Modest and variable efficacy of pre-exposure hydroxocobalamin and dicobalt edetate in a porcine model of acute cyanide salt poisoning.

Background: Dicobalt edetate and hydroxocobalamin are widely used to treat hydrogen cyanide poisoning. However, comparative and quantitative efficacy data are lacking. Although post-exposure treatment is typical, it may be possible to administer these antidotes before exposure to first attenders entering a known site of cyanide release, as supplementary protection to their personal protective equipment.Methods: We established an anaesthetised Gottingen minipig model of lethal bolus potassium cyanide (KCN) injection to simulate high dose hydrogen cyanide inhalation. Doses were similar to human lethal doses of KCN. Dicobalt edetate and hydroxocobalamin were administered shortly before KCN and their effect on metabolic and cardiovascular variables and survival time were measured.Results: Increases in arterial lactate were similar after 0.08 and 0.12 mmol/kg KCN. KCN 0.08 mmol/kg was survived by 4/4 animals with moderate cardiovascular effects, while the 0.12 mmol/kg dose was lethal in 4/4 animals, with a mean time to euthanasia of 28.3 (SEM: 13.9) min. Administration of dicobalt edetate (0.021 mmol/kg, 8.6 mg/kg) or hydroxocobalamin (0.054 mmol/kg, 75 mg/kg) at clinically licenced doses had modest effect on lactate concentrations but increased survival after administration of KCN 0.12 mmol/kg (survival: dicobalt edetate 4/4, hydroxocobalamin 2/4) but not 0.15 mmol/kg (0/4 and 0/4, respectively). In a subsequent larger study, doubling the dose of hydroxocobalamin (0.108 mmol/kg, 150 mg/kg) was associated with a modest but inconsistent increased survival after 0.15 mmol/kg KCN (survival: control 0/8, 75 mg/kg 1/10, 150 mg/kg 3/10) likely due to variable pharmacokinetics.Conclusions: In this porcine study of cyanide exposure, with pre-exposure antidote administration, licenced doses of dicobalt edetate and hydroxocobalamin were effective at just lethal doses but ineffective at less than twice the estimated LD50. The efficacy of a rapidly-administered double-dose of hydroxocobalamin was limited by variable pharmacokinetics. In clinical poisoning scenarios, with delayed administration, the antidotes are likely to be even less effective. New antidotes are required for treatment of cyanide exposures appreciably above the minimum lethal dose.

The Vitamin B12 Analog Cobinamide Is an Effective Antidote for Oral Cyanide Poisoning.

INTRODUCTION: Cyanide is a major chemical threat, and cyanide ingestion carries a higher risk for a supra-lethal dose exposure compared to inhalation but provides an opportunity for effective treatment due to a longer treatment window and a gastrointestinal cyanide reservoir that could be neutralized prior to systemic absorption. We hypothesized that orally administered cobinamide may function as a high-binding affinity scavenger and that gastric alkalinization would reduce cyanide absorption and concurrently increase cobinamide binding, further enhancing antidote effectiveness. METHODS: Thirty New Zealand white rabbits were divided into five groups and were given a lethal dose of oral cyanide poisoning (50 mg). The survival time of animals was monitored with oral cyanide alone, oral cyanide with gastric alkalinization with oral sodium bicarbonate buffer (500 mg), and in combination with either aquohydroxocobinamide or dinitrocobinamide (250 mM). Red blood cell cyanide concentration, plasma cobinamide, and thiocyanate concentrations were measured from blood samples. RESULTS: In cyanide ingested animals, oral sodium bicarbonate alone significantly prolonged survival time to 20.3 ± 8.6 min compared to 10.5 ± 4.3 min in saline-treated controls, but did not lead to overall survival. Aquohydroxocobinamide and dinitrocobinamide increased survival time to 64 ± 41 (p < 0.05) and 75 ± 16.4 min (p < 0.001), respectively. Compared to aquohydroxocobinamide, dinitrocobinamide showed greater systemic absorption and reduced blood pressure. Dinitrocobinamide also markedly increased the red blood cell cyanide concentration. Under all conditions, the plasma thiocyanate concentration gradually increased with time. CONCLUSION: This study demonstrates a promising new approach to treat high-dose cyanide ingestion, with gastric alkalinization alone and in combination with oral cobinamide for treating a supra-lethal dose of orally administered cyanide in rabbits.

Cyanide toxicity in juvenile pigs and its reversal by a new prodrug, sulfanegen sodium.

BACKGROUND: Cyanide (CN) toxicity is a serious clinical problem and can occur with sodium nitroprusside (SNP) administration, accidental smoke inhalation, industrial mishaps, and bio-terrorism. In this study, we induced severe CN toxicity independently with SNP or sodium cyanide (NaCN) in a juvenile pig model to demonstrate reversal of severe CN toxicity with a new antidote, sulfanegen sodium, a prodrug of 3-mercaptopyruvate. METHODS: SNP study: A pilot study in 11 anesthetized, mechanically ventilated juvenile pigs allowed us to determine the dose of SNP to induce CN toxicity. Blood CN, serum lactates, and blood gases were monitored. CN toxicity was defined as the occurrence of severe lactic acidosis accompanied by significant elevation in blood CN levels. Based on this pilot study, 8 anesthetized pigs received a high-dose i.v. infusion of SNP (100 mg/h) for 2 hours to induce CN toxicity. They were then randomized to receive either sulfanegen sodium or placebo. Four pigs received 3 doses of sulfanegen sodium (2.5 g i.v.) every hour after induction of severe CN toxicity, and 4 pigs received placebo. NaCN study: A pilot study was conducted in 4 spontaneously ventilating pigs sedated with propofol plus ketamine to demonstrate hemodynamic and metabolic stability for several hours. After this, 6 pigs were similarly sedated and given NaCN in bolus aliquots to produce CN toxicity ultimately resulting in death. Hemodynamics and metabolic variables were followed to define peak CN toxicity. In another group of 6 pigs, severe CN toxicity was induced by this method, and at peak toxicity, the animals were given sulfanegen sodium (2.5 g i.v.) followed by a repeat dose 60 minutes later in surviving animals. RESULTS: SNP study: The pilot study demonstrated the occurrence of a significant increase in blood CN levels (P < 0.05) accompanied by severe lactic acidemia (P < 0.05) in all pigs receiving a high dose of SNP. Administration of the sulfanegen antidote resulted in progressive significant reduction in blood lactate and CN levels with 100% survival (P < 0.05), whereas the placebo-treated pigs deteriorated and did not survive (P < 0.05). NaCN study: NaCN injection resulted in CN toxicity accompanied by severe lactic acidosis and mortality in all the pigs. Sulfanegen sodium reversed this toxicity and prevented mortality in all the pigs treated with this antidote. CONCLUSIONS: CN toxicity can be successfully induced in a juvenile pig model with SNP or NaCN. The prodrug, sulfanegen sodium, is effective in reversing CN toxicity induced by SNP or NaCN.

Hydroxocobalamin and epinephrine both improve survival in a swine model of cyanide-induced cardiac arrest.

STUDY OBJECTIVE: To determine whether hydroxocobalamin will improve survival compared with epinephrine and saline solution controls in a model of cyanide-induced cardiac arrest. METHODS: Forty-five swine (38 to 42 kg) were tracheally intubated, anesthetized, and central venous and arterial continuous cardiovascular monitoring catheters were inserted. Potassium cyanide was infused until cardiac arrest developed, defined as mean arterial pressure less than 30 mm Hg. Animals were treated with standardized mechanical chest compressions and were randomly assigned to receive one of 3 intravenous bolus therapies: hydroxocobalamin, epinephrine, or saline solution (control). All animals were monitored for 60 minutes after cardiac arrest. Additional epinephrine infusions were used in all arms of the study after return of spontaneous circulation for systolic blood pressure less than 90 mm Hg. A sample size of 15 animals per group was determined according to a power of 80%, a survival difference of 0.5, and an α of 0.05. Repeated-measure ANOVA was used to determine statistically significant changes between groups over time. RESULTS: Baseline weight, time to arrest, and cyanide dose at cardiac arrest were similar in the 3 groups. Coronary perfusion pressures with chest compressions were greater than 15 mm Hg in both treatment groups indicating sufficient compression depth. Zero of 15 (95% confidence interval [CI] 0% to 25%) animals in the control group, 11 of 15 (73%; 95% CI 48% to 90%) in the hydroxocobalamin group, and 11 of 15 (73%; 95% CI 48% to 90%) in the epinephrine group survived to the conclusion of the study (P<.001). The proportion of animals with return of spontaneous circulation at 5 minutes was 4 of 15 (27%; 95% CI 10% to 52%), and that of return of spontaneous circulation at 10 minutes was 11 of 15 (73%; 95% CI 48% to 90%) in the 2 treatment groups. Additional epinephrine infusion after return of spontaneous circulation was administered for hypotension in 2 of 11 (18%; 95% CI 4% to 48%) hydroxocobalamin animals and in 11 of 11 (100%; 95% CI 70% to 100%) of the epinephrine animals (P<.001). At 60 minutes, serum lactate was significantly lower in the hydroxocobalamin group compared with the epinephrine group (4.9 [SD 2.2] versus 12.3 [SD 2.2] mmol/L), and the pH was significantly higher (7.34 [SD 0.03] versus 7.15 [SD 0.07]). Serial blood cyanide levels in the hydroxocobalamin group were also lower than that of the epinephrine group from cardiac arrest through the conclusion of the study. CONCLUSION: Intravenous hydroxocobalamin and epinephrine both independently improved survival compared with saline solution control in our swine model of cyanide-induced cardiac arrest. Hydroxocobalamin improved mean arterial pressure and pH, decreased blood lactate and cyanide levels, and decreased the use of rescue epinephrine therapy compared with that in the epinephrine group.

Some histologic and biochemical evidence for mitigation of cyanide-induced tissue lesions by antioxidant vitamin administration in rabbits.

The effect of antioxidant vitamins on cyanide-induced tissue damage was investigated in New Zealand White rabbits using a combination of colorimetric, spectrophotometric, enzymatic, gravimetric and histological methods. Three groups of rabbits (six per group) were used in a 4-week feeding experiment. One group received pure grower's mash, while a second group was fed mash containing 400 ppm inorganic cyanide. The third group received daily oral doses of vitamins A, C and E, in addition to mash and 400 ppm cyanide. There were significant decreases (P < 0.05) in activities of superoxide dismutase (SOD), catalase and alkaline phosphatase (AP) in the liver, lung and kidney of the two groups given cyanide, but the decreases were significantly lower (P < 0.05) in the group fed antioxidant vitamins. In addition, the antioxidant vitamin supplementation led to marked reductions in the severity of histopathological degeneration in these tissues. These results strongly suggest that cyanide-induced tissue lesions may be relieved by adequate intake of antioxidant vitamin supplements.

Toxicity evaluation of two treatment regimens for cyanide poisoning.

Toxicological evaluation of two recently reported treatment protocols for cyanide--SN (sodium nitrite) + DMAP (4-dimethylaminophenol) and SN + HA (hydroxylamine)--was carried out in male rats. Both treatments produced transient hyperammonaemia and decreased mean arterial pressure. Heart rate decreased and respiratory rate increased, but these changes reached the level of significance only after SN + HA. Histopathological lesions in lung, liver (SN+HA) and kidney (SN+DMAP) were predominantly in the vicinity of blood vessels. The results indicate toxic effects in both treatment groups at a dose known to induce methaemoglobin concentration to the level of antidotal efficiency in cyanide intoxication.

Biochemical changes induced by two new prophylactic regimens for cyanide antagonism.

Clinical efficacy of two pretreatment regimens, sodium nitrite (SN) + hydroxylamine (HA) and SN + 4-dimethylaminophenol (DMAP) were evaluated in rats by studying various biochemical variables at different time intervals. Animals given single subcutaneous (s.c.) co-administration of SN+HA or SN+DMAP showed significantly elevated levels of blood bilirubin indicating hemolytic anemia. Increased levels of blood creatine phosphokinase (CPK), lactate dehydrogenase (LDH) and glutamic oxaloacetic transaminase (GOT) were indicative of aseptic necrosis at the injection site. On account of low methemoglobin reductase activity in human erythrocytes, a reduced sub-clinical dose of HA or DMAP is envisaged in humans.

[Influence of supplementary tyrosine or phenylalanine on bacterial growth and pigmentation of "Pseudomonas aeruginosa" (author's transl)]. / Addition de tyrosine ou de phénylalanine aux cultures de Pseudomonas aeruginosa: influence sur la croissance microbienne et la pigmentation.

Pseudomonas aeruginosa grows readily on synthetic media containing succinate (36 mM) and ammonium chloride as sole source of nitrogen (34 mM) ; addition of tyrosine or phenylalanine (2,7 mM) is followed by an increase of both the growth rate and pyocyanine production. Several molecules structurally related to tyrosine give similar results. Tyrosine partially suppresses the inhibitory effect of both cyanide and azide. The results are discussed with regard to the biosynthesis of aromatic aminoacids and of phenazine pigments.