A40: Antidotes in Depth

Sodium thiosulfate is a safe and effective antidote that detoxifies cyanide by donating a sulfur moiety to form thiocyanate. Thiocyanate is much less toxic than cyanide and is renally eliminated. Sodium thiosulfate works synergistically with nitrites and is probably at least additive to hydroxocobalamin in the detoxification of cyanide. Because sodium thiosulfate does not compromise hemoglobin oxygen saturation, it can be used without nitrites in circumstances where the formation of methemoglobin would be detrimental, as in patients who have elevated levels of carboxyhemoglobin or preexistent methemoglobinemia from smoke inhalation, drug exposure, or congenital dyshemoglobinemias when hydroxocobalamin is unavailable. Based on the mechanism of action of sodium thiosulfate, particularly when used alone, it is unlikely to be as effective as hydroxocobalamin, or work as quickly. A recent study in a swine cyanide model could not show a benefit of sodium thiosulfate as sole therapy or show an added benefit to that offered by hydroxocobalamin.³ Sodium thiosulfate is used prophylactically with nitroprusside to prevent cyanide toxicity. Sodium thiosulfate is also used to treat calcific uremic arteriolopathy (calciphylaxis) theoretically by increasing the solubility of calcium deposits, inducing vasodilation, and acting as a free radical scavenger.^6,24,28,32

In 1933, Chen and colleagues⁸ noted that preexposure treatment with intravenous (IV) sodium thiosulfate protected dogs against three minimum lethal doses of sodium cyanide, and even more remarkable were the synergistic effects obtained by combining sodium thiosulfate with either inhaled amyl nitrite or IV sodium nitrite, which protected the dogs against 10 to 18 minimum lethal doses of cyanide.^7,8

Chemistry

The chemical formula of sodium thiosulfate is Na₂S₂O₃. The molecular weight of sodium thiosulfate is 248 Da. It forms a pentahydrate that is highly water soluble.

Mechanism of Action

The sulfur provided by sodium thiosulfate binds to cyanide with the help of rhodanese (cyanide sulfur transferase) and mercaptopyruvate sulfur transferase.^8,36,38 Sulfane sulfur (a divalent sulfur bound to one other sulfur) is the only sulfur that reacts with cyanide to produce thiocyanate, which is minimally toxic and renally eliminated. In several animal models, sodium thiosulfate protects against several minimum lethal doses of cyanide.^16,20 The addition of rhodanese increases the efficacy of sodium thiosulfate, but the use of rhodanese is impractical in the clinical setting.^20,37 The cationic site on rhodanese is crucial to cleaving the sulfur–sulfur bond of thiosulfate and forming a sulfur–rhodanese complex that readily reacts with cyanide.³⁸

Rhodanese is probably not solely responsible for sulfur–sulfur bond cleavage, as rhodanese is largely a mitochondrial enzyme found in the liver and skeletal muscle, and sodium thiosulfate is a divalent ion that poorly crosses membranes.^{12,20,25,36,38} It is also suggested that both mercaptopyruvate sulfurtransferase and rhodanese are involved in the formation of sulfane sulfur in the liver from sodium thiosulfate, and that serum albumin then carries the sulfane sulfur from the liver to other organs. When cyanide is present, albumin delivers this sulfur to cyanide, forming thiocyanate.^{17,36,37, and 38}

Pharmacokinetics and Pharmacodynamics

Animal Studies.

Sodium thiosulfate is a large divalent anion. Canine studies suggest that sodium thiosulfate rapidly distributes into the extracellular space and then slowly into the cell, perhaps with a carrier facilitating entry into the mitochondria.^15,25 When administered prior to cyanide, thiosulfate converted more than 50% of the cyanide to thiocyanate within 3 minutes and increased the endogenous conversion rate more than 30 times.³⁵ A canine model employing continuous intravenous (IV) infusion of cyanide to induce a respiratory arrest, demonstrated that the IV administration of 500 mg/kg of sodium thiosulfate decreased the serum cyanide concentration and restored respiration within 3 minutes.¹⁰ Thiosulfate is filtered and secreted in the kidney. At low serum concentrations, thiosulfate is largely reabsorbed, whereas at high serum concentrations filtration and secretion predominate.^14,25

Human Studies.

A volunteer study examined the pharmacokinetics of sodium thiosulfate and the fate of thiosulfate.^16,25 After injection of 150 mg/kg, the volume of dis­tribution (Vd) was 0.15 L/kg, the distribution half-life was 23 minutes, and the elimination half-life was 3 hours. The peak serum thiosulfate concentration rose 100 fold. Approximately 50% of the drug was eliminated in 18 hours, most of that within the first 3 hours. Baseline thiosulfate concentrations were higher in starved patients and children, presumably because of their higher protein metabolism to thiosulfate.¹⁶ Normally, the kidney actively reabsorbs thiosulfate, but this study found that with exogenous administration, thiosulfate clearance equaled creatinine clearance.¹⁶

The study of thiosulfate as a cisplatin neutralizer demonstrated a half-life of 80 minutes, and that renal clearance accounted for only 30% of the total clearance.³¹ Oral sodium thiosulfate is poorly absorbed and acts as a laxative.²⁵

A pharmacokinetic study was conducted in healthy volunteers as well as hemodialysis (HD) patients both on and off of HD.¹³ Eight grams of sodium thiosulfate was diluted in 50 mL of 0.9% NaCl and infused over 8 minutes. The use of a population pharmacokinetic model revealed a small Vd (0.226 L/kg), a nonrenal clearance similar to the renal clearance accounting for about 50% of the elimination in both healthy volunteers and HD patients. Total body clearance in the HD patients undergoing HD was double that of the same patients not receiving HD. A one compartment distribution model was assumed due to the absence of rebound concentrations after HD ended. Oral bioavailability was only about 8% and was calculated after 5 g of the IV solution was diluted in 100 mL of water and ingested rapidly.

In 1952, 16 cyanide-poisoned patients survived following the admin­istration of nitrites and sodium thiosulfate.⁷ Even patients who were unconscious or apneic survived following expeditious cardiopulmonary resuscitation and antidotal therapy.⁷ A more recent study in swine evaluated the effect of hydroxocobalamin with sodium thiosulfate versus sodium nitrite and sodium thiosulfate in a model utilizing a continuous infusion of cyanide. There was no difference between the groups with a metabolic acidosis with an elevated lactate concentration 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 with sodium thiosulfate group, beginning at 5 minutes and lasting for the entire 40 minute monitoring period.⁴ A second study in swine done by the same group could not show a benefit to sodium thiosulfate as sole therapy or show an added benefit to hydroxocobalamin in a model following intravenous cyanide exposure.³ All 12 swine in the sodium thiosulfate group died compared to only 1/12 in the hydroxocobalamin group.

Case reports attest to the ability of sodium nitrite and sodium thiosulfate to reverse the effects of cyanide following timely administration.^9,23,25

In the few reported cases of cyanide ingestion treated solely with sodium thiosulfate, all patients had favorable outcomes.²⁵ However, prior to sodium thiosulfate administration, we advocate the use of sodium nitrite, or preferably hydroxocobalamin. As noted, nitrites would be relatively contraindicated for patients who have elevated carboxyhemoglobin or methemoglobin concentrations from smoke inhalation.

Canine experiments reveal that when the nitroprusside infusion rate is greater than 0.5 mg/kg/h, cyanide concentrations in the blood begin to rise. Coadministration of sodium thiosulfate with sodium nitroprusside (which contains five cyanide ions) in a 5:1 molar ratio prevents the rise in cyanide concentration.²⁵ The usual dosage of sodium nitroprusside is 3 μg/kg/min (range 0.25–10 μg/kg/min).²¹ Each mole of nitroprusside has a molecular weight of 298 Da, including the sodium dehydrate. A 70 kg person administered 3 μg/kg/min would receive 12.6 mg/h (0.042 mmol/h) of nitroprusside. This would require 52.4 mg (0.211 mmol) of sodium thiosulfate per hour to detoxify the five cyanide ions liberated from nitroprusside. Prolonged infusion or doses in excess of the detoxifying capability of the body may lead to thiocyanate or cyanide toxicity. Some authors recommend adding 0.5 g sodium thiosulfate to each 50 mg of nitroprusside.²² Although this dose of sodium thiosulfate usually is sufficient to prevent cyanide toxicity from nitroprusside, thiocyanate may accumulate, especially in patients with renal insufficiency. Although thiocyanate is relatively nontoxic compared to cyanide, it may produce dose-dependent tinnitus, miosis, hyperreflexia, and hypothyroidism, especially at serum concentrations greater than 60 μg/mL.²¹ Thiocyanate is hemodialyzable. Nitroprusside-induced cyanide toxicity should be treated by stopping the nitroprusside and administering standard doses of hydroxocobalamin with or without sodium thiosulfate.

Sodium thiosulfate decreases calcification of the medial layer of arteries leading to subcutaneous nodules that typically progress to necrotic skin ulcers as a manifestation of this rare vascular disease associated with chronic kidney failure patients.^1,2,6,24 The dose of sodium thiosulfate is usually 5 to 25 g IV in adults during or after hemodialysis.^24,27,32 Thiosulfate may increase the water solubility of calcium leading to enhanced excretion of calcium thiosulfate, induce vasodilation, and act as a free radical scavenger.^27,28,32 In a uremic rat model, sodium thiosulfate was able to prevent vascular calcifications but also induced a metabolic acidosis and reduced bone strength.²⁹ A patient being treated for calcific uremic arteriolopathy developed a severe anion gap metabolic acidosis following each repeated dose of sodium thiosulfate.³⁰

The toxicity of sodium thiosulfate is low. The LD₅₀ for animals is approximately 3 to 4 g/kg, with death attributed to metabolic acidosis, elevated sodium concentration, and decreased blood pressure and PO₂.²⁰ Sodium thiosulfate is hyperosmolar, delivering a significant sodium load resulting in an osmotic diuretic effect.²⁵ Administering the infusion over 10 to 30 minutes limits some of these adverse effects.²⁵ Adverse effects associated with therapeutic doses include hypotension, nausea, and vomiting.

Sodium thiosulfate is FDA pregnancy Category C. No reports of congenital anomalies in infants born to women exposed to sodium thiosulfate during pregnancy are described.²⁶ Teratogenic effects were not observed in hamster offspring treated with doses of sodium thiosulfate comparable to those that would be used for cyanide toxicity. Sodium thiosulfate should be used in pregnant woman when the potential benefit clearly outweighs any potential risk. It is not known whether sodium thiosulfate is excreted in breast milk.

Cyanide Toxicity

Adults.

In a patient with presumed cyanide poisoning, the adult dose of sodium thiosulfate is 12.5 g (50 mL of 25% solution) administered intravenously either as a bolus injection or infused over 10 to 30 minutes, depending on the severity of the exposure.²⁶ The dose of sodium thiosulfate can be repeated at half the initial dose if manifestations of cyanide toxicity reappear.²⁶

In situations where the formation of methemoglobin by a nitrite would not be harmful, intravenously inject 300 mg of sodium nitrite (10 mL of 3% solution) at a rate of 2.5 to 5 mL/min prior to administration of sodium thiosulfate. The same needle and injection site can be used. The dose of sodium nitrite can be repeated at half the initial dose if manifestations of cyanide toxicity reappear.^26,33

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.¹⁸ Break one amyl nitrite ampule, and hold it in front of the patient’s mouth for 15 seconds on and 15 seconds off. Inhalation of amyl nitrite should be discontinued prior to administration of sodium nitrite. The health care provider must not inhale the amyl nitrite.

In situations where the additional formation of methemoglobin would be harmful, as in patients in whom carboxyhemoglobin or methemoglobin may be present from smoke inhalation, or dyshemoglobinemias or drug-induced methemoglobinemia, the nitrites can be withheld and hydroxocobalamin administered with or without sodium thiosulfate. The initial dose of hydroxocobalamin in adults is 5 g IV over 15 minutes with a second dose administered if warranted.¹¹ 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.

Children.

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.^26,34 The dose can be repeated at half the initial dose if manifestations of cyanide toxicity reappear.

In situations where the formation of methemoglobin by a nitrite would not be harmful, intravenously inject 3% sodium nitrite solution at 0.2 mL/kg (6–8 mL/m² or 6 mg/kg) at a rate of 2.5 to 5 mL/min not to exceed 10 mL or 300 mg, prior to administration of sodium thiosulfate. The same needle and vein can be used. 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, methemoglobin, or sulfhemoglobinemia.⁵ The dose of sodium nitrite can be repeated at half the initial dose if manifestations of cyanide toxicity reappear or at 2 hours after the first dose as prophylaxis.

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

In children, a dose of 70 mg/kg of hydroxocobalamin up to the adult dose has been employed.¹¹ Sodium thiosulfate is often used following hydroxocobalamin to provide an added benefit, although the extent of this added benefit has been questioned.³ 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 thiosulfate is available in 50-mL vials containing 12.5 g in water for injection (USP), with boric acid or sodium hydroxide added to adjust the pH.³⁴ It is 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.²⁶

• Sodium thiosulfate detoxifies cyanide by forming thiocyanate.

• The action of sodium thiosulfate is slower in onset than hydroxocobalamin or the nitrites.

• Thiocyanate is significantly less toxic than cyanide and is renally eliminated.

• Prophylactic administration of sodium thiosulfate along with sodium nitroprusside reduces cyanide toxicity by converting liberated cyanide to thiocyanate.

• Sodium thiosulfate is synergistic with nitrites.

• Sodium thiosulfate may be used following hydroxocobalamin, but ­animal data do not demonstrate an added benefit.

References