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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.
References
1.
Adewusi SR, Akindahunsi AA: Cassava processing, consumption, and cyanide toxicity. J Toxicol
Environ Health. 1994;43:13–23.
CrossRef [PubMed: 8078089]
2.
Anonymous: Confined Spaces. United States Department of Labor Occupational Safety & Health
Administration.http://www.osha.gov/SLTC/confinedspaces/index.html. Accessed April 8, 2013.
3.
Ardelt BK, Borowitz JL, Maduh EU et al.: Cyanide-induced lipid peroxidation in different
organs: subcellular distribution and hydroperoxide generation in neuronal
cells. Toxicology.1994;89:127–137.
CrossRef [PubMed: 8197590]
4.
Arnold IM, Dufresne RM, Alleyne BC et al.: Health implication of occupational exposures to
hydrogen sulfide. J Occup Med.1985;27:373–376.
CrossRef [PubMed: 3159860]
5.
Asif MJ, Exline MC: Utilization of hyperbaric oxygen therapy and induced hypothermia after
hydrogen sulfide exposure. Respir Care. 2012;57:307–310.
CrossRef [PubMed: 22004989]
6.
Atlante A, de Bari L, Bobba A et al.: Cytochrome c, released from cerebellar granule cells
undergoing apoptosis or excytotoxic death, can generate protonmotive force and drive ATP
synthesis in isolated mitochondria. J Neurochem. 2003;86:591–604.
CrossRef [PubMed: 12859673]
7.
Barros RC, Bonagamba LG, Okamoto-Canesin R et al.: Cardiovascular responses to
chemoreflex activation with potassium cyanide or hypoxic hypoxia in awake rats. Auton
Neurosci. 2002;97:110–115.
CrossRef [PubMed: 12132643]
8.
Baud FJ, Barriot P, Toffis V et al.: Elevated blood cyanide concentrations in victims of smoke
inhalation. N Engl J Med.1991;325:1761–1766.
CrossRef [PubMed: 1944484]
9.
Baud FJ, Borron SW, Bavoux E et al.: Relation between plasma lactate and blood cyanide
concentrations in acute cyanide poisoning. BMJ. 1996;312:26–27.
CrossRef [PubMed: 8555853]
10.
Baud FJ, Borron SW, Megarbane B et al.: Value of lactic acidosis in the assessment of the
severity of acute cyanide poisoning. Crit Care Med. 2002;30:2044–2050.
CrossRef [PubMed: 12352039]
11.
Beauchamp RO, Bus JS, Popp JA et al.: A critical review of the literature on hydrogen sulfide
toxicity. Crit Rev Toxicol.1984;13:25–97.
CrossRef [PubMed: 6378532]
12.
Beaver RL, Field WE: Summary of documented fatalities in livestock manure storage and
handling facilities—1975-2004. J Agromedicine. 2007;12:3–23.
CrossRef [PubMed: 18086650]
13.
Bebarta VS, Pitotti RL, Borys DJ et al.: Seven years of cyanide ingestions in the USA: critically
ill patients are common, but antidote use is not. Emerg Med J. 2011;28:155–158.
CrossRef [PubMed: 20511644]
14.
Bechtel L, Holstege C: Forensic analysis of potassium cyanide stored in gelatin capsules. Clin
Toxicol. 2010;48:614.
CrossRef
15.
Beck JF, Bradbury CM, Connors AJ et al.: Nitrite as antidote for acute hydrogen sulfide
intoxication? Am Ind Hyg Assoc J.1981;42:805–809.
CrossRef [PubMed: 7315740]
16.
Beregi JP, Riou B, Lecarpentier Y: Effects of hydroxocobalamin on rat cardiac papillary
muscle. Intensive Care Med.1991;17:175–177.
CrossRef [PubMed: 1649208]
17.
Bhambhani Y, Burnham R, Snydmiller G et al.: Effects of 10-ppm hydrogen sulfide inhalation
on pulmonary function in healthy men and women. J Occup Environ Med. 1996;38:1012–1017.
CrossRef [PubMed: 8899577]
18.
Blackstone E, Morrison M, Roth MB: H2S induces a suspended animation-like state in
mice. Science. 2005;308:518.
CrossRef [PubMed: 15845845]
19.
Blanc P, Hogan M, Mallin K et al.: Cyanide intoxication among silver-reclaiming
workers. JAMA. 1985;253:367–371.
CrossRef [PubMed: 3965790]
[JAMA and JAMA Network Journals Full Text]
20.
Blanco PJ, Rivero AG: First case of illegal euthanasia in Spain: fatal oral potassium cyanide
poisoning. Soud Lek. 2004;49:30–33. [PubMed: 15233029]
21.
Borron SW, Baud FJ, Megarbane B et al.: Hydroxocobalamin for severe acute cyanide
poisoning by ingestion or inhalation. Am J Emerg Med. 2007;25:551–558.
CrossRef [PubMed: 17543660]
22.
Brian MJ: Cyanide poisoning in children in Goroka. PNG Med J.1990;33:151–153.
23.
Broderick KE, Potluri P, Zhuang S et al.: Cyanide detoxification by the cobalamin precursor
cobinamide. Exp Biol Med.2006;231:641–649.
24.
Bronstein AC, Spyker DA, Cantilena LR, LR et al.: 2011 Annual report of the American
Association of Poison Control Centers’ National Poison Data System (NPDS): 29th Annual
Report. Clin Toxicol. 2012;50:911–1164.
CrossRef
25.
Brouard A, Blaisot B, Bismuth C: Hydroxocobalamine in cyanide poisoning. J Toxicol Clin
Exp. 1987;7:155–168. [PubMed: 3656212]
26.
Burnett WW, King EG, Grace M et al.: Hydrogen sulfide poisoning: review of 5 years’
experience. Can Med Assoc J.1977;117:1277–1280. [PubMed: 144553]
27.
Byungkuk N, Hyokyung K, Younghee C et al.: Neurologic sequela of hydrogen sulfide
poisoning. Ind Health. 2004;42:83–87.
CrossRef [PubMed: 14964623]
28.
Callender TJ, Morrow L, Subramanian K et al.: Three-dimensional brain metabolic imaging in
patients with toxic encephalopathy. Environ Res. 1993;60:295–319.
CrossRef [PubMed: 8472660]
29.
Chan A, Balasubramanian M, Blackledge W et al.: Cobinamide is superior to other treatments
in a mouse model of cyanide poisoning. Clin Toxicol. 2010;48:709–717.
CrossRef
30.
Chaturvedi AK, Smith DR, Canfield DV: Blood carbon monoxide and hydrogen cyanide
concentrations in the fatalities of fire and non-fire associated civil aviation accidents, 1991-
1998. Forensic Sci Int. 2001;121:183–188.
CrossRef [PubMed: 11566422]
31.
Chou S, Fay M, Keith S et al.: Toxicological Profile for Hydrogen Sulfide. ATSDR Toxicology
Profile. 2006.
32.
Chou SJ: Hydrogen sulfide: Human health aspects. World Health Organization. Geneva. 2003.
33.
Collman JP, Ghosh S, Dey A et al.: Using a functional enzyme model to understand the
chemistry behind hydrogen sulfide induced hibernation. Proc Natl Acad Sci U S
A. 2009;106:22090–22095.
CrossRef [PubMed: 20007376]
34.
Djerad A, Monier C, Houze P et al.: Effects of respiratory acidosis and alkalosis on the
distribution of cyanide into the rat brain. Toxicol Sci. 2001;61:273–282.
CrossRef [PubMed: 11353136]
35.
Dorevitch S, Forst L, Conroy L et al.: Toxic inhalation fatalities of US construction workers,
1990 to 1999. J Occup Environ Med.2002;44:657–662.
CrossRef [PubMed: 12134529]
36.
Dorevitch S, Marder D: Occupational hazards of municipal solid waste workers. Occup
Med. 2001;16:125–133. [PubMed: 11107229]
37.
Drabek T: Hydrogen sulfide-curiouser and curiouser! Crit Care Med. 2012;40:2255–2256.
CrossRef [PubMed: 22710225]
38.
Durand M, Weinstein P: Thiosulfate in human urine following minor exposure to hydrogen
sulfide: implications for forensic analysis of poisoning. Forensic Toxicol. 2007;25:92–95.
CrossRef
39.
Finnberg A, Junuzovic M, Dragovic L et al.: Homicide by poisoning. Am J Forensic Med
Pathol. 2013;34:38–42.
CrossRef [PubMed: 23361068]
40.
Fortin JL, Desmettre T, Manzon C et al.: Cyanide poisoning and cardiac disorders: 161 cases. J
Emerg Med. 2010;38:467–476.
CrossRef [PubMed: 20185266]
41.
Fortin JL, Ruttimann M, Capellier G et al.: Successful organ transplantation after treatment of
fatal cyanide poisoning with hydroxocobalamin. Clin Toxicol. 2007;45:468–471.
CrossRef
42.
Freeman AG: Optic neuropathy and chronic cyanide toxicity.Lancet. 1986;1:441–442.
CrossRef [PubMed: 2868358]
43.
Fujita Y, Fujino Y, Onodera M et al.: A fatal case of acute hydrogen sulfide poisoning caused
by hydrogen sulfide: hydroxocobalamin therapy for acute hydrogen sulfide poisoning.J Anal
Toxicol. 2011;35:119–123.
CrossRef [PubMed: 21396232]
44.
Fuller DC, Suruda AJ: Occupationally related hydrogen sulfide deaths in the United States from
1984 to 1994. J Occup Environ Med. 2000;42:939–942.
CrossRef [PubMed: 10998771]
45.
Gabbay DS, De Roos F, Perrone J: Twenty-foot fall averts fatality from massive hydrogen
sulfide exposure. J Emerg Med.2001;20:141–144.
CrossRef [PubMed: 11207408]
46.
Gallay A, Van Loock F, Demarest S et al.: Belgian coca-cola-related outbreak: intoxication,
mass sociogenic illness, or both?Am J Epidemiol. 2002;155:140–147.
CrossRef [PubMed: 11790677]
47.
Gill JR, Marker E, Stajic M: Suicide by cyanide: 17 deaths. J Forensic Sci. 2004;49:826–
828. [PubMed: 15317203]
48.
Gregorakos L, Dimopoulos G, Liberi S et al.: Hydrogen sulfide poisoning: management and
complications. Angiology.1995;46:1123–1131.
CrossRef [PubMed: 7495318]
49.
Guidotti TL: Hydrogen sulphide. Occup Med (Lond).1996;46:367–371.
CrossRef [PubMed: 8918153]
50.
Guidotti TL: Hydrogen sulfide: advances in understanding human toxicity. Int J
Toxicol. 2010;29:569–581.
CrossRef [PubMed: 21076123]
51.
Hall AH, Doutre WH, Ludden T et al.: Nitrite/thiosulfate treated acute cyanide poisoning:
estimated kinetics after antidote. J Toxicol Clin Toxicol. 1987;25:121–133.
CrossRef [PubMed: 3586082]
52.
Hall AH, Rumack BH: Clinical toxicology of cyanide. Ann Emerg Med. 1986;15:1067–1074.
CrossRef [PubMed: 3526995]
53.
Hall AH, Rumack BH: Hydroxycobalamin/sodium thiosulfate as a cyanide antidote. J Emerg
Med. 1987;5:115–121.
CrossRef [PubMed: 3295013]
54.
Hall AH, Saiers J, Baud F: Which cyanide antidote? Crit Rev Toxicol. 2009;39:541–552.
CrossRef [PubMed: 19650716]
55.
Hallam DM, Liao J, Choi K: Manure pit injuries: Rare, deadly, and preventable. J Emerg Trauma
Shock. 2012;5:253–256.
CrossRef [PubMed: 22988406]
56.
Harden B: When suicide conflicts with Japan’s polite society. The Washington Post. Page A09.
May 28, 2008.
57.
Hawley C: Hazardous Materials Air Monitoring and Detection Devices. Clifton Park: Delmar
Cengage Learning; 2006.
58.
Hendrickson RG, Chang A, Hamilton RJ: Co-worker fatalities from hydrogen sulfide. Am J
Industrial Med. 2004;45:346–350.
CrossRef
59.
Hernandez T, Lundquist P, Oliveira L et al.: Fate in humans of dietary intake of cyanogenic
glycosides from roots of sweet cassava consumed in Cuba. Nat Toxins. 1995;3:114–117.
CrossRef [PubMed: 7613736]
60.
Hessel PA, Herbert FA, Melenka LS et al.: Lung health in relation to hydrogen sulfide exposure
in oil and gas workers in Alberta, Canada. Am J Industrial Med. 1997;31:554–557.
CrossRef
61.
Himori N, Tanaka Y, Kurasawa M et al.: Dextrorphan attenuates the behavioral consequences
of ischemia and the biochemical consequences of anoxia: possible role of N-methyl-d-aspartate
receptor antagonism and ATP replenishing action in its cerebroprotecting
profile. Psychopharmacology (Berl).1993;111:153–162.
CrossRef [PubMed: 7870946]
62.
Hoidal CR, Hall AH, Robinson MD et al. Hydrogen sulfide poisoning from toxic inhalations of
roofing asphalt fumes. Ann Emerg Med. 1986;15:826–830.
CrossRef [PubMed: 3729106]
63.
Holstege CP, Forrester JD, Borek HA et al.: A case of cyanide poisoning and the use of arterial
blood gas analysis to direct therapy. Hosp Pract. 2012;38:69–74.
CrossRef
64.
Jensen MS, Ahlemeyer B, Ravati A et al.: Preconditioning-induced protection against cyanide-
induced neurotoxicity is mediated by preserving mitochondrial function. Neurochem
Int.2002;40:285–293.
CrossRef [PubMed: 11792457]
65.
Johnson RP, Mellors JW: Arteriolization of venous blood gases: a clue to the diagnosis of
cyanide poisoning. J Emerg Med.1988;6:401–404.
CrossRef [PubMed: 3147294]
66.
Kage S, Ikeda H, Ikeda N et al.: Fatal hydrogen sulfide poisoning at a dye works. Legal
Medicine. 2004;6:182–186.
CrossRef
67.
Kage S, Ito S, Kishida T et al.: A fatal case of hydrogen sulfide poisoning in a geothermal
power plant. J Forensic Sci.1998;43:908–910. [PubMed: 9670519]
68.
Kage S, Kashimura S, Ikeda H et al.: Fatal and nonfatal poisoning by hydrogen sulfide at an
industrial waste site. J Forensic Sci. 2002;47:652–655. [PubMed: 12051356]
69.
Kage S, Takekawa K, Kurosaki K et al.: The usefulness of thiosulfate as an indicator of
hydrogen sulfide poisoning: three cases. Int J Legal Med. 1997;110:220–222.
CrossRef [PubMed: 9274948]
70.
Kanthasamy AG, Ardelt B, Malave A et al.: Reactive oxygen species generated by cyanide
mediate toxicity in rat pheochromocytoma cells. Toxicol Lett. 1997;93:47–54.
CrossRef [PubMed: 9381482]
71.
Kawada T, Yamazaki T, Akiyama T et al.: Cyanide intoxication induced exocytotic epinephrine
release in rabbit myocardium. J Auton Nerv Syst. 2000;80:137–141.
CrossRef [PubMed: 10785279]
72.
Kilburn KH, Warshaw RH: Hydrogen sulfide and reduced-sulfur gases adversely affect
neurophysiological functions. Toxicol Ind Health. 1995;11:185–197.
CrossRef [PubMed: 7491634]
73.
Kirk MA, Gerace R, Kulig KW: Cyanide and methemoglobin kinetics in smoke inhalation victims
treated with the cyanide antidote kit. Ann Emerg Med. 1993;22:1413–1418.
CrossRef [PubMed: 8363114]
74.
Lambert RJ, Kindler BL, Schaeffer DJ: The efficacy of superactivated charcoal in treating rats
exposed to a lethal oral dose of potassium cyanide. Ann Emerg Med. 1988;17:595–598.
CrossRef [PubMed: 3377288]
75.
Lambert TW, Goodwin VM, Stefani D et al.: Hydrogen sulfide (H2S) and sour gas effects on
the eye. A historical perspective.Sci Total Environ. 2006;367:1–22.
CrossRef [PubMed: 16650463]
76.
Lawson-Smith P, Jansen EC, Hilsted L et al.: Effect of hyperbaric oxygen therapy on whole
blood cyanide concentrations in carbon monoxide intoxicated patients from fire accidents. Scand
J Trauma Resusc Emerg Med. 2010;18:32.
CrossRef [PubMed: 20550698]
77.
Li L, Prabhakaran K, Shou Y et al.: Oxidative stress and cyclooxygenase-2 induction mediate
cyanide-induced apoptosis of cortical cells. Toxicol Appl Pharmacol. 2002;185:55–63.
CrossRef [PubMed: 12460737]
78.
Maduh EU, Borowitz JL, Isom GE: Cyanide-induced alteration of the adenylate energy pool in a
rat neurosecretory cell line. J Appl Toxicol. 1991;11:97–101.
CrossRef [PubMed: 2061557]
79.
Martelli A, Testai L, Marino A et al.: Hydrogen sulphide: biopharmacological roles in the
cardiovascular system and pharmaceutical perspectives. Curr Med Chem. 2012;19:3325–3336.
CrossRef [PubMed: 22680638]
80.
Marziaz ML, Frazier K, Guidry PB et al.: Comparison of brain mitochondrial cytochrome c
oxidase activity with cyanide LD(50) yields insight into the efficacy of prophylactics. J Appl
Toxicol.2013;33:50–55.
CrossRef [PubMed: 21751223]
81.
Mathangi DC, Namasivayam A: Calcium ions: its role in cyanide neurotoxicity. Food Chem
Toxicol. 2004;42:359–361.
CrossRef [PubMed: 14871577]
82.
McCabe L, Clayton GD: Air pollution by hydrogen sulfide in Poza Rica, Mexico; an evaluation of
the incident of Nov. 24, 1950. Arch Ind Hyg Occup Med. 1952;6:199–213.
83.
Milazzo S, Lejeune S, Ernst E: Laetrile for cancer: a systematic review of the clinical
evidence. Support Care Cancer.2007;15:583–595.
CrossRef [PubMed: 17106659]
84.
Mills EM, Gunasekar PG, Pavlakovic G et al.: Cyanide-induced apoptosis and oxidative stress in
differentiated PC12 cells. J Neurochem. 1996;67:1039–1046.
CrossRef [PubMed: 8752110]
85.
Morris J: The Brimstone Battles: Death came from a cloud: A silent killer took 9 lives in 1975.
Could it happen again? Houston Chronicle. 2000.
86.
Nagler J, Provoost RA, Parizel G: Hydrogen cyanide poisoning: treatment with cobalt EDTA. J
Occup Med. 1978;20:414–416. [PubMed: 209160]
87.
Nuskova H, Vrbacky M, Drahota Z et al.: Cyanide inhibition and pyruvate-induced recovery of
cytochrome c oxidase. J Bioenerg Biomembr. 2010;42:395–403.
CrossRef [PubMed: 20725851]
88.
Oesterhelweg L, Puschel K: “Death may come on like a stroke of lightening”: phenomenological
and morphological aspects of fatalities caused by manure gas. Inter J Legal Med.2008;122:101–
107.
CrossRef
89.
Okolie NP, Iroanya CU: Some histologic and biochemical evidence for mitigation of cyanide-
induced tissue lesions by antioxidant vitamin administration in rabbits. Food Chem
Toxicol.2003;41:463–469.
CrossRef [PubMed: 12615119]
90.
Olson KR: A practical look at the chemistry and biology of hydrogen sulfide. Antioxid Redox
Signal. 2012;17:32–44.
CrossRef [PubMed: 22074253]
91.
Oluwole OS, Onabolu AO, Sowunmi A: Exposure to cyanide following a meal of cassava
food. Toxicol Lett. 2002;135:19–23.
CrossRef [PubMed: 12243860]
92.
Onabolu AO, Oluwole OS, Bokanga M et al.: Ecological variation of intake of cassava food and
dietary cyanide load in Nigerian communities. Public Health Nutr. 2001;4:871–876. [PubMed:
11527510]
93.
OSHA Alliance Program: Safety Alert: Deadly Hydrogen Sulfide and Shipyard Sewage. OSHA.
2006.
94.
Peters JW: Hydrogen sulfide poisoning in a hospital setting.JAMA. 1981;246:1588–1589.
CrossRef [PubMed: 6115948]
[JAMA and JAMA Network Journals Full Text]
95.
Pettersen JC, Cohen SD: Antagonism of cyanide poisoning by chlorpromazine and sodium
thiosulfate. Toxicol Appl Pharmacol.1985;81:265–273.
CrossRef [PubMed: 2997948]
96.
Policastro MA, Otten EJ: Case files of the University of Cincinnati fellowship in medical
toxicology: two patients with acute lethal occupational exposure to hydrogen sulfide. J Med
Toxicol.2007;3:73–81.
CrossRef [PubMed: 18072164]
97.
Prabhakaran K, Li L, Borowitz JL et al.: Caspase inhibition switches the mode of cell death
induced by cyanide by enhancing reactive oxygen species generation and PARP-1
activation.Toxicol Appl Pharmacol. 2004;195:194–202.
CrossRef [PubMed: 14998685]
98.
Rajdev S, Reynolds IJ: Glutamate-induced intracellular calcium changes and neurotoxicity in
cortical neurons in vitro: effect of chemical ischemia. Neuroscience. 1994;62:667–679.
CrossRef [PubMed: 7870298]
99.
Ravizza AG, Carugo D, Cerchiari EL et al.: The treatment of hydrogen sulfide intoxication:
oxygen versus nitrites. Vet Hum Toxicol. 1982;24:241–242. [PubMed: 7051515]
100.
Reedy SJ, Schwartz MD, Morgan BW: Suicide fads: frequency and characteristics of hydrogen
sulfide suicides in the United States. West J Emerg Med. 2011;12:300–304. [PubMed: 21731786]
101.
Reiffenstein RJ, Hulbert WC, Roth SH: Toxicology of hydrogen sulfide. Annu Rev Pharmacol
Toxicol. 1992;32:109–134.
CrossRef [PubMed: 1605565]
102.
Rella J, Marcus S, Wagner BJ: Rapid cyanide detection using the Cyantesmo kit. J Toxicol Clin
Toxicol. 2004;42:897–900.
CrossRef [PubMed: 15533029]
103.
Richardson DB: Respiratory effects of chronic hydrogen sulfide exposure. Am J Ind
Med. 1995;28:99–108.
CrossRef [PubMed: 7573079]
104.
Rindone JP, Sloane EP: Cyanide toxicity from sodium nitroprusside: risks and management. Ann
Pharmacother.1992;26:515–519. [PubMed: 1533553]
105.
Riou B, Gerard JL, La Rochelle CD et al.: Hemodynamic effects of hydroxocobalamin in
conscious dogs. Anesthesiology.1991;74:552–558.
CrossRef [PubMed: 2001034]
106.
Shou Y, Gunasekar PG, Borowitz JL et al.: Cyanide-induced apoptosis involves oxidative-stress-
activated NF-kappaB in cortical neurons. Toxicol Appl Pharmacol. 2000;164:196–205.
CrossRef [PubMed: 10764633]
107.
Shou Y, Li L, Prabhakaran K et al.: p38 Mitogen-activated protein kinase regulates Bax
translocation in cyanide-induced apoptosis. Toxicol Sci. 2003;75:99–107.
CrossRef [PubMed: 12805646]
108.
Silverman SH, Purdue GF, Hunt JL et al.: Cyanide toxicity in burned patients. J
Trauma. 1988;28:171–176.
CrossRef [PubMed: 3346915]
109.
Smilkstein MJ, Bronstein AC, Pickett HM et al.: Hyperbaric oxygen therapy for severe
hydrogen sulfide poisoning. J Emerg Med. 1985;3:27–30.
CrossRef [PubMed: 4093555]
110.
Snyder JW, Safir EF, Summerville GP et al.: Occupational fatality and persistent neurological
sequelae after mass exposure to hydrogen sulfide. Am J Emerg Med. 1995;13:199–203.
CrossRef [PubMed: 7893309]
111.
Sousa AB, Soto-Blanco B, Guerra JL et al.: Does prolonged oral exposure to cyanide promote
hepatotoxicity and nephrotoxicity? Toxicology. 2002;174:87–95.
CrossRef [PubMed: 11985886]
112.
Spencer PS: Food toxins, ampa receptors, and motor neuron diseases. Drug Metab
Rev. 1999;31:561–587.
CrossRef [PubMed: 10461541]
113.
Stamyr K, Thelander G, Ernstgard L et al.: Swedish forensic data 1992-2009 suggest hydrogen
cyanide as an important cause of death in fire victims. Inhal Toxicol. 2012;24:194–199.
CrossRef [PubMed: 22369195]
114.
Stine RJ, Slosberg B, Beacham BE: Hydrogen sulfide intoxication. A case report and discussion
of treatment. Ann Intern Med. 1976;85:756–758.
CrossRef [PubMed: 187094]
115.
Thier R, Lewalter J, Selinski S et al.: Possible impact of human CYP2E1 polymorphisms on the
metabolism of acrylonitrile. Toxicol Lett. 2002;128:249–255.
CrossRef [PubMed: 11869835]
116.
Tricarico T: Trics of the Trade: New hazmat threat comes to the US. December 3,
2008.http://www.firehouse.com/article/10474076/trics-of-the-trade-new-hazmat-threat-comes-to-
the-us?page=3. Accessed March 25, 2014.
117.
Truong DH, Eghbal MA, Hindmarsh W et al.: Molecular mechanisms of hydrogen sulfide
toxicity. Drug Metab Rev.2006;38:733–744.
CrossRef [PubMed: 17145698]
118.
Truong DH, Mihajlovic A, Gunness P et al.: Prevention of hydrogen sulfide (H2S)-induced
mouse lethality and cytotoxicity by hydroxocobalamin (vitamin B(12a)). Toxicology.2007;242:16–
22.
CrossRef [PubMed: 17976885]
119.
Truscott A: Suicide fad threatens neighbors, rescuers. CMAJ.2008;179:312–313.
CrossRef [PubMed: 18695173]
120.
Tvedt B, Edland A, Skyberg K et al.: Delayed neuropsychiatric sequelae after acute hydrogen
sulfide poisoning: affection of motor function, memory, vision and hearing. Acta Neurol
Scand.1991;84:348–351.
CrossRef [PubMed: 1772008]
121.
Ursulan S: Confined space entry and compliance. Occup Health Saf. 2009;78:32, 34–35.
122.
van Heijst AN, Douze JM, van Kesteren RG et al.: Therapeutic problems in cyanide
poisoning. J Toxicol Clin Toxicol. 1987;25:383–398.
CrossRef [PubMed: 3430655]
123.
Vanhoorne M, de Rouck A, de Bacquer D: Epidemiological study of eye irritation by hydrogen
sulphide and/or carbon disulphide exposure in viscose rayon workers. Ann Occup
Hyg.1995;39:307–315.
CrossRef [PubMed: 7793750]
124.
Vetter J: Plant cyanogenic glycosides. Toxicon. 2000;38:11–36.
CrossRef [PubMed: 10669009]
125.
Vornov JJ, Tasker RC, Coyle JT: Delayed protection by MK-801 and tetrodotoxin in a rat
organotypic hippocampal culture model of ischemia. Stroke. 1994;25:457–464.
CrossRef [PubMed: 8303757]
126.
Wang H, Chanas B, Ghanayem BI: Cytochrome P450 2E1 (CYP2E1) is essential for acrylonitrile
metabolism to cyanide: comparative studies using CYP2E1-null and wild-type mice.Drug Metab
Dispos. 2002;30:911–917.
CrossRef [PubMed: 12124309]
127.
Warenycia MW, Goodwin LR, Benishin CG et al.: Acute hydrogen sulfide poisoning.
Demonstration of selective uptake of sulfide by the brainstem by measurement of brain sulfide
levels. Biochem Pharmacol. 1989;38:973–981.
CrossRef [PubMed: 2930598]
128.
Way JL, Leung P, Cannon E et al.: The mechanism of cyanide intoxication and its
antagonism. Ciba Found Symp.1988;140:232–243. [PubMed: 3073059]
129.
Weaver LR, Jiang S: China seals gas well after leak. CNN International. December 28,
2003.http://edition.cnn.com/2003/WORLD/asiapcf/east/12/26/china.gas/. Accessed March 25,
2014.
130.
Wiseman P: Suicide epidemic grips Japan. USA Today. July 7, 2008.
131.
Woodall GM, Smith RL, Granville GC: Proceedings of the Hydrogen Sulfide Health Research
and Risk Assessment Symposium October 31-November 2, 2000. Inhal Toxicol.2005;17:593–639.
CrossRef [PubMed: 16033755]
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