sodium thiosulfate & sodium nitrite (Rx)

Frequency Not Defined

Sodium nitrite

• Syncope
• Hypotension
• Tachycardia
• Palpitations
• Diaphoresis
• Dyspnea
• Dysrhythmia
• Methemoglobinemia
• Headache
• Dizziness
• Tachypnea
• Blurred vision
• Seizures
• Confusion
• Coma

Sodium thiosulfate

• Hypotension
• Headache
• Disorientation
• Nausea/vomiting
• Salty taste
• Prolonged bleeding time
• Warmth

Cautions

Methemoglobinemia: Sodium nitrite reacts with hemoglobin to form methemoglobin and should be used with caution in patients known to have anemia

Smoke inhalation: Carbon monoxide contained in smoke can result in the formation of carboxyhemoglobin that can reduce the oxygen carrying capacity of the blood; sodium nitrite should be used with caution in patients with smoke inhalation injury because of the potential for worsening hypoxia due to methemoglobin formation

Optimally, the sodium nitrite dose should be reduced in proportion to the oxygen carrying capacity

Use with caution if the diagnosis of cyanide poisoning is uncertain

Coadministration with antihypertensive, phosphodiesterase-5 enzyme or diuretics should be done with caution

Use caution in patients with anemia

Patients with G6PD deficiency are at increased risk of hemolytic crisis

Avoid nitites in pregnancy due to fetal hemoglobin's susceptibility to oxidase stress

Monitoring

• Monitor patients for at least 24-48 hr after administration for adequacy of oxygenation and perfusion and for recurrent signs and symptoms of cyanide toxicity
• When possible, hemoglobin/hematocrit should be obtained 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
• Methemoglobin level: Administrations of sodium nitrite solely to achieve an arbitrary level of methemoglobinemia may be unnecessary and potentially hazardous; therapeutic effects of sodium nitrite do not appear to be mediated by methemoglobin formation alone and clinical responses to sodium nitrite administration have been reported in association with methemoglobin levels <10%
• Administration of sodium nitrite beyond the initial dose should be guided primarily by clinical response to treatment (ie, a second dose should be considered only if there is inadequate clinical response to the first dose)
• Methemoglobin concentrations be closely monitored and kept below 30%; serum methemoglobin levels should be monitored during treatment using co-oximetry, and administration of sodium nitrite should generally be discontinued when methemoglobin levels exceed 30%
• Intravenous methylene blue and exchange transfusion have been reported in the literature as treatments for life-threatening methemoglobinemia

Pregnancy

Life-sustaining therapy should not be withheld; cyanide poisoning is a medical emergency in pregnancy, which can be fatal for pregnant women and fetus if left untreated; if a pregnant woman has known or suspected cyanide poisoning, sodium nitrite injection for sequential use with sodium thiosulfate injection recommended; there are no available data on drug use in pregnant women to establish a drug-associated risk for major birth defects, miscarriage, or adverse maternal or fetal outcomes; if available, consider alternative therapies not associated with methemoglobinemia

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 effects of drug on the fetus

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

Animal data

• There are no intravenous animal studies to evaluate effect of sodium nitrite, sodium thiosulfate, or combination on embryofetal development; in published animal studies, fetal mortality was reported when pregnant guinea pigs were subcutaneously administered sodium nitrite at 1.7 times 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
• In published animal studies, no evidence of embryotoxicity or malformations was reported when sodium thiosulfate was administered orally during organogenesis to pregnant mice, rats, hamsters, or rabbits at 0.2 to 0.9 times the human daily dose of 12.5 g for cyanide poisoning; the sodium thiosulfate studies did not test doses that were comparable to the human dose for cyanide poisoning

Lactation

There are no data on the presence of sodium nitrite or sodium thiosulfate in human or animal milk, effects on breastfed infant, or on milk production; cyanide and thiocyanate (which is formed when sodium thiosulfate combines with cyanide) are present in human milk; because of potential for serious adverse reactions in the breastfed infant, breastfeeding is not recommended during treatment; there are no data to determine when breastfeeding may be safely restarted following administration of drug

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Nitrites create methemoglobins to bind to cyanide

sodium thiosulfate

• Primary route of endogenous cyanide detoxification is by enzymatic transulfuration to thiocyanate (SCN-), which is relatively nontoxic and readily excreted in the urine
• Thought to serve as a sulfur donor in the reaction catalyzed by the enzyme rhodanese, thus enhancing the endogenous detoxification of cyanide

sodium nitrite

• Reacts 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 thereby allowing aerobic metabolism to continue
• Vasodilation has also been cited to account for at least part of the therapeutic effect of sodium nitrite

Pharmacokinetics

Half-Life

• Thiosulfate: 2 hr; 3 days (thiocyanate); 9 days (renal impairment)

Onset

• Methemoglobinemia: 30-60 min

Duration

• Sodium thiosulfate: 55 min (methemoglobinemia)

Metabolism

• Sodium nitrite: 60% is metabolized to ammonia and related small molecules
• Sodium thiosulfate: Enzymatic transulfuration to thiocyanate

Excretion

• Sodium nitrite: Urine (40% excreted unchanged)
• Sodium thiosulfate: Urine (20-50%)

IV Incompatibilities

Y-site: hydroxocobalamin

Storage

Store at controlled room temperature between 20°C and 25°C (68°F - 77°F); excursions permitted to 15-30°C (59 to 86°F)

Protect from direct light

Do not freeze