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Case Report

Dialysis for Thiocyanate Intoxication: A Case Report and Review of the Literature

Nessim, Sharon J.; Richardson, Robert M. A.

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doi: 10.1097/01.mat.0000227670.39719.ec
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Abstract

Cyanide is a naturally occurring poison that exists in many forms. It is present in certain plants and foods, cigarette smoke, and the combustible products of synthetic materials. It is also present in medications such as nitroprusside (NP), which consists of an iron molecule bound to five cyanide molecules and one molecule of nitric oxide. When NP is administered, the nitric oxide is rapidly liberated during infusion (accounting for the vasodilatory effect), whereas the cyanide molecules are released gradually. The toxicity of cyanide relates to its binding to a variety of iron-containing enzymes, the most important of which is the cytochrome a-a3 component of the cytochrome C oxidase complex. This complex is critical for electron transport during oxidative phosphorylation. By binding to this enzyme, cyanide can inhibit aerobic metabolism, leading to lactic acidosis and rapidly resulting in death. Symptoms and signs of cyanide intoxication may include hypotension, tachycardia, tachypnea, headache, nausea, vomiting, dizziness, weakness, restlessness, convulsions and loss of consciousness.

The management of cyanide intoxication consists of supportive care and the use of antidotes, including sodium and/or amyl nitrite, hydroxycobalamin, and sodium thiocyanate.1–5 Under normal circumstances, small amounts of cyanide can be detoxified by binding to circulating methemoglobin, which accounts for 1% to 2% of hemoglobin. Toxicity results when the capacity of methemoglobin to bind cyanide is exceeded. Administration of sodium or amyl nitrite oxidizes hemoglobin to methemoglobin, which then favors the binding of cyanide to the ferric ion of methemoglobin rather than to the cytochrome C oxidase complex. This generally leads to improved oxidative phosphorylation, although caution must be exercised as rising methemoglobin levels can lead to impaired tissue delivery of oxygen.

Hydroxycobalamin is another treatment option that works by combining with cyanide to form cyanocobalamin. The use of this agent appears to be both safe and effective.4,5 Whereas the nitrite compounds and hydroxycobalamin lessen the amount of free cyanide available to cause toxicity, infusion of sodium thiosulfate facilitates removal of cyanide from the body. Specifically, administration of sodium thiosulfate allows for donation of a sulfur atom, converting cyanide to its less toxic metabolite thiocyanate, which is then excreted in the urine.

Although thiocyanate is less toxic than cyanide, it can still lead to toxicity, especially in the context of impaired renal function. Symptoms and signs of thiocyanate toxicity include confusion, hallucinations, delirium, seizures, fatigue, weakness, miosis, tinnitus, and rash. Management of thiocyanate toxicity consists of supportive care and limiting the source of production of thiocyanate. In this text, we present a case of thiocyanate toxicity secondary to an NP infusion in which the patient was successfully treated with continuous venovenous hemodiafiltration (CVVHDF) and review existing data as to the effectiveness of dialysis in the removal of thiocyanate in the face of renal insufficiency.

Case Report

The patient was a 65-year-old woman who had a history of congestive heart failure, with moderate to severe mitral regurgitation. She presented to a community hospital with shortness of breath, upper respiratory tract symptoms, and a fever. An echocardiogram showed normal left ventricular function but severe mitral regurgitation with a mobile mass on the mitral annulus. She was started on antibiotics to treat a possible endocarditis, although all blood cultures were negative. She was also treated with furosemide, intravenous nitroglycerin, and dopamine. She then had a cardiorespiratory arrest, at which time she was intubated and successfully resuscitated. She was subsequently transferred to our hospital for consideration of mitral valve replacement.

On arrival, her chest radiograph and pulmonary artery catheter measurements confirmed congestive heart failure, and afterload reduction was initiated with an intravenous NP infusion at 2.3 μg/kg per minute and hydralazine through a nasogastric tube. Sodium thiosulfate was given concomitantly with the NP to convert cyanide to thiocyanate, and thiocyanate levels were measured daily.

Her baseline creatinine was not known, but after arrest and upon transfer, it was 1.5 to 1.6 mg/dl (130 to 140 μmol/L), corresponding to an estimated creatinine clearance of about 35 ml/min. Over the subsequent 8 days, her creatinine rose to 2.6 mg/dl (230 μmol/l) and then plateaued with maintenance of good urine output with a furosemide infusion. Urine microscopy showed heme-granular casts consistent with acute tubular necrosis. Over the same time period, the NP infusion rate was increased to 2.7 μg/kg per minute to maximize afterload reduction in the face of refractory pulmonary edema. Serial measurements of thiocyanate demonstrated steadily increasing levels, reaching the threshold for toxicity (1.7 mmol/l) 9 days after initiation of the NP. At that time, discontinuation of the NP was attempted, but this was unsuccessful because of increasing difficulty ventilating the patient secondary to worsening pulmonary edema in the face of diminished afterload reduction. The NP infusion, therefore, was continued at the lowest tolerated dose of 1.7 μg/kg per minute. Despite this dose reduction, the thiocyanate level continued to climb, reaching 2.4 mmol/l after 11 days of exposure to NP. The nephrology service was then consulted as to whether dialysis could be used to treat the thiocyanate toxicity, given the inability to withdraw NP.

To manage the patient's thiocyanate intoxication, it was decided to proceed with dialysis, which was started 11 days after the initiation of the NP drip. Although conventional hemodialysis is ordinarily used for treatment of acute intoxications to maximize clearance, continuous renal replacement therapy was chosen as the dialysis modality in this case because of the ongoing infusion of NP (and therefore the ongoing source of production of thiocyanate). It was thought that this would be a safe option, since the intoxication had developed gradually over several days, with the only evidence of toxicity being the measured thiocyanate level. A switch to hemodialysis would have been made promptly if a significant reduction in thiocyanate levels was not observed.

A Prisma dialysis machine was used, with a Polyflux dialysis membrane. Blood flow was set at 100 ml/min. Total clearance achieved was 25 to 29 ml/kg per hour, with approximately 75% to 85% of clearance achieved by hemodialysis and 15% to 25% by hemofiltration. Given the patient's weight of 70 kg, this corresponded to 1500 ml/h of hemodialysis and 250 to 500 ml/h of hemofiltration. Citrate was used for anticoagulation because of a planned imminent surgery for tracheostomy. The dialysate was Normocarb, with normal saline as replacement fluid. The patient's NP level rapidly declined from 2.4 mmol/l immediately before dialysis to 0.9 mmol/l at 16 hours and to 0.6 mmol/L at 20 hours (Figure 1). The NP was successfully weaned off over the subsequent 48 hours, allowing for discontinuation of dialysis.

Figure 1.
Figure 1.:
Plasma thiocyanate levels over time. Dashed line indicates the threshold for thiocyanate toxicity (1.7 mmol/l). CVVHDF was started 11 days after initiation of the NP infusion, with a rapid decrease in thiocyanate levels.

Discussion

Thiocyanate intoxication requires significant cyanide exposure coupled with renal insufficiency limiting the excretion of thiocyanate. There is currently very limited data on dialysis as an adjunct to supportive care and thiosulfate infusion in patients with impaired renal function. In general, important properties of an easily dialyzable substance include low molecular weight, little protein-binding, and small volume of distribution. Thiocyanate is a small molecule (58 g/mol), with a volume of distribution that has been reported to be 0.25 l/kg in healthy control subjects.6 Although protein binding of thiocyanate has been described,7 the exact degree of this binding is not clear.

Some insight into the dialytic clearance of thiocyanate can be gained from data in chronic stable hemodialysis patients. In a study by Cailleux et al.,8 whole blood cyanide and plasma thiocyanate levels were measured in 12 patients on long-term hemodialysis and 16 healthy subjects. In the patients with end-stage renal disease, no difference was noted in the cyanide levels, but there was a significant increase in plasma thiocyanate levels during the interdialytic interval. A more recent study measured cyanide and thiocyanate in 43 hemodialysis patients and 46 healthy control subjects.9 Mean cyanide and thiocyanate levels were found to be significantly higher in dialysis patients, with thiocyanate levels 6 to 7 times greater than in nonsmoking control subjects. The decrease in thiocyanate levels after a 4-hour dialysis session was 19%.

Although the latter study would suggest limited clearance of thiocyanate, it is difficult to extrapolate this to a population of patients with thiocyanate intoxication, who have significantly higher circulating concentrations of thiocyanate.

Given the rarity of cyanide poisoning, the data on its management are limited to anecdotal reports. Over the last 30 years, there have been several case reports describing the effective use of dialysis in the treatment of accidental, intentional, and iatrogenic cyanide or thiocyanate intoxication. The first reported case report was in 1978 in a 6-year-old boy with intractable hypertension requiring treatment with NP. Intermittent hemodialysis over a 26-day period successfully removed thiocyanate from the blood.10 This was followed by a second case of NP-induced cyanide intoxication, in which antidotes and hemodialysis in combination were successfully used to treat the patient. In this case, it was noted that hemodialysis significantly removed thiocyanate but not cyanide from the patient's blood.11 A subsequent case described the successful use of hemodialysis and charcoal hemoperfusion in addition to antidotes to treat cyanide poisoning that resulted from acetonitrile ingestion (present in nail polish remover) as a suicide attempt. 12 Most recently, another case of cyanide ingestion as a suicide attempt was reported. In this instance, hemodialysis was used because of severe, refractory lactic acidosis, and the patient recovered completely within 48 hours.13

Pahl et al.14 looked at the clearance of thiocyanate through dialysis both in vivo in a patient with NP toxicity as well as in vitro. In vivo clearance of thiocyanate was 83 ml/min (as compared with a urea clearance of 130 ml/min). In vitro clearance of thiocyanate was 102 ml/min (vs a urea clearance of 139 ml/min). In the patient who was dialyzed, removal of thiocyanate was confirmed by measuring thiocyanate in the dialysate. A subsequent study assessed the effect of hemodialysis in dogs receiving a constant infusion of cyanide with and without a simultaneous infusion of thiosulfate. Overall, hemodialysis in this study was found to increase the lethal dose of cyanide in the dogs, with the largest protective effect in those receiving a thiosulfate infusion.15

The results of this case provide further supportive data that dialysis is effective at removing thiocyanate in instances where toxic levels are present. Our conclusion is based on an assumption that changes in NP infusion rates and renal function did not contribute significantly to the drop in thiocyanate levels after initiation of dialysis. Although the NP infusion rate had been decreased 2 days before initiation of dialysis, the thiocyanate levels continued to rise despite this. Furthermore, the most significant contributor to removal of thiocyanate in the absence of dialysis is renal excretion, and the patient's renal function did not change significantly before initiation of dialysis. This would make dialytic clearance of thiocyanate the most likely explanation for the rapid normalization of the thiocyanate levels. Although we used a combination of hemodialysis and hemofiltration, the small size of the thiocyanate molecule makes it unlikely that either method of clearance would be superior to the other.

For any given solute, the clearance formula Ct = C0e−Kt/V can be used to estimate the concentration of a solute after removal with stated clearance values, time and volume of distribution, where C0 is the initial concentration of thiocyanate, t is the time after dialysis, K is the clearance, and V is the volume of distribution. In this case, since the solute concentrations at various points in time were known, we used the clearance formula to estimate the volume of distribution of thiocyanate. Based on a clearance of 1750 to 2000 ml/h, a predialysis thiocyanate level of 2.4 mmol/l, and levels of 0.9 and 0.6 mmol/l at 16 and 20 hours, respectively, we estimated the volume of distribution of thiocyanate to be between extracellular fluid volume and total body water—approximately 0.4 l/kg. This volume of distribution is consistent with previously reported values and is in keeping with that of a readily dialyzable drug.

Based on the historical data and the results in our case, we believe that dialysis is a useful and practical adjunct in the management of thiocyanate intoxication in patients with renal insufficiency. Although there have been previous reports documenting the effectiveness of intermittent hemodialysis, ours is the first reported case demonstrating that CVVHDF can be successfully used to achieve significant clearance of thiocyanate. This is especially relevant for patients with thiocyanate intoxication in whom continuous renal replacement therapy would be more appropriate, such as those with hemodynamic instability or those with an ongoing source of thiocyanate production such as a nitroprusside infusion.

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