126: Cyanide and Hydrogen Sulfide

Christopher P. Holstege; Mark A. Kirk

CYANIDE POISONING

History and Epidemiology

Cyanide exposure is associated with smoke inhalation, laboratory mishaps, industrial incidents,

suicide attempts, and criminal activity.39,113Cyanide is a chemical group that consists of one atom

of carbon bound to one atom of nitrogen by three molecular bonds (C≡N). Inorganic cyanides

(also known as cyanide salts) contain cyanide in the anion form (CN–) and are used in numerous

industries, such as metallurgy, photographic developing, plastic manufacturing, fumigation, and

mining. Common cyanide salts include sodium cyanide (NaCN) and potassium cyanide (KCN).

Sodium salts react readily with water to form hydrogen cyanide. Organic compounds that have a

cyano group bonded to an alkyl residue are called nitriles. For example, methyl cyanide is also

known as acetonitrile (CH3CN). Hydrogen cyanide (HCN) is a colorless gas at standard

temperature and pressure with a reported bitter odor. Cyanogen gas, a dimer of cyanide, reacts

with water and breaks down into the cyanide anion. Cyanogen chloride (CNCl) is a colorless gas

that is easily condensed; it is a listed agent by the Chemical Weapons Convention.

Many plants, such as the Manihot spp, Linum spp, Lotus spp, Prunusspp, Sorghum spp,

and Phaseolus spp contain cyanogenic glycosides.111 The Prunus species consisting of apricots,

bitter almond, cherry, and peaches have pitted fruits containing the glucoside amygdalin. When

ingested, amygdalin is biotransformed by intestinal β-d-glucosidase to glucose, aldehyde, and

cyanide (Fig. 126–1). Laetrile, which contains amygdalin, was inappropriately suggested to have

antineoplastic properties despite a lack of evidence to support such claims.83 When laetrile was

administered by intravenous infusion, amygdalin bypassed the necessary enzymes in the

gastrointestinal tract to liberate cyanide and did not cause toxicity. However, ingested laetrile

can cause cyanide poisoning. Despite data demonstrating its lack of utility in the treatment of

cancer, it still is available via the Internet.

FIGURE 126–1.

Biotransformation of cyanogens (A) acetonitrile and (B) amygdalin to cyanide.

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Cassava (Manihot esculenta) root is a major source of food for millions of people in the tropics.

It is a hardy plant that can remain in the ground for up to 2 years and needs relatively little

water to survive. Because the shelf life of a cassava root is short once it is removed from the

stem, cassava root must be processed and sent to market as soon as it is harvested. However,

proper processing must occur to assure the food’s safety. Processed cassava is

called Gari. Linamarin (2-hydroxyixo-buty-nitrite-β-D-glycoside) is the major cyanogenic glycoside

in cassava roots. It is hydrolyzed to hydrogen cyanide and acetone in two steps during the

processing of cassava roots.124 Soaking peeled cassava in water for a single day releases

approximately 45% of the cyanogens, whereas soaking for 5 days causes 90% loss. If processing

is inefficient, linamarin and cyanohydrin, the immediate product of hydrolysis of linamarin,

remain in the food.92 Consumed linamarin is hydrolyzed to cyanohydrin by β-glucosidases of the

microorganisms in the intestines. Cyanohydrin present in the food and formed from linamarin

then dissociates spontaneously to cyanide in the alkaline pH of the small intestines.

Iatrogenic cyanide poisoning may occur during use of nitroprusside for the management of

hypertension. Each nitroprusside molecule contains five cyanide molecules, which are slowly

released in vivo. If endogenous sulfate stores are depleted, as in the malnourished or

postoperative patient, cyanide may accumulate even with therapeutic nitroprusside infusion rates

(2–10 μg/kg/min).

In 1782, the Swedish chemist Carl Wilhelm Scheele first isolated hydrogen cyanide. He reportedly

died from the adverse health effects of cyanide poisoning in 1786. Napoleon III was the first to

employ hydrogen cyanide in chemical warfare, and it was subsequently used on World War I

battlefields. During World War II, hydrocyanic acid pellets (brand name Zyklon B) caused more

than one million deaths in Nazi gas chambers at Auschwitz, Buchenwald, and Majdanek. In 1978,

KCN was used in a mass suicide led by Jim Jones of the People’s Temple in Guyana, resulting in

913 deaths. Other notorious suicide cases include Wallace Carothers, Herman Goring, Heinrich

Himmler, and Ramon Sampedro. In 1982, seven deaths resulted from consumption of cyanide-

tainted acetaminophen in Chicago that subsequently lead to the requirement of tamper-resistant

pharmaceutical packaging. Numerous copycat murders subsequently have occurred using

cyanide-tainted capsules, with the last high-profile case occurring in 2010 involving an Ohio

emergency medicine physician who murdered his wife with a cyanide-laden calcium

capsule.14 Cyanide has also been used for illicit euthanasia.20

Cyanide poisoning accounted for 1148 exposures reported to the American Association of

Poison Control Centers from 2007 to 2011 (Chap. 136).24 One study of poison center data found

that 8.3% of intentional overdose cases died and another 9% developed cardiac arrest but

survived; 74% did not receive an antidote, most likely due to the failure of the initial treatment

team to recognize the poisoning.13 The majority of reported cyanide exposures are unintentional.

These events frequently involve chemists or technicians working in laboratories where cyanide

salts are common reagents.19 The potential for cyanide poisoning also exists following smoke

inhalation, especially following the combustion of materials such as wool, silk, synthetic rubber,

and polyurethane.8,30,108 Ingestion of cyanogenic chemicals (ie, acetonitrile, acrylonitrile, and

proprionitrile) is another source of cyanide poisoning.115 Acetonitrile (C2H3N) and acrylonitrile

(C3H3N) are themselves nontoxic, but biotransformation via cytochrome P450 liberates cyanide

(Fig. 126–1).126

Pharmacology

The dose of cyanide required to produce toxicity is dependent on the form of cyanide, the

duration of exposure, and the route of exposure. However, cyanide is an extremely potent toxin

with even small exposures leading to life-threatening symptoms. For example, an adult oral

lethal dose of KCN is approximately 200 mg. An airborne concentration of 270 ppm (μg/mL) of

hydrogen cyanide (HCN) may be immediately fatal, and exposures >110 ppm for more than 30

minutes are generally considered lifethreatening. The current Occupational Safety and Health

Administration (OSHA) permissible exposure limit (PEL) for both hydrogen cyanide and cyanogen

is 10 ppm as an 8-hour time-weighted average (TWA) concentration. The Immediately

Dangerous to Life or Health (IDLH) value for hydrogen cyanide is 50 ppm.

Acute toxicity occurs through a variety of routes, including inhalation, ingestion, dermal, and

parenteral. Hydrogen cyanide readily crosses membranes because it has a low molecular weight

(27 Da) and is nonionized. After absorption and dissolution in blood, cyanide exists in

equilibrium as the cyanide anion (CN–) and undissociated HCN. Hydrogen cyanide is a weak acid

with a pKa of 9.21. Therefore, at physiologic pH 7.4 it exists primarily as HCN. Rapid diffusion

across alveolar membranes followed by direct distribution to target organs accounts for the

rapid lethality associated with HCN inhalation.

Toxicokinetics

Cyanide is eliminated from the body by multiple pathways. The major route for detoxification of

cyanide is the enzymatic conversion to thiocyanate. Two sulfurtransferase enzymes, rhodanese

(thiosulfate-cyanide sulfurtransferase) and β-mercaptopyruvate-cyanide sulfurtransferase, catalyze

this reaction. The primary pathway for metabolism is rhodanese, which is widely distributed

throughout the body and has the highest concentration in the liver. This enzyme catalyzes the

transfer of a sulfane sulfur from a sulfur donor, such as thiosulfate to cyanide to form

thiocyanate. In acute poisoning, the limiting factor in cyanide detoxification by rhodanese is the

availability of adequate quantities of sulfur donors. The endogenous stores of sulfur are rapidly

depleted, and cyanide metabolism slows. Hence, the efficacy of sodium thiosulfate as an

antidote stems from its normalization of the metabolic inactivation of cyanide. The sulfation of

cyanide is essentially irreversible, and the sulfation product thiocyanate has relatively little

inherent toxicity. Thiocyanate is eliminated in urine. A number of minor pathways of metabolism

(<15% of total) account for cyanide elimination, including conversion to 2-aminothiazoline-4-

carboxylic acid, incorporation into the 1-carbon metabolic pool, or in combination with

hydroxycobalamin to form cyanocobalamin.

Limited human data regarding the cyanide elimination half-life are available. Elimination appears

to follow first-order kinetics,73 although it varies widely in reports (range 1.2–66

hours).8,51,73 Disparity in values may result from the number of samples used to perform

calculations and the effects of antidotal treatment. The volume of distribution of the cyanide

anion varies according to species and investigator, with 0.075 L/kg reported in humans.34

Pathophysiology

Cyanide is an inhibitor of multiple enzymes, including succinic acid dehydrogenase, superoxide

dismutase, carbonic anhydrase, and cytochrome oxidase.80,87 Cytochrome oxidase is an iron

containing metalloenzyme essential for oxidative phosphorylation and, hence, aerobic energy

production. It functions in the electron transport chain within mitochondria, converting catabolic

products of glucose into adenosine triphosphate (ATP). Cyanide induces cellular hypoxia by

inhibiting cytochrome oxidase at the cytochrome a3 portion of the electron transport chain (Fig.

126–2).95,128 Hydrogen ions that normally would have combined with oxygen at the terminal end

of the chain are no longer incorporated. Thus, despite sufficient oxygen supply, oxygen cannot

be utilized, and ATP molecules are no longer formed.78Unincorporated hydrogen ions

accumulate, contributing to acidemia.

FIGURE 126–2.

Pathway of cyanide and hydrogen sulfide toxicity and detoxification.

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Hyperlactemia occurs following cyanide poisoning because of failure of aerobic energy

metabolism. During aerobic conditions, when the electron transport chain is functional, lactate is

converted to pyruvate by mitochondrial lactate dehydrogenase. In this process, lactate donates

hydrogen moieties that reduce nicotinamide adenine dinucleotide (NAD+) to NADH. Pyruvate

then enters the tricarboxylic acid cycle, with resulting ATP formation. When cytochrome a3 within

the electron transport chain is inhibited by cyanide, there is a relative paucity of NAD+and

predominance of NADH, favoring the reverse reaction, in which pyruvate is converted to lactate.

Cyanide is also a potent neurotoxin. Cyanide exhibits a particular affinity for regions of the brain

with high metabolic activity. Central nervous system (CNS) injury occurs via several mechanisms,

including impaired oxygen utilization, oxidant stress, and enhanced release of excitatory

neurotransmitters. Cranial imaging of survivors of cyanide poisoning reveals that injury occurs in

the most oxygen-sensitive areas of the brains, such as the basal ganglia, cerebellum, and

sensorimotor cortex.

Cyanide enhances N-methyl-d-aspartate (NMDA) receptor activity and directly activates the

NMDA receptor, which increases release of glutamate and inhibits voltage-dependent

magnesium blockade of the NMDA receptor. This NMDA receptor stimulation results in

Ca2+ entry into the cytosol of neurons. Cyanide also activates voltage-sensitive calcium

channels64 and mobilizes Ca2+ from intracellular stores.81,98 As a result, cytosolic Ca2+ rises and

activates a series of biochemical reactions that lead to the generation of reactive oxygen species

and nitrous oxide.70,84,106 These reactive oxygen species initiate peroxidation of cellular lipids,

which, together with cyanide-induced inhibition of the respiratory chain, adversely affect

mitochondrial function, initiating cytochrome c release and execution of apoptosis, necrosis, and

subsequent neurodegeneration.6,64,97,107 Experimental studies demonstrate that NMDA inhibitors

such as dextrorphan and dizocilpine, antioxidants, and cyclooxygenase inhibitors all protect

neurons against cyanide-induced damage.61,77,125

Sulfurtransferase metabolism via rhodanese is crucial for detoxification. However, the

aforementioned cyanide-induced metabolic derangement may decrease enzyme detoxification.

Decreased ATP and reactive oxygen species and increased cytosolic Ca2+ stimulate protein kinase

C activity, which in turn inactivates rhodanese.3

Clinical Manifestations

Acute Exposure to Cyanide.

The amount, duration of exposure, route of exposure, and premorbid condition of the individual

influence the time to onset and severity of illness. A critical combination of these factors

overwhelms endogenous detoxification pathways, allowing cyanide to diffusely affect cellular

function within the body. No reliable pathognomonic symptom or toxic syndrome is associated

with acute cyanide poisoning.47 The initial clinical effects of acute cyanide poisoning may be

nonspecific, generalized, and nondiagnostic, thereby making the correct diagnosis difficult to

obtain. Clinical manifestations reflect rapid dysfunction of oxygen-sensitive organs, with central

nervous and cardiovascular findings predominating. The time to onset of symptoms typically is

seconds with inhalation of gaseous HCN or intravenous injection of a water soluble cyanide salt

and several minutes following ingestion of an inorganic cyanide salt. The clinical effects of

cyanogenic chemicals often are delayed, and the time course varies among individuals (ranging

from 3–24 hours), depending on their rate of biotransformation.115 Clinically apparent cyanide

toxicity may occur within hours to days of initiating nitroprusside infusion, although concurrent

administration of thiosulfate or hydroxocobalamin may prevent toxicity (Chap. 63).104

CNS signs and symptoms are typical of progressive hypoxia and include headache, anxiety,

agitation, confusion, lethargy, nonreactive dilated pupils seizures, and coma. A centrally mediated

tachypnea occurs initially, followed by bradypnea and apnea.

Cardiovascular responses to cyanide are complex. Studies of isolated heart preparations and

intact animal models show that the principal cardiac insult is slowing of rate and loss of

contractile force.7 Several reflex mechanisms, including catecholamine release and central

vasomotor activity, may modulate myocardial performance and vascular response in patients

with cyanide poisoning.71 In laboratory investigations, a brief period of increased inotropy caused

by reflex compensatory mechanisms occurs before myocardial depression. Clinically, an initial

period of tachycardia and hypertension may occur, followed by hypotension with reflex

tachycardia, but the terminal event is consistently bradycardia and hypotension. Ventricular

dysrhythmias do not appear to be an important factor.

Pulmonary edema may be found at necropsy.47 Inhalation of HCN may be associated with mild

corrosive injury to the respiratory tract mucosa.

Gastrointestinal toxicity may occur following ingestion of inorganic cyanide and cyanogens and

includes abdominal pain, nausea, and vomiting. These symptoms are caused by hemorrhagic

gastritis, which is frequently identified on necropsy, and are thought to be secondary to the

corrosive nature of cyanide salts. However, if death occurs rapidly, this gastritis may not be seen

at autopsy because development of inflammation occurs over time.47 Following ingestion, a smell

of bitter almonds should not be relied upon to be emitted from the gastrointestinal system as

health care providers in nearly all case reports published do not mention this finding.63

Cutaneous manifestations may vary. Traditionally, a cherry-red skin color is described as a result

of increased venous hemoglobin oxygen saturation, which results from decreased utilization of

oxygen at the tissue level. This phenomenon may be more evident on funduscopic examination,

where veins and arteries may appear similar in color. Despite the inference in the name, cyanide

does not directly cause cyanosis. The occurrence of cyanosis is commonly reported in published

case reports and is likely due to cardiovascular collapse and subsequent poor perfusion.122

Delayed Clinical Manifestations of Acute Exposure.

Survivors of serious, acute poisoning may develop delayed neurologic sequelae. Parkinsonian

symptoms, including dystonia, dysarthria, rigidity, and bradykinesia, are most common.

Symptoms typically develop over weeks to months, but subtle findings can be present within a

few days. Head computerized tomography and magnetic resonance imaging consistently reveal

basal ganglia damage to the globus pallidus, putamen, and hippocampus, with radiologic

changes appearing several weeks after onset of symptoms. Whether delayed manifestations

result from direct cellular injury or secondary hypoxia is unclear. Extrapyramidal manifestations

may progress or resolve. Response to pharmacotherapy with antiparkinsonian agents is generally

disappointing.

Chronic Exposure to Cyanide.

Chronic exposure to cyanide may result in insidious syndromes, including tobacco amblyopia,

tropical ataxic neuropathy, and Leber hereditary optic neuropathy. Tobacco amblyopia is a

progressive loss of visual function that occurs almost exclusively in men who smoke cigarettes.

Affected smokers have lower serum cyanocobalamin and thiocyanate concentrations than

unaffected smoking counterparts, suggesting a reduced ability to detoxify cyanide. Cessation of

smoking and administration of hydroxocobalamin often reverses symptoms. Tropical ataxic

neuropathy is a demyelinating disease associated with improperly processed cassava

consumption.91,112 Neurologic manifestations include Parkinson disease, spastic paraparesis,

sensory ataxia, optic atrophy, and sensorineural hearing loss.122 Concomitant dermatitis and

glossitis suggest an association of high dietary cassava with low vitamin B12 intake. Elevated

thiocyanate concentrations in affected individuals further implicate cyanide as the etiology.

Removal of dietary cassava and institution of vitamin B12 therapy alleviates symptoms. Leber

hereditary optic atrophy, a condition of subacute visual failure affecting men, is thought to be

caused by rhodanese deficiency.42

Chronic exposure to cyanide is associated with thyroid disorders.1Thiocyanate is a competitive

inhibitor of iodide entry into the thyroid, thereby causing the formation of goiters and the

development of hypothyroidism. Chronic exposure to cyanide in animals is associated with

hydropic degeneration in hepatocytes and epithelial cells of the renal proximal tubules; however,

these morphologic lesions are not linked to functional alternations.111

Diagnostic Testing

Because of nonspecific symptoms and delay in laboratory cyanide confirmation, the clinician

must rely on historical circumstances and some initial findings to raise suspicion of cyanide

poisoning and institute therapy (Table 126–1).

TABLE 126–1. Cyanide Poisoning: Emergency Management Guidelines

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Laboratory findings suggestive of cyanide poisoning reflect the known metabolic abnormalities,

which include metabolic acidosis, elevated lactate concentration, and increased anion gap.

Elevated venous oxygen saturation results from reduced tissue extraction.65 A venous oxygen

saturation >90% from superior vena cava or pulmonary artery blood indicates decreased oxygen

utilization. This finding is not specific for cyanide and could represent cellular poisoning from

other agents such as carbon monoxide, clenbuterol, hydrogen sulfide, and sodium azide, or

medical conditions such as sepsis high-output cardiac syndromes and left to right intracardiac

shunts.

Hyperlactatemia is found in numerous critical illnesses and typically is a nonspecific finding.

However, a significant association exists between blood cyanide and serum lactate

concentrations.9,10 ABG analysis of whole blood may provide additional information. Arterial pH

correlates inversely with cyanide concentration.10 The finding of a narrow arterial–venous oxygen

difference also may suggest cyanide toxicity.

Cyanide results in nonspecific electrocardiographic (ECG) findings.40Rhythm disturbances such as

sinus tachycardia, bradydysrhythmias, atrial fibrillation, ventricular tachycardia, and ventricular

fibrillation are all reported, as are elevation or depression of the ST segment, shortened ST

segments, and fusion of the T wave into the QRS complex.

Blood cyanide concentration determination can confirm toxicity, but this determination is not

available in a sufficiently rapid manner to affect initial treatment. Whole blood or serum can be

analyzed, with most reports utilizing whole blood for cyanide detection. In mammals, including

primates, whole-blood concentrations are twice serum concentrations as a result of cyanide

sequestration in red blood cells. Background whole-blood concentrations in nonsmokers range

between 0.02 and 0.5 μg/mL.52,59 Higher blood concentrations suggest toxicity. Coma and

respiratory depression are associated with whole blood concentrations >2.5 μg/mL and death

with concentrations >3 μg/mL. Detecting urinary cyanide is difficult, and urinary thiocyanate is a

more readily detectable and useful marker of cyanide exposure. Serum thiocyanate

concentrations are of little value in assessing patients with acute poisoning because of little

correlation with symptoms but are useful in confirming exposure.

A semiquantitative assay that uses calorimetric paper test strips may immediately detect cyanide.

Cyantesmo test strips currently are used by water treatment facilities to detect cyanide. An

investigation of the utility of these strips in clinical practice found that the test strips

incrementally increased to a deep blue color over a progressively longer portion of the test strip

with increasing concentrations of cyanide in the blood.102These strips accurately and rapidly

detected, in a semiquantifiable manner, CN concentrations >1 μg/mL.

Management

Because cyanide poisoning is rare, it is easy to overlook the diagnosis unless there is an obvious

history of exposure. Thus, the most critical step in treatment is considering the diagnosis in

high-risk situations (Table 126–1) and initiating empiric therapy with 100% oxygen and either

hydroxycobalamin or the cyanide antidote kit. The initial care (Table 126–1) of the cyanide-

poisoned patient begins by directing attention to airway patency, ventilatory support, and

oxygenation. Acidemia should be treated with adequate ventilation and sodium bicarbonate

administration.

Intravenous access should be rapidly obtained and blood samples sent for renal function,

glucose, and electrolyte determinations. A whole-blood cyanide concentration can be obtained

for later confirmation of exposure. ABG analysis and serum lactate concentration will help assess

acid–base status. Initiation of crystalloid and infusion of vasopressor for hypotension are

warranted.

First responders should exercise extreme caution when entering potentially hazardous areas such

as chemical plants and laboratories where a previously healthy person is “found down.” Exposure

to cyanide may occur by multiple routes, including ingestion, inhalation, dermal, and parenteral.

For patients with inhalation exposure, removal from the area of exposure is critical. Further

decontamination is generally unnecessary. Decontamination of the cyanide-poisoned patient

occurs concurrently with initial resuscitation. The health care provider should always be

protected from potential dermal contamination by using personal protective devices such as

water-impervious gowns, gloves, and eyewear. For patients with cutaneous exposure, remove

their clothing, brush any powder off the skin, and flush the skin with water. Particular attention

should be given to open wounds because CN– or HCN is readily absorbed through abraded skin.

Instillation of activated charcoal often is considered ineffective because of low binding of

cyanide (1 g activated charcoal only adsorbs 35 mg cyanide). However, a potentially lethal oral

dose of cyanide (ie, a few hundred milligrams) is within the adsorptive capacity of a typical 1

g/kg dose of activated charcoal. Prophylactic activated charcoal administration improved survival

in animals given an LD100 dose of KCN.74 Based on the potential benefits and minimal risks,

activated charcoal may be considered in the patient with an intact protected airway.

Although either hydroxocobalamin or the cyanide antidote kit can be administered as soon as

cyanide poisoning is suspected, hydroxocobalamin is preferred. Hydroxocobalamin is a

metalloprotein with a central cobalt atom that complexes cyanide, forming cyanocobalamin

(vitamin B12). Cyanocobalamin is eliminated in the urine or releases the cyanide moiety at a rate

sufficient to allow detoxification by rhodanese. One molecule of hydroxocobalamin binds one

molecule of cyanide, yielding a molecular weight binding ratio of 50:1. The US-approved adult

starting dose is 5 g administered by intravenous infusion over 15 minutes. Depending upon the

severity of the poisoning and the clinical response, a second dose of 5 g may be administered

by intravenous infusion for a total dose of 10 g. Hydroxocobalamin has few adverse effects,

which include allergic reaction and a transient reddish discoloration of the skin, mucous

membranes, and urine.25,21,53 No hemodynamic adverse effects other than a potential mild

transient rise of blood pressure are observed16,105 (Antidotes in Depth: A41).

The cyanide antidote kit contains amyl nitrite, sodium nitrite, and sodium thiosulfate. Both

thiosulfate and nitrite individually have antidotal efficacy when given alone in animal models of

cyanide poisoning, but they have even greater benefit when they are given in

combination.80 Thiosulfate donates the sulfur atoms necessary for rhodanese-mediated cyanide

biotransformation to thiocyanate. The mechanism of nitrite is less clear. Traditional rationale

relies on the ability of nitrite to generate methemoglobin. Because cyanide has a higher affinity

for methemoglobin than for cytochrome a3, cytochrome oxidase function is restored. However,

improved hepatic blood flow and nitric oxide formation are alternate explanations (Antidotes in

Depth: A39 and A40). Amyl nitrite is contained within glass pearls that are crushed and

intermittently inhaled or intermittently introduced into the ventilator system to initiate

methemoglobin formation. The amyl nitrite pearls are reserved for cases where intravenous

access is delayed or not possible. Intravenous sodium nitrite is preferred and is supplied as a 10-

mL volume of 3% solution (300 mg). Adverse effects of nitrites include excessive methemoglobin

formation and, because of potent vasodilation, hypotension and tachycardia. Avoiding rapid

infusion, monitoring blood pressure, and adhering to dosing guidelines will limit adverse effects.

Because of the potential for excessive methemoglobinemia during nitrite treatment, pediatric

dosing guidelines are available (Table 126–2). Sodium thiosulfate is the second component of

the cyanide antidote kit. It is supplied as 50 mL of 25% solution (12.5 g). It is a substrate for the

reaction catalyzed by rhodanese that is essentially irreversible, converting a highly toxic entity to

a relatively harmless compound. However, thiocyanate does have its own toxicity in the presence

of kidney failure, including abdominal pain, vomiting, rash, and CNS dysfunction. Thiosulfate

itself is not associated with significant adverse reactions. The pediatric dose of thiosulfate is

adjusted for weight.

TABLE 126–2. Cyanide Management: Pediatric Sodium Nitrite Guidelinesa

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In Europe, 4-dimethylaminophenol (4-DMAP), rather than sodium nitrite, is the methemoglobin-

inducer of choice.54 It generates methemoglobin more rapidly than sodium nitrite, with peak

methemoglobin concentrations at 5 minutes after 4-DMAP rather than 30 minutes after sodium

nitrite. The dose of 4-DMAP is 3 mg/kg and is coadministered with thiosulfate. As with sodium

nitrite, its major adverse effect is excessive methemoglobin formation and potential for

hypotension. Cobalt in the form of dicobalt edetate has been used as a cyanide chelator, but its

usefulness is limited by serious adverse effects such as hypotension, cardiac dysrhythmias,

decreased cerebral blood flow, and angioedema.22,86 The cobalamin precursor cobinamide has

been used both prophylactically and therapeutically to treat experimental cyanide toxicity, and

when given at high enough doses, it has rescued animals from cyanide-induced apnea and

coma.23 Cobalamin has been used in France to treat human cyanide exposure, either alone or

combined with sodium thiosulfate. Cobinamide is an investigational treatment that has a much

greater affinity for cyanide ion than cobalamin.29 Hyperbaric oxygen has been considered in the

past, but recent evidence suggests no benefit in cyanide poisoning.76

In animal models, the antioxidant vitamins A, C, and E diminish the extent of tissue damage

caused by subacute cyanide intoxication.89 This is especially important in the tropics, where the

majority of dietary staples are cyanophoric crops such as cassava.

Patients who do not survive cyanide poisoning are suitable organ donors. Heart, liver, kidney,

pancreas, cornea, skin, and bone have been successfully transplanted following cyanide

poisoning.41

HYDROGEN SULFIDE POISONING

History and Epidemiology

Hydrogen sulfide (H2S) exposures are often dramatic and can be fatal. The American Association

of Poison Control Centers’ National Poison Data System reported 5383 exposures from 2007

through 2011 (Chap. 136). Only 1534 of these exposures required evaluation at a health care

facility, 457 reported moderate or major effects, and 36 deaths occurred.24 Over a 10 year period

from 1983 to 1992, 5563 exposures and 29 deaths attributed to hydrogen sulfide were reported

in the National Poison Data System.110 Most often, serious consequences of hydrogen sulfide

exposures occur through workplace exposures, but they can also occur in environmental

disasters and most recently in suicides.

Bacterial decomposition of proteins generates hydrogen sulfide, and the gas is produced in

many industrial activities. Decay of the sulfur-containing products such as fish, sewage, and

manure produce hydrogen sulfide. Industrial sources include pulp paper mills, heavy-water

production, the leather industry, roofing asphalt tanks, vulcanizing of rubber, viscose rayon

production, and coke manufacturing from coal.31 It is a major industrial hazard in oil and gas

production, particularly in sour gas fields (natural gas containing sulfur).

Between 1990 and 1999, hydrogen sulfide poisoning was associated with the deaths of 18% of

US construction workers killed by toxic inhalation.35 Many died while working in confined spaces

such as sewers or sewer manholes. Agricultural workers operating near livestock manure storage

tanks are at greatest risk of harm from an inhalation exposure.12,55 Poisoned workers are “knocked

down,” prompting coworkers to attempt a rescue. Numerous case reports describe multiple

victims because the would-be rescuers often themselves become victims when they attempt a

rescue in an environment having high concentrations of hydrogen sulfide.12,35,55 Studies report that

up to 25% of fatalities involve rescuers.35,44,58

OSHA and a variety of occupational organizations such as the American Industrial Hygiene

Association, the National Institute of Occupational Safety and Health, the American Shipbuilding

Association, and the US Chemical Safety Board recognize the serious dangers of hydrogen

sulfide exposures in the workplace and continue to promote safety alerts and educational

programs.93

Natural sources of hydrogen sulfide are volcanoes, caves, sulfur springs, and underground

deposits of natural gas.31,101 Hydrogen sulfide is also implicated in several environmental disasters.

In 1950, 22 people died and 320 were hospitalized in Poza Rica, Mexico, when a local natural

gas facility inadvertently released hydrogen sulfide into the air.82Hydrogen sulfide claimed nine

lives when a sour gas well failed, releasing a cloud of the poisonous gas into the Denver City,

Texas community in 1975.85 In 2003, a gas drilling incident in southwest China released natural

gas and a cloud of hydrogen sulfide into a populated area, killing more than 200 people,

injuring 9000, and necessitating the evacuation of more than 40,000.129

Recently, a large number of suicides called “chemical suicides” or “detergent suicides” have been

attributed to mixing common household chemicals such as pesticides or fungicides and toilet

bowl cleaners to create hydrogen sulfide gas.116,119 This practice is of concern because the recipes

are easily found on Internet sites, precursor chemicals are readily accessible from the cleaning

section of many local stores, first responders are at risk of harmful toxic effects from exposure,

and the toxic gas can inadvertently expose groups of people in nearby buildings. In Japan, it is

reported that more than 500 people killed themselves in the first half of 2008 by this

means.130 Information resources on the Internet are implicated for the widespread practice and

prompted police to request purging the suicide recipes from Internet sites.56 In the United States,

chemical suicides from hydrogen sulfide are likely underreported but rose from 2 in 2008 to 19

in 2010.100 In as many as 80% of incidents, first responders report exposures following attempted

rescue of victims.100 Suicide victims using this method to harm themselves inadvertently cause

injuries and evacuations because of the toxic gas permeating buildings. One incident in Japan

caused 90 people to become ill from the toxic gas as it permeated an apartment building, and

another resulted in 350 people evacuating a building.119

Pharmacology and Toxicokinetics

Hydrogen sulfide is a colorless gas, more dense than air, with an irritating odor of “rotten eggs.”

It is highly lipid soluble, a property that allows easy penetration of biologic membranes. Systemic

absorption usually occurs through inhalation, and it is rapidly distributed to tissues.101

The tissues most sensitive to hydrogen sulfide are those with high oxygen demand. The systemic

toxicity of hydrogen sulfide results from its potent inhibition of cytochrome oxidase, thereby

interrupting oxidative phosphorylation.31 Hydrogen sulfide binds to the ferric (Fe3+) moiety of

cytochrome a3 oxidase complex with a higher affinity than does cyanide. The resulting inhibition

of oxidative phosphorylation produces cellular hypoxia and anaerobic metabolism.31,131

Cytochrome oxidase inhibition is not the sole mechanism of toxicity. Other enzymes are inhibited

by hydrogen sulfide and may contribute to its toxic effects.101 Besides producing cellular hypoxia,

hydrogen sulfide alters brain neurotransmitter release and transmission through potassium

channel–mediated hyperpolarization of neurons, potentiate NMDA receptors, and other neuronal

inhibitory mechanisms.90,101 A proposed mechanism of death is poisoning of the brainstem

respiratory center through selective uptake by lipophilic white matter in this region.127 The

olfactory nerve is a specific target of great interest. Not only does the toxic gas cause olfactory

nerve paralysis, but it is thought to be a portal of entry into the central nervous system because

of its direct contact with the brain.131 It is also cytotoxic through formation of reactive sulfur and

oxygen species. It may also react with iron to fuel the Fenton reaction causing free radical

injury117 (Chaps. 12 and 13).

In addition to systemic effects, hydrogen sulfide reacts with the moisture on the surface of

mucous membranes to produce intense irritation and corrosive injury. The eyes and nasal and

respiratory mucous membranes are the tissues most susceptible to direct injury.75,131Despite skin

irritation, it has little dermal absorption.

Along with nitric oxide and carbon monoxide, researchers recently recognized hydrogen sulfide

as a signaling molecule of the cardiovascular, inflammatory, and nervous systems, and therefore,

they proposed to add hydrogen sulfide as the “third endogenous gaseous transmitter.” In 2005,

a report in Science demonstrated mice inhaling a low dose of hydrogen sulfide, which decreased

their metabolic demands and caused them to enter a “suspended animationlike state.”18 This

report propelled researchers into studies probing the biosynthesis, metabolism, and physiological

responses of hydrogen sulfide in hopes of developing future beneficial therapies to combat the

adverse consequences of ischemia/reperfusion injury.37,90 The research results reveal fascinating

and sometimes puzzling and contradictory results. Administering hydrogen sulfide to rodents

appears to switch off metabolic demands and protect some species from ischemic insults. On

the contrary, large animal models have yet to show global protection but support local, organ-

specific protective effects. In total, these studies reveal hydrogen sulfide to have complex

interactions that are variable among organ systems and species while clearly demonstrating a

dose-dependent effect with higher exposures producing the well-known toxic effects. Besides its

ability to attenuate metabolic demands during ischemia, hydrogen sulfide influences many

signaling pathways and has vasodilating, neuromodulating, antiinflammatory, antiapoptotic, and

antioxidant effects. Using hydrogen sulfide as a therapy requires additional investigation, but

several hydrogen sulfide donating drugs are already in clinical trials.79 Researchers’ enthusiastic

pursuit of a better understanding of hydrogen sulfide with an intent to create innovative

therapies will likely also benefit our understanding of its mechanisms of toxicity and potentially

lead to new treatments for toxic exposures.

Inhaled hydrogen sulfide enters the systemic circulation where it dissociates into hydrosulfide

ions (HS-), sulfide (S–2), and sulfate (SO2–4). Once dissociated, hydrosulfide ions interact with

metalloproteins, disulfide containing enzymes, and thio dimethyl S transferase.32Hydrogen sulfide

and dissociation products are then rapidly metabolized by oxidation, methylation, and binding to

metalloproteins. The major pathway of detoxification is enzymatic and nonenzymatic oxidation of

sulfides and sulfur to thiosulfate and polysulfides.131,90 Other pathways, such as methylation to

dimethyl sulfide and conversion to sulfite or sulfate by oxidized glutathione, also may play a role

in detoxification and elimination.31,131 Sulfhemoglobin is not found in significant concentrations in

the blood of animals or fatally poisoned humans.90,96

Clinical Manifestations

Acute Manifestations.

Hydrogen sulfide poisoning should be suspected whenever a person is found unconscious in an

enclosed space, especially if the odor of rotten eggs is noted. The primary target organs of

hydrogen sulfide poisoning are those of the CNS and respiratory system. The clinical findings

reported in two large series are listed in Table 126–3.4,26

TABLE 126–3. Hydrogen Sulfide Poisoning

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Hydrogen sulfide poisoning has a distinct dose response, and the intensity of exposure likely

accounts for the diverse clinical findings in the reports. The odor threshold is between 0.01 and

0.3 ppm, and a strong intense odor is noted at 20 to 30 ppm. Mild mucous membrane irritation

occurs at 20 to 100 ppm. Olfactory nerve paralysis occurs at 100 to 150 ppm rapidly

extinguishing the ability to perceive the gas odor at higher concentrations. Prolonged exposure

can occur when the extinction of odor recognition is misinterpreted as dissipation of the gas.

Strong irritation of the upper respiratory tract and eyes and ARDS occur at 150 to 300 ppm. At

>500 ppm, hydrogen sulfide produces systemic effects. Rapid unconsciousness and

cardiopulmonary arrest occur at concentrations >700 ppm. At 1000 ppm, breathing may cease

after one to two breaths.11,49,101

Hydrogen sulfide reacts with the moisture on the surface of mucous membranes to produce

intense irritation and corrosive injury. Mucous membrane irritation of the eye produces

keratoconjunctivitis. If exposure persists, damage to the epithelial cells produces reversible

corneal ulcerations (“gas eye”) and, rarely, irreversible corneal scarring.75,123The irritant effects on

the respiratory tract include rhinitis, bronchitis, and ARDS.4,26,131

Neurologic manifestations are common and may be severe. Hydrogen sulfide’s rapid and deadly

onset of clinical effects have been termed the “slaughterhouse sledgehammer” effect. In one

case series, 75% of 221 patients with acute hydrogen sulfide exposure lost consciousness at the

time of exposure.26 If the patient is rapidly removed from the exposure, recovery may be prompt

and complete. Hypoxia from respiratory compromise can cause secondary neurologic

effects.11,31,131,50Neurologic outcome can be quite variable, ranging from no neurologic impairment

to permanent sequelae. Delayed neuropsychiatric sequelae may occur after acute

exposures.27 Most evidence suggests that the early rapid CNS effects are direct neurotoxic effects

of hydrogen sulfide, whereas the permanent neurologic sequelae result from hypoxia secondary

to respiratory insufficiency.11,131 Reported neuropsychiatric changes include memory failure

(amnestic syndrome), lack of insight, disorientation, delirium, and dementia.31,131 Neurosensory

abnormalities include transient hearing impairment, vision loss, and anosmia. Motor symptoms

are likely caused by injury to the basal ganglia and result in ataxia, position/intention tremor,

and muscle rigidity.120 Common neuropathologic findings observed on neuroimaging and at

autopsy are subcortical white matter demyelination and globus pallidus degeneration.27

Acute exposures also affect other organ systems. Myocardial hypoxia or direct toxic effects of

hydrogen sulfide on cardiac tissue may cause cardiac dysrhythmias, myocardial ischemia, or

myocardial infarction.48Because unresponsiveness is rapid, trauma from falls should not be

overlooked.4,45 In a report, 7% of patients experiencing a “knockdown” had associated traumatic

injuries.4

Chronic Manifestations.

Most data about chronic low-level exposures to hydrogen sulfide come from oil and gas

industry workers. Mucous membrane irritation seems to be the most prominent problem in

patients with low-concentration exposures. Workers report nasal, pharyngeal, and eye irritation,

fatigue, headache, dizziness, and poor memory with low-concentration, chronic exposures. The

chronic irritating effects of hydrogen sulfide were thought to be the cause of reduced lung

volumes observed in sewer workers.103 Volunteer studies have not demonstrated significant

cardiovascular effects after long term exposure to concentrations less than 10 ppm.17 The liver,

kidneys, and endocrine system are unaffected. No studies demonstrate increased incidences of

cancer with low-level exposures.31

Rapid loss of consciousness from hydrogen sulfide exposure was a well-known and, amazingly,

accepted part of the workplace in the gas and oil industry for many years.60 Some workers

experienced repeated “knockdowns,” and these workers reported an increased incidence of

respiratory diseases and cognitive deficits. Single or repeated high-concentration exposures

resulting in unconsciousness can cause serious cognitive dysfunction. The acute effects of rapid

loss of consciousness are most likely due to hydrogen sulfide neurotoxicity. Although a clear

association exists between knock-down and chronic neurologic sequelae, many of the case

reports are complicated by associated apnea or hypoxemia from respiratory failure, asphyxia or

exposure to other xenobiotics in a confined space, head injury from a fall, or near drowning in

liquid manure or sludge.131 The association of neurotoxic sequelae are less clear with protracted

low-concentration exposures. Case series suggest that low-concentration exposures can cause

subtle changes that can be measured by only the most sensitive neuropsychiatric tests.72

Epidemiologic data regarding the effects of low-concentration environmental exposures to

hydrogen sulfide are clouded in populations exposed to complex mixtures of pollutants. Other

malodorous sulfur compounds (eg, methyl mercaptan and methyl sulfide) are generated as

byproducts of pulp mills. Study populations exposed to this complex mixture of pollutants

demonstrate a dose-related increase in nasal symptoms, cough, nausea, and vomiting.31

These changes are nonspecific, and the many of the cases have a poorly documented exposure

assessment. Currently, the association of protracted and low-concentration hydrogen sulfide

exposure with chronic neurological sequelae remains controversial and needs further study.50,131

The strong odor of low concentrations of hydrogen sulfide can magnify irritant effects by

triggering a strong psychological response.131 The odor of hydrogen sulfide at low levels has

been the alleged source of mass psychogenic illness cases.46 Clinical, epidemiologic, and

toxicologic analyses suggested that 943 cases of illness in Jerusalem were caused by the odor of

low concentrations of hydrogen sulfide gas. The most frequent associated symptoms are

headaches; faintness; dizziness; nausea; chest tightness; dyspnea and tachypnea; eye, nose, and

throat irritation; weakness; and extremity numbness. Low concentration exposure to hydrogen

sulfide may produce nonspecific signs and symptoms that could closely mimic psychogenic

illness. Attempting to identify true toxicity from a powerful emotional reaction can be extremely

difficult.46 Therefore, symptomatic patients must be assessed for toxicity even when mass

psychogenic illness is suspected.

Diagnostic Testing

In hydrogen sulfide poisoning, diagnostic testing is of limited value for clinical decision making

following acute exposures, confirmation of acute exposures, occupational monitoring, and

forensic analysis following fatal accidents.

Clinicians must base management decisions on history, clinical presentation, and diagnostic tests

that infer the presence of hydrogen sulfide because no method is available to rapidly and

directly measure the gas or its metabolites. Circumstances surrounding the patient’s illness often

provide the best evidence for hydrogen sulfide poisoning (Table 126–3). At the bedside, the

smell of rotten eggs on clothing or emanating from the blood, exhaled air, or gastric secretions

suggests hydrogen sulfide exposure. In addition, darkening of silver jewelry is a clue to exposure.

Paper impregnated with lead acetate changes color when exposed to hydrogen sulfide and is

used to detect its presence in the patient’s exhaled air but is not rapidly available.31

Specific tests for confirming hydrogen sulfide exposure are not readily available in clinical

laboratories. Therefore, directly measuring the gas in atmospheric air samples by monitoring

devices provides stronger evidence of hydrogen sulfide as the causative agent. Epidemiologic

data show hydrogen sulfide as one of the most common causes of death and injury from toxic

inhalation in confined spaces, especially manholes and sewers.36 Recognizing confined spaces as

extremely hazardous environments, OSHA published the Confined Space Entry Standard to

protect workers.2 It mandates training, rescue procedures, and atmospheric testing before entry,

including measuring for the presence of hydrogen sulfide. Because of OSHA’s regulations, most

emergency response teams are equipped to investigate toxic environments from hazardous

materials incidents using a “four-gas detection unit” that measures hydrogen sulfide by

electrochemical sensors along with measurements for atmospheric oxygen concentration and the

presence of explosive gases and carbon monoxide.121 In general, the clinician must interpret

environmental detection results with caution. Toxic gases may dissipate prior to atmospheric air

sample collection, leading to negative results, or interfering gases can trigger false positive

readings on detection devices.57 A positive reading on a field device does not equate to

confirmation of that specific gas. Clinical decision making should consider correlation with other

circumstantial and clinical data and not rely solely on detection results.

In acute poisoning, readily available diagnostic tests that are biomarkers of hydrogen sulfide

poisoning may be useful but are nonspecific. ABG analysis demonstrating metabolic acidosis

with an associated elevated serum lactate concentration is expected, and oxygen saturation

should be normal unless ARDS is present. Hydrogen sulfide, like cyanide, decreases oxygen

consumption and is reflected as an elevated mixed venous oxygen measurement. Because

sulfhemoglobin typically is not generated in patients with hydrogen sulfide poisoning, an oxygen

saturation gap is not expected.90,96

After serious injury from hydrogen sulfide, diagnostic testing for neurologic structure and

function may show abnormalities for weeks or months. Brain MRI and head CT studies

demonstrate structural changes, such as globus pallidus degeneration and subcortical white

matter demyelination. Neuropsychological testing after serious hydrogen sulfide poisoning

demonstrates specific abnormalities in cortical functions, such as concentration, attention, verbal

abstraction, and short-term retention. Single-photon emission computed tomography

(SPECT)/PET brain scans define neurotoxin-induced lesions that correlate well with clinical

neuropsychological testing.28

No clinically available biological markers or direct measurements of hydrogen sulfide and its

metabolites exists, therefore, confirming poisoning is challenging for clinicians, researchers, and

forensic specialists.90 Whole blood sulfide concentrations >0.05 mg/L are considered abnormal.

Reliable measurements are ensured only if the concentration is obtained within 2 hours after the

exposure and analyzed immediately.101

In acute exposures, blood and urine thiosulfate concentrations may be reflective of

exposure.69 Urinary thiosulfate excretion may be useful to monitor chronic low-concentration

exposure in the workplace. However, one study could not demonstrate a correlation between the

degree of exposure and change in urine thiosulfate from baseline measurements.38 Another study

analyzed the value of blood and urine thiosulfate from data collected in case series of fatal and

nonfatal hydrogen sulfide victims.66,68 Because thiosulfate was detected in the urine but sulfide

and thiosulfate were not detected in the blood of nonfatal exposures, this report concluded that

thiosulfate in urine is the only indicator to prove hydrogen sulfide poisoning in nonfatal cases.

Sulfide concentrations obtained in postmortem investigations may be useful, but their use

requires rapid sample collection because sulfide concentrations rise with tissue

decomposition.101 In addition to blood sulfide concentrations, sulfide and thiosulfate

concentrations are at their highest in lung and brain.67 If death is rapid, urinary thiosulfate

concentrations may be nondetectable despite blood sulfide and thiosulfate concentrations 10-

fold or greater than normal concentrations.67 At autopsy, a greenish discoloration of the gray

matter, viscera, and bronchial secretions may be noted.67,88

Management

The initial treatment (Table 126–4) is immediate removal of the victim from the contaminated

area into a fresh air environment. High-flow oxygen should be administered as soon as possible.

Optimal supportive care has the greatest influence on the patient’s outcome. Because death

from inhalation of hydrogen sulfide is rapid, limited human cases reaching the hospital for

treatment are reported in the literature. Most patients experience significant delays before

receiving treatment. Therefore, specific treatments and antidotal therapies do not show definitive

improvement in patient outcome.

TABLE 126–4. Hydrogen Sulfide Poisoning: Emergency Management

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The proposed toxic mechanisms, animal studies, and human case reports suggest that oxygen

therapy is beneficial for hydrogen sulfide poisoning.31,33,99,131 Proposed mechanisms for the

beneficial effects of oxygen are competitive reactivation of oxidative phosphorylation by

inhibiting hydrogen sulfide–cytochrome binding, enhanced detoxification by catalyzing oxidation

of sulfides and sulfur, and improved oxygenation in the presence of ARDS. Recent studies

demonstrate hydrogen sulfide’s binding to cytochrome oxidase is readily reversible in the

presence of oxygen.33 Other studies show an inverse relationship between tissue concentrations

of hydrogen sulfide and oxygen.90Increased oxygen concentrations enhance the consumption of

hydrogen sulfide through metabolic pathways, while oxygen deprivation results in the

accumulation of hydrogen sulfide in tissue.90 All patients suspected of hydrogen sulfide

poisoning should receive supplemental oxygen. In case reports, poisoned patients receiving HBO

had favorable clinical outcomes.5,62,109 However, no clinical data is available to suggest HBO is

superior to normobaric oxygen for acute poisoning or preventing delayed neurological sequelae.

The similarities in the toxic mechanism between hydrogen sulfide and cyanide created an

interest in the use of nitrite-induced methemoglobin as an antidote. Methemoglobin protects

animals from toxicity of hydrogen sulfide poisoning in both pretreatment and postexposure

treatment models. Nitrite-generated methemoglobin acts as a scavenger of sulfide. The affinity

of hydrogen sulfide for methemoglobin is greater than that for cytochrome oxidase. When

hydrogen sulfide binds to methemoglobin, it forms sulfmethemoglobin.15 Because hydrogen

sulfide poisoning is rare, no studies have evaluated the clinical outcomes of patients treated with

sodium nitrite. Animal studies suggest that nitrite must be given within minutes of exposure to

ensure effectiveness.15However, several human case reports showed rapid return of normal

sensorium when nitrites were administered soon after exposure.62,94,114Patients with suspected

hydrogen sulfide poisoning who have altered mental status, coma, hypotension, or dysrhythmias

should receive sodium nitrite by slow infusion at the same dose given for cyanide poisoning.

Sodium thiosulfate is of no benefit in the treatment of hydrogen sulfide. In addition, only a

single in vivo mouse model and a single case report with a fatal outcome is published to

suggest a beneficial effect of hydroxocobalamin as an antidote for hydrogen sulfide

poisoning.43,118 Additional research is warranted to determine its usefulness for hydrogen sulfide

poisoning.

Treatment of patients with hydrogen sulfide poisoning requires optimal supportive care.

Treatments and antidotes beyond supportive care are not of proven clinical benefit. Because

hydrogen sulfide toxicity is severe and research studies suggest potential benefits of nitrite

therapy, it should be considered for seriously ill patients exposed to hydrogen sulfide. This

therapy should be initiated after optimum supportive care has been ensured.

Only a few inhalation risks are similar to hydrogen sulfide in their ability to rapidly “knock-down”

victims. Some examples include low-oxygen environments in an enclosed space, hydrogen

cyanide, volatile nerve agents, and carbon monoxide. The etiology may be unclear early in the

patient’s emergency care and require clinicians to make treatment decisions without

confirmatory evidence of poisoning. Clinicians faced with victims of “knock-down” syndrome

should search for clues, such as victims’ activities (eg, working at a manure pit), reports of

chemicals detected at the scene by first responders, or suggestive clinical signs. The critical

decision is whether to administer specific antidotes empirically. Vapor exposure to volatile nerve

agents would likely result in miosis and require antidotes such as atropine, pralidoxime, and

benzodiazapines. Which cyanide antidotes to administer in a “knock-down” situation, if any, is

most difficult. The basic aims are to gather as many facts and suggestive clues as possible,

weigh the risk benefits for treatment or not, and treat early in the course. All this while

meticulous attention to optimal supportive care is required.

SUMMARY

Both cyanide and hydrogen sulfide are high risk xenobiotics.

There are particular metabolic risks and concerns with regard to exposure to both

xenobiotics because they bind specifically to the ferric moiety of the cytochrome

a3 oxidase complex.

Odor recognition is unreliable and is not a definitive approach to diagnosis.

The laboratory evaluation usually is not timely for diagnostic purposes.

Decontamination, removal from the site of exposure, and oxygen are essential.

Acknowledgment

Gary E. Isom, PhD, contributed to this chapter in previous editions.

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