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SODIUM NITROPRUSSIDE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Sodium nitroprusside is a powerful antihypertensive and vasodilator. It is commonly used to treat severe hypertension. It is also used to produce controlled hypotension for the reduction of bleeding during surgery, and to treat acute congestive heart failure.

Specific Substances

    1) Disodium pentacyanonitrosylferrate (2-)dihydrate
    2) Sodium nitroferricyanide
    3) Nitroprusside, sodium
    4) CAS 14402-89-2

Available Forms Sources

    A) FORMS
    1) Sodium nitroprusside is available as 50 mg intravenous powder for solution (Prod Info NITROPRESS(R) injection for IV infusion, 2007).
    B) USES
    1) Sodium nitroprusside is commonly used to treat severe hypertension. It is also used to produce controlled hypotension for the reduction of bleeding during surgery, and to treat acute congestive heart failure (Prod Info NITROPRESS(R) injection for IV infusion, 2007).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Sodium nitroprusside is commonly used to treat severe hypertension. It is also used to produce controlled hypotension for the reduction of bleeding during surgery, and to treat acute congestive heart failure.
    B) PHARMACOLOGY: Sodium nitroprusside, a potent vasodilator, dilates both venules and arteries through the release of nitric oxide.
    C) TOXICOLOGY: Each molecule of sodium nitroprusside contains 5 cyanide ions which can be released when exposed to UV light and result in cyanide toxicity. Also, in patients with renal insufficiency, metabolism to thiosulfate and thiocyanate can result in toxicity.
    D) EPIDEMIOLOGY: While sodium nitroprusside is commonly used for severe hypertension, cyanide toxicity or thiocyanate toxicity from sodium nitroprusside use are uncommon.
    E) WITH THERAPEUTIC USE
    1) Excessive hypotension may occur with nitroprusside and may be resolved with discontinuation of the drug since the direct effect of the drug clears promptly within 10 minutes of discontinuation. The overall incidence of cyanide toxicity associated with nitroprusside appears to be infrequent. Extravasation can cause tissue sloughing and necrosis.
    2) RISK FACTORS: Risk factors for the development of nitroprusside-induced cyanide toxicity includes: hypoalbuminemia, cardiopulmonary bypass procedures, renal impairment, or the administration of moderate to high doses of nitroprusside.
    F) WITH POISONING/EXPOSURE
    1) Acute toxicity following an overdose is characterized by vasodilation and hypotension, possibly complicated by nausea, vomiting, sweating, headache, palpitation, and chest pain.
    2) CYANIDE TOXICITY: Associated with high rate or prolonged infusion. Manifestations include metabolic acidosis, CNS dysfunction, rising mixed venous oxygen content, tachycardia and hypertension. Severe acidosis and tachyphylaxis may occur with increasing blood cyanide concentrations. Patients with depleted thiosulfate stores (malnourished, recent surgery) may be at increased risk. SODIUM THIOSULFATE SHORTAGE: Typically, sodium thiosulfate is administered with sodium nitroprusside to avoid cyanide toxicity that can be associated with a prolonged or high rates of infusion. Since 2011, there has been a national US shortage of sodium thiosulfate and only-one FDA approved distributor. Patients may require closer monitoring (ie, cyanide levels) to avoid toxicity in the absence or unavailability of sodium thiosulfate.
    3) THIOCYANATE TOXICITY: Associated with long-term infusions (usually more than 6 days) in patients simultaneously treated with sodium thiosulfate; may develop with shorter infusions in patients with renal insufficiency. Manifestations include abdominal pain, weakness, tinnitus, vomiting, tremor, agitation, disorientation, progressing to lethargy, seizures and coma in severe cases.
    0.2.20) REPRODUCTIVE
    A) There are no reports of human or animal teratogenicity with nitroprusside. Nitroprusside has been used in the therapy of severe preeclampsia.

Laboratory Monitoring

    A) Cyanide toxicity is a clinical diagnosis, because of the delays inherent in obtaining cyanide concentrations.
    B) Monitor vital signs and mental status.
    C) Obtain an ECG and institute continuous cardiac monitoring.
    D) Monitor serum electrolytes, renal function, serum lactate, arterial blood gases and mixed venous oxygen saturation if cyanide toxicity is a concern.
    E) Monitor thiocyanate concentrations in patients with prolonged infusions, those with renal insufficiency and those receiving simultaneous thiosulfate infusions.

Treatment Overview

    0.4.6) PARENTERAL EXPOSURE
    A) TREATMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. In patients with hypotension, discontinue infusion; hypotension generally resolves quickly once exposure ceases. Administer intravenous fluids if not contraindicated by patient's underlying condition, 10 to 20 mL/kg 0.9% saline. Central venous pressure monitoring may be useful to avoid volume overload. Monitor carefully for evidence of more severe toxicity.
    B) TREATMENT OF SEVERE TOXICITY
    1) Treatment should include volume expansion, pressors as needed for hypotension, ventilatory support, and hydroxocobalamin or the cyanide antidote kit. CYANIDE TOXICITY: Metabolic acidosis and increasing tolerance to the drug are early signs of cyanide toxicity necessitating drug discontinuation. Dyspnea, worsening acidosis, seizures or impaired mental status suggest cyanide toxicity. Treat with hydroxocobalamin. Sodium nitrite followed by sodium thiosulfate (cyanide antidote kit) is an alternative treatment for cyanide toxicity. THIOCYANATE TOXICITY: Suspect toxicity in patients with prolonged infusions, those with renal insufficiency and those with simultaneous thiosulfate infusion. Discontinue sodium nitroprusside infusion. If severe thiocyanate toxicity develops (encephalopathy, seizures, coma), hemodialysis is indicated. SEIZURES: Evaluate clinically for cyanide or thiocyanate toxicity and treat accordingly. Control with benzodiazepines.
    C) DECONTAMINATION
    1) Gastrointestinal decontamination is not recommended; administered via the parenteral route.
    D) AIRWAY MANAGEMENT
    1) Ensure adequate ventilation and perform endotracheal intubation early in patients with severe CNS depression.
    E) CYANIDE ANTIDOTE
    1) A cyanide antidote, either hydroxocobalamin OR the sodium nitrite/sodium thiosulfate kit, should be administered to symptomatic patients.
    F) HYDROXOCOBALAMIN
    1) Hydroxocobalamin should be given if any laboratory or clinical signs or symptoms of cyanide toxicity develop. ADULT: Administer 5 g (two 2.5 g vials, each reconstituted with 100 mL sterile 0.9% saline) as an IV 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. PEDIATRIC: Limited experience; a dose of 70 mg/kg has been used in pediatric patients.
    G) SODIUM NITRITE/SODIUM THIOSULFATE
    1) Sodium nitrite/sodium thiosulfate kit is administered as follows: SODIUM NITRITE: ADULT: 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). 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: 50 mL (12.5 g) of a 25% solution; 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.
    H) METHEMOGLOBINEMIA
    1) If excessive methemoglobinemia occurs in the setting of cyanide toxicity, METHYLENE BLUE SHOULD NOT BE USED as it will cause the release of cyanide from the cyanomethemoglobin complex. In this instance, emergency exchange transfusion would be the treatment of choice.
    I) PATIENT DISPOSITION
    1) HOME CRITERIA: There is no data to support home management, and sodium nitroprusside is generally only used in the hospital setting.
    2) OBSERVATION CRITERIA: Patients who are symptomatic should be observed with frequent monitoring of vital signs and mental status.
    3) ADMISSION CRITERIA: Patients with sodium nitroprusside toxicity, or secondary cyanide or thiocyanate toxicity should be monitored in an ICU setting.
    4) CONSULT CRITERIA: Consult a medical toxicologist or poison center for any patients with suspected cyanide toxicity or thiocyanate toxicity from sodium nitroprusside that does not respond to stopping the infusion.
    J) PITFALLS
    1) Early recognition of signs of cyanide or thiocyanate accumulation is paramount. It can be difficult to distinguish these clinical scenarios from sodium nitroprusside adverse events such as hypotension.
    K) PHARMACOKINETICS
    1) Sodium nitroprusside has a half-life of 1 to 2 minutes and is eliminated renally.
    L) DIFFERENTIAL DIAGNOSIS
    1) Adverse effects of direct sodium nitroprusside toxicity can appear clinically similar to cyanide or thiocyanate accumulation and toxicity.

Range Of Toxicity

    A) TOXICITY: CYANIDE: Infusion of more than 500 mcg/kg sodium nitroprusside at a rate of greater than 2 mcg/kg/min causes generation of cyanide at a rate faster than most patients can eliminate it. THIOCYANATE: Toxicity generally does not develop in patients with normal renal function before 7 days of continuous therapy at moderate doses. May develop in 3 days in patients with renal insufficiency who are not undergoing hemodialysis.
    B) THERAPEUTIC DOSES: Initial infusion of 0.3 mcg/kg/min titrated to clinical response to a maximum of 10 mcg/kg/min.

Clinical Effects

Summary Of Exposure

    A) USES: Sodium nitroprusside is commonly used to treat severe hypertension. It is also used to produce controlled hypotension for the reduction of bleeding during surgery, and to treat acute congestive heart failure.
    B) PHARMACOLOGY: Sodium nitroprusside, a potent vasodilator, dilates both venules and arteries through the release of nitric oxide.
    C) TOXICOLOGY: Each molecule of sodium nitroprusside contains 5 cyanide ions which can be released when exposed to UV light and result in cyanide toxicity. Also, in patients with renal insufficiency, metabolism to thiosulfate and thiocyanate can result in toxicity.
    D) EPIDEMIOLOGY: While sodium nitroprusside is commonly used for severe hypertension, cyanide toxicity or thiocyanate toxicity from sodium nitroprusside use are uncommon.
    E) WITH THERAPEUTIC USE
    1) Excessive hypotension may occur with nitroprusside and may be resolved with discontinuation of the drug since the direct effect of the drug clears promptly within 10 minutes of discontinuation. The overall incidence of cyanide toxicity associated with nitroprusside appears to be infrequent. Extravasation can cause tissue sloughing and necrosis.
    2) RISK FACTORS: Risk factors for the development of nitroprusside-induced cyanide toxicity includes: hypoalbuminemia, cardiopulmonary bypass procedures, renal impairment, or the administration of moderate to high doses of nitroprusside.
    F) WITH POISONING/EXPOSURE
    1) Acute toxicity following an overdose is characterized by vasodilation and hypotension, possibly complicated by nausea, vomiting, sweating, headache, palpitation, and chest pain.
    2) CYANIDE TOXICITY: Associated with high rate or prolonged infusion. Manifestations include metabolic acidosis, CNS dysfunction, rising mixed venous oxygen content, tachycardia and hypertension. Severe acidosis and tachyphylaxis may occur with increasing blood cyanide concentrations. Patients with depleted thiosulfate stores (malnourished, recent surgery) may be at increased risk. SODIUM THIOSULFATE SHORTAGE: Typically, sodium thiosulfate is administered with sodium nitroprusside to avoid cyanide toxicity that can be associated with a prolonged or high rates of infusion. Since 2011, there has been a national US shortage of sodium thiosulfate and only-one FDA approved distributor. Patients may require closer monitoring (ie, cyanide levels) to avoid toxicity in the absence or unavailability of sodium thiosulfate.
    3) THIOCYANATE TOXICITY: Associated with long-term infusions (usually more than 6 days) in patients simultaneously treated with sodium thiosulfate; may develop with shorter infusions in patients with renal insufficiency. Manifestations include abdominal pain, weakness, tinnitus, vomiting, tremor, agitation, disorientation, progressing to lethargy, seizures and coma in severe cases.

Heent

    3.4.3) EYES
    A) WITH POISONING/EXPOSURE
    1) Transient blindness has been reported rarely after sodium nitroprusside overdose.
    2) BLINDNESS: A 4-year-old girl inadvertently received 234 mg nitroprusside over 60 hours (5.4 micromol/kg/min) following surgery for coarctation of the aorta. She developed blindness with dilated pupils but had otherwise normal ophthalmologic and neurologic exams and normal head CT. Vision began to improve 4 hours after nitroprusside was discontinued and was normal by 8 hours (Olgunturk et al, 1992).
    3.4.4) EARS
    A) WITH THERAPEUTIC USE
    1) Patients with cyanide toxicity may develop tinnitus (Thomas et al, 2009; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Moffett & Price, 2008; Prod Info NITROPRESS(R) injection, 2004; Grossman et al, 1998).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) HYPOTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) Excessive hypotension may occur with nitroprusside and may be resolved with discontinuation of the drug since the direct effect of the drug clears promptly within 10 minutes of discontinuation (Prod Info NITROPRESS(R) injection for IV infusion, 2007).
    b) Severe hypotension may occur (Thomas et al, 2009; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Moffett & Price, 2008).
    c) Hypotension complicated by nausea, vomiting, sweating, headache and palpitations may acutely occur following excessive infusion rates of nitroprusside. Plasma concentrations of nitroprusside do not accurately correlate with hypotensive effect (Hewick et al, 1987).
    d) Severe hypotension developed in two patients immediately after 2 mg nitroprusside in 4 mL D5W was sprayed onto the internal mammary artery to relieve arterial spasm after coronary artery bypass grafting (Tatar et al, 1994)
    B) BRADYCARDIA
    1) WITH THERAPEUTIC USE
    a) Bradycardia and PVCs progressing to cardiorespiratory failure have been reported as complications of cyanide toxicity.
    C) TACHYCARDIA
    1) WITH THERAPEUTIC USE
    a) CYANIDE TOXICITY: Patients with cyanide toxicity may develop tachycardia (Thomas et al, 2009; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Moffett & Price, 2008; Prod Info NITROPRESS(R) injection, 2004).
    D) HYPERTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) Patients with sodium nitroprusside induced cyanide toxicity may develop tachyphylaxis with progressively worsening hypertension despite escalation nitroprusside doses.
    b) A 14-year-old girl with a history of spina bifida, severe kyphoscoliosis, hydrocephalus and seizures developed cyanide toxicity (cyanide level 3.1 mcg/mL) after receiving increasing doses of sodium nitroprusside (total dose 200 mg; 4.8 mg/kg over 56 hours) for severe intractable hypertension (despite escalating doses of nitroprusside, atenolol, and furosemide) after renal transplantation. Following treatment with sodium nitrite, sodium thiocyanate, and hemodialysis, hypertension resolved she recovered completely with no neurological sequelae and excellent graft function (Quinlan et al, 2008).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) HYPERVENTILATION
    1) WITH THERAPEUTIC USE
    a) Hyperpnea progressing to cardiorespiratory failure secondary to cyanide toxicity has been reported.

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) ANXIETY
    1) WITH THERAPEUTIC USE
    a) Acute onset of anxiety, restlessness, muscle twitching, and diaphoresis has been observed following excessive nitroprusside infusion rates.
    B) SEIZURE
    1) WITH THERAPEUTIC USE
    a) CYANIDE TOXICITY: May produce headache, vertigo, and agitation, followed by combative behavior, stupor, seizures, and death.
    b) THIOCYANATE TOXICITY: Thiocyanate at high concentrations causes a neurotoxic syndrome manifested by toxic psychosis, hyperreflexia, confusion, weakness, tinnitus, seizures, and coma.
    C) COMA
    1) WITH THERAPEUTIC USE
    a) CYANIDE TOXICITY: Patients with cyanide toxicity may develop delirium and coma (Thomas et al, 2009; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Moffett & Price, 2008; Prod Info NITROPRESS(R) injection, 2004; Grossman et al, 1998).
    D) HEADACHE
    1) WITH THERAPEUTIC USE
    a) CYANIDE TOXICITY: Patients with cyanide toxicity may develop headache (Thomas et al, 2009; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Moffett & Price, 2008; Prod Info NITROPRESS(R) injection, 2004; Grossman et al, 1998).
    E) ASTHENIA
    1) WITH THERAPEUTIC USE
    a) CYANIDE TOXICITY: Patients with cyanide toxicity may develop weakness (Thomas et al, 2009; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Moffett & Price, 2008; Prod Info NITROPRESS(R) injection, 2004; Grossman et al, 1998).
    F) CENTRAL NERVOUS SYSTEM FINDING
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 58-year-old man with a history of hypertension (210/120 mg on admission) and a type B aortic dissection was immediately started on nitroprusside (1 mcg/kg/min drip) with the infusion continued for 24 hours at a rate of up to 18 mcg/kg/min. The following day the patient was scheduled for aortic angiography and vascular repair. Acute renal failure had also developed (BUN 108 mg/dL, Cr 4 mg/dL). During a procedure to insert a thoracic endoprosthesis, a sudden rise in blood pressure required an increase in the nitroprusside infusion and boluses of urapidil and clonidine. Approximately 15 minutes after the infusion was increased, the patient developed agitation, hallucinations and impaired speech. Oxygen saturation decreased to 91% with a pH of 7.2 and a lactate concentration of 3.5 mmol/L. Nitroprusside was stopped and general anesthesia was given to complete the procedure. The patient was stable and transferred to ICU and made a satisfactory recovery. In this case, the patient had clinical evidence of nitroprusside intoxication (nitroprusside tachyphylaxis, restlessness, a sudden change in behavior, and reduced O2 saturation A/V difference) due to a nitroprusside infusion rate of greater than 2 mcg/kg/min (recommended range: 0.3 to 10 mcg/kg/min) and renal insufficiency (Nicoletta et al, 2007).
    b) CASE REPORT: A 53-year-old man with ischemic cardiomyopathy and congestive heart failure developed confusion, disorientation, agitation, hallucinations and impaired concentration and attention 2 days after a nitroprusside infusion was started. Other medications at this time included dobutamine, digoxin, bumetanide, enalapril, ranitidine, aspirin, hydroxyzine and temazepam. Nitroprusside was discontinued and his mental status improved. Hydroxyzine and temazepam were then discontinued. Nitroprusside was resumed and within 2 days the patient again became confused, agitated and disoriented; symptoms resolved a second time when nitroprusside was discontinued (Harmon & Wohlreich, 1995).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) PRERENAL AZOTEMIA
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 65-year-old man with congestive heart failure and pneumonia was treated with dobutamine and diuretics with some improvement. Nitroprusside was added and as the dose was increased his urine output declined, hypoxemia worsened and BUN and creatinine increased (maximum BUN 81 mg/dL and creatinine 4.3 mg/dL) despite improved cardiac output (Reid & Muther, 1987). Renal function returned to normal after nitroprusside was discontinued.

Acid-Base

    3.11.2) CLINICAL EFFECTS
    A) ACIDOSIS
    1) WITH THERAPEUTIC USE
    a) Metabolic acidosis accompanied by an increase in blood lactate or lactate-pyruvate ratio and an increase in the mixed venous blood oxygen tension are early signs of cyanide toxicity (Prod Info NITROPRESS(R) injection, 2004).
    b) Cyanide toxicity and metabolic acidosis may occur with prolonged treatment (greater than 24 hours) and high (greater than 2 to 3 mcg/kg per minute) doses (Thomas et al, 2009; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Moffett & Price, 2008; Prod Info NITROPRESS(R) injection, 2004; Grossman et al, 1998).
    c) CASE REPORT: A 2-month-old infant developed high anion gap metabolic acidosis (pH 7.27, pCO2 12 mmHg, pO2 281 mmHg, HCO3 5 mmol/L), increased plasma lactic acid concentration (122 mmol/L), tachycardia (190 bpm), seizures, and respiratory distress after receiving an intravenous infusion of sodium nitroprusside 2 to 2.4 mcg/kg/min for 7 days. The infusion was stopped and exchange transfusion was immediately performed. Following administration of 2 volumes, the patient's metabolic acidosis and respiratory distress resolved, and he was eventually discharged without neurologic sequelae (Baek et al, 2010).
    d) CASE REPORT: A 67-year-old woman with a history of obesity, hypertension, cardiac disease, chronic renal failure and diabetes mellitus was admitted with congestive heart failure. She underwent 3 vessel coronary artery bypass surgery and mitral annuloplasty without complication; she was extubated within 20 hours and all infusions except nitroprusside were discontinued. She had several minor post surgical complications including atrial arrhythmias, progressive oliguria and remained on nitroprusside to manage her hypertension. By day 4, her lactate level had rose to 7.2 mmol/L with a worsening base deficit. Over the next 18 hours, her serum lactate rose to 18 mmol/L (peaked at 22 mmol/L) and she developed a new onset of restlessness, tachycardia and hypotension. She was reintubated due to worsening respiratory function and uncompensated acidosis. Continuous hemodialysis was also started. In total, the patient had received 319 mg of nitroprusside for 70 hours that had been stopped about 12 hours prior to the rise in lactate and was consistent with her worsening renal function. After other potential clinical effects were ruled out, cyanide toxicity was suspected. Thiocyanate and cyanide levels were measured using fresh and residual blood from the previous 96 hours; thiocyanate was low and cyanide levels were normal as reported several days later. However, the patient was still treated with hydroxocobalamin on postoperative day 5. Her lactate level rapidly improved along with improved respiratory function. She was off all vasoactive medications and extubated within 24 hours. She continued to progress well and was discharged to home on day 20 (Udeh et al, 2015).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) METHEMOGLOBINEMIA
    1) WITH THERAPEUTIC USE
    a) Theoretically, methemoglobin may be formed during nitroprusside administration, however, it would be rapidly converted to cyanmethemoglobin. Significant methemoglobin is not expected unless the patient has a genetic deficiency for methemoglobin reductase.
    b) Clinically significant methemoglobinemia (greater than 10%) occurs rarely (Thomas et al, 2009; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Moffett & Price, 2008; Prod Info NITROPRESS(R) injection, 2004; Grossman et al, 1998).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) EXTRAVASATION INJURY
    1) WITH THERAPEUTIC USE
    a) Extravasation can cause tissue sloughing and necrosis (Thomas et al, 2009; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Moffett & Price, 2008).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) SPASM
    1) WITH THERAPEUTIC USE
    a) CYANIDE TOXICITY: Patients with cyanide toxicity may develop muscle spasms (Thomas et al, 2009; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Moffett & Price, 2008; Prod Info NITROPRESS(R) injection, 2004; Grossman et al, 1998).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) HYPOTHYROIDISM
    1) WITH THERAPEUTIC USE
    a) Reversible hypothyroidism may result following prolonged therapy of sodium nitroprusside presumably due to the antithyroid action of thiocyanate (Nourok et al, 1964).
    b) CASE REPORT: Hypothyroidism developed in a 35-year-old woman with accelerated hypertension following continuous infusion of nitroprusside over a period of 21 days. Total dose was approximately 4 g. Serum thiocyanate concentrations of 95 mcg/mL was recorded during the 21 days of therapy. The drug was discontinued and the patient was treated with peritoneal dialysis. Serum thiocyanate levels decreased and the patient recovered fully from the hypothyroid state (Nourok et al, 1964).

Reproductive

    3.20.1) SUMMARY
    A) There are no reports of human or animal teratogenicity with nitroprusside. Nitroprusside has been used in the therapy of severe preeclampsia.
    3.20.2) TERATOGENICITY
    A) LACK OF INFORMATION
    1) There are no reports of human or animal teratogenicity with nitroprusside.
    3.20.3) EFFECTS IN PREGNANCY
    A) HYPOTENSION
    1) Nitroprusside has been used successfully as an adjunct to therapy of severe PREECLAMPSIA (Paull, 1975) and to induce hypotension during surgery for intracerebral aneurysm in pregnancy (Donchin et al, 1978).
    B) FETAL DISTRESS
    1) FETAL SIDE EFFECTS in the preeclamptic patient consisted of transient decreased heart rate (90 beats/min) which returned to normal 2 hours following surgery. Loss of beat-to-beat variations was observed in another report (Donchin et al, 1978).
    2) It is suggested that nitroprusside may be a useful drug for the short-term treatment of severe eclampsia, but should be discontinued if tachyphylaxis develops or more than 0.5 mcg/kg/minute is required (Naulty et al, 1981).
    C) PREGNANCY CATEGORY
    SODIUM NITROPRUSSIDEC
    Reference: Briggs et al, 1998

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Cyanide toxicity is a clinical diagnosis, because of the delays inherent in obtaining cyanide concentrations.
    B) Monitor vital signs and mental status.
    C) Obtain an ECG and institute continuous cardiac monitoring.
    D) Monitor serum electrolytes, renal function, serum lactate, arterial blood gases and mixed venous oxygen saturation if cyanide toxicity is a concern.
    E) Monitor thiocyanate concentrations in patients with prolonged infusions, those with renal insufficiency and those receiving simultaneous thiosulfate infusions.
    4.1.2) SERUM/BLOOD
    A) TOXICITY
    1) No general consensus exists regarding the most appropriate means to monitor nitroprusside toxicity (Linakis et al, 1991).
    a) CYANIDE
    1) The diagnosis of cyanide toxicity must be made clinically, because of the long delay in obtaining plasma cyanide concentrations. Cyanide toxicity should be considered in any patient with metabolic acidosis, or increasing mixed venous oxygen tension (Curry & Arnold-Capell, 1991).
    2) Routine monitoring of cyanide concentrations is probably not warranted, and is unnecessary in patients receiving simultaneous sodium thiosulfate (Apple et al, 1996).
    3) Cyanide concentrations in plasma correlate best with clinical evidence of cyanide toxicity in patients receiving nitroprusside therapy (Alaniz & Watts, 2005).
    4) Cyanide from nitroprusside infusion initially distributes primarily to erythrocytes; toxic effects do not occur until cyanide redistributes from erythrocytes to tissues. Thus, whole blood cyanide concentration may overestimate toxicity (Alaniz & Watts, 2005).
    5) A poor correlation exists between the dose or duration of nitroprusside and cyanide concentrations (Linakis et al, 1991; Ram et al, 1989).
    6) Generally, blood cyanide concentrations are considered toxic if they are greater than 500 mcg/L; however, patients do not consistently display signs or symptoms at these concentrations (Linakis et al, 1991).
    b) THIOCYANATE
    1) Routine monitoring of serum thiocyanate levels is probably not warranted in asymptomatic patients (Apple et al, 1996; Kunathai et al, 1989).
    2) Thiocyanate levels may be appropriate to monitor during prolonged nitroprusside use, at unusually high infusion rates, in patients receiving sodium thiosulfate to prevent cyanide toxicity, or in patients with renal insufficiency (Alaniz & Watts, 2005; Apple et al, 1996).
    3) Generally, serum thiocyanate concentrations are toxic if they are greater than 100 mg/L; however, patients do not consistently display signs or symptoms at these levels (Linakis et al, 1991).
    B) LABORATORY INTERFERENCE
    1) Toxic concentrations of thiocyanate increased glucose values obtained using the NOVA Stat Profile 5 Plus (Stat Profile) and increased total calcium, chloride and creatinine values measured using the Kodak Ektachem 700 Analyzer (E700). Ionized calcium values measured using the Stat Profile were decreased by toxic concentration of thiocyanate. Alanine aminotransferase activity using the E700 was decreased by cyanide concentrations of 100 micromol/L (Randell & StLouis, 1996).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.2) DISPOSITION/PARENTERAL EXPOSURE
    6.3.2.1) ADMISSION CRITERIA/PARENTERAL
    A) Patients with sodium nitroprusside toxicity, or secondary cyanide or thiocyanate toxicity should be monitored in an ICU setting.
    6.3.2.2) HOME CRITERIA/PARENTERAL
    A) There is no data to support home management, and sodium nitroprusside is generally only used in the hospital setting.
    6.3.2.3) CONSULT CRITERIA/PARENTERAL
    A) Consult a medical toxicologist or poison center for any patients with suspected cyanide toxicity or thiocyanate toxicity from sodium nitroprusside that does not respond to stopping the infusion.
    6.3.2.5) OBSERVATION CRITERIA/PARENTERAL
    A) Patients who are symptomatic should be observed with frequent monitoring of vital signs and mental status.

Monitoring

    A) Cyanide toxicity is a clinical diagnosis, because of the delays inherent in obtaining cyanide concentrations.
    B) Monitor vital signs and mental status.
    C) Obtain an ECG and institute continuous cardiac monitoring.
    D) Monitor serum electrolytes, renal function, serum lactate, arterial blood gases and mixed venous oxygen saturation if cyanide toxicity is a concern.
    E) Monitor thiocyanate concentrations in patients with prolonged infusions, those with renal insufficiency and those receiving simultaneous thiosulfate infusions.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Gastrointestinal decontamination is not recommended; administered via the parenteral route.

Abstracts

Case Reports

    A) ADULT
    1) ACUTE EFFECTS: A 53-year-old hypertensive man who required sodium nitroprusside therapy postcraniotomy for intracerebral bleeding presented 7 days later with coma and cerebral edema which were reversed with anti-cyanide management, hemodialysis, and discontinuation of nitroprusside therapy. Somnolence, tachypnea, mild metabolic acidosis, and subsequently coma developed following the administration of nitroprusside (2.5 mcg/kg/minute initially, which was maintained at a mean of 1 mcg/kg/minute over 7 days) to control severe hypertension. A CT scan demonstrated severe edema involving the left hemisphere, obliteration of the left ventricular system, and hypodense areas in left parieto-occipital area. The administration of 4-dimethylaminophenol 250 mg as an IV bolus, followed by sodium thiosulfate 12.5 grams in 50 mL of D5W, oxygen, and hemodialysis was successful and the patient regained consciousness 4 hours later. A CT scan 24 hours later revealed a significant reduction of edema and ventricular compression. Cyanide and thiocyanate levels were not determined(Ram et al, 1989).
    2) CYANIDE POISONING: A 23-year-old woman with a recent diagnosis of severe cardiomyopathy was admitted to the hospital and started on sodium nitroprusside (at the maximum rate of 3 mcg/kg/min) and initially showed some clinical improvement but became clinically unstable by day 4. She required intubation for respiratory failure that was further complicated by a cardiac arrest (ie, pulseless electrical activity) which responded to resuscitation. At this time, cyanide toxicity was suspected and it was confirmed that patient had not received sodium thiosulfate during her admission; sodium nitrite (300 mg) and sodium thiosulfate (12.5 g) were administered. Cyanide levels were 6.289 mg/L pretreatment and 0.128 mg/L post treatment. Despite these measures, the patient remained critically ill requiring increasing vasopressors for cardiogenic shock and hemodialysis for acute renal failure. The family ultimately made the decision to withdraw care and the patient died. The authors reported that sodium thiosulfate was previously routinely ordered per standardized order sets with sodium nitroprusside prior to the national shortage of sodium thiosulfate (Katzung et al, 2015).
    B) PEDIATRIC
    1) A 14-year-old girl with a history of spina bifida, severe kyphoscoliosis, hydrocephalus and seizures developed cyanide toxicity (cyanide level 3.1 mcg/mL) after receiving increasing doses of sodium nitroprusside (total dose 200 mg; 4.8 mg/kg over 56 hours) for severe intractable hypertension after renal transplantation. Following treatment with sodium nitrite, sodium thiocyanate, and hemodialysis, she recovered completely with no neurological sequelae (Quinlan et al, 2008).
    2) In one study, medical records of 63 postoperative pediatric cardiac surgical patients (mean age 4.9 +/- 5.8 years, median 21 months, range, 0.3 month to 18.8 years) treated with sodium nitroprusside (mean total dose, 1.24 +/- 0.82 mcg/kg/min; range, 0.1 to 4.1; mean duration of therapy, 42.7 +/- 52.5 hours; range, 4 to 281) for hypertension were evaluated for cyanide and thiocyanate concentrations, dosing, and signs and symptoms of toxicity. Overall, 7 of 63 (11%) patients had toxic cyanide concentrations. These patients had significantly higher sodium nitroprusside mean dose and cumulative dose. A mean dose of 1.8 mcg/kg/min was an independent predictor of elevated cyanide concentrations (greater than 0.5 mg/L), with 89% sensitivity and 88% specificity. Although adverse effects from cyanide toxicity were not reliable indicators of elevated cyanide concentrations, the best predictor was the mean dose of sodium nitroprusside (Moffett & Price, 2008).
    3) CYANIDE TOXICITY: Severe hypotension may occur. Cyanide toxicity and metabolic acidosis may occur with prolonged treatment (greater than 24 hours) and high (greater than 2 to 3 mcg/kg per minute) doses. Signs of cyanide toxicity include headache, coma, delirium, weakness, muscle spasms, hypotension, tachycardia, and tinnitus. Clinically significant methemoglobinemia (greater than 10%) occurs rarely. Extravasation can cause tissue sloughing and necrosis (Thomas et al, 2009; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Moffett & Price, 2008; Prod Info NITROPRESS(R) injection, 2004; Grossman et al, 1998).

Range Of Toxicity

Summary

    A) TOXICITY: CYANIDE: Infusion of more than 500 mcg/kg sodium nitroprusside at a rate of greater than 2 mcg/kg/min causes generation of cyanide at a rate faster than most patients can eliminate it. THIOCYANATE: Toxicity generally does not develop in patients with normal renal function before 7 days of continuous therapy at moderate doses. May develop in 3 days in patients with renal insufficiency who are not undergoing hemodialysis.
    B) THERAPEUTIC DOSES: Initial infusion of 0.3 mcg/kg/min titrated to clinical response to a maximum of 10 mcg/kg/min.

Therapeutic Dose

    7.2.1) ADULT
    A) ROUTE OF ADMINISTRATION
    1) INTRAVENOUS INFUSION
    a) INITIAL DOSE: The initial infusion rate should never exceed 0.3 mcg/kg/min, but this dose may be increased gradually to a MAXIMUM of 10 mcg/kg/min, depending on clinical response (Prod Info NITROPRESS(R) intravenous injection, 2013).
    b) If more than 500 mcg/kg of sodium nitroprusside is administered faster then 2 mcg/kg/min, cyanide is generated faster than most patients can eliminate it (Prod Info NITROPRESS(R) intravenous injection, 2013). The addition of 1 g of sodium thiosulfate to each 100 mg of sodium nitroprusside for infusion may help to prevent cyanide toxicity in patients receiving prolonged or high dose infusions (Prod Info NITROPRESS(R) injection for IV infusion, 2007).
    7.2.2) PEDIATRIC
    A) ROUTE OF ADMINISTRATION
    1) INTRAVENOUS
    a) INITIAL DOSE: 0.3 to 0.5 mcg/kg/minute continuous IV infusion. Titrate dose upward every 15 to 20 minutes until desired response is attained (Prod Info NITROPRESS(R) intravenous injection, 2013; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Grossman et al, 1998; Fivush et al, 1997; George & Friedman, 1986).
    b) MAINTENANCE: 0.5 to 8 mcg/kg/min continuous IV infusion (Kleinman et al, 2010; Flynn & Tullus, 2009; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Tabbutt et al, 2008; Motta et al, 2005; Grossman et al, 1998; Fivush et al, 1997; Deal et al, 1992; Caglar et al, 1986; George & Friedman, 1986; Artman et al, 1983). For hypertensive crisis, may use up to 10 mcg/kg/minute, but for no longer than 10 minutes (Prod Info NITROPRESS(R) intravenous injection, 2013; Flynn & Tullus, 2009; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).

Minimum Lethal Exposure

    A) ADULT
    1) The lowest published lethal doses (LDLo) reported in humans are as follows (RTECS, 2006):
    1) TDLo - (IV) HUMAN: 10 milligrams/kilogram
    2) TDLo - (IV) MAN: 29 milligrams/kilogram/1 week intermittent

Maximum Tolerated Exposure

    A) ADULT
    1) In a review of 23 cases of suspected cyanide toxicity after nitroprusside infusion, the onset of cyanide toxicity ranged from 50 minutes up to 14 days, the infusion rates were between 26 to 120 mcg/kg/min, and the total dose was from 13 to 2878 mg nitroprusside (Rindone & Sloane, 1992). Toxicity onset may be proceeded by metabolic acidosis, tachyphylaxis to the hypotensive effect of nitroprusside, and changes in mental status (Rindone & Sloane, 1992).
    2) With low dose SNP infusion rates (less than 3 micrograms/kilogram/minute), lasting less than 72 hours, toxicity is rarely observed (Cohn & Burke, 1979).
    3) The lowest published toxic dose (TDLo) reported in a human is 3360 micrograms/kilogram/14 hours continuous infusion (RTECS, 2006).
    4) CYANIDE: Infusion of more than 500 mcg/kg sodium nitroprusside at a rate of greater than 2 mcg/kg/min causes generation of cyanide at a rate faster than most patients can eliminate it (Prod Info NITROPRESS(R) injection, 2004).
    5) THIOCYANATE: Toxicity generally does not develop in patients with normal renal function before 7 days of continuous therapy at moderate doses (2 to 5 mcg/kg/min). May develop in 3 days in patients with renal insufficiency who are not undergoing hemodialysis (Curry & Arnold-Capell, 1991).
    B) CHILDREN
    1) CASE REPORT: A 14-year-old girl with a history of spina bifida, severe kyphoscoliosis, hydrocephalus and seizures developed cyanide toxicity (cyanide level 3.1 mcg/mL) after receiving increasing doses of sodium nitroprusside (total dose 200 mg; 4.8 mg/kg over 56 hours) for severe intractable hypertension after renal transplantation. Following treatment with sodium nitrite, sodium thiocyanate, and hemodialysis, she recovered completely with no neurological sequelae (Quinlan et al, 2008).
    2) In a study of 22 children who received nitroprusside after repair of structural heart disease, no clinical or laboratory evidence of thiocyanate toxicity was described. Average infusion rates in these children ranged from 0.5 to 3.1 mcg/kg/min (mean 1.27 mcg/kg/min), mean duration of infusion was 34.4 hours (range 12 to 73 hours) and the mean total dose was 2.6 mg/kg (range 0.6 to 9.1 mg/kg) (Kunathai et al, 1989).
    3) In one study, medical records of 63 postoperative pediatric cardiac surgical patients (mean age 4.9 +/- 5.8 years, median 21 months, range, 0.3 month to 18.8 years) treated with sodium nitroprusside (mean total dose, 1.24 +/- 0.82 mcg/kg/min; range, 0.1 to 4.1; mean duration of therapy, 42.7 +/- 52.5 hours; range, 4 to 281) for hypertension were evaluated for cyanide and thiocyanate concentrations, dosing, and signs and symptoms of toxicity. Overall, 7 of 63 (11%) patients had toxic cyanide concentrations. These patients had significantly higher sodium nitroprusside mean dose and cumulative dose. A mean dose of 1.8 mcg/kg/min was an independent predictor of elevated cyanide concentrations (greater than 0.5 mg/L), with 89% sensitivity and 88% specificity. Although adverse effects from cyanide toxicity were not reliable indicators of elevated cyanide concentrations, the best predictor was the mean dose of sodium nitroprusside (Moffett & Price, 2008).

Toxicity Information

    7.7.1) TOXICITY VALUES

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) CONCENTRATION LEVEL
    a) Generally, blood cyanide and serum thiocyanate concentrations are toxic if they are greater than 500 mcg/L and greater than 100 mg/L, respectively; however, patients do not consistently display signs or symptoms at these levels (Linakis et al, 1991). Blood cyanide and thiocyanate concentrations can be monitored, but a poor correlation exists between the dose or duration of nitroprusside and cyanide concentrations (Vesey et al, 1974).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Nitroprusside relaxes arterial and venous smooth muscles resulting in vasodilatation and decreased blood pressure.

Toxicologic Mechanism

    A) Following IV administration, nitroprusside is rapidly metabolized to cyanogen (cyanide radical). Like cyanide, it inhibits electron transport in mitochondrial cytochrome oxidase, thus inhibiting cellular respiration.
    B) The toxicity of nitroprusside has been attributed to cyanogen; however, the role of cyanogen in nitroprusside poisoning has been questioned, and it has been theorized that some toxic effects may be caused by profound hypotension (Prod Info NITROPRESS(R) injection for IV infusion, 2007).
    C) Tachyphylaxis following continued nitroprusside infusions has been shown in the presence of high levels of blood cyanide with no acidosis present. It is suggested that cyanide interferes with vascular smooth muscle relaxation (Cottrell et al, 1978). Posner et al (1976) postulated tachyphylaxis was due to accumulation of cyanide in the blood which then blocks utilization of oxygen at the level of the cytochrome oxidase system, resulting in acute tissue hypoxia and tachyphylaxis.

Physicochemical

Molecular Weight

    A) 297.95

References

General Bibliography

    1) AMA Department of DrugsAMA Department of Drugs: AMA Evaluations Subscription, American Medical Association, Chicago, IL, 1992.
    2) Alaniz C & Watts B: Monitoring cyanide toxicity in patients receiving nitroprusside therapy. Ann Pharmacotherapy 2005; 39:388-389.
    3) Apple FS, Lowe MC, Googins MK, et al: Serum thiocyanate concentrations in patients with normal or impaired renal function receiving nitroprusside. Clin Chem 1996; 42(11):1878-1879.
    4) Artigas A, Bernard GR, Carlet J, et al: The American-European consensus conference on ARDS, part 2: ventilatory, pharmacologic, supportive therapy, study design strategies, and issues related to recovery and remodeling.. Am J Respir Crit Care Med 1998; 157:1332-1347.
    5) Artman M , Parrish MD , & Graham TP : Congestive heart failure in childhood and adolescence: recognition and management. Am Heart J 1983; 105(3):471-480.
    6) Baek JG , Jeong HL , Park JS , et al: Successful treatment by exchange transfusion of a young infant with sodium nitroprusside poisoning. Korean J Pediatr 2010; 53(8):805-808.
    7) Berlin CM Jr: Treatment of cyanide poisoning in children. Pediatrics 1970; 46:793-796.
    8) Berlin: Treatment of cyanide poisoning in children. Pediatr 1970a; 46:793-796.
    9) Brophy GM, Bell R, Claassen J, et al: Guidelines for the evaluation and management of status epilepticus. Neurocrit Care 2012; 17(1):3-23.
    10) Brower RG, Matthay AM, & Morris A: Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Eng J Med 2000; 342:1301-1308.
    11) Caglar MK, Dilmen U, Senses DA, et al: Sodium nitroprusside for hypertensive emergencies in children. Turk J Pediatr 1986; 28(2):97-103.
    12) Cataletto M: Respiratory Distress Syndrome, Acute(ARDS). In: Domino FJ, ed. The 5-Minute Clinical Consult 2012, 20th ed. Lippincott Williams & Wilkins, Philadelphia, PA, 2012.
    13) Chamberlain JM, Altieri MA, & Futterman C: A prospective, randomized study comparing intramuscular midazolam with intravenous diazepam for the treatment of seizures in children. Ped Emerg Care 1997; 13:92-94.
    14) Chin RF , Neville BG , Peckham C , et al: Treatment of community-onset, childhood convulsive status epilepticus: a prospective, population-based study. Lancet Neurol 2008; 7(8):696-703.
    15) Choonara IA & Rane A: Therapeutic drug monitoring of anticonvulsants state of the art. Clin Pharmacokinet 1990; 18:318-328.
    16) Cohn JN & Burke LP: Nitroprusside. Ann Intern Med 1979; 91:752-757.
    17) Cottrell JE, Casthely P, & Brodie JD: Mechanism and prevention of tachyphylaxis and cyanide toxicosis after nitroprusside-induced hypotension. Surg Forum 1978a; 29:308-310.
    18) Cottrell JE, Casthely P, & Brodie JD: Prevention of nitroprusside-induced cyanide toxicity with hydroxocobalamin. N Engl J Med 1978; 298:809-811.
    19) Curry SC & Arnold-Capell P: Toxic effects of drugs used in the ICU. Nitroprusside, nitroglycerin, and angiotensin-converting enzyme inhibitors. Crit Care Clin 1991; 7(3):555-581.
    20) Deal JE , Barratt TM , & Dillon MJ : Management of hypertensive emergencies. Arch Dis Child 1992; 67(9):1089-1092.
    21) DiNapoli J, Hall AH, & Drake R: Cyanide and arsenic poisoning by intravenous injection. Ann Emerg Med 1989; 18:308-311.
    22) Donchin Y, Amirau B, & Sahar: Sodium nitroprusside for aneurysm surgery in pregnancy. Br J Anaesth 1978; 50:849.
    23) Fivush B , Neu A , & Furth S : Acute hypertensive crises in children: emergencies and urgencies. Curr Opin Pediatr 1997; 9(3):233-236.
    24) Flynn JT & Tullus K: Severe hypertension in children and adolescents: pathophysiology and treatment. Pediatr Nephrol 2009; 24(6):1101-1112.
    25) George BL & Friedman WF : Treatment of cardiac failure in infants. Compr Ther 1986; 12(2):8-14.
    26) Graham DL, Laman D, & Theodore J: Acute cyanide poisoning complicated by lactic acidosis and pulmonary edema. Arch Intern Med 1977; 137:1051-1055.
    27) Grossman E , Ironi AN , & Messerli FH : Comparative tolerability profile of hypertensive crisis treatments. Drug Saf 1998; 19(2):99-122.
    28) Haas CF: Mechanical ventilation with lung protective strategies: what works?. Crit Care Clin 2011; 27(3):469-486.
    29) Hall AH & Rumack BH: Hydroxycobalamin/sodium thiosulfate as a cyanide antidote. J Emerg Med 1987; 5:115-121.
    30) Harmon C & Wohlreich MM: Sodium nitroprusside-induced delirium. Psychosomatics 1995; 36:83-85.
    31) Hegenbarth MA & American Academy of Pediatrics Committee on Drugs: Preparing for pediatric emergencies: drugs to consider. Pediatrics 2008; 121(2):433-443.
    32) Hewick DS, Butler AR, & Glidewell C: Sodium nitroprusside: pharmacological aspects of its interaction with hydroxocobalamin and thiosulphate. J Pharmacol 1987; 39:113-117.
    33) Hobel M, Engeser P, & Nemeth L: The antidote effect of thiosulphate and hydroxocobalamin in formation of nitroprusside intoxication of rabbits. Arch Toxicol 1980; 46:207-213.
    34) Howland MA: Sodium Thiosulfate. In: Nelson LS, Lewin NA, Howland MA, et al, eds. Goldfrank's Toxicologic Emergencies, 9th ed. McGraw Hill Medical, New York, NY, 2011, pp 1692-1694.
    35) Hvidberg EF & Dam M: Clinical pharmacokinetics of anticonvulsants. Clin Pharmacokinet 1976; 1:161.
    36) Johnson RP & Mellors JW: Arteriolization of venous blood gases: a clue to the diagnosis of cyanide poisoning. J Emerg Med 1988; 6:401-404.
    37) Johnson WS, Hall AH, & Rumack BH: Cyanide poisoning successfully treated without 'therapeutic methemoglobin levels'. Am J Emerg Med 1989; 7:437-440.
    38) Katzung KG, Topeff JM, Leroy JM, et al: Prolonged Sodium Nitroprusside Infusion Resulting in Fatal Cyanide Poisoning During National Sodium Thiosulfate Shortage. Clin Toxicol 2015; 53(7):671-671.
    39) Kleinman ME, Chameides L, Schexnayder SM, et al: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Part 14: pediatric advanced life support. Circulation 2010; 122(18 Suppl.3):S876-S908.
    40) Kollef MH & Schuster DP: The acute respiratory distress syndrome. N Engl J Med 1995; 332:27-37.
    41) Krapez JR, Vesey CJ, & Adams L: Effects of cyanide antidotes used with sodium nitroprusside infusions: sodium thiosulfate and hydroxocobalamin given prophylactically to dogs. Br J Anaesth 1981; 53:793-803.
    42) Kraut JA & Madias NE: Metabolic acidosis: pathophysiology, diagnosis and management. Nat Rev Nephrol 2010; 6(5):274-285.
    43) Kunathai S, Sholler GF, Celermajer JM, et al: Nitroprusside in children after cardiopulmonary bypass: a study of thiocyanate toxicity. Pediatr Cardiol 1989; 10(3):121-124.
    44) Linakis JG, Lacouture PG, & Woolf A: Monitoring cyanide and thiocyanate concentrations during infusion of sodium nitroprusside in children. Pediatr Cardiol 1991; 12:214-218.
    45) Loddenkemper T & Goodkin HP: Treatment of Pediatric Status Epilepticus. Curr Treat Options Neurol 2011; Epub:Epub.
    46) Manno EM: New management strategies in the treatment of status epilepticus. Mayo Clin Proc 2003; 78(4):508-518.
    47) Marrs TC: Antidotal treatment of acute cyanide poisoning. Adverse Drug React Acute Poisoning Rev 1988; 4:179-206.
    48) Moffett BS & Price JF: Evaluation of sodium nitroprusside toxicity in pediatric cardiac surgical patients. Ann pharmacother 2008; 42(11):1600-1604.
    49) Motta P, Mossad E, Toscana D, et al: Comparison of phenoxybenzamine to sodium nitroprusside in infants undergoing surgery. J Cardiothorac Vasc Anesth 2005; 19(1):54-59.
    50) NHLBI ARDS Network: Mechanical ventilation protocol summary. Massachusetts General Hospital. Boston, MA. 2008. Available from URL: http://www.ardsnet.org/system/files/6mlcardsmall_2008update_final_JULY2008.pdf. As accessed 2013-08-07.
    51) Naulty J, Cefae RC, & Lewis PE: Fetal toxicity of nitroprusside in the pregnant ewe. Am J Obstet Gynecol 1981; 139:703.
    52) Nessim SJ & Richardson RM: Dialysis for thiocyanate intoxication: a case report and review of the literature. ASAIO J 2006; 52(4):479-481.
    53) Nicoletta G, Cascelli M, Marchesini L, et al: A probable case of nitroprusside intoxication. Minerva Anestesiol 2007; 73(9):471-473.
    54) Nourok DS, Glassock RJ, & Soloman DH: Hypothyroidism following prolonged sodium nitroprusside therapy. Am J Sci 1964; 248:129-138.
    55) Olgunturk FR, Yener A, Tunaoglu FS, et al: Temporary blindness due to sodium nitroprusside overdosage in a postoperative patient: an unusual adverse effect. Clin Pediatr (Phila) 1992; 31(6):380-381.
    56) Patel CB, Laboy V, & Venus B: Use of sodium nitroprusside in post-coronary bypass surgery. A plea for conservatism. Chest 1986; 89:663-667.
    57) Paull J: Clinical report of the use of sodium nitroprusside in severe pre-eclampsia. Anesth Intens Care 1975; 3:72.
    58) Peberdy MA , Callaway CW , Neumar RW , et al: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care science. Part 9: post–cardiac arrest care. Circulation 2010; 122(18 Suppl 3):S768-S786.
    59) Product Information: CYANOKIT(R) 2.5g IV injection, hydroxocobalamin IV injection. Merck Lipha Sante, Lyon, France, 2006.
    60) Product Information: NITHIODOTE intravenous injection solution, sodium nitrite intravenous injection solution and sodium thiosulfate intravenous injection solution. Hope Pharmaceuticals (per manufacturer), Scottsdale, AZ, 2011.
    61) Product Information: NITROPRESS(R) injection for IV infusion, Sodium Nitroprusside injection for IV infusion. Hospira, Inc., Lake Forest, IL, 2007.
    62) Product Information: NITROPRESS(R) injection, sodium nitroprusside injection. Hospira,Inc, Lake Forest, IL, 2004.
    63) Product Information: NITROPRESS(R) intravenous injection, sodium nitroprusside intravenous injection. Hospira, Inc. (per DailyMed), Lake Forest, IL, 2013.
    64) Product Information: diazepam IM, IV injection, diazepam IM, IV injection. Hospira, Inc (per Manufacturer), Lake Forest, IL, 2008.
    65) Product Information: dopamine hcl, 5% dextrose IV injection, dopamine hcl, 5% dextrose IV injection. Hospira,Inc, Lake Forest, IL, 2004.
    66) Product Information: lorazepam IM, IV injection, lorazepam IM, IV injection. Akorn, Inc, Lake Forest, IL, 2008.
    67) Product Information: norepinephrine bitartrate injection, norepinephrine bitartrate injection. Sicor Pharmaceuticals,Inc, Irvine, CA, 2005.
    68) Product Information: sodium thiosulfate IV injection, sodium thiosulfate IV injection. American Regent Inc, Shirley, NY, 2003.
    69) Quinlan C, Gill D, Waldron M, et al: Cyanide poisoning in the post-transplantation patient-a cautionary tale. Pediatr nephrol 2008; 23(12):2273-2275.
    70) RTECS: Registry of Toxic Effects of Chemical Substances. National Institute for Occupational Safety and Health. Cincinnati, OH (Internet Version). Edition expires 2006; provided by Truven Health Analytics Inc., Greenwood Village, CO.
    71) Ram Z, Spiegelman R, & Findler G: Delayed postoperative neurological deterioration from prolonged sodium nitroprusside administration. J Neurosurg 1989; 71:605-607.
    72) Randell EW & StLouis P: Interference in glucose and other clinical chemistry assays by thiocyanate and cyanide in a patient treated with nitroprusside. Clin Chem 1996; 42(3):449-453.
    73) Reid GM & Muther RS: Nitroprusside-induced acute azotemia. Am J Nephrol 1987; 7(4):313-315.
    74) Rindone JP & Sloane EP: Cyanide toxicity from sodium nitroprusside: risks and management. Ann Pharmacother 1992; 26:515-519.
    75) Saunders JP & Himwich WA: Properties of the transsulfurase responsible for the conversion of cyanide to thiocyanate. Am J Physiol 1950; 163:404-409.
    76) Schulz V, Bonn R, & Kindler J: Kinetics of elimination of thiocyanate in 7 healthy subjects and in 8 subjects with renal failure. Klin Wochenschr 1979; 57:243-247.
    77) Scott R, Besag FMC, & Neville BGR: Buccal midazolam and rectal diazepam for treatment of prolonged seizures in childhood and adolescence: a randomized trial. Lancet 1999; 353:623-626.
    78) Sreenath TG, Gupta P, Sharma KK, et al: Lorazepam versus diazepam-phenytoin combination in the treatment of convulsive status epilepticus in children: A randomized controlled trial. Eur J Paediatr Neurol 2009; Epub:Epub.
    79) Stellpflug SJ, Gardner RL, Leroy JM, et al: Hydroxocobalamin hinders hemodialysis. Am J Kidney Dis 2013; 62(2):395-395.
    80) Stolbach A & Hoffman RS: Respiratory Principles. In: Nelson LS, Hoffman RS, Lewin NA, et al, eds. Goldfrank's Toxicologic Emergencies, 9th ed. McGraw Hill Medical, New York, NY, 2011.
    81) Tabbutt S, Nicolson SC, Dominguez TE, et al: Perioperative course in 118 infants and children undergoing coarctation repair via a thoracotomy: a prospective, multicenter experience. J Thorac Cardiovasc Surg 2008; 136(5):1229-1236.
    82) Tatar H, Cicek S, Suer H, et al: Use of topical sodium nitroprusside to relieve perioperative spasm of the internal mammary artery: a word of caution. J Thorac Cardiovasc Surg 1994; 108(2):387-.
    83) Thomas C, Svehla L, & Moffett BS: Sodium nitroprusside induced cyanide toxicity in pediatric patients. Expert Opin Drug Saf 2009; 8(5):599-602.
    84) Turchen SG, Manoguerra AS, & Whitney C: Severe cyanide poisoning following suicidal ingestion of an acetonitrile-containing cosmetic. Am J Emerg Med 1991; 9:264-267.
    85) Udeh CI, Ting M, Arango M, et al: Delayed presentation of nitroprusside-induced cyanide toxicity. Ann Thorac Surg 2015; 99(4):1432-1434.
    86) Vesey CJ, Cole PV, & Linnell JC: Some metabolic effects of sodium nitroprusside in man. Br Med J 1974; 2:140-142.
    87) Wesson DE, Foley R, & Sabatini S: Treatment of acute cyanide intoxication with hemodialysis. Am J Nephrol 1985; 5:121-126.
    88) Willson DF, Truwit JD, Conaway MR, et al: The adult calfactant in acute respiratory distress syndrome (CARDS) trial. Chest 2015; 148(2):356-364.
    89) Wilson DF, Thomas NJ, Markovitz BP, et al: Effect of exogenous surfactant (calfactant) in pediatric acute lung injury. A randomized controlled trial. JAMA 2005; 293:470-476.
    90) Yamamoto HA: Nitroprusside intoxication: protection of alpha-ketoglutarate and thiosulphate. Food Chem Toxicol 1992; 30(10):887-890.
    91) Zerbe NF & Wagner BK: Use of vitamin B12 in the treatment and prevention of nitroprusside-induced cyanide toxicity. Crit Care Med 1993; 21(3):465-467.