Interference of thiosulfate with potentiometric analysis of cyanide in blood and its elimination

Studies with cyanide in combination with various antidotal regimens indicated that sodium thiosulfate interfered with the potentiometric determination of cyanide. The basis for this interference is ascribed to an enhanced biotransformation of thiosulfate in the presence of blood. A microdiffusion technique, coupled with a silver/sulfide ion-specific electrode, caused falsely elevated cyanide levels when samples contained thiosulfate. The contaminant causing the falsely elevated cyanide level is believed to be sulfide anion. This sulfide contaminant can be removed by oxidation with hydrogen peroxide, and the excess hydrogen peroxide subsequently can be eliminated with sodium sulfite. The toxicologic implication of the potentiometric determination of cyanide in the presence of sodium thiosulfate is important because sodium thiosulfate is employed widely as an antidote in cyanide poisoning.     

Successful Use of Hydroxocobalamin and Sodium Thiosulfate in Acute Cyanide Poisoning: A Case Report with Follow‐up

Hydroxocobalamin is an effective first‐line antidote used mainly in monotherapy of cyanide poisonings, while the opinions are different on the effects of its combination with sodium thiosulfate. A 58‐year‐old male committed a suicide attempt by ingesting of 1200–1500 mg of potassium cyanide; he was unconscious for 1–1.5 min. after ingestion with the episode of generalized seizures. On admission to the ICU, the patient was acidotic (pH 7.28; HCO₃ 14.0 mmol/L, base excess ?12.7 mmol/L, saturation O₂ 0.999) with high serum lactate (12.5 mmol/L). Hydroxocobalamin was administered 1.5 hr after ingestion in two subsequent intravenous infusions at a total dose of 7.5 g. The infusion was followed by continuous intravenous administration of 1 mL/hr/kg of 10% sodium thiosulfate at a total dose of 12 g. No complications and adverse reactions were registered. Serum lactate decreased to 0.6 mmol/L the same day, and arterial blood gases became normal (pH 7.49; HCO₃ 27.2 mmol/L, base excess 2.2 mmol/L, saturation O₂ 0.994). The follow‐up examination 5 months later revealed no damage of basal ganglia and cerebellum on magnetic resonance imaging. The neurological examination revealed no pathological findings. On the ocular coherence tomography, the retinal nerve fibres layer was normal. In visual evoked potentials, there was a normal evoked complex on the left eye and minor decrease in amplitude on the right eye. Combination of hydroxocobalamin and sodium thiosulfate can have a positive effect on the survival without long‐term neurological and visual sequelae in the cases of massive cyanide poisonings due to the possibility of a potentiation or synergism of hydroxocobalamin effects by sodium thiosulfate. This synergism can be explained by the different time‐points of action of two antidotes: the initial and immediate effect of hydroxocobalamin, followed by the delayed, but more persistent effect of sodium thiosulfate.     

Effects of thiosulfate on cyanide pharmacokinetics in dogs

One method to treat cyanide poisoning involves the administration of a combination of sodium thiosulfate and sodium nitrite. Sodium thiosulfate is believed to exert its antidotal effect by serving as a sulfur donor, thereby increasing the rate of rhodanese catalyzed biotransformation of cyanide to thiocyanate. To gain insight into the mechanism of action of thiosulfate on cyanide toxicity, a pharmacokinetic analysis of cyanide distribution and metabolism with and without sodium thiosulfate was conducted in mongrel dogs. A compartmental model for thiocyanate, the major metabolite of cyanide, was developed from plasma concentrations determined at various times after iv administration of thiocyanate; sodium thiosulfate did not alter thiocyanate-model parameters. The model for thiocyanate was coupled to a model for cyanide, and model based equations were fitted to the blood levels of both cyanide and thiocyanate that were measured after iv administration of cyanide. This kinetic analysis showed that thiosulfate increased the rate of conversion of cyanide to thiocyanate over 30-fold. The mechanism of thiosulfate protection appeared to be due to extremely rapid formation of thiocyanate in the central compartment, which thereby limited the amount of cyanide distribution to sites of toxicity.     

Cerebral cytochrome a,a3 inhibition by cyanide in bloodless rats

Brain cytochrome a,a3 inhibition is presumed to be the site of lethal histotoxic hypoxia in cyanide poisoning perhaps because of the relative inability of the brain to metabolize cyanide. However, only limited data are available about cyanide toxic effects and possible antagonism in the in vivo brain. In this study, in situ, multiple wavelength, spectrophotometric monitoring of brain cytochrome a,a3 was used to observe oxidation-reduction (redox) responses of cerebral cytochrome a,a3 to intravenous potassium cyanide administration. Bloodless rats prepared by perfluorochemical emulsion (FC-43) exchange transfusion allowed monitoring of cyanide-cytochrome a,a3 interaction without spectral interference by hemoglobin. We found that cyanide-induced transient increases in cytochrome a,a3 reduction level and subsequent redox recovery kinetics were similar in bloodless and normal blood circulated rats. Electroencephalographic activity was maintained until a 50% increase in the reduction level of cytochrome a,a3 was induced with cyanide. Pre-treatment with the cyanide antagonist sodium thiosulfate also protected brain cytochrome a,a3 from cyanide-mediated redox state changes by approximately 4-fold both in normal blood circulated controls and during FC-43 circulation. These latter results indicate that sodium thiosulfate, presumably acting at tissue sites of rhodanese activity, can prevent cerebral cytochrome a,a3 reduction by cyanide even in the virtual absence of blood or circulating proteins.     

Acetonitrile serum concentrations and cyanide blood levels in a case of suicidal oral acetonitrile ingestion.

Acute acetonitrile toxicity is mainly dependent on the release of cyanide via hepatic metabolism. Although evaluated in animals, few data are available concerning the toxicokinetic parameters of acetonitrile and acetonitrile-liberated cyanide in human. This paper reports a case of suicidal oral acetonitrile ingestion of about 5 mL without severe symptoms of intoxication in a previously healthy adult male with a body weight of 60 kg. Acetonitrile serum concentrations as well as cyanide blood levels were determined over the whole hospitalization. The elimination half-lives calculated from these data were 32 h for acetonitrile and 15 h for cyanide. After sodium thiosulfate bolus application, the cyanide blood level rapidly decreased to 10% of the initial value, indicating that sodium thiosulfate sufficiently detoxifies acetonitrile-liberated cyanide. Since cyanide levels again increased to maximal values about 4.5 h after sodium thiosulfate application, continued thiosulfate therapy is required as predicted by the long elimination half-lives of acetonitrile and acetonitrile-liberated cyanide. Determination of cyanide and acetonitrile concentrations is recommended for the estimation of optimal individual sodium thiosulfate dosage.     

Efficacy of oral administration of sodium thiosulfate in a large,swine model of oral cyanide toxicity

IntroductionCyanide is a deadly poison, particularly with oral exposure where larger doses can occur before symptoms develop. Prior studies and multiple governmentagencies highlight oral cyanide as an agent with the potential for use in a terrorist attack. Currently, there are no FDA approved antidotes specific to oralcyanide. An oral countermeasure that can neutralize and prevent absorption of cyanide from the GI tract after oral exposure is needed. Our objective was toevaluate the efficacy of oral sodium thiosulfate on survival and clinical outcomes in a large, swine model of severe cyanide toxicity.MethodsSwine (45-55kg) were instrumented, sedated, and stabilized. Potassium cyanide (8 mg/kg KCN) in saline was delivered as a one-time bolus via an orogastric tube. Three minutes after cyanide, animals randomized to the treatment group received sodium thiosulfate (510 mg/kg, 3.25 M solution) via orogastric tube. Our primary outcome was survival at 60 minutes after exposure. We compared survival between groups by log-rank, Mantel-Cox analysis and trended labs and vital signs.ResultsAt baseline and time of treatment all animals had similar weights, vital signs, and laboratory values. Survival at 60 min was 100% in treated animals compared to 0% in the control group (p=0.0027). Animals in the control group became apneic and subsequently died by 35.0 min (20.2,48.5) after cyanide exposure. Mean arterial pressure was significantly higher in the treatment group compared to controls (p=0.008). Blood lactate (p=0.02) and oxygen saturation (p=0.02) were also significantly different between treatment and control groups at study end.ConclusionOral administration of sodium thiosulfate improved survival, blood pressure, respirations, and blood lactate concentrations in a large animal model of acute oral cyanide toxicity.     

Cholestatic hepatitis caused by acute gold potassium cyanide poisoning.

INTRODUCTION: Poisoning after oral ingestion of gold potassium cyanide is rarely reported. A case of suicidal ingestion of gold potassium cyanide (potassium dicyanoaurate; CAS# 13967-50-5) is described. CASE REPORT: A 27-year-old man attempted suicide by ingesting 5 mL gold potassium cyanide solution. He developed vomiting, hyperamylasemia, and hepatic dysfunction. Cyanide poisoning was not detected but acute gold toxicity was noted. Pathologic findings of the liver showed centrilobular cholestasis with eosinophilic degeneration. The whole blood and serum gold were 4361 and 6011 microg/L, respectively, and the 24-hour urine gold was 429 microg/d in samples obtained on day 4. CONCLUSION: Gold-induced hepatotoxicity has been seen infrequently in patients receiving gold therapy. Reported agents include sodium aurothiomalate, sodium aurothiopropranol sulfonate, aurothioglucose, aurothiopolypeptide (Auro-detoxin), auric sulfide, and gold thiosulfate, our report adds gold potassium cyanide.     

Hemodialysis Complications of Hydroxocobalamin: A Case Report

Hydroxocobalamin is a new antidote approved by the FDA for the treatment of cyanide poisoning. Our report describes a patient with cyanide poisoning who survived after treatment with hydroxocobalamin and complications we encountered with hemodialysis. A 34-year-old female presented to the emergency department after a syncopal event and seizures. Her systolic blood pressure was 75 mmHg, her QRS complex progressively widened, and pulses were lost. She was intubated and resuscitated with fluids, sodium bicarbonate for her QRS widening and vasopressors. Venous blood gas demonstrated a pH of 6.36 with an O₂ saturation of 99%. Due to the acidemia with a normal pulse oximetry, simultaneous venous and arterial blood gases were obtained. Venous gas demonstrated a pH of 6.80 with a PO₂ of 222 mmHg, an O₂ saturation of 99%. The arterial blood gas showed a pH of 6.82, a PO₂ 518 mmHg, an O₂ saturation of 100%. Cyanide was suspected and hydroxocobalamin and sodium thiosulfate were given. Within 40 min of hydroxocobalamin administration, vasopressors were discontinued. Initially, nephrology attempted dialysis for metabolic acidosis; however, the dialysis machine repeatedly shut down due to a “blood leak”. This was an unforeseen effect attributed to hydroxocobalamin. Cyanide level, drawn 20 min after the antidote was completed, was elevated at 22 mcg/dL. Her urinary thiocyanate level could not be analyzed due to an “interfering substance”. Hydroxocobalamin is an effective antidote. However, clinicians must be aware of its effects on hemodialysis machines which could delay the initiation of this important treatment modality in the severely acidemic patient.     

Resolution of thiosulfate interference in cyanide determination.

Sodium thiosulfate is commonly employed as an antidote for cyanide intoxication. Unfortunately, thiosulfate decomposes to sulfur dioxide which ultimately interferes with the colorimetric microdiffusion analysis of cyanide. Therefore, it is no longer reliable to determine cyanide blood concentrations after therapy with sodium thiosulfate has been instituted. A procedure has been developed to prevent sodium thiosulfate from interfering with the standard colorimetric method for cyanide determination. Although thiosulfate is still degraded to polythionic acids, this procedure takes advantage of the difference in pK_a values of hydrogen cyanide and the various acidic polythionic acids formed upon the acidification of the thiosulfate anion. To ascertain if this modification would circumvent thiosulfate interference under in vivo conditions, mice receiving potassium cyanide were treated subsequently with sodium thiosulfate and the apparent concentration of cyanide in the blood was determined. These studies indicate that the interference of cyanide analysis caused by the presence of thiosulfate anion in biological samples can be resolved.     

硝普钠致氰化物中毒及其防治

硝普钠为快速短效血管扩张剂,临床用于治疗高血压危象和严重心力衰竭。硝普钠在体内迅速代谢为氰化物,并进一步代谢为硫氰酸盐。因此,大剂量持续应用硝普钠易致氰化物和硫氰酸盐蓄积中毒。患者在应用硝普钠过程中若出现神经系统抑制、代谢性酸中毒及心血管系统不稳定等应考虑为氰化物或硫氰酸盐中毒,须立即停药,给予支持治疗以及解毒剂。常用解毒剂有:亚硝酸钠、亚甲蓝、硫代硫酸钠及羟钴胺等。硝普钠应用>3d应监测硫氰酸盐血浓度,也应监测氰化物血浓度。硫代硫酸钠与硝普钠联用可预防氰化物毒性反应。伴有肾损害的患者可用非诺多泮代替硝普钠。     

Enzyme therapy in cyanide poisoning: Effect of rhodanese and sulfur compounds

Crystalline bovine liver rhodanese (thiosulfate: cyanide sulfurtransferase, EC 2.8.1.1) was evaluated as an antidote in combination with different sulfur compounds against cyanide poisoning in mice. The prophylactic antidote effect, when the antidote was injected i.v. 1 min prior to i.p. injection of cyanide, was dependent on both the dose of the enzyme and the dose of the sulfur compound. An optimal dose of the enzyme of about 2,000 U/kg (3 mg/kg of pure enzyme) was found. This enzyme dose combined with 2 mmol/kg of sodium thiosulfate raised the LD₅₀ for potassium cyanide 7.6 times. When thiosulfate was replaced with equimolar doses of ethanethiosulfonate and propanethiosulfonate, the corresponding values were 10.3 and 9.3 times, respectively. Maximum antidote effect was obtained when the doses of ethanethiosulfonate and propanethiosulfonate were raised to 4 mmol/kg, increasing the LD₅₀ for cyanide 20.8 and 15.4 times, respectively. On the other hand, when given without rhodanese, ethanethiosulfonate and propanethiosulfonate were no better antidotes than thiosulfate.Rhodanese and a sulfur compound given therapeutically to mice when symptoms of cyanide poisoning had occurred, also had a very good antidote effect. The prophylactic antidote effect of rhodanese plus thiosulfate rapidly decreased with increasing time interval between injection of the antidote and cyanide. Thus, when rhodanese and thiosulfate were given 20 min prior to cyanide, the antidote effect was of the same order as that of thiosulfate alone. The antidote effect of the latter did not decrease significantly within the same time interval.Enzyme activity in plasma decreased rapidly after i.v. injection of rhodanese, and enzyme activity in urine was detected following injection. No appreciable inactivation occurred when the enzyme was incubated with whole blood in vitro, but a strong and rapid inhibition, about 85%, of the enzyme occurred in fresh mouse urine in vitro.     

Clinical features and management of cyanide poisoning

The pathophysiology, clinical features, and management of cyanide toxicity are reviewed and sources of cyanide are listed. Cyanide is a deadly poison that is found in many foods and household and industrial products, including some that are readily available. Cyanide binds with cytochrome oxidase, the enzyme responsible for oxidative phosphorylation, and paralyzes cellular respiration. Because the tissues cannot use oxygen that is delivered, aerobic metabolism ceases. The signs and symptoms of cyanide poisoning reflect the extent of cellular hypoxia. Manifestations may include respiratory abnormalities (progressing from tachypnea and dyspnea to respiratory depression and apnea), hemodynamic instability, metabolic acidosis, and, possibly, local irritant effects after oral ingestion of cyanide. The mainstays of therapy are 100% oxygen and specific antidotes to cyanide. Sequential treatment with amyl nitrite by inhalation, intravenous sodium nitrite 3%, and intravenous sodium thiosulfate 25% is directed toward decreasing the amount of cyanide available for cellular binding. Nitrites convert hemoglobin to methemoglobin, which reacts with cyanide to form cyanomethemoglobin. Sodium thiosulfate serves as a source of sulfur groups, which are needed for conversion of cyanide to thiocyanate, a compound that is relatively less toxic and is excreted renally. Supportive care also is important. Cobalt EDTA, hydroxocobalamin, and aminophenols have also been used but are not considered standard treatments. Cyanide poisoning is a medical emergency that requires prompt recognition and immediate and aggressive treatment.     

In vivo studies on rhodanese encapsulation in mouse carrier erythrocytes

Resealed erythrocytes containing sodium thiosulfate and rhodanese (CRBC) are being employed as a new approach in the antagonism of cyanide intoxication. In earlier in vitro studies, the behavior of red blood cells containing rhodanese and sodium thiosulfate was investigated with regard to their properties and their capability of metabolizing cyanide to thiocyanate. The present studies are concerned with the properties of these rhodanese-containing carrier erythrocytes in the intact animal. These carrier erythrocytes were administered intravenously and the survival of the encapsulated enzyme was compared with the administration (iv) of free exogenous enzyme. Also, the amount of leakage of the encapsulated rhodanese from the red blood cell was determined. The survival of the carrier red blood cell. prepared by hypotonic dialysis, was found to be characterized by a biphasic curve. There was an initial rapid loss of approximately 40 to 50% of the carrier cells with a t1/2 = 2.5 hr. Subsequently the remaining resealed annealed carrier erythrocytes persisted in the vascular system with a t1/2 = 8.5 days. When free exogenous rhodanese was administered directly into the vascular system, it was rapidly eliminated with a t1/2 = 53 min. Red blood cells containing sodium thiosulfate and rhodanese apparently are effective in vivo in the biotransformation of cyanide. In animals pretreated with encapsulated rhodanese and sodium thiosulfate, blood cyanide concentrations are appreciably decreased with a concomitant increase in thiocyanate ion, a metabolite of cyanide. When erythrocytes, which contained no rhodanese or sodium thiosulfate, were subjected to hypotonic dialysis, cyanide was not metabolized to any appreciable extent. Furthermore, carrier erythrocytes containing rhodanese and sodium thiosulfate were found to increase the protection against the lethal effects of cyanide by approximately twofold. The ability of these carrier erythrocytes alone to metabolize cyanide and to antagonize the lethal effects of cyanide reflects the potential of this new antidotal approach in the antagonism of chemical toxicants.     

The in vivo effects of cyanide and its antidotes on rat brain cytochrome oxidase activity.

The in vivo effects of sodium cyanide and its antidotes, sodium nitrite, sodium thiosulfate and 4-dimethylaminophenol (DMAP), as well as the alpha-adrenergic blocking agent phentolamine, on rat brain cytochrome oxidase were studied. The course of inhibition was time-dependent and a peak of 40% was attained between 15 and 20 min after the s.c. injection of 1.3 LD50 (12 mg/kg) of cyanide. Pronounced dose-dependence was observed in the inhibition of the enzyme, at this relatively low, but lethal dose. Further observation was impossible because of rapidly lethal effects of cyanide. In animals artificially ventilated with room air, observation was possible up to 60 min. However, maximum inhibition was also 40%. When antidotes were applied 30 min after 20 mg/kg of cyanide, marked reactivation of cytochrome oxidase activity was observed with all antidotes (particularly with thiosulfate) except for phentolamine which had no effect. Prevention of methemoglobin forming with toluidine blue did not affect the reactivating ability of nitrite or DMAP, thus suggesting more complex protective mechanisms then simple methemoglobin formation. The high efficacy of thiosulfate may be attributed to its rhodanese catalyzed, direct binding to free blood cyanide, leading thus to its dissociation from cytochrome oxidase. The theory that cytochrome oxidase inhibition is a basic mechanism of cyanide toxicity could not be disproved.     

Acute cyanide intoxication treated with a combination of hydroxycobalamin,sodium nitrite,and sodium thiosulfate

An 80-year-old diabetic patient was admitted to the hospital because of sudden unconsciousness and severe metabolic acidosis. His son reported the possibility of cyanide poisoning. Clinical data and the detection of cyanide in blood and gastric material confirmed this possibility. Supportive therapy and the following antidotes--sodium nitrite two doses 300 mg i.v., sodium thiosulfate 3 g i.v., and hydroxocobalamin 4 g in 24 hours--were administered immediately and the patient completely recovered in 48 hours. Our observations suggest that timely and appropriate use of antidotes for cyanide intoxication may prevent death, even in aged diabetic patients.     

Effects of oxygen on the antagonism of cyanide intoxication: cytochrome oxidase, in vitro

Since oxygen was reported to be an effective cyanide antagonist in vivo, particularly in the presence of the classic antidotal combination of sodium nitrite and sodium thiosulfate, in vitro studies were initiated in an attempt to investigate the mechanism of oxygen-mediated cyanide antagonism. The effect of oxygen on cyanide-inhibited cytochrome oxidase with and without cyanide antagonist(s) was investigated in a purified membraneous enzyme system prepared from rat liver mitochondria. Cyanide produced a concentration dependent inhibition of cytochrome oxidase, and 100% oxygen did not alter the inhibition produced by KCN either in the presence or absence of sodium thiosulfate. However, the addition of sodium thiosulfate and rhodanese to the assay reactivated the cyanide-inhibited cytochrome oxidase. Kinetic analysis indicated rhodanese competes with cytochrome oxidase for cyanide, and oxygen had no effect on this coupled reaction. In conclusion, the in vivo antidotal properties of oxygen cannot be attributed to oxygen-mediated reactivation of cyanide-inhibited cytochrome oxidase or an oxygen-mediated acceleration of rhodanese detoxification.     

Severe keloids caused by hydrogen cyanide injury: a case report

The purpose of this study was to report severe keloids caused by hydrogen cyanide injury. Hydrogen cyanide poisoning is still a problem as an occupational disease in China. We report a 37-year-old man with severe hydrogen cyanide poisoning. The patient fell on the floor after inhalation of hydrogen cyanide and was burned on his back by hydrocyanic acid. Sequential treatment included amyl nitrite by inhalation, intravenous sodium nitrite 3%, and intravenous sodium thiosulfate 25%. Other treatment consisted of incision of the trachea, mannitol and furosemide, antibiotics, and nutrient support measures. The patient also received hyperbaric oxygen therapy; during the first treatment, he became apneic and cardiopulmonary resuscitation was supplied in the hyperbaric oxygen chamber. He eventually recovered, but a large amount of keloids developed on his back and buttocks.     

Cyanide intoxication in sheep; therapeutics

Various cyanide antidotes were evaluated by comparing the effects of delay in time of therapy following oral administration of sodium cyanide in sheep. Successful therapy of lethal doses of sodium cyanide could be accomplished with the more potent antidotes for up to 30 minutes following administration of sodium cyanide. Either 660 mg/kg sodium thiosulfate or 1 mg/kg p-aminopropriophenone were effective antidotes for moderate lethal doses (7.6 mg/kg) of sodium cyanide. The conventional low dosage nitrite/thiosulfate (6.7 mg/kg and 67 mg/kg) was much less effective. Larger doses (15.2 mg/kg) of sodium cyanide were effectively antagonized by either 660 mg/kg sodium thiosulfate alone or in combination with 1.5 mg/kg p-aminopropriophenone or 22 mg/kg sodium nitrite. At high cyanide dosage, p-aminopropriophenone alone was less effective than sodium thiosulfate alone. Sodium thiosulfate at high dosage appears to be the antidote of choice. This more closely satisfies the requirements of high efficacy and low toxicity for an antidote. Sodium nitrate or other antidotes may be used in conjunction with sodium thiosulfate, but their use is not necessary for high efficacy.     

The efficacy of alpha-ketoglutaric acid in the antagonism of cyanide intoxication

It has been reported that compounds containing carbonyl groups can readily react with cyanide. Pyruvic acid, an alpha-ketocarboxylic acid, has been shown to antagonize the lethal effects of cyanide. It is suggested that its mechanism of action rests in its ability to react with or "bind" cyanide. In this study, alpha-ketoglutaric acid, also an alpha-ketocarboxylic acid, was evaluated for its ability to counteract the lethal effects of cyanide. alpha-Ketoglutaric acid increased the LD50 value of cyanide (6.7 mg/kg) by a factor of five, a value statistically equivalent to that ascertained in mice pretreated with sodium thiosulfate and sodium nitrite. The combination of alpha-ketoglutaric acid and sodium thiosulfate increased the LD50 value of cyanide to 101 mg/kg. Addition of sodium nitrite to the alpha-ketoglutaric acid/sodium thiosulfate regimen increased the LD50 value of cyanide to 119 mg/kg. Unlike sodium nitrite, no induction of methemoglobin formation was observed with alpha-ketoglutaric acid pretreatment. It is apparent from these studies that the administration of alpha-ketoglutaric acid in conjunction with sodium thiosulfate resulted in fewer animal deaths than sodium nitrite and sodium thiosulfate without the dangerous formation of methemoglobin.