Sodium Nitrite (Monograph)

Drug class: Antidotes
Chemical name: sodium;nitrite
Molecular formula: NNaO₂
CAS number: 100447-64-1

Introduction

Sodium nitrite, an inorganic salt, is a cyanide antidote.

Uses for Sodium Nitrite

Acute Cyanide Poisoning

Sodium nitrite injection is indicated for sequential use with sodium thiosulfate for the treatment of acute cyanide poisoning that is judged to be serious or life-threatening.

If clinical suspicion of cyanide poisoning is high, administer sodium nitrite and sodium thiosulfate without delay and in conjunction with appropriate airway, ventilatory, and circulatory support. Sodium nitrite causes hypotension and methemoglobin formation, which diminishes oxygen carrying capacity. Because of these risks, sodium nitrite and sodium thiosulfate should be used with caution in patients where the diagnosis of cyanide poisoning is uncertain.

Comprehensive treatment of acute cyanide intoxication requires support of vital functions. Administration of sodium nitrite and sodium thiosulfate should be considered adjunctive to appropriate supportive therapies. Airway, ventilatory and circulatory support, and oxygen administration should not be delayed in order to administer sodium nitrite and sodium thiosulfate. The expert advice of a regional poison control center may be obtained by calling 1-800-222-1222.

The human data supporting the use of sodium thiosulfate and sodium nitrite for cyanide poisoning consists primarily of published case reports. There are no randomized controlled clinical trials. Nearly all the human data describing the use of sodium thiosulfate report its use in conjunction with sodium nitrite. Dosing recommendations for humans have been based on theoretical calculations of antidote detoxifying potential, extrapolation from animal experiments, and a small number of human case reports.

There have been no human studies to prospectively and systematically evaluate the safety of sodium thiosulfate or sodium nitrite in humans. Available human safety information is based largely on anecdotal case reports and case series of limited scope.

Sodium Nitrite Dosage and Administration

General

Sodium nitrite is available in the following dosage form(s) and strength(s):

Injection: 300 mg/10 mL (30 mg/mL) in a single-dose vial; also available in a kit with sodium thiosulfate injection 12.5 g/50 mL (250 mg/mL) in single-dose vials for the treatment of cyanide poisoning.

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Pediatric Patients

Dosage and Administration

Sodium nitrite and sodium thiosulfate should be administered as early as possible after a diagnosis of acute life-threatening cyanide poisoning has been established. Both drugs are administered by slow IV injection. Sodium nitrite should be administered first, followed immediately by sodium thiosulfate. (See Table 1 for dosage recommendations.) Blood pressure must be monitored during infusion. The rate of infusion should be decreased if significant hypotension is noted.

If signs of poisoning reappear, repeat treatment using one-half the original dose of both sodium nitrite and sodium thiosulfate.

In patients with known anemia, it is recommended that the dosage of sodium nitrite should be reduced proportionately to the hemoglobin concentration.

Patients should be monitored for at least 24–48 hours after sodium thiosulfate administration for adequacy of oxygenation and perfusion and for recurrent signs and symptoms of cyanide toxicity. When possible, obtain hemoglobin/hematocrit when treatment is initiated. Measurements of oxygen saturation using standard pulse oximetry and calculated oxygen saturation values based on measured PO₂ are unreliable in the presence of methemoglobinemia.

The safety of administering other cyanide antidotes simultaneously with sodium nitrite has not been established. If a decision is made to administer another cyanide antidote with sodium nitrite, these drugs should not be administered concurrently in the same IV line.

Adults

Dosage and Administration

Sodium nitrite and sodium thiosulfate should be administered as early as possible after a diagnosis of acute life-threatening cyanide poisoning has been established. Both drugs are administered by slow IV injection. Sodium nitrite should be administered first, followed immediately by sodium thiosulfate. (See Table 2 for dosage recommendations.) Blood pressure must be monitored during infusion. The rate of infusion should be decreased if significant hypotension is noted.

If signs of poisoning reappear, repeat treatment using one-half the original dose of both sodium nitrite and sodium thiosulfate.

In patients with known anemia, it is recommended that the dosage of sodium nitrite should be reduced proportionately to the hemoglobin concentration.

Patients should be monitored for at least 24–48 hours after sodium thiosulfate administration for adequacy of oxygenation and perfusion and for recurrent signs and symptoms of cyanide toxicity. When possible, obtain hemoglobin/hematocrit when treatment is initiated. Measurements of oxygen saturation using standard pulse oximetry and calculated oxygen saturation values based on measured PO₂ are unreliable in the presence of methemoglobinemia.

The safety of administering other cyanide antidotes simultaneously with sodium nitrite has not been established. If a decision is made to administer another cyanide antidote with sodium nitrite, these drugs should not be administered concurrently in the same IV line.

Cautions for Sodium Nitrite

Contraindications

• None.

Warnings/Precautions

Hypotension

Sodium nitrite has been associated with severe hypotension, methemoglobinemia, and death at doses less than twice the recommended therapeutic doses. Hypotension may occur concurrently or separately. Sodium nitrite should be used to treat life-threatening cyanide poisoning. When the diagnosis of cyanide poisoning is uncertain and/or the patient is not in extremis, special consideration should be given to administration of sodium nitrite if the patient is known or suspected to have diminished oxygen or cardiovascular reserve (e.g., smoke inhalation victims, pre-existing anemia, substantial blood loss, cardiac or respiratory compromise) or to be at higher risk of developing methemoglobinemia (e.g., congenital methemoglobin reductase deficiency).

Methemoglobinemia

Supportive care alone may be sufficient treatment without administration of antidotes for many cases of cyanide intoxication, particularly in conscious patients without signs of severe toxicity. Monitor patients closely to ensure adequate perfusion and oxygenation during treatment with sodium nitrite. Monitor methemoglobin levels and administer oxygen during treatment with sodium nitrite whenever possible. When sodium nitrite is administered to humans, a wide range of methemoglobin concentrations occur. Methemoglobin concentrations as high as 58% have been reported after two 300-mg doses of sodium nitrite administered to an adult. Sodium nitrite should be used with caution in the presence of other drugs that may cause methemoglobinemia such as procaine and nitroprusside. Sodium nitrite should be used with caution in patients who may be particularly susceptible to injury from vasodilation and its related hemodynamic sequelae. Hemodynamics should be monitored closely during and after administration of sodium nitrite, and infusion rates should be slowed if hypotension occurs.

Anemia

Use sodium nitrite with caution in patients with known anemia. Patients with anemia will form more methemoglobin (as a percentage of total hemoglobin) than persons with normal red blood cell (RBC) volumes. Optimally, these patients should receive a sodium nitrite dose that is reduced in proportion to their oxygen carrying capacity.

Smoke Inhalation Injury

Use sodium nitrite with caution in persons with smoke inhalation injury or carbon monoxide poisoning because of the potential for worsening hypoxia due to methemoglobin formation.

Neonates and Infants

Neonates and infants may be more susceptible than adults and older pediatric patients to severe methemoglobinemia when sodium nitrite is administered. Follow reduced dosing guidelines in pediatric patients.

G6PD Deficiency

Because patients with G6PD deficiency are at increased risk of a hemolytic crisis with sodium nitrite administration, consider alternative therapeutic approaches in these patients. Monitor patients with known or suspected G6PD deficiency for an acute drop in hematocrit. Exchange transfusion may be needed for patients with G6PD deficiency who receive sodium nitrite.

Use with Other Drugs

Use sodium nitrite with caution in the presence of concomitant antihypertensive medications, diuretics or volume depletion due to diuretics, or drugs known to increase vascular nitric oxide, such as PDE5 inhibitors.

Specific Populations

Pregnancy

Cyanide readily crosses the placenta. Cyanide poisoning is a medical emergency in pregnancy, which can be fatal for the pregnant woman and fetus if left untreated. Treatment for cyanide poisoning should not be withheld because of potential concerns regarding the effects of sodium nitrite on the fetus. Therefore, if a pregnant woman has known or suspected cyanide poisoning, sodium nitrite for sequential use with sodium thiosulfate is recommended. There are no available data on sodium nitrite use in pregnant women to establish a drug-associated risk for major birth defects, miscarriage, or adverse maternal or fetal outcomes. Cyanide readily crosses the placenta.

There are no IV toxicology studies in animals to evaluate the effect of sodium nitrite on embryofetal development. In published animal studies, fetal mortality was reported when pregnant guinea pigs were subcutaneously administered sodium nitrite at 1.7 times the maximum recommended human dose (MRHD) of 450 mg sodium nitrite when maternal and fetal methemoglobin concentrations were at their peak. In other published studies, no evidence of malformations were reported in guinea pigs, mice, or rats; however, severe anemia, reduced growth, and increased pup mortality was reported when pregnant rats were treated with 4.7 times the MRHD of sodium nitrite via drinking water during gestation and throughout lactation.

Sodium nitrite produces methemoglobin. Fetal hemoglobin is oxidized to methemoglobin more easily than adult hemoglobin. In addition, the fetus has lower levels of methemoglobin reductase than adults. Based on animal studies, prenatal exposure to sodium nitrite resulted in impaired neural development likely the result of prenatal hypoxia. If available, consider alternative therapy not known to be associated with methemoglobinemia.

Lactation

There are no data on the presence of sodium nitrite in human or animal milk, the effects on the breastfed infant, or the effects on milk production. Cyanide is present in human milk. Because of the potential for serious adverse reactions in the breastfed infant, breastfeeding is not recommended during treatment with sodium nitrite. There are no data to determine when breastfeeding may be safely restarted following the administration of sodium nitrite.

Pediatric Use

There are case reports in the medical literature of sodium nitrite in conjunction with sodium thiosulfate being administered to pediatric patients with cyanide poisoning; however, there have been no clinical studies to evaluate the safety or efficacy of sodium nitrite in the pediatric population. As for adult patients, dosing recommendations for pediatric patients have been based on theoretical calculations of antidote detoxifying potential, extrapolation from animal experiments, and a small number of human case reports. Sodium nitrite must be used with caution in patients <6 months of age because they may be at higher risk of developing severe methemoglobinemia compared to older children and adults. The presence of fetal hemoglobin, which is oxidized to methemoglobin more easily than adult hemoglobin, and lower methemoglobin reductase levels compared to older children and adults may contribute to risk. Mortality attributed to sodium nitrite was reported following administration of an adult dose (300 mg IV followed by a second dose of 150 mg) to a 17-month old child.

Geriatric Use

Sodium nitrite is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Renal Impairment

Sodium nitrite is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Common Adverse Effects

Most common adverse reactions are syncope, hypotension, tachycardia, palpitations, dysrhythmia, methemoglobinemia, headache, dizziness, blurred vision, seizures, confusion, and coma.

Drug Interactions

Specific Drugs

Formal drug interaction studies have not been conducted with sodium nitrite injection.

Actions

Mechanism of Action

Exposure to a high dose of cyanide can result in death within minutes due to the inhibition of cytochrome oxidase resulting in arrest of cellular respiration. Specifically, cyanide binds rapidly with cytochrome a3, a component of the cytochrome c oxidase complex in mitochondria. Inhibition of cytochrome a3 prevents the cell from using oxygen and forces anaerobic metabolism, resulting in lactate production, cellular hypoxia and metabolic acidosis. In massive acute cyanide poisoning, the mechanism of toxicity may involve other enzyme systems as well.

The synergy resulting from treatment of cyanide poisoning with the combination of sodium nitrite and sodium thiosulfate is the result of differences in their primary mechanisms of action as antidotes for cyanide poisoning.

Sodium nitrite:Sodium nitrite is thought to exert its therapeutic effect by reacting with hemoglobin to form methemoglobin, an oxidized form of hemoglobin incapable of oxygen transport but with high affinity for cyanide. Cyanide preferentially binds to methemoglobin over cytochrome a3, forming the nontoxic cyanomethemoglobin. Methemoglobin displaces cyanide from cytochrome oxidase, allowing resumption of aerobic metabolism. Vasodilation has also been cited to account for at least part of the therapeutic effect of sodium nitrite. It has been suggested that sodium nitrite-induced methemoglobinemia may be more efficacious against cyanide poisoning than comparable levels of methemoglobinemia induced by other oxidants. Also, sodium nitrite appears to retain some efficacy even when the formation of methemoglobin is inhibited by methylene blue.

Sodium thiosulfate: The primary route of endogenous cyanide detoxification is by enzymatic transulfuration to thiocyanate (SCN), which is relatively nontoxic and readily excreted in the urine. Sodium thiosulfate is thought to serve as a sulfur donor in the reaction catalyzed by the enzyme rhodanese, thus enhancing the endogenous detoxification of cyanide.

Advice to Patients

• When feasible, patients should be informed of the possibility of life-threatening hypotension and methemoglobin formation.

• Where feasible, patients should be informed of the need for close monitoring of blood pressure and oxygenation.

• Advise women that breastfeeding is not recommended during treatment with sodium nitrite injection.

Additional Information

AHFSfirstRelease^™. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

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