Nitroprusside toxicity: blood chemistry
Mechanism of Action
After parenteral injection, sodium nitroprusside enters red blood cells, where it receives an electron from the iron (Fe2+) of oxyhemoglobin. This nonenzymatic electron transfer results in an unstable nitroprusside radical and methemoglobin (Hgb Fe3+). The former moiety spontaneously decomposes into five cyanide ions and the active nitroso (NO) group. The cyanide ions can be involved in one of three possible reactions: binding to methemoglobin to form cyanmethemoglobin; undergoing a reaction in the liver and kidneycatalyzed by the enzyme rhodanase (thiosulfate + cyanide); or binding to tissue cytochrome oxidase, which interferes with normal oxygen utilization. Its principal toxicity results from this inactivation of cytochrome oxidase (at cytochrome a3), thus uncoupling mitochondrial oxidative phosphorylation and inhibiting cellular respiration, even in the presence of adequate oxygen stores. Cellular metabolism shifts from aerobic to anaerobic, with the consequent production of lactic acid. Consequently, the tissues with the highest oxygen requirements (brain and heart) are the most profoundly affected by acute cyanide poisoning.
The last of the above reactions (binding to tissue cytochrome oxidase) is responsible for the development of acute cyanide toxicity, characterized by metabolic acidosis, cardiac arrhythmias, tachycardia, hypertension, CNS dysfunction and increased venous oxygen content (as a result of the inability to utilize oxygen). Another early sign of cyanide toxicity is the acute resistance to the hypotensive effects of increasing doses of sodium nitroprusside (tachyphylaxis).
Cyanide toxicity is a clinical diagnosis, because cyanide blood concentrations are usually not available in time to help treatment of acute toxicity. Monitor serum electrolytes, serum lactate, arterial blood gases (looking for metabolic acidosis) and mixed venous oxygen saturation (which would be elevated) if cyanide toxicity is a concern.
Cyanide toxicity can usually be avoided if the dose is less than 0.5 mg/kg/h. Patients with cyanide toxicity should be mechanically ventilated with 100% oxygen. Treatment with sodium thiosulfate (150 mg/kg over 15 min) or 3% sodium nitrate (5 mg/kg over 5 min)
Thiocyanate is slowly cleared by the kidney. Thiocyanate toxicity is associated with long-term infusions (usually more than 6 days) in patients simultaneously treated with sodium thiosulfate. It may develop with shorter infusions in patients with renal insufficiency. Manifestations include abdominal pain, weakness, tinnitus, vomiting, tremor, agitation, disorientation, progressing to lethargy, seizures and coma in severe cases. The risk of cyanide toxicity is not increased by renal failure, however. Methemoglobinemia from excessive doses of sodium nitroprusside or sodium nitrate can be treated with methylene blue, which reduces methemoglobin to hemoglobin.
Monitor thiocyanate levels in patients with prolonged infusions, those with renal insufficiency and those receiving simultaneous thiosulfate infusions.