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Clinical Associate Professor College of Pharmacy University of Michigan Clinical Pharmacist University of Michigan Health System UHB2D301 Box 0008 1500 East Medical Center Drive Ann Arbor, Michigan 48109-0008 fax 734/936-7027 calaniz{at}umich.edu
Resident Physician Department of Internal Medicine University of Michigan
Published Online, January 11, 2005. www.theannals.com, DOI 10.1345/aph.1E226
Upon infusion, nitroprusside interacts with oxyhemoglobin, forming methoxyhemoglobin and releasing 5 cyanide radicals (cyanogen) and nitric oxide.1 Cyanogen and nitric oxide are rapidly cleared via interactions with sulfhydryl groups in tissues and erythrocytes. Cyanogen also reacts with methemoglobin to produce cyanomethemoglobin, which is not considered to be toxic.1 Remaining cyanogen is converted to thiocyanate via sulfotransferation in the liver.
Cyanide that is released during nitroprusside infusion primarily distributes into erythrocytes, yet this does not impart the toxic effects.2 Rather, toxic effects occur as cyanide distributes into the tissues, leading to blockade of oxidative phosphorylation. Normally, adults can detoxify about 50 mg of nitroprusside with existing sulfur stores.1 However, certain conditions (eg, malnutrition, surgery) or higher rates of nitroprusside infusion (ie, >2 µg/kg/min) may lead to depletion of sulfur stores and accumulation of cyanogens, resulting in clinical toxicity. Onset of clinical toxicity may occur in as little as a few minutes, depending on sulfur ion stores. Accumulation of cyanogen in patients unable to maintain adequate conversion to thiocyanate results in tissue anoxia, anaerobic metabolism, and lactic acidosis. Profound toxicity may result in death.
Optimal cyanide serum concentration monitoring in patients receiving nitroprusside therapy entails measurement of cyanide concentration in the plasma, which best correlates with toxicity.3,4 However, laboratories may analyze whole blood cyanide concentrations which, due to the significant distribution into erythrocytes, may be elevated without manifestations of toxicity.4 Cyanide assays at our institution are whole blood measurements. Consequently, the measured blood concentrations of cyanide in our patients receiving nitroprusside may be confounding and difficult to interpret. Evaluation of a patient who is receiving nitroprusside therapy for cyanide toxicity should be based on a constellation of clinical evidence such as sinus tachycardia, restlessness, agitation, and seizures, and laboratory findings such as elevation of lactate level and anion gap metabolic acidosis.3 Tachyphylaxis to nitroprusside therapy may also be an indicator of cyanide toxicity.
As a means to decrease, and in most cases eliminate, the risk of cyanide toxicity associated with nitroprusside administration, sodium thiosulfate should be routinely added to the infusion bag to provide a constant source of sulfur donors to facilitate conversion of cyanide to thiocyanate. Although essentially eliminating the risk of cyanide toxicity, patients should be monitored for thiocyanate toxicity, which clinically resembles cyanide toxicity (without acidosis), by means of measurement of thiocyanate serum concentrations. In cases of thiocyanate toxicity, benzodiazepines may be used to manage agitation or seizures, and hemodialysis may be used to enhance thiocyanate elimination.
References
This article has been cited by other articles:
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  K. E. Broderick, M. Balasubramanian, A. Chan, P. Potluri, J. Feala, D. D. Belke, A. McCulloch, V. S. Sharma, R. B. Pilz, T. D. Bigby, et al. The Cobalamin Precursor Cobinamide Detoxifies Nitroprusside-Generated Cyanide Experimental Biology and Medicine, June 1, 2007; 232(6): 789 - 798. [Abstract] [Full Text] [PDF]
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