Blood Cyanide Levels Research Articles

Comparative toxicities of aliphatic nitriles

Aliphatic nitriles have been postulated to manifest their toxicity through cyanide liberation. We have investigated the signs of toxicity and effect of equitoxic LD 50 doses of saturated and unsaturated aliphatic mono- and dinitriles on tissue and blood cyanide levels, tissue glutathione levels and cytochrome c oxidase activities. Signs of toxicity were classified into cholinomimetic effects observed with unsaturated nitriles and central nervous system effects observed with saturated nitriles and potassium cyanide (KCN). Hepatic and blood cyanide levels 1 h after treatment were highest following malononitrile (MCN) and decreased in the order of propionitrile (PCN) > KCN > butyronitrile > acrylonitrile (VCN) > allylcyanide > fumaronitrile > acetonitrile. The order differed in brain where KCN preceded MCN and PCN. Hepatic and brain cytochrome c oxidase were significantly inhibited and corresponded to their cyanide levels. No significant inhibition of cytochrome c oxidase was observed in vitro. VCN was the only nitrile which significantly reduced tissue GSH levels. In conclusion, toxic expression of aliphatic nitriles depends not only upon cyanide release but also on their degree of Unsaturation. With unsaturated aliphatic nitriles cyanide release plays a minimal role in their toxicity.

BLOOD CARBOXYHAEMOGLOBIN AND CYANIDE LEVELS IN FIRE SURVIVORS

Blood carboxyhaemoglobin and cyanide concentrations were measured in 53 fire survivors, 36 of whom had clinical evidence of smoke inhalation. Carboxyhaemoglobin and cyanide levels were raised only in patients with smoke inhalation. Blood carboxyhaemoglobin measurement can be used to confirm the diagnosis of severe smoke inhalation in cases in which the clinical data are inconclusive, provided that the time of sampling after exposure is taken into account. A nomogram has been constructed for this purpose. There is no quick method of measuring blood cyanide levels, but the close relation between cyanide and carboxyhaemoglobin levels suggests that carboxyhaemoglobin concentrations, which can be rapidly and easily measured, could be used to identify those who might benefit from treatment with cyanide antidotes.

Consumption of vitamin B12 during sodium nitroprusside administration in humans.

In view of evidence suggesting possible participation of cobalamin in cyanide metabolism, the effects of sodium nitroprusside (SNP) infusion on blood cyanide and plasma thiocyanate levels and serum vitamin B12 levels were examined in ten patients undergoing major orthopedic procedures. Whole blood cyanide concentrations increased significantly (P less than 0.001) from 3.6 +/- 1.1 to 65.7 +/- 16.2 micrograms/dl, and total serum B12 values decreased significantly (P less than 0.005) from 482 +/- 56 to 267 +/- 42 pg/ml, three hours after SNP therapy. Plasma thiocyanate did not change. Cyanide released from SNP converts hydroxocobalamin to cyanocobalamin, which is readily excreted in urine. These variables were not changed in six patients (control) who received trimethaphan. In vitro experiments revealed that none of the serum factor(s) nor nitroprusside interfered with the assay of B12. Hydroxocobalamin may be an appropriate adjunct during SNP therapy.

A Pharmacologic and Toxicological Study of Amygdalin

Six patients with advanced cancer were treated with amygdalin (laetrile) at dosages similar to those employed by laetrile practitioners. Amygdalin given intravenously at 4.5 g/sq m/day was largely excreted unchanged in the urine and produced no clinical or laboratory evidence of toxic reaction. Amygdalin given orally at 0.5 g three times daily produced significant blood cyanide levels to 2.1 microgram/mL. No clinical or laboratory evidence of toxic reaction was seen in the six patients taking oral amygdalin at this dosage. One patient, however, challenged with a large intake of raw almonds, had transient symptoms of cyanide toxic reaction with escalating blood cyanide levels. This small study indicates that amygdalin in the doses employed produces few clinical side effects. A definite hazard of cyanide toxic reaction must be assumed, however, and possible long-term side effects remain unknown.

Blood cyanide levels in mice after administration of amygdalin.

Oral doses of amygdalin and intraperitoneal (i.p.) doses of potassium cyanide (KCN) in the near-lethal range were administered to CD2F1 female mice. Blood cyanide levels were then measured as a function of time. The maximum cyanide level after amygdalin administration was reached at about 11/2 to 2 h and was within the range of values seen after KCN administration. Behaviour of mice correlated with the time of maximum blood cyanide level. Acute distress was observed at times when the cyanide level was highest. There was great variability in the nature and magnitude of the response in individual mice. The ability of the contents of various regions of the gastrointestinal tract and of tumour tissue to release cyanide from amygdalin was assessed. Stomach and upper intestine had little activity while the lower end and the faeces released large amounts. Again, there was a large variation between mice. These results are interpreted to mean that enteric contents are primarily responsible for the release of cyanide from ingested amygdalin. Freshly minced tumour tissue released negligible amounts of cyanide. Ten-fold higher doses of amygdalin administered i.p. produced very small increases in blood cyanide levels and no toxic behaviour. The doses used are comparable to doses which might be ingested by patients receiving oral amygdalin or Laetrile and indicate that oral amygdalin is potentially extremely dangerous.

On the acute toxicities of the combustion products of various fibers, with special reference to blood cyanide and Po2 values.

The blood cyanide and Po2 levels in different parts of the body were determined in the rabbit exposed to HCN. After urethane anesthesia, the rabbit was made to inhale HCN gas through a tracheal cannula. In addition to pure HCN gas produced by addition of NaCN to H2SO4, the combustion products from PAN (polyacrylonitrile), silk and wool were used respectively. After ultimate cessation of respiration, the chest was opened and the blood samples were taken from the three places, the left and right heart (ventricles) and the descending vena cava and cyanide and Po2 values were determined. The survival time was the shortest in PAN group among the combustion experiments. Silk group followed it. The decreasing order of the blood cyanide levels was silk, PAN, HCN and wool groups with respect to all sampling sites. There was not significant difference in cyanide levels among silk, PAN and HCN groups. The left heart showed the highest cyanide values of all the sampling places. Significant positive correlation was present between postmortem cyanide and Po2 values. Inhalation of relatively large amount of HCN and the concomitant inability of cardiac function to maintain the systemic circulation effectively at the last stage were considered to contribute largely to the unequal distribution of cyanide with the highest level in the left heart blood.

Cyanide toxicity following nitroprusside induced hypotension.

Several recently reported deaths following the use of sodium nitroprusside have been attributed to the accumulation of the nitroprusside metabolite, cyanide. In this study, brief nitroprusside infusions (mean = 36 minutes) were administered in currently recommended doses during intracranial surgery. The peak blood cyanide following the infusions was 65.2 +/- 17.5 microgram per cent (mean +/- SE) (n = 13). It occurred within 45 minutes after infusion. The highest cyanide level detected was 205 microgram per cent, which is within the range of reported lethal blood cyanide levels. Metabolic acidosis developed in the four patients with the highest blood cyanide levels (range 90-205 microgram per cent). This occurred between 45 and 180 minutes following the cyanide peak. Blood ATP levels were depressed in the same patients. These findings are indicative of disturbed aerobic metabolism. We conclude that there is evidence of cyanide toxicity when nitroprusside is infused into patients using currently recommended doses. We recommend that for short infusions the dose of sodium nitroprusside should not exceed 0.5 mg/kg.

Sodium nitroprusside: factors which attenuate its action. Studies with the isolated gracilis muscle of the dog.

In a laboratory preparation of the isolated, acutely denervated, and separately perfused canine gracilis muscle we have made the following observations: 1. At physiological pH, sodium nitroprusside significantly decreases the vascular resistance; 2. At physiological pH, cyanide significantly attenuates the effect of sodium nitroprusside; 3. In an acidaemic milieu, our data suggest that the effect of sodium nitroprusside may be attenuated. We speculate that patients who manifest resistance to the hypotensive effect of sodium nitroprusside may not normally eliminate the cyanide that is released from the biodegradation of sodium nitroprusside. They accumulate free cyanide which interferes with the action of sodium nitroprusside at the receptor level, leading to administration of more nitroprusside and setting in motion a positive feedback vicious cycle. When one is faced with the problem of an abnormal response to sodium nitroprusside in a fit patient, although many factors may be involved, we suggest that the possibility of rising blood cyanide levels and acidosis be given high priority.

Cyanide release from sodium nitroprusside in the dog.

Thirty-nine dogs (including eight from a previous study) were given during a one-hour infusion either low (less than 1.0 mg/kg) or high doses (greater than 1.0 mg/kg) of sodium nitroprusside in the presence or absence of circulating methemoglobin. In animals given low doses, the metabolic effects were relatively mild and consistent with those accounted for by a reduction in arterial pressure to 40 torr. In animals given high doses (with the same arterial pressure), metabolic alterations were significantly magnified and oxygen extraction was decreased. Animals pretreated with methemoglobin and given high doses of nitroprusside (again at the same arterial pressure) showed no toxic effect of nitroprusside. In separate studies, blood and tissue levels of cyanide were measured in dogs given high doses of nitroprusside (2.5-3.5 mg/kg) in the presence or absence of methemoglobin. In dogs given methemoglobin, 60 per cent of the administered cyanide (as nitroprusside) was recovered in the blood (as cyanmethemoglobin) after a one-hour infusion. Thereafter, blood cyanide levels declined over three hours to 25 per cent of peak levels, presumably by conversion to thiocyanate, since tissue levels of cyanide were negligible. In dogs not given methemoglobin, blood cyanide levels qualitatively followed a similar pattern but quantitatively were a fourth to a third those of pretreated dogs, and tissue levels of cyanide became elevated. It is concluded that in the dog nitroprusside, acutely administered, causes cyanide toxicity at doses exceeding 1.0-1.5 mg/kg, that the release of cyanide from nitroprusside in blood is rapid and in large quantities, that detoxification (presumably by conversion of cyanide to thiocyanate) is likewise fairly rapid but insufficient to prevent toxicity, and that protection is provided by methemoglobin.

Smoking in pregnancy--effects on birth weight and on cyanide and thiocyanate levels in mother and baby.

A total of 45 expectant mothers (20 smokers and 25 non-smokers) and their babies was studied and, after 14 smokers and 14 non-smokers had been closely matched for age, height, parity and social class, significant differences were observed between smokers and non-smokers in the birth weights of the babies and in cyanide and thiocyanate levels in maternal blood and urine.

Acute combined effects of HCN and CO, with the use of combustion products from PAN (polyacrylonitrile)--gauze mistures.

The combustion product from gauze-PAN (Polyacrylonitrile) micture was used as a material for the evaluation of the combined effects of CO and HCN. Rats and mice were exposed for 30 min. to the combustion products. In mice experiments, the time at which animals turned laterally and were killed, was measured. In experiments with rats, blood COHb and cyanide determinations were made, in addition to the observation of the behavior. Exposure room gas concentrations (O2, CO2, CO, HCN) were determined and temperature in the combustion room was measured during heating. Preliminary experiments with PAN, ranging from 2g to 10g, on mice showed that HCN is responsible for the toxicity of the combustion products from this fiber. In mixture experiments all animals died during exposure. In experiments with mice (8g of total weight of mixed sample), animals in groups with larger proportion of PAN turned over and died earlier and this was explained by higher HCN concentration. In rats experiments (10g), this held true for severe impairment, however, as to the death time, this was not the case. There was a long interval between severe impairment and death in groups with larger proportion of PAN. The larger amount of HCN was produced as temperature rises. A linear relation between COHb concentration and CT (concentration-time) product was shown. There was not a linear relation between blood COHb and cyanide levels. Judging from the blood analyses data, it seemed probable that there is neither an additive nor a synergistic action between CO and HCN with respect to lethal effects.

Sodium Nitroprusside

Sodium nitroprusside is a potent, effective, and readily reversible direct vasodilating agent. It is broken down by hemoglobin into cyanide, which is in part detoxified by liver and kidney to thiocyanate. Some cyanide, especially in nitroprusside- "resistant" individuals who need large amounts of the drug, appears to remain free to cause cyanide poisoning. Patients requiring inordinate amounts probably should not continue to receive the drug, although maximum dosage limits for long-term therapy are not established. Blood thiocyanate levels do not indicate the extent to which free cyanide is limiting oxygen utilization in essential tissue, nor do blood cyanide levels. Metabolic acidosis, elevated lactate levels, elevated lactate/pyruvate ratios, and elevated mixed venous blood oxygen content are at present the best indications of the presence of cyanide poisoning during nitroprusside administration. Nitroprusside appears useful for induction of hypotension during surgery, and for treatment of hypertensive emergencies from all causes, although continuance for more than a few days is probably unwise. The reductions of cardiac afterload and ventricular filling pressure by nitroprusside appear useful in treatment of severe myocardial failure or infarction, but studies of myocardial cyanide toxicity are needed before complete acceptance of this therapy is warranted. Initial dose rates between 0.5 and 1.5 mug/kg/min are recommended only as starting points for very careful titration. Total projected intra-operative dosage should be calculated as quickly as possible and should not exceed 3-3.5 mg/kg. It is hoped that future studies will reveal the maximum dose of nitroprusside that can safely be metabolized in a 24-hour period, and may indicate that cofactors of rhodanase such as thiosulfate, or cobalamins such as hydroxocobalamin, can be administered with nitroprusside to prevent cyanide poisoning.

Cyanide and thiocyanate levels in blood and urine of workers with low-grade exposure to cyanide.

The concentrations of free cyanide in the blood and in the urine, and the levels of “free” thiocyanate (oxidized to cyanide and distilled) as well as “total” thiocyanate (directly determined and quite unspecific) were determined in the urine of 140 volunteers.