Sodium nitrite can cause serious adverse reactions and death in humans, even at doses less than twice the recommended therapeutic dose. Sodium nitrite causes hypotension and methemoglobin formation, which diminishes oxygen-carrying capacity. Hypotension and methemoglobin formation can occur concurrently or separately. Because of these risks, sodium nitrite should be used to treat acute life-threatening cyanide poisoning and should be used with caution in patients in whom the diagnosis of cyanide poisoning is uncertain.
Closely monitor patients to ensure adequate perfusion and oxygenation during treatment with sodium nitrite. Consider alternative therapeutic approaches in patients known to have diminished oxygen or cardiovascular reserve (eg, smoke inhalation victims, preexisting anemia, cardiac or respiratory compromise), and in those at higher risk of developing methemoglobinemia (eg, congenital methemoglobin reductase deficiency) as they are at greater risk of potentially life-threatening adverse events related to the use of sodium nitrite.
Note: Dosing in pediatric patients expressed in multiple units (mg/kg, mL/kg, mL/m2), use extra caution. Consultation with a clinical toxicologist or poison control center is highly recommended.
Cyanide poisoning: Note: Hydroxocobalamin is the preferred cyanide antidote; if hydroxocobalamin is unavailable, then sodium nitrite may be used in conjunction with sodium thiosulfate. Administer sodium nitrite first, followed immediately by the administration of sodium thiosulfate (Howland 2019). Sodium nitrite is generally discontinued for methemoglobin levels >30%.
Sodium nitrite (30 mg/mL, 3%): Infants, Children, and Adolescents: IV: 6 mg/kg (0.2 mL/kg or 6 to 8 mL/m2 of a 3% solution); maximum dose: 300 mg (10 mL of a 3% solution) (Howland 2019; manufacturer's labeling). Monitor patients for 24 to 48 hours; if symptoms return, repeat both sodium nitrite and sodium thiosulfate at one-half the original doses.
Dosage adjustment for patients who are unable to tolerate significant methemoglobinemia (eg, patients with comorbidities that compromise oxygen delivery, such as heart disease, lung disease, etc): Hemoglobin-dependent dosing (when rapid bedside testing is available) to prevent fatal methemoglobinemia (Berlin 1970):
Dosing Based on Hgb Level | |
---|---|
Hemoglobin Level (g/dL) |
Dose of 3% Sodium Nitrite Solution (Maximum dose: 10 mL/dose) |
7 |
0.19 mL/kg |
8 |
0.22 mL/kg |
9 |
0.25 mL/kg |
10 |
0.27 mL/kg |
11 |
0.3 mL/kg |
12 |
0.33 mL/kg |
13 |
0.36 mL/kg |
14 |
0.39 mL/kg |
Sodium thiosulfate: Infants, Children, and Adolescents: IV: 250 to 412.5 mg/kg (1 to 1.65 mL/kg of a 25% solution); maximum dose: 12.5 g/dose (50 mL of a 25% solution) (Holstege 2019; Howland 2019; Mintegi 2013; manufacturer's labeling). Monitor the patient for 24 to 48 hours; if symptoms return, repeat both sodium nitrite and sodium thiosulfate at one-half the original doses.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosage adjustments provided in the manufacturer’s labeling; however, renal elimination of sodium nitrite and sodium thiosulfate is significant and risk of adverse effects may be increased in patients with renal impairment.
There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).
(For additional information see "Sodium nitrite and sodium thiosulfate: Drug information")
Note: Consultation with a clinical toxicologist or poison control center is highly recommended.
Cyanide poisoning: IV: Note: Administer sodium nitrite first, followed immediately by the administration of sodium thiosulfate.
Sodium nitrite: 300 mg (10 mL of a 3% solution); may repeat at one-half of the original dose if symptoms of cyanide toxicity return
Alternatively, in patients who are unable to tolerate significant methemoglobinemia (eg, patients with comorbidities that compromise oxygen delivery, such as heart disease, lung disease), dosing may be based on hemoglobin levels (when rapid bedside testing is available) to prevent fatal methemoglobinemia; see table (Berlin, 1970):
Hemoglobin Level (g/dL) |
Dose of 3% Sodium Nitrite Solution (maximum dose: 10 mL) |
---|---|
7 |
0.19 mL/kg |
8 |
0.22 mL/kg |
9 |
0.25 mL/kg |
10 |
0.27 mL/kg |
11 |
0.3 mL/kg |
12 |
0.33 mL/kg |
13 |
0.36 mL/kg |
14 |
0.39 mL/kg |
Sodium thiosulfate: 12.5 g (50 mL of a 25% solution); may repeat at one-half the original dose if symptoms of cyanide toxicity return
Note: Monitor the patient for 24 to 48 hours; if symptoms return, repeat both sodium nitrite and sodium thiosulfate at one-half the original doses.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
No dosage adjustment provided in manufacturer’s labeling; however, renal elimination of sodium nitrite and sodium thiosulfate is significant and risk of adverse effects may be increased in patients with renal impairment.
No dosage adjustment provided in the manufacturer’s labeling (has not been studied).
See individual agents.
There are no contraindications listed within the manufacturer’s labeling.
Concerns related to adverse effects:
• Hypotension: [US Boxed Warning]: Sodium nitrite may cause severe hypotension resulting in diminished oxygen-carrying capacity; serious adverse effects may occur at doses less than twice the recommended therapeutic dose. Monitor for adequate perfusion and oxygenation; ensure patient is euvolemic. Use with caution in patients where the diagnosis of cyanide poisoning is uncertain, patients with pre-existing diminished oxygen or cardiovascular reserve (eg, smoke inhalation victims [due to the presence of carbon monoxide], anemia, substantial blood loss, and cardiac or respiratory compromise) and in patients who may be susceptible to injury from vasodilation; the use of hydroxocobalamin is recommended in these patients.
• Methemoglobinemia: [US Boxed Warning]: Sodium nitrite may cause methemoglobin formation resulting in diminished oxygen-carrying capacity; serious adverse effects may occur at doses less than twice the recommended therapeutic dose. Monitor for adequate perfusion and oxygenation. Use with caution in patients where the diagnosis of cyanide poisoning is uncertain, patients with pre-existing diminished oxygen or cardiovascular reserve (eg, smoke inhalation victims [due to the presence of carbon monoxide], anemia, substantial blood loss, and cardiac or respiratory compromise), and in patients at greater risk for developing methemoglobinemia (eg, congenital methemoglobin reductase deficiency); the use of hydroxocobalamin is recommended in these patients. Use with caution with concomitant medications known to cause methemoglobinemia (eg, nitroglycerin, phenazopyridine). Sodium nitrite is generally discontinued for methemoglobin levels >30%. Intravenous methylene blue and exchange transfusion have been used to treat life-threatening methemoglobinemia.
Disease-related concerns:
• Anemia: Use with caution; patients with anemia will form more methemoglobin. Dosage reduction in proportion to oxygen-carrying capacity is recommended.
• Glucose-6-phosphate dehydrogenase deficiency: Patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency, especially children, are at an increased risk for hemolytic crisis following sodium nitrite administration; consider alternative treatment options (eg, hydroxocobalamin) if possible. Monitor for an acute drop in hematocrit; exchange transfusion may be necessary.
• Renal impairment: Use with caution; sodium nitrite and sodium thiosulfate undergo substantial renal excretion. Risk for adverse events may be increased.
Special populations:
• Older adult: Use with caution due to the likelihood of decreased renal function.
• Fire victims: Fire victims may present with both cyanide and carbon monoxide poisoning. In this scenario, hydroxocobalamin is the agent of choice for cyanide intoxication since the induction of methemoglobinemia (due to sodium nitrite) is contraindicated until carbon monoxide levels return to normal due to the risk of severe tissue hypoxia. Methemoglobinemia decreases the oxygen-carrying capacity of hemoglobin and the presence of carbon monoxide prevents hemoglobin from releasing oxygen to the tissues. In these patients, sodium thiosulfate may be used alone to promote the clearance of cyanide; however, hydroxocobalamin is still the preferred cyanide antidote because sodium thiosulfate has a slow onset of action.
• Pediatric: Methemoglobin reductase, which is responsible for converting methemoglobin back to hemoglobin, has reduced activity in pediatric patients. In addition, infants and young children have some proportion of fetal hemoglobin which forms methemoglobin more readily than adult hemoglobin. Therefore, pediatric patients (eg, neonates and infants <6 months of age) are more susceptible to excessive nitrite-induced methemoglobinemia. Hydroxocobalamin will circumvent this problem and may be a more effective and rapid alternative.
• Sulfite hypersensitivity: The presence of sulfite hypersensitivity should not preclude the use of this medication.
Other warnings/precautions:
• Appropriate use: Cyanide poisoning: Due to the risk for serious adverse effects, use with caution in patients where the diagnosis of cyanide poisoning is uncertain. However, if clinical suspicion of cyanide poisoning is high, treatment should not be delayed. Signs of cyanide poisoning may include altered mental status, cardiovascular collapse, chest tightness, mydriasis, nausea/vomiting, dyspnea, hyper-/hypotension, plasma lactate ≥8 mmol/L. Treatment of cyanide poisoning should include external decontamination and supportive therapy. Consider immediate consultation with a poison control center at 1-800-222-1222.
• Initiation of treatment: Collection of pretreatment blood cyanide concentrations does not preclude administration and should not delay administration in the emergency management of highly suspected or confirmed cyanide toxicity. Pretreatment levels may be useful as postinfusion levels may be inaccurate.
• Return of symptoms: Patients receiving treatment for acute cyanide poisoning must be monitored for return of symptoms for 24-48 hours; repeat treatment (one-half the original dose) should be administered if symptoms return.
• Smoke inhalation: Use nitrites cautiously in patients with cyanide poisoning related to smoke inhalation because methemoglobinemia and carboxyhemoglobinemia (from carbon monoxide) may worsen oxygen-carrying capacity.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Injection, solution [combination package]:
Nithiodote: Sodium nitrite 300 mg/10 mL (10 mL) and sodium thiosulfate 12.5 g/50 mL (50 mL)
Kit (Nithiodote Intravenous)
300MG/10ML&12.5 gm/50 mL (per mL): $3.80
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IV: Administer both components undiluted via slow IV injection as soon as possible after diagnosis of acute, life-threatening cyanide poisoning. Administer sodium nitrite at a rate of 2.5 to 5 mL/minute, followed immediately by the administration of sodium thiosulfate over 10 to 30 minutes (Howland 2011; Howland 2019). Decrease rate of infusion in the event of significant hypotension, nausea, or vomiting. Simultaneous administration of blood products (whole blood, packed red cells, platelet concentrate, and/or fresh frozen plasma) should preferentially be done using separate lines (use contralateral extremities if peripheral lines are used).
IV: Administer via slow IV injection as soon as possible after diagnosis of acute, life-threatening cyanide poisoning. Administer sodium nitrite first at a rate of 2.5 to 5 mL/minute, followed immediately by sodium thiosulfate over 10 to 30 minutes (Howland 2019); some recommend slower administration of sodium nitrite (≥5 minutes [ATSDR 2022]). Decrease the rate of infusion in the event of significant hypotension. Simultaneous administration of blood products (whole blood, packed red cells, platelet concentrate, and/or fresh frozen plasma) should preferentially be done using separate lines (use contralateral extremities if peripheral lines are used).
Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F); do not freeze. Protect from direct light.
Pharmacy supply of emergency antidotes: Guidelines suggest that at least 600 mg of sodium nitrite and 25 g of sodium thiosulfate be stocked, especially in hospitals which serve industrial areas. Suggested amount is stated to be a sufficient quantity to treat 1 patient weighing 100 kg for an initial 8- to 24-hour period (Dart 2018); actual amount to be stocked should take into account site-specific and population-specific needs.
Treatment of acute, life-threatening cyanide poisoning (FDA approved in pediatric patients [age not specified] and adults).
None known.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the drug interactions program by clicking on the “Launch drug interactions program” link above.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the drug interactions program
Alfuzosin: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Amifostine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Amifostine. Management: When used at chemotherapy doses, hold blood pressure lowering medications for 24 hours before amifostine administration. If blood pressure lowering therapy cannot be held, do not administer amifostine. Use caution with radiotherapy doses of amifostine. Risk D: Consider therapy modification
Amisulpride (Oral): May enhance the hypotensive effect of Hypotension-Associated Agents. Risk C: Monitor therapy
Antipsychotic Agents (Second Generation [Atypical]): Blood Pressure Lowering Agents may enhance the hypotensive effect of Antipsychotic Agents (Second Generation [Atypical]). Risk C: Monitor therapy
Arginine: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Barbiturates: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Benperidol: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Blood Pressure Lowering Agents: May enhance the hypotensive effect of Hypotension-Associated Agents. Risk C: Monitor therapy
Brimonidine (Topical): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Bromperidol: May diminish the hypotensive effect of Blood Pressure Lowering Agents. Blood Pressure Lowering Agents may enhance the hypotensive effect of Bromperidol. Risk X: Avoid combination
Dapsone (Topical): May enhance the adverse/toxic effect of Methemoglobinemia Associated Agents. Risk C: Monitor therapy
Diazoxide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
DULoxetine: Blood Pressure Lowering Agents may enhance the hypotensive effect of DULoxetine. Risk C: Monitor therapy
Herbal Products with Blood Pressure Lowering Effects: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Hypotension-Associated Agents: Blood Pressure Lowering Agents may enhance the hypotensive effect of Hypotension-Associated Agents. Risk C: Monitor therapy
Iloperidone: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Levodopa-Foslevodopa: Blood Pressure Lowering Agents may enhance the hypotensive effect of Levodopa-Foslevodopa. Risk C: Monitor therapy
Local Anesthetics: Methemoglobinemia Associated Agents may enhance the adverse/toxic effect of Local Anesthetics. Specifically, the risk for methemoglobinemia may be increased. Risk C: Monitor therapy
Lormetazepam: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Methemoglobinemia Associated Agents: May enhance the adverse/toxic effect of Sodium Nitrite. Combinations of these agents may increase the likelihood of significant methemoglobinemia. Risk C: Monitor therapy
Molsidomine: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Naftopidil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Nicergoline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Nicorandil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Nitric Oxide: May enhance the adverse/toxic effect of Methemoglobinemia Associated Agents. Combinations of these agents may increase the likelihood of significant methemoglobinemia. Risk C: Monitor therapy
Nitroprusside: Blood Pressure Lowering Agents may enhance the hypotensive effect of Nitroprusside. Risk C: Monitor therapy
Obinutuzumab: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Management: Consider temporarily withholding blood pressure lowering medications beginning 12 hours prior to obinutuzumab infusion and continuing until 1 hour after the end of the infusion. Risk D: Consider therapy modification
Pentoxifylline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Pholcodine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Pholcodine. Risk C: Monitor therapy
Phosphodiesterase 5 Inhibitors: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Prilocaine: Methemoglobinemia Associated Agents may enhance the adverse/toxic effect of Prilocaine. Combinations of these agents may increase the likelihood of significant methemoglobinemia. Management: Monitor for signs of methemoglobinemia when prilocaine is used in combination with other agents associated with development of methemoglobinemia. Avoid use of these agents with prilocaine/lidocaine cream in infants less than 12 months of age. Risk C: Monitor therapy
Prostacyclin Analogues: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Quinagolide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Silodosin: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Sodium nitrite causes methemoglobin formation resulting in diminished oxygen-carrying capacity; fetal hemoglobin may be more susceptible to excessive nitrite-induced methemoglobinemia; however, cyanide crosses the placenta; untreated cyanide poisoning may cause maternal and fetal death.
In general, medications used as antidotes should take into consideration the health and prognosis of the mother; antidotes should be administered to pregnant patients if there is a clear indication for use and should not be withheld because of fears of teratogenicity (Bailey 2003). However, sodium nitrite/sodium thiosulfate is not the preferred treatment of cyanide toxicity (Anseeuw 2013) and other treatments may be preferred for use during pregnancy (Culnan 2018). Therapies not associated with methemoglobinemia should be considered when available.
Monitor for adequate oxygenation and perfusion and for recurrent signs and symptoms of cyanide toxicity for at least 24 to 48 hours after administration; blood pressure and heart rate during and after infusion; hemoglobin/hematocrit; co-oximetry; serum lactate levels; venous-arterial PO2 gradient; serum methemoglobin and oxyhemoglobin. Pretreatment cyanide levels may be useful diagnostically.
Sodium nitrite: Promotes the formation of methemoglobin which competes with cytochrome oxidase for the cyanide ion. Cyanide combines with methemoglobin to form cyanomethemoglobin, thereby freeing the cytochrome oxidase and allowing aerobic metabolism to continue.
Sodium thiosulfate: Serves as a sulfur donor in rhodanese-catalyzed formation of thiocyanate (much less toxic than cyanide).
Sodium nitrite:
Onset of action (Methemoglobinemia):
Peak methemoglobin concentration, mean (7%): 30 to 60 minutes.
Half-life (conversion of methemoglobin to normal hemoglobin): ~55 minutes.
Metabolism: To ammonia and other metabolites.
Excretion: Urine (~40% as unchanged drug).
Sodium thiosulfate:
Distribution: IV: Vd: Thiosulfate: 0.15 L/kg (Howland 2011); Thiocyanate: 0.25 L/kg.
Half-life elimination: Thiosulfate: ~3 hours (Howland 2011); Thiocyanate: 2.7 days; Prolonged with renal impairment to ~9 days.
Excretion: Urine (~20% to 50% thiosulfate as unchanged drug).
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