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1318 SECTION 15: Toxicology dimethyl mercury exposure. Most patients with symptomatic organic mercury poisoning are left with residual neurologic deficits. Environ mental decontamination and removal of the patient, family members, and coworkers from a site of ongoing contamination play a critical role in preventing injury to others. OTHER METALS AND METAL SALTS Other metals and their salts may cause toxicity (Table 203-7). Metal salts typically cause early GI irritation (nausea, vomiting, diarrhea, cramping, and hemorrhage) with subsequent neurologic, renal, hematologic, and cutaneous abnormalities. Symptoms are often vague, and without an explicit history of metal salt exposure, patients are usually misdiag nosed. 37 Metal fume fever is the clinical syndrome of fever, chills, body ache, headache, and fatigue resulting from inhalation of dust or fumes containing zinc, aluminum, or magnesium oxide. Treatment universally involves removal of the patient from the source, topical decontamination, administration of activated char coal (if exposure involves ingestion), and supportive care, including aggressive fluid and electrolyte repletion and hemodialysis, if required. Indications for chelation and its efficacy in treating metal toxicity vary with the specific metal ( Table 203-7). 18,19,36,38 Consult with a medical toxicologist or a regional poison control center for specific indications and drug doses. REFERENCES The complete reference list is available online at www.TintinalliEM.com.

ications for chelation and its efficacy in treating metal toxicity vary with the specific metal ( Table 203-7). 18,19,36,38 Consult with a medical toxicologist or a regional poison control center for specific indications and drug doses. REFERENCES The complete reference list is available online at www.TintinalliEM.com. TABLE 203-7 Source, Manifestations, and Treatments for Patients Poisoned by Less Common Metals Metal Poisoning Source Acute Clinical Manifestations Chronic Clinical Manifestations Specific Treatment Bismuth Antidiarrheals (bismuth subsalicylate), impregnated surgical packing paste Abdominal pain, acute renal failure Myoclonic encephalopathy Dimercaprol (limited evidence) Cadmium Contaminated soil in cadmium-rich areas; alloys used in welding, soldering, jewelry, and batteries Ingestion: hemorrhagic gastroenteritis Inhalation: pneumonitis, acute respiratory distress syndrome Proteinuria, osteomalacia (itai-itai or ouch-ouch disease), lung cancer (questionable) Ingestion: succimer (limited evidence; not generally indicated) Pneumonitis: chelation not indicated Chromium Corrosion inhibitors (e.g., heating systems), pigment production, leather tanning, metal finishing, dietary supplements, prosthetic joints Skin irritation and ulceration, contact dermatitis; GI irritation, renal and pulmonary failure Mucous membrane irritation, perforation of nasal septum, chronic cough, contact dermatitis, skin ulcers (“chrome holes”), lung cancer Acetylcysteine (animal studies suggest efficacy as chelator) Cobalt “Hard metal dust” (tungsten–cobalt mixture), flexible magnets, drying agents, prosthetic joints Contact dermatitis, asthma Metal lung disease (spectrum ranging from alveolitis to fibrosis), cardiomyopathy, thyroid hyperplasia Acetylcysteine (animal studies suggest efficacy as chelator) Copper Leaching from copper pipes and containers; fungicide (copper sulfate); welding (copper oxide) Ingestion: resembles iron poisoning; blue vomitus (copper salts), hepatotoxicity, hemolysis, methemoglobinemia Inhalation: metal fume fever (self-limited fever, chills, cough, dyspnea) Hepatotoxicity (childhood cirrhosis or idiopathic copper toxicosis) Dimercaprol for hepatic or hematologic toxicity Succimer in mild poisoning Silver Colloidal (metallic) silver used for medicinal purposes as oral solutions, aerosols, and douches; cauterizing and antiseptic agent (silver nitrate); jewelry, wire Mucosal irritation (silver oxide and nitrate) Argyria (permanent skin discoloration due to silver deposition and melanocyte stimulation) Selenium (possible role) Thallium Rodenticides (use prohibited in the United States); contaminated herbal products; medical radioisotope (minuscule dose); most poisonings related to homicide Early: nausea, vomiting, abdominal pain, tachycardia Intermediate (>24 h): painful ascending neuropathy, cardiac dysrhythmias, altered mental status Delayed (2 wk): alopecia Sensorimotor neuropathy, psychosis, dermatitis, hepatotoxicity Multidose activated charcoal Prussian blue, 125 milligrams/kg PO every 12 h (usually dissolved in 50 mL of 15% mannitol) Zinc Smelting, electroplating, military smoke bombs, zinc lozenges, welding/galvanizing (zinc oxide) Ingestion: nausea, vomiting, abdominal pain (resembles iron poisoning) Inhalation: mucosal irritation, metal fume fever (zinc oxide) Copper deficiency, sideroblastic anemia, neutropenia Edetate calcium disodium Supportive care for metal fume fever Industrial Toxins Chip Gresham Frank LoVecchio  INTRODUCTION A hazardous chemical is defined by the U.S. Occupational Safety and Health Administration as any chemical that has been scientifically shown to be a health hazard (causes acute or chronic health effects) or a physical hazard (e.g., combustible liquid, explosive, flammable).

s Chip Gresham Frank LoVecchio  INTRODUCTION A hazardous chemical is defined by the U.S. Occupational Safety and Health Administration as any chemical that has been scientifically shown to be a health hazard (causes acute or chronic health effects) or a physical hazard (e.g., combustible liquid, explosive, flammable). The Occupational Safety and Health Administration estimates that there are 575,000 chemicals in the workplace, with 53,000 being potentially haz ardous. 1 Considering that unplanned exposures and contamination can occur at any time during manufacturing, transport, storage, usage, or disposal of these chemicals, inevitably, emergency physicians can expect to occasionally be responsible for the management and care of a hazardous materials patient (see Chapter 5, “Disaster Preparedness”). When managing a patient exposed to an industrial chemical, it is helpful to refer to the Material Safety Data Sheet and adhere to the recom mendations regarding decontamination. Although the Material Safety Data Sheet will also include “first aid” recommendations (Table 204-1), the provider should also consult with a medical toxicologist or a regional poison control center to discuss case-specific hazards, optimal treatments, and dispositions. Although many exposures produce immediate effects, some agents may result in delayed onset of symptoms that require at least 24 hours of observation (Table 204-2). CHAPTER Tintinalli_Sec15_p1187-1332.indd 1318 8/2/19 8:40 PM

l poison control center to discuss case-specific hazards, optimal treatments, and dispositions. Although many exposures produce immediate effects, some agents may result in delayed onset of symptoms that require at least 24 hours of observation (Table 204-2). CHAPTER Tintinalli_Sec15_p1187-1332.indd 1318 8/2/19 8:40 PM CHAPTER 204: Industrial Toxins 1319 carbonaceous sputum, tachypnea, retractions, accessory muscle use, wheezing, or cyanosis. Copious airway secretions, hypoxia, broncho spasm, and pulmonary edema indicate lower airway injury, and with the potential for sudden deterioration in patients with upper airway injury, there should be a low threshold for endotracheal intubation. Pertinent laboratory studies include arterial blood gas analysis with carboxyhemoglobin, methemoglobin, and lactate levels; whole-blood cyanide levels if persistent acidosis occurs (although this will not change immediate management); ECG monitoring; and chest radiography. The role for diagnostic or therapeutic bronchoscopy in inhaled toxin expo sure is controversial. PHOSGENE Phosgene was first used as a chemical agent of warfare in World War I, where it was responsible for 80% of all chemical gas fatalities. Phosgene is no longer stockpiled by the U.S. military; however, it has widespread use in manufacturing and industry as a chemical precursor in the production of plastics, pharmaceuticals, dyes, polyurethane, and pes ticides. 7,8 The heating of chlorinated fluorocarbons (Freon ® ) will also form phosgene gas and has caused poisonings in the refrigerator/air conditioner manufacturing and repairing industry. Phosgene release and contamination can be insidious. The gas is relatively water insoluble and therefore has poor warning properties. Only mild initial eye, nose, throat, and upper airway irritation are expected, and these may be entirely absent. 7 Classically, when released, phosgene forms a white cloud with a characteristic odor of newly mown hay. The major injury is an acid burn to lower airways as phosgene reaches the alveoli and hydrolyzes to carbon dioxide and hydrochloric acid. Acylation of alveolar capillary membranes results in diffuse capillary leak and noncardiogenic pulmonary edema, which may be delayed for up to 24 hours. 10,11 Symptoms are typically dyspnea and chest tightness. If the exposure is massive, immediate dyspnea and mucous membrane and eye irritation TABLE 204-1 Agents Absorbed Through Intact Skin That May Result in Systemic Toxicity* Acrylamide Acrylonitrile, acetonitrile, propionitrile Aniline Chlordane Dinitrophenol Hydrocarbons: benzene, gasoline, toluene, xylene (all slowly absorbed) Hydrogen cyanide, cyanide salts Hydrogen fluoride (hydrofluoric acid) Metals (organic mercury, thallium) Methyl bromide Methylene chloride (slow) Nerve agents Nitrates Nitrobenzene Pesticides Phenol T2 toxin (biologic)

niline Chlordane Dinitrophenol Hydrocarbons: benzene, gasoline, toluene, xylene (all slowly absorbed) Hydrogen cyanide, cyanide salts Hydrogen fluoride (hydrofluoric acid) Metals (organic mercury, thallium) Methyl bromide Methylene chloride (slow) Nerve agents Nitrates Nitrobenzene Pesticides Phenol T2 toxin (biologic) *Many toxins may be absorbed through abraded skin. TABLE 204-2 Toxins With Delayed Onset of Symptoms or Requiring Prolonged Monitoring Agent Potential Delayed Toxicity Acrylonitrile, acetonitrile, propionitrile Cyanide toxicity Aniline Methemoglobinemia Arsine Hemolysis Ethylene oxide Pulmonary edema and neurotoxicity Methyl bromide Pulmonary edema Methylene chloride Carbon monoxide toxicity, dysrhythmias Phosphine Pulmonary edema Zinc phosphide Pulmonary edema TABLE 204-3 Toxic Industrial Exposures That Cause Respiratory Symptoms Agent Irritant Signs/Symptoms/ Findings Treatment Phosgene Mild/none I—Eye and upper airway irritation; possibly none D—Dyspnea, noncardiogenic pulmonary edema Supplemental oxygen only if hypoxemic (Sa o2 <92%) Respiratory supportive care Consider nebulized β-agonists Mandatory rest Ocular care Chlorine Yes I—Eye and upper airway irritation, nausea and vomiting (low-level exposure) D—Pulmonary edema (high-level exposure) Humidified oxygen Respiratory supportive care Consider nebulized β-agonists Consider nebulized sodium bicarbonate Ocular care Nitrogen dioxide Yes I—Dyspnea with tran sient improvement D—Worsening dyspnea due to pulmonary edema 24–72 h after exposure; methemoglobinemia Humidified oxygen Respiratory supportive care Consider early corticosteroid treatment Ammonia Yes I—Coughing, hoarseness, bronchospasm, eye and upper airway irritation Humidified oxygen Consider nebulized β-agonists Consider nebulized anticholinergics Respiratory supportive care Ocular care Abbreviations: D = delayed; I = immediate; Sa o2 = arterial oxygen saturation. Children are more sensitive to chemical exposures; higher minute volumes, smaller airway diameters, and lesser ability to clear secretions make them more susceptible to inhaled toxins, and thinner, more permeable skin with a larger body surface-to-mass ratio increases the potential for dermal absorption. 3-5 A pregnant woman should be treated as any other adult patient.6 This chapter discusses industrial toxins that produce primarily respiratory toxicity (Table 204-3) or metabolic toxicity. Toxic chemicals discussed elsewhere include nerve agents and vesicants (see Chapter 8, “Chemical Disasters”); hydrocarbons (see Chapter 199, “Hydrocarbons and Volatile Substances”); acids and alkalis (see Chapter 200, “Caustic Ingestions”); organophosphates and carbamates (see Chapter 201, “Pesticides”); metals (see Chapter 203, “Metals and Metalloids”); oxidants (see Chapter 207, “Dyshemoglobinemias”); and carbon monoxide (see Chapter 222, “Carbon Monoxide”).  RESPIRATORY TOXINS Determinants of airborne agent toxicity primarily include factors such as concentration of the inhaled toxin, duration of exposure, and whether the exposure occurred in an enclosed space (Table 204-3). Other influ ential factors include vapor density, allergic or nonallergic bronchospastic response, exertional state or metabolic rate of the victim, and unique host susceptibility such as underlying reactive airway disease, history of smoking, or extreme age. Aspiration of gastric contents may cause further pulmonary insult. General management of the patient with toxic inhalation injury begins with removal from the source and supplemental oxygen for hypoxemia. Irrigate the eyes and skin as appropriate.

underlying reactive airway disease, history of smoking, or extreme age. Aspiration of gastric contents may cause further pulmonary insult. General management of the patient with toxic inhalation injury begins with removal from the source and supplemental oxygen for hypoxemia. Irrigate the eyes and skin as appropriate. Toxin-specific treatments are discussed later in this chapter, although in general, inhaled bronchodilators and steroids for bronchospasm may be considered, especially if the patient has underlying reactive airway disease. Prophylactic antibiotics are not indicated. The physical examination should include inspection of the upper airway for evidence of singed nasal hair, soot in the oropharynx, facial or oropharyngeal burns, stridor, hoarseness, dysphagia, cough, Tintinalli_Sec15_p1187-1332.indd 1319 8/2/19 8:40 PM

eactive airway disease. Prophylactic antibiotics are not indicated. The physical examination should include inspection of the upper airway for evidence of singed nasal hair, soot in the oropharynx, facial or oropharyngeal burns, stridor, hoarseness, dysphagia, cough, Tintinalli_Sec15_p1187-1332.indd 1319 8/2/19 8:40 PM 1320 SECTION 15: Toxicology TABLE 204-4 Sources of Cyanide •   Burning of: wool, nylon, silk, acrylic, polyurethane, melamine, polyacrylonitrile, polyamide plastics •   Industries: fabrication of plastics, electroplating, mining, photography, precious metal reclamation, solvents, hair removal from hides •   Fumigants and fertilizers •   Vermin extermination: cyanide spread into burrows and dens •   Chemistry laboratories •   Medicinal: laetrile (amygdalin),* sodium nitroprusside •   Plants: seeds from Prunus species (apricots, cherries, plums, peaches), cassava, bamboo shoots •   Illicit phencyclidine manufacturing •   Cigarette smoke •   Vehicle exhaust *No longer available in the United States, but widely available via the Internet and sold outside the United States. may occur. The onset of dyspnea or pulmonary edema within 4 hours of exposure suggests a very poor prognosis.10 Recovery usually occurs with respiratory supportive care and management of acute lung injury (noncardiogenic pulmonary edema). 12 Do not provide supplemental oxygen until symptoms and signs of hypoxia develop or arterial oxygen saturation falls, and then administer at the lowest fraction of inspired oxygen to maintain arterial oxygen saturation above 94%. Pharmacologic therapy recommendations, based on case reports and animal models, include early corticosteroids and nebulized β-agonists, nebulized N-acetylcysteine, and NSAIDs. 12,14,15 Exertion increases pulmonary edema from phosgene, so rest is mandatory.11 If patients require intubation and mechanical ventilation for respiratory failure, a protective ventilation strategy with low tidal volume, low plateau pressures, and high positive end-expiratory pressure should be used. 16,17 Observe and monitor even asymptomatic patients for 24 hours after acute exposure. CHLORINE Chlorine is widely available in the industrial sector, in the setting of laboratories, paper manufacturing, swimming pool maintenance, and municipal water treatment. 18-21 Chlorine gas also has potential for use as an unconventional weapon.22 When dispersed, this dense green-yellow gas has an acrid, pungent odor and, unlike phosgene, has excellent warning properties. Chlorine gas has intermediate water solubility, which is consistent with the observation that moderately exposed World War I soldiers exhibited both central airway damage and pulmonary edema. Early inflammatory injury results from the formation of hydro chloric and hypochlorous acids and oxidants upon contact with moist membranes. 24 Immediate ocular and upper airway irritation along with nausea and vomiting are common following mild exposures.18,25,26 More significant exposure results in coughing, hoarseness, and pulmonary edema, usually within 6 hours, with some exposures leading to acute respiratory distress syndrome. 19,27 Severe exposures may produce pul monary infiltrates or edema visible on radiographs or CT scan. 28 Care is primarily supportive, with the use of humidified oxygen and bronchodilators as needed. 26 Prophylactic antibiotics are not recommended. Nebulized sodium bicarbonate as a neutralizing therapy may improve pulmonary function during the initial 4 hours of treatment, but the long-term benefits are unproven. 20,29,30 Uncontrolled studies of both parenteral and inhaled steroids show improvement in airway resistance and arterial oxygenation but no improvement in the out come with severe lung injury.

lizing therapy may improve pulmonary function during the initial 4 hours of treatment, but the long-term benefits are unproven. 20,29,30 Uncontrolled studies of both parenteral and inhaled steroids show improvement in airway resistance and arterial oxygenation but no improvement in the out come with severe lung injury. 31 Chlorine causes dermal injury at high concentration, and skin decontamination may be required. In patients with ocular symptoms, the cornea should be evaluated for a chemical burn. A moderately symptomatic patient should be observed for 24 hours, monitoring for delayed onset of respiratory complications. NITROGEN DIOXIDE Nitrogen dioxide and other nitrogen oxides are encountered in the form of silo gas (“silo filler disease”), as products of combustion, in industrial processes, or as components of military blast weapons, smokes, and obscurants. 32,33 These oxides have limited water solubility that results in primarily lower airway toxicity. 34 Initial exposure may produce only very mild initial discomfort, but slow conversion of nitrogen dioxide to nitric acid in the alveoli results in delayed alveolar injury and pulmonary edema. 32,35-37 Thus, a triphasic illness typically is seen with initial dyspnea and flulike symptoms, transient improvement, and then worsening dyspnea, which heralds the onset of pulmonary edema 12 hours after exposure.33,35,37-39 Treatment is supportive. Case reports describe benefit with early corticosteroid treatment for acute lung injury following nitrogen dioxide exposure, 39 although overall evidence is inconclusive.31 AMMONIA Ammonia is widely available; it is found in household and industrial chemicals and fertilizers and used in the synthesis of plastics and explosives. 40 Ammonia is a highly water-soluble, colorless, alkaline, corrosive gas with a characteristic pungent odor that rapidly reacts with wet surfaces to form ammonium hydroxide. Ammonia has good warning properties due to its odor and immediate symptoms of mucous membrane, eye, and throat irritation. Lower airway involve ment resulting in bronchospasm, pulmonary edema, residual reactive airway disease, and even permanent lung injury has been described following massive exposures, especially in those who were entrapped in enclosed spaces. Treatment is supportive with humidified oxygen and bronchodila tors. The use of anticholinergics to control airway secretions has been reported. 42 Concentrated ammonia, such as 8.4% ammonia hydroxide, is hazardous to the eyes, and symptomatic patients should undergo ocular irrigation followed by evaluation for corneal burns.  METABOLIC TOXINS CYANIDE Cyanide has an infamous history. It was the agent used by Nazi Germany (Zyklon B) in the gas chambers during the Holocaust, by Jim Jones in the mass cult suicide at the People’s Temple in Guyana (commonly called “Jonestown”), for murder in over-the-counter drug-tampering incidents, and at the World Trade Center bombing in 1993. 43,44 Cyanide can be generated through natural and industrial processes and house and structure fires ( Table 204-4).  PATHOPHYSIOLOGY Cyanide inhibits many metabolic processes, with its most toxic effect from binding with very high affinity to the ferric ion cytochrome a portion of cytochrome oxidase within the mitochondria, resulting in an abrupt cessation of electron transport and oxidative phosphorylation, thus inhibiting aerobic metabolism. 44 Thus, following an acute exposure, organs and tissues with high oxygen consumption are the first and most severely affected. Cassava, a tropical root that is the food staple in many countries, contains the cyanogenic glycosides linamarin and lotaustralin that liberate cyanide when metabolized in the body.

etabolism. 44 Thus, following an acute exposure, organs and tissues with high oxygen consumption are the first and most severely affected. Cassava, a tropical root that is the food staple in many countries, contains the cyanogenic glycosides linamarin and lotaustralin that liberate cyanide when metabolized in the body. 45 Chronic exposure to dietary cyanide is linked to tropical ataxic neuropathy and is endemic in countries where cassava consumption is high. 46,47 The primary mechanism for detoxification of cyanide is its metabo lism in the liver by rhodanese to thiocyanate, a nontoxic compound that is renally excreted. Toxicity occurs when this mechanism is rapidly overwhelmed.  CLINICAL FEATURES Clinical presentation of the cyanide-poisoned patient depends on the cyanide-containing compound, the route, concentration and duration of Tintinalli_Sec15_p1187-1332.indd 1320 8/2/19 8:40 PM

e, a nontoxic compound that is renally excreted. Toxicity occurs when this mechanism is rapidly overwhelmed.  CLINICAL FEATURES Clinical presentation of the cyanide-poisoned patient depends on the cyanide-containing compound, the route, concentration and duration of Tintinalli_Sec15_p1187-1332.indd 1320 8/2/19 8:40 PM CHAPTER 204: Industrial Toxins 1321 TABLE 204-5 Signs and Symptoms of Acute Cyanide Toxicity Cardiovascular Tachycardia Hypertension Bradycardia Hypotension Cardiovascular collapse Asystole Mild Severe CNS Headache Drowsiness Seizures Coma Mild Severe Pulmonary Dyspnea Tachypnea Apnea Mild Severe exposure, and the time since exposure. The onset of symptoms following inhalational exposure to hydrogen cyanide gas is immediate.48 Exposure to concentrations <50 parts per million causes restlessness, anxiety, palpitations, dyspnea, and headache. 49 Higher concentrations of hydrogen cyanide gas cause severe dyspnea, loss of consciousness, seizures, and cardiac dysrhythmias. Coma, cardiovascular collapse, and death may occur immediately on exposure to very high levels. The median lethal dose for humans from hydrogen cyanide gas is estimated to be 200 parts per million for a 30-minute exposure and 600 to 700 parts per million for a 5-minute exposure. 49 The onset of symptoms following ingestion of a cyanide salt typically occurs within minutes. The median lethal dose of potassium or sodium cyanide in an untreated adult is estimated at 140 to 250 milligrams, but death has been reported with ingestion of as little as 50 milligrams, and survival has been reported with much larger ingestions when antidotes are used. The typical seriously poisoned patient has an altered level of con sciousness and is hyperventilating, hypotensive, and bradycardic (Table 204-5). 43,50 Cutaneous manifestations vary, but, importantly, the patient is not initially cyanotic, as cyanide does not significantly alter the oxygen-carrying capacity of hemoglobin. However, cyanosis does follow if there is significant respiratory compromise or arrest. The smell of bitter almonds and a cherry-red skin color (attributed to an increased venous hemoglobin oxygen saturation) are often used in describing cyanide poisoning; however, these findings are unreliable and should not be used to exclude cyanide poisoning. Severe unexplained metabolic acidosis is a consistent clinical feature (Table 204-6).51 In victims of smoke inhalation, toxic cyanide levels correlate with plasma lactate levels >90 milligrams/dL (>10 mmol/L), independent of the carbon monoxide level.52 The decision to institute antidotal treatment of cyanide poisoning must be made long before confirmatory laboratory studies can be obtained. Although cyanide levels are not closely correlated with toxicity, they can be used to retrospectively confirm a clinical diagnosis or for forensic purposes. A variety of methods are available to measure cyanide in the environment and in biologic fluids, but whole-blood cyanide level is the most commonly available test. Symptoms of poisoning are delayed following the ingestion of compounds that require metabolic activation to release free cyanide, such as acetonitrile, a solvent sold commercially as a cosmetic nail remover, and amygdalin from apricot pits. 54 The slow release of cyanide by the spontaneous degradation of sodium nitroprusside, which is increased by exposure to sunlight, also results in delayed toxicity, particularly during prolonged or high-dose infusions.55  TREATMENT Good supportive care with 100% oxygen along with crystalloids and vasopressors for hypotension is paramount.

f cyanide by the spontaneous degradation of sodium nitroprusside, which is increased by exposure to sunlight, also results in delayed toxicity, particularly during prolonged or high-dose infusions.55  TREATMENT Good supportive care with 100% oxygen along with crystalloids and vasopressors for hypotension is paramount. 56 There are multiple TABLE 204-6 Anticipated Laboratory Findings in Cyanide Poisoning Test Result Cause Serum electrolytes Elevated anion gap Lactic acidosis from anaerobic metabolism Arterial blood gases Metabolic acidosis Normal Pa o2 Oxygenation initially normal Lactate >90 milligrams/dL (>10 mmol/L) Correlates with toxic cyanide level Measured oxygen saturation by co-oximetry Normal Hemoglobin retains normal oxygen-carrying capacity Measured arterial-mixed venous oxygen difference Decreased Decreased tissue oxygen consumption Whole-blood cyanide level Toxic >0.5 microgram/mL (>12 mmol/L) Fatal >2.5 micrograms/mL (>60 mmol/L) Note: plasma cyanide levels are roughly one tenth of the wholeblood cyanide levels Fire victims Elevated carboxyhemoglobin level Carbon monoxide generated by incomplete combustion Synergistic toxicity with cyanide Abbreviation: Pao2 = partial pressure of arterial oxygen. antidotes for cyanide poisoning with variation in regional availabil ity.50,57-59 The two antidotes most commonly used in the United States are hydroxocobalamin (Cyanokit® ) and the cyanide antidote kit (containing nitrites and thiosulfate). While their efficacy is similar, their mechanisms of action vary greatly and are described in further detail later in this chapter. Due to the production of methemoglobin by the nitrites in the cyanide antidote kit, hydroxocobalamin should be considered the first-line therapy in cyanide poisoning if exposure involves fire smoke or any other potential source of concomitant carbon monox ide poisoning. 60-64 The decision to administer a cyanide antidote is straightforward when faced with a critically ill patient with clear history of cyanide exposure. More difficult management decisions arise in patients with smoke inhalation who may have carbon monoxide exposure as well as suspected cyanide exposure and in patients who are critically ill and acidotic without any known history of cyanide exposure. Consultation with a toxi cologist or the regional poison control center is advised. However, there are some cases that should be treated empirically without delay. Patients who have been exposed to smoke and/or fire and present with a Glasgow Coma Scale score of <10 with signs of end-organ damage (i.e., cardiac arrest, seizures, respiratory distress) should be empirically treated with hydroxocobalamin or thiosulfate; a carboxyhemoglobin level >10% and/ or lactate level of >8 mmol/L strengthen this decision. 62,65 Hydroxocobalamin (vitamin B12a) is a metalloprotein with a cobalt center that binds cyanide, removing it from cytochrome oxidase and forming cyanocobalamin, which is then eliminated via the kidneys. The dose of hydroxocobalamin in an adult patient is 5 grams IV over 15 minutes (Table 204-7). A second dose of 5 grams IV may be repeated once (for a total of 10 grams) if the patient’s condition warrants. 66 The pediatric dose is 70 milligrams/kg (maximum dose of 5 grams) IV over 15 minutes and may be repeated once if the patient’s condition warrants. Hydroxocobalamin has a low toxicity profile; side effects include transient hypertension, a reddish discoloration of the skin and mucous membranes, TABLE 204-7 Treatment of Cyanide Poisoning With Hydroxocobalamin 100% oxygen IV crystalloids and vasopressors for hypotension +/– Sodium bicarbonate for acidemia And Hydroxocobalamin Adults: 5 grams IV over 15 min. If needed, may repeat 5 grams for a total of 10 grams.

sh discoloration of the skin and mucous membranes, TABLE 204-7 Treatment of Cyanide Poisoning With Hydroxocobalamin 100% oxygen IV crystalloids and vasopressors for hypotension +/– Sodium bicarbonate for acidemia And Hydroxocobalamin Adults: 5 grams IV over 15 min. If needed, may repeat 5 grams for a total of 10 grams. Children: 70 milligrams/kg (maximum, 5 grams) IV over 15 min. If needed, may repeat once. Tintinalli_Sec15_p1187-1332.indd 1321 8/2/19 8:40 PM 1322 SECTION 15: Toxicology TABLE 204-8 Treatment of Cyanide Poisoning With Cyanide Antidote Kit 100% oxygen IV crystalloids and vasopressors for hypotension +/– Sodium bicarbonate for acidemia And Adults

Children: 70 milligrams/kg (maximum, 5 grams) IV over 15 min. If needed, may repeat once. Tintinalli_Sec15_p1187-1332.indd 1321 8/2/19 8:40 PM 1322 SECTION 15: Toxicology TABLE 204-8 Treatment of Cyanide Poisoning With Cyanide Antidote Kit 100% oxygen IV crystalloids and vasopressors for hypotension +/– Sodium bicarbonate for acidemia And Adults Amyl nitrite inhaler; crack vial and inhale over 30 s. * Sodium nitrite 3% solution: 10 mL (300 milligrams) IV given over no less than 5 min. † Sodium thiosulfate 25% solution: 50 mL (12.5 grams) IV. Repeat sodium thiosulfate once at half dose (25 mL) if symptoms persist. Children Amyl nitrite inhaler; crack vial and hold in front of nose for 15–30 s. *† Sodium nitrite 3% solution: adjusted according to hemoglobin level, given IV over no less than 5 min † (monitor methemoglobin level <30%). Hemoglobin (grams/100 mL) Sodium Nitrite 3% Solution (mL/kg) 7 0.19 8 0.22 9 0.25 10 0.27 11 0.30 12 0.33 13 0.36 14 0.39 Sodium thiosulfate 25% solution: 1.65 mL/kg IV. Repeat sodium thiosulfate once at half dose (0.825 mL/kg) if symptoms persist. *Not necessary if IV is in place. †Avoid nitrites in the presence of severe hypotension if diagnosis is unclear or there is potential concomitant carbon monoxide poisoning; use sodium thiosulfate only. and rare anaphylactic reactions. Due to the discoloration of body fluids caused by hydroxocobalamin, interference with chemistry and co-oximetry tests as well as hemodialysis machines has been reported; therefore, blood samples should be collected prior to administration. 68-71 The cyanide antidote kit has been well established for cyanide poi soning, although its use is declining and it has been removed from the commercial market in some countries. 72-74 The antidotes contained in the cyanide treatment kit include ampules of amyl nitrite for inhalation, 10-mL vials of 3% sodium nitrite (300 milligrams), and 50-mL vials of 25% sodium thiosulfate (12.5 grams) ( Table 204-8). Treatment of profound acidemia with sodium bicarbonate appears to enhance the effect of the nitrites and thiosulfate. The rationale for using nitrites is based on their ability to form met hemoglobin, which binds cyanide more avidly than the ferric iron of cytochrome oxidase, thus removing cyanide from the cytochrome and enabling the mitochondria to reactivate electron transport and oxidative metabolism. 76 Inhaled amyl nitrite is a temporizing measure when IV access has not been established, but amyl nitrite is not needed when sodium nitrite can be given IV. Nitrites do have significant side effects, including hypotension and the development of excessive methemoglo binemia, which will further decrease oxygen delivery with concomitant carbon monoxide poisoning. 57,75,77 However, hypotension is not a contraindication to nitrite therapy in severe cyanide poisoning. In children, the sodium nitrite dose is adjusted according to the hemoglobin level to keep the methemoglobin level less than 30% (Table 204-8). 49,77 If hemoglobin values are not available, the empiric dose of sodium nitrite for a child less than 25 kg is based on the 10-gram hemoglobin concentration. Sodium thiosulfate, given after the administration of sodium nitrite, enhances the activity of the enzyme rhodanese, which catalyzes the transfer of sulfate from sodium thiosulfate to cyanide to form thiocya nate, a less toxic form that is excreted by the kidneys. 57,72,75 Animal studies using lethal doses of cyanide demonstrate that the therapeutic effects of sodium nitrite and sodium thiosulfate are synergistic.

e enzyme rhodanese, which catalyzes the transfer of sulfate from sodium thiosulfate to cyanide to form thiocya nate, a less toxic form that is excreted by the kidneys. 57,72,75 Animal studies using lethal doses of cyanide demonstrate that the therapeutic effects of sodium nitrite and sodium thiosulfate are synergistic. 72,73,75 However, sodium thiosulfate has very limited toxicity in comparison with nitrites and should be used as a sole therapy for victims of cyanide poisoning from inhalation injury if there is a concern for concomitant carbon monoxide exposure if hydroxocobalamin is unavailable. 78,79 The fetus is sensitive to the adverse effects of methemoglobinemia, so nitrate therapy should be avoided. Animal models have shown that sodium thiosulfate does not cross the placenta and appears to protect the fetus from nitroprusside in cyanide toxicity 80; if available, it should be considered first in early pregnancy. 62 There are limited data on the safety of hydroxocobalamin in pregnancy, but its benefits outweigh the risk in significant cyanide poisoning and should be administered if it is the only antidote available. Two other antidotes are available, which are primarily used in Europe. Dimethylaminophenol is a rapid methemoglobin inducer developed in Germany for the treatment of cyanide poisoning. 57-59,75 Clinical efficacy is similar to sodium nitrite. The adult dose is 250 milligrams (5 mL of 5% solution) IV over 1 minute, used in combination with sodium thiosulfate. Dicobalt edetate is a cobalt compound with a high affinity for cyanide. Although highly effective as a cyanide antidote, the toxicity of dicobalt edetate is greater when cyanide is not present, limiting its use to cases where the presence of cyanide is unequivocal. 43,44,57-59,75 The adult dose for dicobalt edetate is 300 milligrams IV over approximately 1 minute. If there is inadequate clinical response after 5 minutes, a sec ond dose of 300 milligrams IV may be given. The data on hyperbaric oxygen for treatment of cyanide poisoning are conflicting, because studied patients also received multiple therapies, so improvement cannot be contributed solely to hyperbaric oxygen. 81-83 The lack of supportive evidence and impracticality make hyperbaric oxygen therapy an unproven endeavor in acute cyanide toxicity.  DISPOSITION AND FOLLOW-UP Patients who receive cyanide antidotal therapy should be admitted for observation. Patients who have ingested a substance that may result in delayed toxicity (up to 6 hours) should also be admitted. Full recovery is anticipated in many cases of severe poisoning in which treatment is initiated rapidly and cardiac arrest has not yet occurred. Recovery despite cardiac arrest also has been reported, but anoxic encephalopathy may ensue. HYDROGEN SULFIDE Hydrogen sulfide is a colorless, flammable gas that may be encountered in industries such as oil and gas or as a natural product of organic decomposition, such as sewer or manure gas. 84,85 Hydrogen sulfide can be made by mixing common household products, a method well documented in suicides. 86 Regardless of its source, it is among the most common causes of fatal gas inhalation exposures. Fatal exposures usually occur in enclosed spaces that may claim additional victims as would-be rescuers are poisoned upon entering. 87 Large industrial or natural releases of hydrogen sulfide may produce fatalities in unconfined spaces.88  PATHOPHYSIOLOGY The mechanism of toxicity is similar to that of cyanide, with disruption of oxidative phosphorylation through inhibition of cytochrome oxidase 3, except this impairment reverses rapidly when hydrogen sulfide exposure ceases. 89 Cellular asphyxia and impaired adenosine triphosphate production promote anaerobic metabolism with lactate accumulation and metabolic acidosis.

nide, with disruption of oxidative phosphorylation through inhibition of cytochrome oxidase 3, except this impairment reverses rapidly when hydrogen sulfide exposure ceases. 89 Cellular asphyxia and impaired adenosine triphosphate production promote anaerobic metabolism with lactate accumulation and metabolic acidosis.  CLINICAL FEATURES Hydrogen sulfide is one of the few chemical asphyxiants that also possesses irritative properties, such that respiratory and ocular irritation are common following exposure. 85,90 However the characteristic odor of “rotten eggs” may not be noticed due to olfactory fatigue from persistent low-level exposures or from acute olfactory paralysis seen at high hydrogen sulfide levels. In high concentrations, rapid loss of consciousness, seizures, and death Tintinalli_Sec15_p1187-1332.indd 1322 8/2/19 8:40 PM