Cyanide Poisoning Compromises Gene Pathways Modulating Cardiac Injury in Vivo.

Smoke inhalation from a structure fire is a common route of cyanide poisoning in the U.S. Cyanide inhibits cellular respiration, often leading to death. Its rapid distribution throughout the body can result in injuries to multiple organs, and cyanide victims were reported to experience myocardial infarction and other cardiac complications. However, molecular mechanisms of such complications are yet to be elucidated. While FDA-approved CN antidotes such as sodium thiosulfate and hydroxocobalamin are clinically used, they have foreseeable limitations during mass casualty situations because they require intravenous administration. To facilitate the development of better antidotes and therapeutic treatments, a global view of molecular changes induced by cyanide exposure is necessary. As an exploratory pursuit, we performed oligonucleotide microarrays to establish cardiac transcriptomes of an animal model of nose-only inhalation exposure to hydrogen cyanide (HCN), which is relevant to smoke inhalation. We also profiled cardiac transcriptomes after subcutaneous injection of potassium cyanide (KCN). Although the KCN injection model has often been used to evaluate medical countermeasures, this study demonstrated that cardiac transcriptomes are largely different from that of the HCN inhalation model at multiple time points within 24 h after exposure. Pathway analysis identified that HCN-induced transcriptomes were enriched with genes encoding mediators of pathways critical in modulation of cardiac complications and that a large number of such genes were significantly decreased in expression. We utilized the upstream regulatory analysis to propose drugs that can be potentially employed to treat cyanide-induced cardiac complications.

An inhalational swine model for the characterization of physiological effects and toxicological profile associated with cyanide poisoning.

Cyanides are highly toxic compounds that have been used as weapons of terrorism throughout history. Cyanide (CN) is acutely toxic by all routes of administration; however, inhalation is the main exposure route. To adequately test effective countermeasures against inhalational CN threats, robust and well-characterized animal models are needed. This paper describes the initial development of a hydrogen cyanide (HCN) exposure swine model for documenting the physiological effects and toxicological profile during and after HCN inhalation exposure. Animals were implanted with telemetry transmitters for heart rate (HR), blood pressure, and electrocardiogram monitoring, and vascular access ports for serial blood collections. Nine female swine were exposed to HCN concentrations of 500 ± 6 ppm while breathing parameters were monitored real-time. Inhaled HCN doses ranged from 2.02 to 2.83 mg/kg. Clinical signs included vocalization, agitation, salivation, respiratory distress and apnea. After HCN exposure initiation, systemic arterial pressure fell dramatically with a concomitant increase in HR. Blood samples were collected to determine CN blood levels using LC-MS/MS and blood gas analysis. In summary, the developed HCN inhalation swine model permitted documentation of the physiological effects associated with CN poisoning. This model could be used to evaluate potential CN medical countermeasures in the event of a public health emergency stemming from inhalational CN threats.

Physiologically based pharmacokinetic modeling of hydrogen cyanide levels in human breath.

Hydrogen cyanide (HCN) is a potent and fast-acting toxin increasingly recognized as an important cause of death in fire victims. Prompt diagnosis and treatment of cyanide poisoning are essential to avoid fatalities. Unfortunately, there are at present few rapid diagnostic methods. A noninvasive methodology would be to use HCN in exhaled air as a marker for systemic exposure. To explore this possibility, we developed a preliminary physiologically based pharmacokinetic model. The model suggests that breath HCN levels following inhalation exposure at near-lethal and lethal conditions are 0.1-1 ppm, i.e., one to two orders of magnitude higher than the background breath level of about 0.01 ppm in unexposed subjects. Hence, our results imply that breath analysis may be used as a rapid diagnostic method for cyanide poisoning.

Mass-casualty Response to the Kiss Nightclub in Santa Maria, Brazil.

On January 27, 2013, a fire at the Kiss Nightclub in Santa Maria, Brazil led to a mass-casualty incident affecting hundreds of college students. A total of 234 people died on scene, 145 were hospitalized, and another 623 people received treatment throughout the first week following the incident.1 Eight of the hospitalized people later died.1 The Military Police were the first on scene, followed by the state fire department, and then the municipal Mobile Prehospital Assistance (SAMU) ambulances. The number of victims was not communicated clearly to the various units arriving on scene, leading to insufficient rescue personnel and equipment. Incident command was established on scene, but the rescuers and police were still unable to control the chaos of multiple bystanders attempting to assist in the rescue efforts. The Municipal Sports Center (CDM) was designated as the location for dead bodies, where victim identification and communication with families occurred, as well as forensic evaluation, which determined the primary cause of death to be asphyxia. A command center was established at the Hospital de Caridade Astrogildo de Azevedo (HCAA) in Santa Maria to direct where patients should be admitted, recruit staff, and procure additional supplies, as needed. The victims suffered primarily from smoke inhalation and many required endotracheal intubation and mechanical ventilation. There was a shortage of ventilators; therefore, some had to be borrowed from local hospitals, neighboring cities, and distant areas in the state. A total of 54 patients1 were transferred to hospitals in the capital city of Porto Alegre (Brazil). The main issues with the response to the fire were scene control and communication. Areas for improvement were identified, namely the establishment of a disaster-response plan, as well as regularly scheduled training in disaster preparedness/response. These activities are the first steps to improving mass-casualty responses.

Swedish forensic data 1992-2009 suggest hydrogen cyanide as an important cause of death in fire victims.

Between 60 and 80% of all deaths related to fire are attributed to toxic fumes. Carbon monoxide (CO) is commonly thought to be the major cause. However, hydrogen cyanide (HCN) is also formed. Still, the exact contribution of HCN to fire-related fatalities is unknown. The aim of the study was to investigate the impact of HCN in relation to CO as a cause of death in fire victims. Data on carboxyhemoglobin (COHb) and blood cyanide from deceased fire victims in the period 1992-2009 were collected from two Swedish nationwide forensic databases (ToxBase and RättsBase). The databases contain data on COHb and/or cyanide from 2303 fire victims, whereof 816 on both COHb and cyanide. Nonparametric statistical tests were used. Seventeen percent of the victims had lethal or life-threatening blood cyanide levels (>1 µg/g) and 32% had lethal COHb levels (>50% COHb). Over 31% had cyanide levels above 0.5 µg/g, an indication of significant HCN exposure. The percentages may be underestimates, as cyanide is quickly eliminated in blood also after death. Our results support the notion that HCN contributes more to the cause of death among fire victims than previously thought.

Drying and processing protocols affect the quantification of cyanogenic glucosides in forage sorghum.

BACKGROUND: Cyanogenic glucosides are common bioactive products that break down to release toxic hydrogen cyanide (HCN) when combined with specific ß-glucosidases. In forage sorghum, high concentrations of the cyanogenic glucoside dhurrin lead to reduced productivity and sometimes death of grazing animals, especially in times of drought, when the dhurrin content of stunted crops is often higher. The aim of this study was to develop harvesting protocols suitable for sampling in remote areas. RESULTS: Dhurrin concentration in air- and oven-dried leaves was the same as in fresh leaves, with no subsequent losses during storage. Dhurrin concentration was halved when leaves were freeze-dried, although activity of the endogenous dhurrinase was preserved. Direct measurement of dhurrin concentration in methanolic extracts using liquid chromatography/mass spectrometry (LC/MS) gave similar results to methods that captured evolved cyanide. A single freezing event was as effective as fine grinding in facilitating complete conversion of dhurrin to cyanide. CONCLUSION: Direct measurement of dhurrin using LC/MS is accurate but expensive and not appropriate for fieldwork. Air drying provides an accurate, low-cost method for preparing tissue for dhurrin analysis, so long as the specific ß-glucosidase is added. It is recommended that comparative studies like the one presented here be extended to other cyanogenic species.

Hydroxocobalamin treatment of acute cyanide poisoning from apricot kernels.

Clinical experience with hydroxocobalamin in acute cyanide poisoning via ingestion remains limited. This case concerns a 35-year-old mentally ill woman who consumed more than 20 apricot kernels. Published literature suggests each kernel would have contained cyanide concentrations ranging from 0.122 to 4.09 mg/g (average 2.92 mg/g). On arrival, the woman appeared asymptomatic with a raised pulse rate and slight metabolic acidosis. Forty minutes after admission (approximately 70 min postingestion), the patient experienced headache, nausea and dyspnoea, and was hypotensive, hypoxic and tachypnoeic. Following treatment with amyl nitrite and sodium thiosulphate, her methaemoglobin level was 10%. This prompted the administration of oxygen, which evoked a slight improvement in her vital signs. Hydroxocobalamin was then administered. After 24 h, she was completely asymptomatic with normalised blood pressure and other haemodynamic parameters. This case reinforces the safety and effectiveness of hydroxocobalamin in acute cyanide poisoning by ingestion.

Empiric management of cyanide toxicity associated with smoke inhalation.

Enclosed-space smoke inhalation is the fifth most common cause of all unintentional injury deaths in the United States. Increasingly, cyanide has been recognized as a significant toxicant in many cases of smoke inhalation. However, it cannot be emergently verified. Failure to recognize the possibility of cyanide toxicity may result in inadequate treatment. Findings suggestive cyanide toxicity include: (1) a history of an enclosed-space fire scene in which smoke inhalation was likely; (2) the presence of oropharyngeal soot or carbonaceous expectorations; (3) any alteration of the level of consciousness, and particularly, otherwise inexplicable hypotension (systolic blood pressure ≤90 mmHg in adults). Prehospital studies have demonstrated the feasibility and safety of empiric treatment with hydroxocobalamin for patients with suspected smoke inhalation cyanide toxicity. Although United States Food and Drug Administration (FDA)-approved since 2006, the lack of efficacy data has stymied the routine use of this potentially lifesaving antidote. Based on a literature review and on-site observation of the Paris Fire Brigade, emergency management protocols to guide empiric and early hydroxocobalamin administration in smoke inhalation victims with high-risk presentations are proposed.

Carbon monoxide poisoning in a 55-year-old man after a suicide attempt.

A flight team was activated for a scene call in rural Vermont for a patient with apparent carbon monoxide (CO) poisoning. Per ground emergency medical services (EMS) personnel, this 55-year-old man with a history of coronary artery disease (CAD) was found unresponsive in his parked vehicle in his garage. "Dryer hose" tubing ran from the tailpipe into the rear window of his sedan. EMS providers also stated that a variety of unidentified pills were found on the floormat. There were no pill bottles in the vehicle or in the home to identify the medications. Whether the pills had been consumed was unclear. Ground EMS removed the patient from the vehicle and immediately placed the patient on high-flow oxygen. The duration of the exposure was unknown.

[Assessment of exposure to hydrogen cyanide in fire fatalities in the aspects of endogenous hydrogen cyanide production as a result of putrefaction processes in the deceased]. / Ocena ekspozycji na cyjanowodór u smiertelnych ofiar pozarów w aspekcie powstawania w zwlokach endogennego cyjanowodoru w procesach gnilno-rozkladowych.

On account of endogenous hydrogen cyanide (HCN) production in the deceased, it is not easy to assess exposure to HCN in people who died in fire involving closed rooms (flats, garages, cellars, etc). In the paper, the authors present the results of blood determinations of hydrogen cyanide in fatalities of explosions and fires occurring in coal-mines, as well as fires in closed rooms. It has been demonstrated that the time of exposure to a high temperature and the temperature itself hamper autolysis processes that lead to production of endogenous HCN in fire fatalities.

Genotoxicity surveillance programme in workers dismantling World War I chemical ammunition.

PURPOSE: To evaluate the effectiveness of personal protective measures in a dismantling plant for chemical weapons from World War I of the Belgian Defence. METHODS: Seventeen NIOSH level B-equipped plant workers exposed to arsenic trichloride (AsCl(3)) in combination with phosgene or hydrogen cyanide (HCN) were compared to 24 NIOSH level C-protected field workers occasionally exposed to genotoxic chemicals (including AsCl(3)-phosgene/HCN) when collecting chemical ammunition, and 19 matched referents. Chromosomal aberrations (CA), micronuclei (MNCB and MNMC), sister chromatid exchanges (SCE) and high frequency cells (HFC) were analysed in peripheral blood lymphocytes. Urinary arsenic levels and genetic polymorphisms in major DNA repair enzymes (hOGG1(326), XRCC1(399), XRCC3(241)) were also assessed. RESULTS: SCE and HFC levels were significantly higher in plant-exposed versus referent subjects, but MNCB and MNMC were not different. MNCB, SCE and HFC levels were significantly higher and MNMC levels significantly lower in field-exposed workers versus referents. AsCl(3) exposure was not correlated with genotoxicity biomarkers. CONCLUSIONS: Protective measures for plant-exposed workers appear adequate, but protection for field-exposed individuals could be improved.

[Acute encephalopathy caused by cyanogenic fungi in 2004, and magic mushroom regulation in Japan].

Two topics, related to mushroom poisoning of recent interest in Japan, have been presented. In autumn 2004, 59 cases of acute encephalopathy were reported across 9 prefectures in Japan (24 from Akita Prefecture with 8 deaths; age 48-93, average 70; female 14, male 10). Of 24 cases, 20 had kidney dysfunction. Four poisoned subjects showed no kidney trouble. Of the 24 poisoning cases, 23 people ate Pleurocybella porrigens, and one ate Grifola frondosa. The latter subject (female, late 40's) was receiving dialysis for more than 35 years. In August, she felt dizziness, headache and tinnitus. She visited hospital and asked to stay there. In the hospital she ate 5g of stewed G. frondosa and 10g of the same fungus boiled with chicken and taro on different days. Fourteen to 18 days after the eatings, she developed cramps and lost consciousness, and fell into a coma. Her cramp and coma continued for about 10 days almost until her death. Her symptoms caused by G. frondosa were similar to those observed for the above 23 cases of P. porrigens ingestion. Therefore, we concluded that encephalopathy experienced in Akita Prefecture caused by was the cyanogenic fungi such as P. porrigens , G. frondosa, Pleurotus eringii etc. Although the amounts of mushrooms eaten by poisoned subjects were not so clear, we estimated that the amounts of hydrogen cyanide (HCN) taken into human bodies exceeded the detoxication limit of HCN, resulting in HCN poisoning. However, it has not been proved that the encephalopathy is directly or indirectly caused by the HCN poisoning. Many typhoons came across Japan and landed 10 times in 2004, and mushroom size was larger than usual one, and HCN contents in fruit-bodies seemed to be increased especially in the late-stage of their growth. Thirteen species of magic mushrooms were prohibited by the law from 2002 in Japan. They include Copelandia (Panaeolus) cyanescens, Panaeolus papilionaceus, Panaeolus sphinctrinus, Panaeolus subbalteatus, Psilocybe argentipes, Psilocybe cubensis, Psilocybe fasciata, Psilocybe lonchophorus, Psilocybe subaeruginascens, Psilocybe subcaerulipes, Psilocybe subcubensis, Psilocybe tampanensis, and Psilocybe venenata.

Phenylacetonitrile in locusts facilitates an antipredator defense by acting as an olfactory aposematic signal and cyanide precursor.

Many aggregating animals use aposematic signals to advertise their toxicity to predators. However, the coordination between aposematic signals and toxins is poorly understood. Here, we reveal that phenylacetonitrile (PAN) acts as an olfactory aposematic signal and precursor of hypertoxic hydrogen cyanide (HCN) to protect gregarious locusts from predation. We found that PAN biosynthesis from phenylalanine is catalyzed by CYP305M2, a novel gene encoding a cytochrome P450 enzyme in gregarious locusts. The RNA interference (RNAi) knockdown of CYP305M2 increases the vulnerability of gregarious locusts to bird predation. By contrast, the elevation of PAN levels through supplementation with synthetic PAN increases the resistance of solitary locusts to predation. When locusts are attacked by birds, PAN is converted to HCN, which causes food poisoning in birds. Our results indicate that locusts develop a defense mechanism wherein an aposematic compound is converted to hypertoxic cyanide in resistance to predation by natural enemies.

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.

[The effect of high temperature on the levels of selected endogenous compounds]. / Wplyw wysokiej temperatury na poziom wybranych zwiazków endogennych.

The authors present their research on the levels of carboxyhemoglobin, hydrogen cyanide and ethyl alcohol in the blood of 23 fatalities found in the extreme conditions (methane explosion, fire, high temperature) associated with a mining disaster. Determinations of the presence of carboxyhemoglobin, hydrogen cyanide, and ethyl alcohol were performed as soon as the blood samples were collected from the deceased. The concentration of ethyl alcohol ranged from 0.2 per thousand to 1.3 per thousand in 18 cases. Blood HbCO levels tested within the range of 11% to 83% in 17 cases. In six cases, HbCO tested negative, and the injuries found at autopsy indicated these individuals to have been killed at the moment of the explosion. Blood cyanide content tested negative in all the examined cases. The extreme conditions of the mining disaster, especially high temperature, to which the bodies were exposed, did not have any effect either on endogenous cyanide or carboxyhemoglobin, causing, however, a significant increase in the level of ethyl alcohol in the blood.

Potential interference by hydroxocobalamin on cooximetry hemoglobin measurements during cyanide and smoke inhalation treatments.

STUDY OBJECTIVE: Concentrated aqueous solutions of hydroxocobalamin (OHCob) are administered intravenously for cyanide poisoning victims, many of whom also have concurrent smoke inhalation. Because of its intense light absorbance in visible wavelengths (absorption peak at 532 nm), we investigate potential interference effects of OHCob on total hemoglobin concentration (tHb), carboxyhemoglobin (COHb), methemoglobin (MetHb), and oxyhemoglobin (Hb-O2) cooximetry measurement values in blood. METHODS: In vivo cooximetry measurements were conducted with 3 specific pathogen-free white New Zealand rabbits (3.80+/-0.21 kg) during the intravenous infusion of OHCob (625 mg during a 100-minute period). Resultant changes in tHb, Hb-O2, COHb, and MetHb values were measured and correlated with respect to estimated in vivo OHCob concentrations. In vitro measurements were conducted with rabbit blood to confirm in vivo measurements. RESULTS: The introduction of OHCob clearly interfered with the cooximetry measurements of each of the hemoglobin component fractions in whole blood and resulted in altered measurement values from the baseline values. The presence of OHCob in blood interferes with cooximetry measurements of COHb, MetHb, and Hb-O2. The increase in measured COHb fraction with increasing concentrations of OHCob was most notable. CONCLUSION: The presence of OHCob in blood interferes with cooximetry measurements of COHb, MetHb, and Hb-O2. These effects need to be considered during OHCob treatment of cyanide poisoning, particularly in smoke inhalation victims with potential for concurrent carbon monoxide exposure, because it may lead to potentially erroneous reported COHb levels.

Prospective study of hydroxocobalamin for acute cyanide poisoning in smoke inhalation.

STUDY OBJECTIVE: To assess outcomes in patients treated with hydroxocobalamin at the fire scene or in the ICU for suspected smoke inhalation-associated cyanide poisoning. METHODS: Adult smoke inhalation victims with suspected cyanide poisoning as determined by soot in the face, mouth, or nose or expectorations and neurologic impairment received an intravenous infusion of hydroxocobalamin 5 g (maximum 15 g) at the fire scene or in the ICU in this observational case series conducted from 1987 to 1994. Blood cyanide specimens were collected before administration of hydroxocobalamin. The threshold for cyanide toxicity was predefined as greater than or equal to 39 micromol/L. RESULTS: The sample included 69 patients (mean age 49.6 years; 33 men), of whom 39 were comatose. Out-of-hospital deaths were excluded. Fifty of the 69 patients (72%) admitted to the ICU survived after administration of hydroxocobalamin. In the group in which cyanide poisoning was confirmed a posteriori (n=42), 67% (28/42) survived after administration of hydroxocobalamin. The most common adverse events were chromaturia (n=6), pink or red skin discoloration (n=4), hypertension (n=3), erythema (n=2), and increased blood pressure (n=2). No serious adverse events were attributed to hydroxocobalamin. Laboratory tests revealed transient alterations in renal and hepatic function consistent with the critical condition of the patients and mild anemia consistent with progressive hemodilution. CONCLUSION: Empiric administration of hydroxocobalamin was associated with survival among 67% of patients confirmed a posteriori to have had cyanide poisoning. Hydroxocobalamin was well tolerated irrespective of the presence of cyanide poisoning. Hydroxocobalamin appears to be safe for the out-of-hospital treatment of presumptive cyanide poisoning from smoke inhalation.