Nitroprusside Toxicity

By Lewis Nelson, MD

A 60-year-old man came to the emergency department complaining of chest pain. He had a history of untreated hypertension, and on his arrival in the emergency department his blood pressure was 220/130 mm Hg. A diagnosis of aortic dissection was confirmed, and because the dissection was distally located, the decision was made to manage the patient with medical therapy rather than surgical repair of the dissection.

After treatment with esmolol and an infusion of sodium nitroprusside 200 µg/ minute was initiated, the patient's blood pressure decreased to 170/100 mm Hg. The nitroprusside infusion was continued and the patient was transferred to the intensive care unit.

Two days later, the patient began to mumble and talk insensibly, although his level of consciousness remained normal. Arterial blood gas analysis revealed a pH of 7.35 and a PCO2 of 37 mm Hg. The patient's lactate level was slightly elevated and his renal function was moderately abnormal.

The patient was given 12.5 gm of sodium thiosulfate and his antihypertensive therapy was changed to labetolol, resulting in a modest improvement in his mental status. Results of laboratory testing subsequently indicated an undetectable serum cyanide level and an elevated level of thiocyanate, indicating nitroprusside poisoning.

MECHANISMS OF TOXICITY
Sodium nitroprusside contains an iron molecule coordinated to five cyanide molecules and one molecule of nitric oxide. The nitric oxide-formerly known as endothelial--derived relaxation factor--is what produces the dramatic arterial and venous dilation associated with this commonly used critical care drug. The nitric oxide molecule is rapidly released during infusion, whereas the cyanide molecules are liberated gradually.

In most patients, cyanide release from sodium nitroprusside is slow enough that the body's innate detoxification mechanisms can eliminate the poison before it interferes with cellular respiration. However, patients who are infirm and poorly nourished and those who are receiving very rapid infusions of sodium nitroprusside may not be able to eliminate the cyanide quickly enough to avert toxic effects. In rare cases, previous exposure of the photosensitive nitroprusside solution to sunlight may cleave the cyanide from the molecule prematurely and lead to poisoning on intravenous administration.

Detoxification occurs when cyanide and methemoglobin combine to form cyanomethemoglobin, a safe but non-oxygen-carrying form of hemoglobin. Cyanide has a high affinity for methemoglobin, which normally accounts for 1% to 2% of hemoglobin. In addition, nitroprusside itself may enhance the oxidation of hemoglobin to methemoglobin, ensuring a reliable mechanism for detoxification. Elimination involves the rhodanese-mediated transfer of sulfur either directly to the cyanide, transforming it into the substantially less toxic thiocyanate, or to the cyanomethemoglobin, not only producing thiocyanate but also regenerating methemoglobin.

Thiocyanate is eliminated slowly by the kidney and has a half-life of approximately four days in patients with normal renal function. Therefore, although cyanide poisoning would not develop in patients receiving large infusions of nitroprusside at a moderate rate, thiocyanate intoxication could occur with such an infusion, particularly if kidney function was not optimal.

DIFFERENTIAL DIAGNOSIS
Superficially, cyanide and thiocyanate toxicity seem similar and their shared association with nitroprusside administration often complicates the differential diagnosis. If the diagnosis is unsure, it is best to err on the side of cyanide, which is considerably more hazardous. Patients with moderate poisoning of either kind may present with malaise, headache, abdominal pain, altered mental status, and seizures. However, only patients with cyanide poisoning experience metabolic acidosis with an elevated lactate level, a critical finding suggesting inhibition of oxidative metabolism.

The patient's pharmacy or nursing record is often key in making the distinction. An extremely rapid nitroprusside infusion--more than 1.5 mg/kg administered over a few hours or more than 4 µg/kg a minute for more than 12 hours--may overwhelm the capacity of rhodanese for detoxifying cyanide. A prolonged infusion--anything longer than two days--may exhaust a patient's endogenous thiosulfate stores, precluding the transfer of sulfur. Interestingly, because of their large burden of retained sulfate, patients with renal failure may have a reduced susceptibility to cyanide poisoning, but their risk of accumulating thiocyanate is increased.

The diagnosis of nitroprusside poisoning is usually made on the basis of clinical findings, because laboratory results are seldom available quickly enough. The only routine laboratory test with diagnostic implications is a serum lactate level, which will usually be higher than 10 mmol/L in patients with acute cyanide poisoning. The absence of lactate-associated metabolic acidosis, however, would strengthen a suspicion of thiocyanate poisoning, particularly in a patient with impaired renal function.

TREATMENT
Patients who are strongly suspected of having cyanide poisoning should immediately receive a standard dose of intravenous sodium thiosulfate; 12.5 gm is the current recommendation for an adult. Sodium thiosulfate is the final component in the cyanide antidote kit and is notably benign. The first two ingredients, amyl nitrite and sodium nitrite, generate methemoglobin. Their administration is not critical to antidotal activity, and although potentially beneficial, the agents may also produce such undesirable effects as hypotension and reduced oxygen delivery.

Thiocyanate poisoning is disturbing but is usually not life threatening. Treatment centers on reducing the formation of additional thiocyanate, either by slowing the infusion rate or by substituting a different vasodilator. Hemodialysis is also effective for treating thiocyanate poisoning.

Because cyanide poisoning is predictable when rapid infusions of nitroprusside are given for prolonged periods of time, patients who require such therapy should also receive 5 to 10 gm of thiosulfate a day included in the infusion. Hydroxocobalamin has also been used successfully as prophylaxis against nitroprusside poisoning, and may be particularly beneficial in patients who could have thiocyanate poisoning, because it does not mediate conversion of cyanide to thiocyanate.

Suggested Reading Baud FJ, et al.: Elevated blood cyanide concentraitons in victims of smoke inhalation. N Engl J Med 325:1761, 1991. Friederich JA and Butterworth JF: Sodium nitroprusside: Twenty years and counting. Anesth Analg 81:152, 1995. Johanning RJ, et al.: A retrospective study of sodium nitroprusside use and assessment of the potential risk of cyanide poisoning. Pharmacotherapy 15:773,1995. Johnson RP and Mellors JW: Arteriolization of venous glood gases: A clue to the diagnosis of cyanide poisoning. J Emerg Med 6:410, 1988. Nightingale SL: From the Food and Drug Administration: New labeling for sodium nitroprusside emphasizes risk of cyanide toxicity. JAMA 265:847, 1991. Zerbe NF and Wagner BK: Use of vitamin B12 in the treatment and prevention of nitroprusside-induced cyanide toxicity. Crit Care Med 21:465, 1993.

Dr. Nelson is director of the medical toxicology fellowship and associate director of the New York City Poison Control Center. He is also an assistant professor in the department of surgery/emergency medicine at New York University School of Medicine.

Emerg Med 32(10):71-75, 2000