomotoric aphasia. She also experienced severe rigid-akinetic syndrome, dysarthria, dysphagia and generalized dystonia several weeks later. MRI showed lesions in the caudate and lentiform nuclei, precentral cortex and cerebellum with a cortical precentral perfusion defect consistent with pseudolaminar cortical necrosis. On two occasions, a progressive loss of dopamine transporter suggestive of nigral neuronal apoptosis was observed by SPECT with beta-CIT (SPECT by [I-123] 2 beta-carbomethoxy-3-beta-(4-iodophenyl)-Tropan). FDG-PET and HMPAO SPECT showed striatal and frontal hypometabolism and hypoperfusion (Zaknun et al, 2005).
h) CASE REPORT: A parkinsonian syndrome, consisting of akinesia and rigidity, was reported in a 20-year-old man following a suicide attempt with cyanide. An MRI revealed hypoxic-ischemic changes as evidenced by decreased signals of the T1 image and increased signals on the T2 image of the lentiform and caudate nuclei, and a slightly increased T1 image signal in the cerebellar white matter. A CT scan showed hypodense areas in the putamen and the caudate nuclei. Following IV administration of a dye, fluorine 18-fluoro-2-deoxy-glucose (F-18 FDG), a PET/CT scan demonstrated diminished FDG uptake in the caudate nuclei and the cerebellum, and the absence of accumulation in bilateral putamen (Sarikaya et al, 2006).

a) CASE REPORT: After drinking a beverage laced with potassium cyanide prepared by another individual, a 17-year-old boy developed profound coma and died 4 days later. The neuropathological findings showed acute hypoxic-ischemic encephalopathy with edema, narrowing of the sulci and flattening of the gyri, autolysis of basal ganglia, and pseudolaminar cortical necrosis (Riudavets et al, 2005).
b) CASE REPORT: A 32-year-old woman developed a gait disturbance progressing to writhing on the ground, decreased conscious state, Glasgow Coma Score fluctuating between 6 and 11, pulse between 120 and 130 bpm, hypotension, tachypnea, and fixed and dilated pupils after taking 6 amygdalin tablets. She was intubated and developed marked metabolic acidosis, nephrogenic diabetes insipidus and profound hypotension despite fluid administration. A blood sample revealed a thiocyanate level of 445 micromol/L. After 16 hours of supportive care, she was awake, orientated and extubated. She was discharged after 3 days, symptomatically well (O'Brien et al, 2005).
c) CASE REPORT: A 27-year-old male soldier was found in his barracks unresponsive, pulseless, and in respiratory distress after ingesting tobacco contaminated with potassium cyanide and heroin. Following successful resuscitation and supportive care, the patient regained consciousness, but complained of pain in his left upper and left lower extremities, with limited range of motion of his arm. Over the course of several months, the patient continued to experience moderate to severe pain (pain scale of 7/10), with numbness of his left shoulder and upper extremity and extending down to his fourth and fifth digit, and paresthesias in his left foot. Following a 4-day inpatient treatment with IV ketamine and ropivacaine therapy, the patient had complete resolution of pain and improved range of motion. At a four-month follow-up, the patient's pain continued to be well-controlled (pain scale averaging 2/10) (Lenart et al, 2010).

a) Most victims of acute poisoning either die acutely or fully recover. However, cases of patients developing neurological sequelae such as personality changes, paranoid psychosis, memory deficits, and extrapyramidal syndromes have been reported (Feldman & Feldman, 1990; Grandas et al, 1989; Jouglard et al, 1971; Jouglard et al, 1974; Uitti et al, 1985; Borgohain et al, 1995; Rosenow et al, 1995) (Kales et al, 1997).
b) In 2 patients, neurological sequelae of oral cyanide intoxication were evaluated clinically and neuropsychologically. The clinical syndrome was characterized by extrapyramidal motor and cerebral symptoms such as bradykinesia, hypomimea, slowed speech, anteropulsion, and marked retropulsion, but with little tremor (Rosenow, 1995).
c) Delayed onset of generalized dystonia followed a suicide attempt with potassium cyanide by a 27 year old woman (Borgohain et al, 1995).

a) SUMMARY: Chronic exposure may produce headache, vertigo, tremors, weakness, fatigue, dizziness, confusion, functional changes in hearing, motor aphasia, optic neuropathy, seizures, paresis/hemiparesis, myelopathy, and permanent mental impairment. Demyelinating nervous effects have been indicated by epidemiological studies of populations ingesting naturally occurring plant glucosides, most notably inadequately processed cassava.
b) CENTRAL NERVOUS SYSTEM: A case of progressive mental deterioration, hypoacusis, lower facial deficit, homolateral palpebral ptosis, and fronto-occipital headache has been reported following chronic exposure (Mentesana, 1961).
c) SEIZURES have been reported from chronic occupational exposure (Finkel, 1983).
d) HEADACHE: Frequent headaches, vertigo, fatigue, poor appetite, and sleeping disturbances have been described in workers chronically exposed to cyanide (Saia et al, 1970; Colle, 1972).
e) NEUROPATHY: Study results are mixed. Optic neuropathy, sensory ataxia, and spastic paresis with myelopathy of the corticospinal tracts have been ascribed to the high cyanide content of unprocessed cassava (Casadei et al, 1990; Cliff et al, 1986; Freeman, 1988; van Heijst et al, 1994).

a) Nausea, vomiting, and abdominal pain may occur, especially after ingestion of cyanide salts (Hall & Rumack, 1986; Singh et al, 1989; Vogel et al, 1981).
b) The odor of bitter almonds in expired breath or gastric contents of patients may not be detected by a significant portion of the population (Hall & Rumack, 1986; HSDB , 1991).

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

a) Nausea with occasional vomiting has been described in workers chronically exposed to cyanide (Colle, 1972; Saia et al, 1970). Anemia has also been reported (Gettler & St George, 1934).

a) ALMOND ODOR: 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 (Bonnichsen & Maely, 1966).

a) CASE SERIES: Of 16 patients with cyanide poisoning in Taiwan, 4 died and all were preceded by polyuria. The authors suggested an association between the development of diabetes insipidus, a terminal sign of brain injury, and poor prognosis in cyanide poisonings (Deng & Yang, 1994).

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

a) METABOLIC ACIDOSIS: Elevated anion gap metabolic acidosis and elevated serum lactate levels are frequently found in cyanide poisoning (Zakharov et al, 2015; Garlich et al, 2012; Singh et al, 1989; Hall & Rumack, 1986; Vogel et al, 1981) .
b) CASE REPORT: A 30-year-old woman developed severe metabolic acidosis (pH 6.74; bicarbonate 5 mmol/L; anion gap 33 mmol/L) with high levels of lactic acid (19.3 mmol/L) after injecting herself with cyanide subcutaneously (blood cyanide ion level 4.6 mcg/mL) . After 4 hours of hemodialysis and 48 hours of supportive care, she recovered and was discharged without further sequelae (Prieto et al, 2005).
c) CASE REPORT: A 32-year-old woman developed severe metabolic acidosis (pH 7.09; bicarbonate 6 mmol/L; PaCO2 18 mmHg) after taking 6 amygdalin tablets. A blood sample revealed a thiocyanate level of 445 micromol/L. After 16 hours of supportive care, she recovered and was discharged 3 days later, symptomatically well (O'Brien et al, 2005).
d) CASE REPORT: A 17-year-old boy developed severe metabolic acidosis, hypotension, and bradycardia after unintentionally ingesting a beverage containing 1.5 g potassium cyanide. An initial blood gas analysis revealed a pH of 7.11, a bicarbonate level of 7 mEq/L, a lactic acid level of 20.3 mmol/L, and an anion gap of 38 mEq/L. Despite administration of antidote therapy and supportive care, the patient continued to show hemodynamic instability. An MRI revealed complete cerebellar infarction, and the patient was declared brain dead approximately 60 hours post-ingestion (Peddy et al, 2006).
e) LACTIC ACIDOSIS: The degree of lactic acidosis correlates with the severity of cyanide poisoning (Naughton, 1974; Trapp, 1970).
f) CASE REPORT: A 24-year-old man presented to the emergency department unresponsive (Glasgow Coma Scale score of 8) and foaming at the mouth approximately 2 hours after reportedly ingesting potassium cyanide. Laboratory data revealed metabolic acidosis (pH 6.9, pCO2 24 mmHg, HCO3 4.8 mmol/L), a serum lactate level of 29 mmol/L, and a blood cyanide concentration of 4.02 mcg/mL. Urine drug screen was positive for acetaminophen and benzodiazepines. An ECG demonstrated atrial fibrillation with a QRS of 116 ms and a QTc of 572 msec, with a heart rate of 116 beats/min. Treatment included administration of IV fluids, IV sodium bicarbonate, and an IV infusion of hydroxocobalamin. Following hydroxocobalamin therapy, the patient's serum lactate normalized to 1.4 mmol/L, his acidosis resolved (pH 7.49), and a repeat ECG revealed normal sinus rhythm, with narrowing of his QRS complex (92 msec), a shortening of his QTc interval (406 msec) and a decrease in his heart rate to 71 beats/min. The patient was discharged to an inpatient psychiatric unit within 48 hours of presentation (Johnson et al, 2015).
g) CASE REPORT: A 33-year-old woman presented to the emergency department comatose (Glasgow Coma Scale [GCS] score of E1M1V2). An ECG indicated first-degree atrioventricular block and bradycardia (40 bpm), and arterial blood gas analysis revealed high anion gap metabolic acidosis (pH 6.81, PaCO2 24.7 mmHg, HCO3 3.8 mmol/L, anion gap 36.2). With supportive therapy, including administration of IV sodium bicarbonate and IV fluids, the patient regained consciousness (GCS E4M6Vt) 4 hours post-admission, with gradual improvement of laboratory parameters. Interview of the patient revealed that she had ingested a "small" amount of potassium cyanide (serum cyanide level was 3.5 mg/L) in a suicide attempt. The patient was discharged 7 days later following an uneventful recovery. There was no evidence of neurological sequelae at 6 months follow-up (Hsiao et al, 2015).

a) DERMAL ABSORPTION: Cyanide has been said to be absorbed through intact skin and carries a "skin designation" for workplace exposures (ACGIH, 1986) (ACGIH, 1990).

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

a) Dermal contact with the moist solid material can result in itching and skin irritation or ulceration, whereas liquid or solid sodium cyanide can cause pain and second-degree burns after a few minutes' contact (CHRIS, 1990) (Proctor et al, 1988).

a) Chronic occupational cyanide exposure has been associated with irritation of skin and mucous membranes; such complaints occurred with exposure to highly alkaline aerosols or solutions of cyanide salts (Finkel, 1983; Hartung, 1982; Proctor et al, 1988). Papules, scarlet rash, eczema, and itching have been reported (HSDB, 1990).

a) Workers, such as electroplaters and picklers, who are daily exposed to cyanide solutions may develop a "cyanide" rash, characterized by itching, and by macular, papular, and vesicular eruptions (Lewis, 1992).
b) CASE REPORT: A 30-year-old woman developed severe hypotension, coma, and severe metabolic acidosis after injecting herself with cyanide subcutaneously (blood cyanide ion level 4.6 mcg/mL). Six macular, erythematous lesions (1-3 cm in diameter) on her left arm and hemithorax were noted on physical examination. These lesions developed into blisters with epidermal necrosis. After 4 hours of hemodialysis and 48 hours of supportive care, she recovered and was discharged without further sequelae (Prieto et al, 2005).

a) DERMAL ABSORPTION: Hydrogen cyanide gas was absorbed through the skin of dogs and guinea pigs; the outcome was fatal at high enough concentrations (Walton & Witherspoon, 1926).

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

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

a) THYROID ABNORMALITIES: Chronically cyanide-exposed workers have developed enlarged thyroid glands and decreased iodine uptake, presumably because of interference from the presence of the thiocyanate natural cyanide detoxification product (HSDB, 1990) (Finkel, 1983; Proctor et al, 1988).

a) RELATED AGENTS

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

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

a) It may be feasible to use a modified commercial six-wavelength hemoglobin photometer (Radiometer OSM3) for easy and rapid analysis of methemoglobin and methemoglobin cyanide in small samples of blood (Zijlstra & Buursma, 1993).

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).

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).
b) ADVERSE EFFECTS/CONTRAINDICATIONS

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).

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.

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).
b) ADVERSE EFFECTS/CONTRAINDICATIONS

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

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.

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.

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).

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.

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

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).
m) CASE REPORT: A 24-year-old man developed metabolic acidosis with an elevated serum lactate level (29 mmol/L), and atrial fibrillation with a widened QRS complex (116 ms), a prolonged QTc interval (572 msec), and a heart rate of 116 beats/min after a reported intentional ingestion of potassium cyanide (blood cyanide concentration at ED presentation was 4.02 mcg/mL). Treatment included administration of IV fluids, IV sodium bicarbonate and an IV infusion of hydroxocobalamin 5 g. At 35 minutes, 2 hours, and 3 hours post-hydroxocobalamin administration, the patient's serum lactate level gradually decreased to 19, 11.4, and 6.5 mmol/L, respectively. Within 7 hours of presentation, the patient's serum lactate level normalized (1.4 mmol/L), his acidosis resolved, and a repeat ECG revealed a return to normal sinus rhythm with a heart rate of 71 beats/min, and a QRS and QTc of 92 msec and 406 msec, respectively. Within 48 hours of presentation, the patient was discharged to an inpatient psychiatric unit (Johnson et al, 2015).

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
d) SODIUM THIOSULFATE

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).

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 .

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).

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).

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).

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):

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

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:
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).

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).

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
d) METHYLENE BLUE
e) TOLUIDINE BLUE OR TOLONIUM CHLORIDE (GERMANY)

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.

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).

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

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)

a) ADULT DOSE: One to two 20 mL ampules (300 to 600 mg) IV over about 1 to 5 minutes (Prod Info Kelocyanor(R), 1987) (Davison, 1969).
b) PEDIATRIC DOSE: Pediatric doses have not been established by manufacturers. In Israel the recommended pediatric dose is 0.5 milliliter/kilogram, not to exceed 20 mL (Pers Comm, Uri Taitelman,MD, 1963).

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

a) Stroma-free methemoglobin, oxidized hemoglobin to the ferric form in which the cell membrane has been removed, attenuates lethality and prevents hemodynamic changes in animal models (Breen et al, 1996; Ten Eyck et al, 1985) (Ten Eyck et al, 1986). The advantage to this treatment is that it provide exogenous methemoglobin without compromising oxygen-carrying capacity of native hemoglobin. Removal of the cell membrane eliminates the antigenicity problem (Marrs, 1988).
b) AVAILABILITY: It has not been studied in human poisoning cases and is not available for human administration.

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

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).

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).

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. It 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.

a) ADULT DOSE: 5 g (two 2.5 g vials each reconstituted with 100 mL sterile 0.9% saline) administered as an intravenous infusion over 15 minutes. For severe poisoning, a second dose of 5 g may be infused intravenously over 15 minutes to 2 hours, depending on the patient's condition (Prod Info CYANOKIT(R) 2.5g IV injection, 2006).
b) PEDIATRIC DOSE: A dose of 70 mg/kg has been used in pediatric patients, based on limited post-marketing experience outside the US (Prod Info CYANOKIT(R) 2.5g IV injection, 2006).
c) INDICATIONS: Known or suspected cyanide poisoning.
d) ADVERSE EFFECTS: Transient hypertension, allergic reactions (including anaphylaxis), nausea, headache, rash. Hydroxocobalamin's deep red color causes red-colored urine in all patients, and erythema of the skin in most (Prod Info CYANOKIT(R) 2.5g IV injection, 2006).
e) LABORATORY INTERFERENCE: Because of its' color, hydroxocobalamin interferes with colorimetric determination of various laboratory parameters. It may artificially increase serum creatinine, bilirubin, triglycerides, cholesterol, total protein, glucose, albumin , alkaline phosphatase and hemoglobin. It may artificially decrease serum ALT and amylase. It may artificially increase urinary pH, glucose, protein, erythrocytes, leukocytes, ketones, bilirubin, urobilinogen, and nitrate (Prod Info CYANOKIT(R) 2.5g IV injection, 2006).
f) HEMODIALYSIS INTERFERENCE: Dialysis machines have a spectrophotometric safety measure that can shut down after detecting blood leaking across the dialysis membrane. Hydroxocobalamin has a deep red color and can permeate the dialysis membrane, coloring the dialysate and causing the hemodialysis machine to shut down erroneously. In one case report, a patient with cyanide poisoning underwent dialysis after receiving 5 g of IV hydroxocobalamin because of refractory acidemia, reduced kidney function and hyperkalemia. A blood leak alarm caused the dialysis machine to shut down erroneously, delaying therapy, and resulting in the death of the patient (Stellpflug et al, 2013).
g) Hydroxocobalamin, 5 to 20 grams administered intravenously, has been shown to be effective, as sole antidotal therapy, for acute cyanide poisoning following cyanide salt ingestion or inhalation, as well as cyanide poisoning following smoke inhalation (Borron et al, 2007b; 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).

a) OBTAIN AND PREPARE for administration a CYANIDE ANTIDOTE KIT, consisting of sodium nitrite and sodium thiosulfate.
b) SODIUM NITRITE
c) SODIUM THIOSULFATE

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%.

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).

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 .

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).

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).

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).

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):

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

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

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.

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).

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.

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).

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).
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).

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

a) In vitro and animal studies show that alpha-ketoglutaric acid binds with cyanide and thereby antagonizes cyanide-induced inhibition of brain cytochrome oxidase (Norris et al, 1990).
b) Alpha-ketoglutaric acid administered with sodium thiosulfate abolished the cyanide-induced decrease in brain gamma-aminobutyric acid in mice (Yamamoto, 1990).
c) It has not been studied in human poisoning cases and is not available for human administration.

a) Animal and in vitro studies show that chlorpromazine can decrease peroxidation of lipid membranes and prevent cyanide-induced calcium influx believed to be responsible for neurotoxicity (Johnson et al, 1986; Maduh et al, 1988).
b) It has not been studied in human poisoning cases.

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.

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).

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

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)

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).

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. It 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.

a) ADULT DOSE: 5 g (two 2.5 g vials each reconstituted with 100 mL sterile 0.9% saline) administered as an intravenous infusion over 15 minutes. For severe poisoning, a second dose of 5 g may be infused intravenously over 15 minutes to 2 hours, depending on the patient's condition (Prod Info CYANOKIT(R) 2.5g IV injection, 2006).
b) PEDIATRIC DOSE: A dose of 70 mg/kg has been used in pediatric patients, based on limited post-marketing experience outside the US (Prod Info CYANOKIT(R) 2.5g IV injection, 2006).
c) INDICATIONS: Known or suspected cyanide poisoning.
d) ADVERSE EFFECTS: Transient hypertension, allergic reactions (including anaphylaxis), nausea, headache, rash. Hydroxocobalamin's deep red color causes red-colored urine in all patients, and erythema of the skin in most (Prod Info CYANOKIT(R) 2.5g IV injection, 2006).
e) LABORATORY INTERFERENCE: Because of its' color, hydroxocobalamin interferes with colorimetric determination of various laboratory parameters. It may artificially increase serum creatinine, bilirubin, triglycerides, cholesterol, total protein, glucose, albumin , alkaline phosphatase and hemoglobin. It may artificially decrease serum ALT and amylase. It may artificially increase urinary pH, glucose, protein, erythrocytes, leukocytes, ketones, bilirubin, urobilinogen, and nitrate (Prod Info CYANOKIT(R) 2.5g IV injection, 2006).
f) HEMODIALYSIS INTERFERENCE: Dialysis machines have a spectrophotometric safety measure that can shut down after detecting blood leaking across the dialysis membrane. Hydroxocobalamin has a deep red color and can permeate the dialysis membrane, coloring the dialysate and causing the hemodialysis machine to shut down erroneously. In one case report, a patient with cyanide poisoning underwent dialysis after receiving 5 g of IV hydroxocobalamin because of refractory acidemia, reduced kidney function and hyperkalemia. A blood leak alarm caused the dialysis machine to shut down erroneously, delaying therapy, and resulting in the death of the patient (Stellpflug et al, 2013).
g) In a controlled pilot study of male smokers, administration of 5 grams of intravenous 5% hydroxocobalamin significantly decreased whole blood cyanide levels (Forsyth et al, 1992).

a) OBTAIN AND PREPARE for administration a CYANIDE ANTIDOTE KIT, consisting of sodium nitrite and sodium thiosulfate.
b) SODIUM NITRITE
c) SODIUM THIOSULFATE

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%.

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).

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 .

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).

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).

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).

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):

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

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.

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).

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.

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).

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).
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).

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

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

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.

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).

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.

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)

1) LDLo (UNK) DOG: 15 mg/kg (Sax & Lewis, 1989)
2) LDLo (Subcutaneous) RABBIT: 13 mg/kg (Sax & Lewis, 1989)

1) LCLo (INHL) HUMAN: 92 ppm/10 minutes (Sax & Lewis, 1989)
2) LCLo (INHL) MOUSE: 500 mg/m(3)/10 minutes (Sax & Lewis, 1989)

1) LDLo (Subcutaneous) MOUSE: 39 mg/kg (Sax & Lewis, 1989)
2) LDLo (Subcutaneous) DOG: 5 mg/kg (Sax & Lewis, 1989)
3) LCLo (INHL) DOG: 79 ppm/8 hours (ITI, 1988)
4) LDLo (Subcutaneous) RABBIT: 20 mg/kg (Sax & Lewis, 1989)
5) LCLo (INHL) RABBIT: 207 ppm/30 minutes (Sax & Lewis, 1989)

1) LDLo (ORAL) CAT: 18 mg/kg (Sax & Lewis, 1989)
2) LDLo (Subcutaneous) CAT: 20 mg/kg (Sax & Lewis, 1989)
3) LDLo (Subcutaneous) DOG: 19 mg/kg (Sax & Lewis, 1989)
4) LDLo (Subcutaneous) RAT: 44 mg/kg (Sax & Lewis, 1989)

1) LDLo (ORAL) HUMAN: 5.7 mg/kg (Sax & Lewis, 1989)
2) LCLo (INHL) HUMAN: 200 ppm/5 minutes (Sax & Lewis, 1989)
3) LCLo (INHL) HUMAN: 120 mg/m(3)/1 hour (Sax & Lewis, 1989)
4) LCLo (INHL) HUMAN: 200 mg/m(3)/10 minutes (Sax & Lewis, 1989)
5) LCLo (INHL) MAN: 400 mg/m(3)/2 minutes (Sax & Lewis, 1989)
6) LCLo (INHL) HUMAN: 5,000 mg/m(3) (ITI, 1988)
7) LDLo (Subcutaneous) HUMAN: 1 mg/kg (Sax & Lewis, 1989)
8) LDLo (UNK) MAN: 14.71 mg/kg (Sax & Lewis, 1989)
9) LDLo (ORAL) DOG: 4 mg/kg (Sax & Lewis, 1989)
10) LDLo (Subcutaneous) CAT: 11 mg/kg (Sax & Lewis, 1989)
11) LDLo (ORAL) RABBIT: 4 mg/kg (Sax & Lewis, 1989)

1) LDLo (ORAL) HUMAN: 2,857 mcg/kg (RTECS, 1990)
2) LDLo (IM) RAT: 8 mg/kg (RTECS, 1990)
3) LDLo (IP) GUINEA PIG: 8 mg/kg (RTECS, 1990)
4) LDLo (Subcutaneous) GUINEA PIG: 8 mg/kg (RTECS, 1990)
5) LDLo (IV) GUINEA PIG: 5 mg/kg (RTECS, 1990)
6) LDLo (INTRAARTERIAL) GUINEA PIG: 5 mg/kg (RTECS, 1990)
7) LDLo (IV) DOG: 5 mg/kg (RTECS, 1990)
8) LDLo (Subcutaneous) FROG: 60 mg/kg (RTECS, 1990)

1) LDLo (ORAL) MAN: 6,557 mcg/kg (Sax & Lewis, 1989)
2) LDLo (ORAL) HUMAN: 2,857 mcg/kg (Sax & Lewis, 1989)
3) LDLo (UNK) MAN: 2,206 mcg/kg (Sax & Lewis, 1989)
4) LDLo (Subcutaneous) DOG: 6 mg/kg (Sax & Lewis, 1989)
5) LDLo (Subcutaneous) RABBIT: 2,200 mcg/kg (Sax & Lewis, 1989)

a) Patients treated with only supportive measures have survived severe poisoning with whole blood cyanide levels of 2.3 to 4.65 micrograms/milliliter (Vogel et al, 1981; Saincher et al, 1992).
b) Patients treated with specific antidotes have survived severe poisoning with whole blood cyanide levels of 3.85 to 40 micrograms/milliliter (1,538 micromoles/liter) (Litovitz et al, 1983; Hall & Rumack, 1986; Hall & Rumack, 1986) 1987; (Feihl et al, 1982).
c) Significant symptoms of poisoning generally occur with whole blood cyanide levels of 1 microgram/milliliter (38.5 micromoles/liter) or greater (Hall & Rumack, 1986).
d) Blood cyanide levels and associated symptoms (Graham et al, 1977):
e) Blood cyanide levels after chronic exposure to cyanide fumes and cyanide aerosols (Chandra et al, 1980):
f) Post mortem blood cyanide levels after ingestion -
g) Blood cyanide levels in smoke inhalation victims:
h) CASE REPORT - A blood cyanide level of 6.9 mg/L was reported in a 29-year-old man who intentionally ingested approximately 1250 mg of cyanide in the form of potassium dicyanoaurate (Kampe et al, 2000).

1) ppm:
2) mg/m3: 5
3) Ceiling Value:
4) Skin Designation: Yes
5) Notation(s): Not Listed

a) 39 mg/kg

a) 3 mg/kg

a) 3.7 mg/kg

a) 5991 mcg/kg

a) 8500 mcg/kg

a) 6500 mcg/kg

a) 4 mg/kg

a) 5 mg/kg
b) 10 mg/kg

a) 9 mg/kg

a) 3660 mcg/kg

a) 6440 mcg/kg