A39: Antidotes in Depth

Sodium nitrite is an effective cyanide antidote when administered in a timely fashion and followed by sodium thiosulfate, which acts in synergy. The utility of amyl nitrite, a volatile drug available in ampules that can be broken and administered by inhalation while sodium nitrite is being prepared to administer intravenously, is questioned.¹³ Although the exact mechanism of action of the nitrites is unclear, the production of methemoglobin is both therapeutic in cyanide poisoning and potentially life-threatening if nitrites are administered to a patient with impaired oxygen carrying capacity, from elevated concentrations of carboxyhemoglobin, methemoglobin, or sulfhemoglobin from any cause. In the latter cases, hydroxocobalamin and or sodium thiosulfate can still be administered intravenously without causing harm.

Expanding on earlier work that demonstrated the limited role of methylene blue and the efficacy of sodium nitrite in cyanide poisoned dogs, inhaled amyl nitrite prevented the development of cyanide-induced seizures and muscular rigidity.⁴ Amyl nitrite administered by inhalation protected dogs from up to four minimum lethal doses of sodium cyanide (a total of 24 mg/kg subcutaneously). In the regimen used, therapy was started within 5 to 7 minutes of exposure and was continued for several hours. The frequency of inhalation was based on clinical response. These experimental results led to the use of inhaled amyl nitrite for patients poisoned by cyanide. The same authors discovered that intravenous (IV) use of sodium thiosulfate alone protected against three minimum lethal doses of cyanide in dogs and that the combination of sodium thiosulfate with either inhaled amyl nitrite or IV sodium nitrite protected against 10 to 18 minimum lethal doses, respectively.^3,5

Chemistry

The chemical formula for sodium nitrite is NaNO₂ and for amyl nitrite is C₅H₁₁NO₂. Sodium nitrite has a molecular weight of 69 Da and amyl nitrite has a molecular weight of 117 Da. Amyl nitrite is volatile even at low temperatures and is highly flammable.

Cyanide quickly and reversibly binds to the ferric iron in cytochrome oxidase, inhibiting effective energy production throughout the body. The ferric iron in methemoglobin preferentially combines with cyanide, producing cyanomethemoglobin. This drives the reaction toward cyanomethemoglobin and liberates cyanide from cytochrome oxidase. Stroma-free methemoglobin is effective against four minimum lethal doses of cyanide in rats.²⁰ Nitrites oxidize the iron in hemoglobin to produce methemoglobin. Because nitrites are accepted antidotes for cyanide poisoning, for many years methemoglobin formation was assumed to be their sole antidotal mechanism of action.^14,24 Other, faster methemoglobin inducers, such as 4-dimethyaminophenol and hydroxylamine, also are effective as cyanide antidotes.^14,22 The production of methemoglobin by nitrite is slow, but when methylene blue is administered to prevent methemoglobin formation, nitrite remains an effective antidote.^14,24 Reasoning that nitrite-induced vasodilation might be part of the mechanism of action, investigators considered the antidotal actions of other vasodilators. The α-adrenergic antagonists and ganglionic blockers only demonstrate antidotal activity when administered with sodium thiosulfate.²⁴ It is possible that the benefits of nitrites given shortly after cyanide result from reversal of cyanide-induced circulatory effects rather than reversal of the effects of cyanide on cytochrome oxidase.²¹ Experimental evidence in organ damage induced by hypoxia or hypotension suggests that the benefits of nitrite may be related to its conversion to nitric oxide, a potent vasodilator. The conversion to nitric oxide appears to occur only in tissues or blood with the lowest oxygen concentrations.^6,15

The pharmacokinetics of sodium nitrite are not established. Most ­studies were directed at measuring methemoglobin levels rather than nitrite concentrations.²²

Sodium nitrite administered intramuscularly to dogs is not effective as a cyanide antidote unless atropine is given as pretreatment.²³ Most likely the rapid reversal of cyanide-induced bradycardia by atropine allows sufficiently rapid absorption of sodium nitrite, which then can be effective.²³ In one study, 300 mg IV sodium nitrite produced peak methemoglobin levels of 10% to 18% in healthy adults, and values of 7% when 4 mg/kg was administered.^3,17 Inhalation of crushed amyl nitrite ampules in human volunteers produces insignificant amounts of methemoglobin and causes headache, fatigue, dizziness, and hypotension.¹²

The package insert states that approximately 40% of sodium nitrite is renally eliminated unchanged, while the remainder is metabolized to ammonia and other related molecules.¹⁷

Maximal benefits of sodium nitrite are realized experimentally when sodium nitrite is given prophylactically, but benefits are still evident even when sodium nitrite is administered following cyanide poisoning. Sodium nitrite is clearly effective soon after administration, even when methemoglobin levels are low. Thus a target methemoglobin concentration should not be used to determine the correct dose of sodium nitrite, although care must be taken to avoid excessive methemoglobinemia.¹¹ Administration of sodium nitrite should always be followed by sodium thiosulfate. Sodium thiosulfate donates a sulfur, which, with the help of rhodanese (cyanide sulfur transferase) and mercaptopyruvate sulfurtransferase, carries sulfane sulfur to bind to cyanide, producing thiocyanate. Thiocyanate is a much less toxic substance than cyanide and is renally eliminated.⁴

As early as 1952, the literature reported 16 cyanide-poisoned patients who survived following administration of nitrites and sodium thiosulfate.³ Even patients who were unconscious or apneic survived when given timely cardiopulmonary resuscitation and antidotal therapy.³ Case reports attest to the ability of amyl nitrite, sodium nitrite, and sodium thiosulfate to reverse the effects of cyanide if they are administered in a timely fashion.^8,25 A 34 year-old man who ingested 1 g potassium cyanide became comatose within 45 minutes. One hour after ingestion, he arrived in the emergency department, became apneic, and was intubated. His blood pressure was 134/84 mm Hg and pulse 84 beats/min with fixed and dilated pupils. At 1 hour 15 minutes, he was given 300 mg sodium nitrite intravenously over 20 minutes, followed by 12.5 g sodium thiosulfate. Seizure activity that began just prior to sodium nitrite infusion resolved rapidly, and by the time the sodium thiosulfate was infused, his pupils were reactive and spontaneous respirations had returned.⁸

In another case, a 4 year-old boy ingested twelve 50 mg tablets of laetrile (amygdalin), became unresponsive, and developed seizures within 90 minutes.¹⁰ Upon arrival at a second hospital, the patient required intubation, had no blood pressure, and had dilated minimally responsive pupils. Arterial blood gas analysis revealed: pH, 6.85; PCO₂, 15 mm Hg; PO₂, 169 mm Hg on 100% oxygen with an anion gap of 26 mEq/L. His vital signs improved with intermittent inhalation of amyl nitrite pearls. Six hours after ingestion (and 1 hour 45 minutes after amyl nitrite administration), sodium nitrite and sodium thiosulfate obtained from another hospital were administered. Within 30 minutes of completion of 5 mL (0.33 mL/kg) 3% sodium nitrite solution by IV infusion, spontaneous respirations returned, and his blood pressure and pulse normalized. Over the next 3 hours, his mental status and acid–base status improved. Fifteen hours after ingestion, he was alert, oriented, and extubated. Elevated whole blood cyanide concentrations verified the ingestion.

A study in swine evaluated the effect of hydroxocobalamin plus sodium thiosulfate versus sodium nitrite and sodium thiosulfate in a model utilizing a continuous infusion of cyanide. There was no difference between the groups in metabolic acidosis with elevated lactate concentrations at times 20 and 40 minutes or in cardiac output and pulse rate at 40 minutes, or in mortality. The mean arterial pressure was higher in the hydroxocobalamin plus sodium thiosulfate group, beginning at 5 minutes and lasting for the entire 40 minute monitoring period.¹

Amyl nitrite and sodium nitrite may work in part by inducing methemoglobinemia, but excessive methemoglobinemia is potentially lethal. Therefore, nitrite dosages must be carefully calculated to avoid excessive methemoglobinemia, especially in cases where other coexisting conditions, such as carboxyhemoglobin, sulfhemoglobin, and anemia, might compromise hemoglobin oxygen saturation.^9,16 Children are particularly at risk for medication errors because of dosage miscalculations. A reported death from methemoglobinemia was caused by the administration of an adult dose of sodium nitrite to a 17 month-old child suspected of ingesting a toxic amount of cyanide.²

Nitrites are potent vasodilators, resulting in transient hypotension. Other common adverse effects include headache, tachycardia, palpitations, dysrhythmia, blurred vision, nausea, and vomiting.^3,17

The nitrites are FDA Pregnancy Category C. There are no adequate studies in pregnant women, and nitrites should only be used in pregnant women when the potential benefit exceeds the potential risk. Sodium nitrite has caused fetal death in humans as well as animals.¹⁷ The fetus is particularly sensitive to methemoglobinemia with the potential for prenatal hypoxia. High concentrations of nitrites in maternal drinking water have led to teratogenic effects.

Hydroxocobalamin is also FDA Pregnancy Category C; however, even with the limited data available it may have a lesser risk than nitrite use for a pregnant woman.⁷

It is not known whether nitrites are excreted in breast milk, but the risk is likely to exceed the benefit.

Adults

Sodium nitrite 300 mg (10 mL of 3% solution) should be injected intravenously at a rate of 2.5 to 5 mL/min. The dose can be repeated at half the initial dose if manifestations of cyanide toxicity reappear.^17,18

Amyl nitrite can be used prior to IV administration of sodium nitrite, but only as a temporizing measure until IV sodium nitrite can be administered. Time is better spent administering IV sodium nitrite. Break one amyl nitrite ampule, and hold it in front of the patient’s mouth for 15 seconds on and 15 seconds off.^7,18 Inhalation of amyl nitrite should be discontinued prior to sodium nitrite administration. The health care provider should be extremely careful not to inhale the amyl nitrite to prevent lightheadedness and syncope. Immediately following the completion of the sodium nitrite infusion, 50 mL of 25% solution (12.5 g) sodium thiosulfate should be infused intravenously. The same needle and vein can be used, and the dose of the thiosulfate can be repeated at half the initial dose whenever manifestations of cyanide toxicity.¹⁸

In situations where additional methemoglobin formation would be harmful, as in patients with carbon monoxide poisoning, it may be safer to withhold the nitrite and only administer the IV hydroxocobalamin with or without sodium thiosulfate. Sodium thiosulfate can be administered through a separate IV line following the hydroxocobalamin. The initial dose of hydroxocobalamin in adults is 5 g IV over 15 minutes with a second dose administered if warranted.⁷

Children

Intravenously inject 0.2 mL/kg (6 to 8 mL/m² BSA) or 6 mg/kg of 3% sodium nitrite solution, at a rate of 2.5 to 5 mL/min, not to exceed 10 mL or 300 mg.^17,18 Based on an in vitro calculation, this dose would be safe for a child with a hemoglobin of 7 g/dL in the absence of other factors that could compromise hemoglobin oxygen saturation, such as carboxyhemoglobin or sulfhemoglobin.² The dose can be repeated at half the initial dose if manifestations of cyanide toxicity reappear (Table 126–2).¹⁸

The dose of sodium thiosulfate in children is 1 mL/kg using a 25% solution (250 mg/kg or approximately 30–40 mL/m2 of BSA) not to exceed 50 mL (12.5 g) total dose immediately following administration of sodium nitrite.^17,19 The dose can be repeated at half the initial dose if manifestations of cyanide toxicity reappear. The same needle and vein can be used.

Amyl nitrite inhalation can be used in children at the same dose and with the same precautions as mentioned above for adults.

In situations where additional formation of methemoglobin would be harmful, as in patients with smoke inhalation from a fire in which other toxic gases may coexist, the nitrite can be withheld and hydroxocobalamin administered with or without sodium thiosulfate. In children, a dose of 70 mg/kg of hydroxocobalamin up to the adult dose has been employed.⁷

Care must be taken not to administer the hydroxocobalamin and sodium thiosulfate through the same IV line since a physical incompatibility occurs, inactivating the hydroxocobalamin.

Sodium nitrite is available in ampules containing 300 mg in 10 mL (3% concentration) water for injection (USP).¹⁸ It contains no additives or preservatives. It is also available in a kit known as Nithiodote, containing one vial of sodium nitrite (300 mg in 10 mL water for injection) with one vial of sodium thiosulfate (12.5 g in 50 mL water for injection), with boric acid or sodium hydroxide added to adjust the pH.¹⁷

• Sodium nitrite is an effective cyanide antidote when administered in a timely fashion and followed by sodium thiosulfate for a synergistic effect.

• The production of methemoglobin is both therapeutic in cyanide ­poisoning and potentially life threatening if nitrites are administered to a patient with impaired oxygen carrying capacity from elevated ­levels of carboxyhemoglobin, sulfhemoglobin, or methemoglobin from any cause.

• In situations where additional methemoglobin formation would be harmful, as in patients with carbon monoxide poisoning, it may be safer to withhold the nitrite and administer IV hydroxocobalamin with or without sodium thiosulfate.

References