A simple, rapid and sensitive semimicro method for the measurement of cyanide in blood.

Conventional methods do not meet the clinical need for rapid cyanide measurements. We report a procedure which can provide a result in 10 min. It should be of particular interest to laboratories serving cardiac or renal units which use the hypotensive agent sodium nitroprusside, and burns units to which fire victims may be admitted suffering the effects of HCN from inhaled smoke. A sample of blood (100 microL) is mixed with H3PO4, containing a surfactant, and the HCN is trapped in an alkaline mixture of 1,2-dinitrobenzene and 4-nitrobenzaldehyde in 2-methoxyethanol. The catalytic action of cyanide, which produces purple 2-nitrophenylhydroxylamine, is stopped with acetone after 6 min. The absorbance measured at 560 nm shows a linear relationship with the cyanide concentration, but the slope varies with the ambient temperature. Since KCN added to both 50 mmol/L NaOH and blood gives similar assay results, any inaccuracy arising from changes in temperature can be avoided by running standards at the same time as the blood sample.

Plasma catecholamine levels in porcine Escherichia coli septicaemia and following treatment with buprenorphine or naloxone.

Changes in plasma catecholamine levels in response to the induction of shock and following treatment with buprenorphine or naloxone were determined in a porcine model of Escherichia coli septicaemia. Thirty animals were anaesthetised with alpha-chloralose and infused with live E. coli over 2 hr. One hour after starting the infusion, cardiac index, mean arterial pressure, and pH had decreased significantly (P < 0.001), and there was a significant increase in mixed venous blood lactate concentrations (P < 0.001). This was associated with significant increases in plasma concentrations of adrenaline and noradrenaline (P < 0.001). There was a strong correlation between the extent of the increase in circulating catecholamines and the severity of shock (as reflected by haemodynamic changes and lactic acidosis) as well as significantly higher peak plasma catecholamine concentrations (P < 0.01) and dramatic terminal increases in circulating catecholamines in nonsurviving animals. Animals were randomly divided into three groups and received either naloxone or buprenorphine or an equivalent volume of normal saline and were monitored for a further 3 hr. Both naloxone and buprenorphine produced significant improvements in cardiac index (P < 0.05) and limited the development of acidosis (P < 0.05). This was not associated with any further increase in plasma catecholamine concentrations; indeed, catecholamine levels tended to decrease in treated animals but continued to increase in controls. In summary, we have shown a correlation between the increase in plasma catecholamines and the severity of shock in this model. In addition, we observed that the beneficial effects of treatment with buprenorphine or naloxone were not accompanied by any further increase in plasma catecholamine concentrations.

Effect of transdermal nicotine patches on cigarette smoking: a double blind crossover study.

The effect of transdermal nicotine patches on ad libitum cigarette smoking was examined in 30 subjects by measuring behavioural, biochemical and subjective aspects of smoking during a week of smoking without patches, and then a week each of nicotine and placebo patches in a randomised double blind crossover design. While wearing nicotine patches the subjects did not reduce the number of cigarettes smoked, but their expired carbon monoxide was reduced by 14%, they obtained less satisfaction from their cigarettes, and reported fewer and weaker urges to smoke. Down-regulation of nicotine intake from cigarettes was imprecise, such that when subjects wore nicotine patches their post-cigarette plasma nicotine concentration increased to an average of 45 ng/ml compared with 37 ng/ml in both no patch and placebo patch conditions. As the nicotine patches produced a plasma nicotine concentration of 15.9 ng/ml in abstinent subjects, this suggests a 22% reduction in nicotine intake from cigarettes while wearing nicotine patches. No serious symptoms of nicotine overdose were reported. It is suggested that the continuous absorption of nicotine from the patch may cause a build-up of acute tolerance to both toxic and pleasant subjective effects from smoking.

Lack of effect of ACTH in porcine Escherichia coli septic shock.

The cardiovascular and metabolic responses to treatment with ACTH(1-24) were investigated in a porcine model of septicaemia. Sixteen anaesthetised, instrumented animals were infused with live Escherichia coli over 2 hr. During the first hour of the infusion, significant reductions in cardiac index, mean arterial pressure, and pH were observed together with a significant increase in mixed venous blood lactate concentrations and packed cell volumes. ACTH(1-24) 160 micrograms kg-1, given 1 hr after starting the E. coli infusion (n = 8), had no significant effect on these haemodynamic or metabolic measurements when compared with the control group (n = 8). These results do not support the suggestion that intravenous ACTH(1-24) reverses cardiovascular depression in septicaemic shock.

Decay of nitroprusside. I: In vitro.

The apparent intravascular decomposition of nitroprusside (SNP) has been attributed to photolysis and artefactual generation of cyanide (HCN) during assay, leading some workers to believe that large doses of SNP may be infused safely if light is excluded. However, we have shown that HCN is not produced from SNP during analysis. Significant amounts of HCN were formed only when SNP was first incubated with blood. The yield of HCN was a function of the temperature, pH and time of incubation. The time for release of 50% of the HCN from SNP 5 mumol litre-1 at 37 degrees C in blood was 26.6 min with greater than 90% yield in 2 h, and in plasma the optimum pH was about 7.5. A u.v. method for measuring SNP suggests that, at clinically appropriate blood concentrations, SNP is confined to plasma.

Decay of nitroprusside. II: In vivo.

Clinical experience suggests that nitroprusside (SNP) concentrations decay more rapidly in vivo than in vitro. Plasma concentrations of SNP were measured therefore in 20 patients at the end of an infusion, with mean arterial pressure (MAP) and cyanide (HCN) concentrations. Plasma SNP concentrations (20-243 micrograms litre-1; mean = 123.5 micrograms litre-1), were related to infusion rate (r = 0.66, P less than 0.001), and declined rapidly to a mean (SD) of 7.7 (4.5) micrograms litre-1 in 15 min. The decay of SNP correlated closely with the increase in arterial pressure (mean MAP vs log mean plasma SNP concentrations: r = -0.993, P less than 0.001), and was probably biphasic: mean (SD) T1/2 alpha = 0.89 (0.62) min, T1/2 beta = 14.3 (12) min. Mean plasma HCN and mean plasma SNP concentrations decreased together (r = 0.955, P less than 0.001), thus confirming that in vivo decomposition of the drug is the source of HCN.

Beneficial effects of buprenorphine (a partial opiate agonist) in porcine Escherichia coli septicaemia: a comparison with naloxone.

The cardiovascular and metabolic responses to treatment with naloxone or buprenorphine (a partial opiate agonist) were investigated in a porcine model of septicaemia. Animals anaesthetised with alpha-chloralose were infused with live E. coli over two hours. They were then divided into three groups and received either naloxone (2 mg kg-1 + 1.5 mg kg-1 hr-1) or buprenorphine (0.3 mg kg-1) or an equivalent volume of normal saline. Treatment was started one hour after commencing the infusion, by which time a significant fall in cardiac index (CI), stroke index (SI), mean arterial pressure (MAP), and pH had occurred in all groups, together with a significant rise in mixed venous blood lactate and packed cell volume. Treatment with both naloxone and buprenorphine resulted in significant improvements in CI, pH, and base excess and in a fall in mixed venous lactate and packed cell volume. Although no significant effect on survival was seen at three hours after the start of treatment, buprenorphine may prove to be a suitable alternative to naloxone in the management of septic shock.

Cardiovascular actions of trimetaphan nitroprusside. Comparison with sodium nitroprusside in greyhounds.

Trimetaphan nitroprusside (TNP) is a new potent hypotensive agent developed to induce and maintain decreases in arterial pressure unaccompanied by resistance. This study investigated its properties and compared them with those of sodium nitroprusside (SNP) in anaesthetized greyhounds. The mean dose response to TNP was obtained by measuring haemodynamic changes in five dogs. With increasing doses, stepwise decreases in mean arterial pressure and progressive increases in heart rate occurred: cardiac index did not change significantly. In a further six greyhounds, SNP and TNP were alternately infused to induce and maintain a 30% reduction in arterial pressure for 30 min. Both drugs were short-acting, decreased systemic vascular resistance and caused tachycardia. Infusion of TNP produced lower plasma and red cell cyanide concentrations; SNP maintained hypotension with significantly less tachycardia. We conclude that there was no outstanding advantage of TNP over SNP when given as a short-term infusion in greyhounds.

Comparison of tests used to distinguish smokers from nonsmokers.

Questionnaire and biochemical measures of smoking were studied in 211 hospital outpatients. Eleven different tests of smoke intake were compared for their ability to categorize smokers and nonsmokers correctly. The concentration of cotinine, whether measured in plasma, saliva, or urine, was the best indicator of smoking, with sensitivity of 96-97 per cent and specificity of 99-100 per cent. Thiocyanate provided the poorest discrimination. Carbon monoxide measured as blood carboxyhaemoglobin or in expired air gave sensitivity and specificity of about 90 per cent. Sensitivities of the tests were little affected by the presence among the claimed nonsmokers of a group of 21 "deceivers" who concealed their smoking. It is concluded that cotinine is the measure of choice, but for most clinical applications carbon monoxide provides an acceptable degree of discrimination and is considerably cheaper and simpler to apply.

Sodium thiosulphate decreases blood cyanide concentrations after the infusion of sodium nitroprusside.

Plasma and red cell cyanide, and plasma thiocyanate, concentrations were measured in 30 patients undergoing elective nitroprusside-induced hypotension. One randomly selected group (n = 15), who received 0.21-0.70 mg kg-1 over periods of 50-160 min, were given a bolus of sodium thiosulphate 10.6-38.5 mg kg-1 immediately on cessation of the nitroprusside administration. The other group, who received infusions of 0.11-0.85 mg kg-1 for periods of 59-197 min, received no antidote. Cyanide concentrations, expressed as a percentage of the immediate post-infusion values, were significantly lower in the treated group in all subsequent blood samples (at 10, 30 and 60 min; plasma cyanide P less than 0.05; red cell cyanide P less than 0.001). Improved cyanide metabolism was further demonstrated by a sharp increase in mean plasma thiocyanate concentration (P less than 0.05) in the group receiving the antidote.

Acute poisoning with gold cyanide.

A case of deliberate ingestion of an electroplating solution containing gold cyanide is described. Despite the use of an antidote, and supportive treatment for cyanide poisoning, the patient died after 13 hours. Sublethal cyanide and high red blood cell gold levels suggest acute gold toxicity as the most likely cause of death. Evidence for this is discussed and recommendations are made for the treatment of cyanide poisoning.

The antidotal action of thiosulfate following acute nitroprusside infusion in dogs.

The authors previously demonstrated in dogs that a bolus dose of sodium thiosulfate maintained enhanced cyanide metabolism throughout a 1-h infusion of sodium nitroprusside (SNP). To further test this antidotal action, a bolus dose of thiosulfate (150 mg . kg-1) was given to eight dogs at the end of a 60-min near-lethal infusion of nitroprusside (3 mg . kg-1). Within 2 min of the antidote, mean plasma thiocyanate levels (70.3 mumol . l-1) were significantly higher than those of seven control dogs given nitroprusside only (45.9 mumol . l-1, P = 0.002) and plateaued at 153.8 mumol . l-1 within 60 min, while the control values only reached 79.1 mumol . l-1 (P less than 0.001). Although differences between plasma cyanide levels in the two groups only attained significance 1 h after administering the antidote (0.8 vs. 2.74 mumol . l-1, P = 0.03), red blood cell cyanide concentrations were significantly lower in the antidote group within 5 min (166 vs. 225 mumol . l-1, P = 0.004) and remained so throughout the 2-h observation period. Compared with the controls, there was an impressive reduction in mean half-lives of plasma cyanide (25.1 vs. 74.1 min) and red blood cell cyanide (22.4 vs. 203.6 min). Similarly, peak cyanide levels occurred much sooner following the antidote (mean times: plasma cyanide 2.9 vs. 5.9 min; red blood cell cyanide 0.25 vs. 11 min).(ABSTRACT TRUNCATED AT 250 WORDS)

Two automated methods for measuring plasma thiocyanate compared.

In an interlaboratory comparison of two continuous-flow analytical procedures for measuring thiocyanate, we used ferric nitrate (y) and p-phenylenediamine/pyridine (x) as colorimetric reagents to measure its concentrations in plasma of 100 consecutive patients attending a peripheral vascular disease clinic. The results correlated well (r = 0.987, p less than 0.001; y = 0.938x + 1.2 mumol/L). However, there were small, systematic, positive differences between the phenylenediamine values and the corresponding ferric nitrate values (paired t = 5.4, p less than 0.001). These differences were linearly related to the means of the pairs of results (r = 0.42, p less than 0.001; y = 0.0739x - 2). Nevertheless, when we used previously determined cutoff points the two sets of SCN concentrations concurred completely in classifying the 100 patients as smokers or nonsmokers. On the basis of self-classification by 71 of these subjects, the measurement techniques had a sensitivity of 91% and a specificity of 75%; when five patients claiming to be nonsmokers but found to have abnormally high values for carboxyhemoglobin (2.7 - 6.9%) were reclassified as smokers, specificity increased to 89%.

Blood cyanide and thiocyanate concentrations produced by long-term therapy with sodium nitroprusside.

Blood cyanide (HCN) or plasma thiocyanate (SCN) concentrations, or both, were measured in 30 patients (ages 11 months-72 yr) receiving sodium nitroprusside (SNP) for 12-314 h. Sequential measurements in three of these patients (infused 5, 12 and 13 days) showed that HCN concentrations varied with dose rate, while SCN concentrations increased linearly with increasing SNP dose. The accumulated data confirmed that the rate of administration (0.3-6.5 micrograms kg-1 min-1) determined the plasma HCN concentrations (0-3.8 mumol litre-1; y = 0.267 X -0.0733; r = 0.64; n = 51; P less than 0.001). Thus, if prolonged exposure to plasma HCN concentrations greater than 1 mumol litre-1 is to be avoided, the maximum safe sustained dose rate of SNP will lie near to 4 micrograms kg-1 min-1. Likewise, the SCN results (30--880 mumol litre-1) confirmed the close relationship between plasma concentrations and the total SNP dose (0.44-32.9 mg kg-1; y = 24.6x + 74.9; r = 0.95, n = 51, P less than 0.001). Therefore, we suggest that, to avoid SCN toxicity (plasma SCN greater than 1.75 mumol litre-1), in the absence of SCN monitoring, the total SNP dose should be less than 70 mg kg-1 in patients with normal renal function.