Hydrogen Sulfide

Abstract

Hydrogen sulfide (HS), cyanide, azide, and carbon monoxide are collectively referred to as or chemical asphyxiants because of their ability to disrupt aerobic cellular respiration. Exposure to H₂S is associated with a “knockdown” effect and may be rapidly fatal. The American Association of Poison Control Centers reported 766 H₂S exposures in 2013, with 327 treated in a healthcare facility and 10 deaths [1]. Hydrogen sulfide is the second most common cause of fatal gas inhalation in the workplace [2]. Olfactory fatigue to the smell of H₂S occurs quickly and has led to fatal poisoning of rescuers on multiple occasions [3, 4].

Hydrogen sulfide (H₂S), cyanide, azide, and carbon monoxide are collectively referred to as cellular asphyxiants or chemical asphyxiants because of their ability to disrupt aerobic cellular respiration. Exposure to H₂S is associated with a “knockdown” effect and may be rapidly fatal. The American Association of Poison Control Centers reported 766 H₂S exposures in 2013, with 327 treated in a healthcare facility and 10 deaths [1]. Hydrogen sulfide is the second most common cause of fatal gas inhalation in the workplace [2]. Olfactory fatigue to the smell of H₂S occurs quickly and has led to fatal poisoning of rescuers on multiple occasions [3, 4].

Hydrogen sulfide is known as “sewer gas ” and is naturally produced by the putrefaction of organic substances such as sewage, manure, offal, and fish in ships’ holding tanks. Decomposition of sulfur-containing proteins by bacteria produces H₂S. Hydrogen sulfide gas can therefore be anticipated whenever organic material containing sulfur is in an anaerobic environment.

Major industrial uses for H₂S include production of elemental sulfur, inorganic sulfides, and sulfuric acid. Hydrogen sulfide is also found as an additive in high-pressure lubricants and cutting oils. Hydrogen sulfide is a commonly encountered toxin in several industries including paper making, leather tanning, and most notably, oil and natural gas production. “Sour gas ” refers specifically to natural gas that contains significant quantities of hydrogen sulfide; H₂S must be removed from the gas prior to its use as fuel [5].

Hydrogen sulfide is also naturally produced and liberated from volcanos and undersea vents. One example occurs in the Puna District on the island of Hawaii, where an active volcano emits H₂S, typically in concentrations of less than 20 parts per billion (ppb) [6]. A similar volcanic off-gassing site exists in the City of Rotorua on the north island of New Zealand [7] (Table 1).

Table 1 Selected natural and industrial sources of hydrogen sulfide

In 2007, the first case of “detergent suicide” was reported in Japan. This method of suicide involves mixing a commercially available, sulfur-containing product with an acidic toilet bowl cleaner to produce hydrogen sulfide gas. Instructions and ingredient lists were published and rapidly popularized through internet message boards. By 2008, an epidemic of detergent suicides was underway in Japan, with nationwide deaths due to hydrogen sulfide poisoning increasing from 27 in 2007 to 1,027 in 2008 [8]. In the United States, hydrogen sulfide suicides increased from 2 in 2008, to 10 in 2009, and 18 in 2010 [9]. Detergent suicides have caused evacuation of commercial and residential buildings; fatalities among family members with secondary exposure have also been reported [8, 10].

Biochemistry and Clinical Pharmacology

Hydrogen sulfide is normally present in small amounts in the human body. As a component of intestinal gas, H₂S has been found in concentrations of 1–4 ppm with some high levels of 18 ppm [11]. Hydrogen sulfide is synthesized in small amounts in neuronal cells and within the cardiovascular system, in addition to being released from intracellular sulfur stores. Recent studies demonstrate many physiological effects of endogenous H₂S, and it has been proposed as the third gasotransmitter , a family of small molecules that participate in cell signaling via diffusion across cell membranes [12].

Hydrogen sulfide appears to be an important vasoactive agent similar to nitric oxide. It has been reported to have an inotropic effect and alter the growth of vascular endothelial cells [13]. There is also a link between H₂S and insulin release [14]. In the CNS, there appear to be physiological roles in GABA and NMDA transmission [15]. Hydrogen sulfide can reduce reactive oxygen species both directly and via increasing glutathione production, protecting neuronal cells from death [16]. Hydrogen sulfide is currently being investigated for neuroprotective, cardioprotective, antioxidant, and anti-inflammatory effects, with several experimental H₂S-donating drugs under study [12]. At higher doses, however, predictable toxic effects of H₂S occur that are discussed in detail below.

Hydrogen sulfide is a colorless gas, slightly heavier than air, with a relative vapor density of 1.19, and is slightly less volatile than water at room temperature. It has a molecular weight of 34.08 g/mol. Hydrogen sulfide has a water solubility (3.2 g/L at 30 °C) between ammonia, which is highly soluble, and chlorine, which has low solubility. Its metabolism is rapid; no bioaccumulation occurs [11]. H₂S smells like rotten eggs. However, olfactory fatigue and the loss of the ability to smell H₂S can occur in seconds. The odor threshold is reported in the range of 1–130 ppb, with olfactory fatigue occurring around 100 ppm [17].

The principle pathway of exposure is via inhalation. It has minimal absorption through the gastrointestinal tract and intact skin. Hydrogen sulfide is highly lipid soluble and rapidly diffuses across cellular membranes. Following human exposure, distribution to tissues is rapid [18].

Hydrogen sulfide is metabolized by three major pathways . The primary metabolic elimination pathway is via oxidation of sulfide to thiosulfate, which is converted into sulfate, ultimately being excreted in the urine [19]. Hydrogen sulfide is also metabolized by methylation and reactions with metalloproteins or disulfide-containing proteins. Though in vitro studies demonstrated H₂S-induced sulfhemoglobinemia , recent evidence suggests that clinically significant sulfhemoglobinemia does not occur in acute hydrogen sulfide poisoning [20].

Pathophysiology of Toxic Effects

Hydrogen sulfide causes cellular anoxia by the inhibition of mitochondrial cytochrome c oxidase. This inhibition results in disruption of the electron transport chain, impairing oxidative metabolism and the resultant production of ATP. Tissues with high metabolic demands (e.g., brain and heart) are therefore especially susceptible [11].

Hydrogen sulfide also may reduce disulfide bridges in proteins, which is thought to be the mechanism of its inhibition of succinate dehydrogenase. Because of its water solubility, H₂S has irritant effects on moist mucous membranes but also may result in distal airway injury if a high respiratory rate is maintained while exposed. Minimal H₂S is excreted via the lungs.

Hydrogen sulfide directly stimulates carotid arterial chemoreceptors, causing an increased respiratory rate . Noncardiogenic pulmonary edema may develop prior to respiratory arrest. Terminal respiratory depression likely results from H₂S being selectively taken up by respiratory center of the brainstem with an end point similar to anoxia. The underlying mechanism is thought to be inhibition of monoamine oxidase [21, 22].

Clinical Presentation and Life-Threatening Complications

Two common adverse effects occur after H₂S poisoning: mucous membrane irritation and systemic toxicity. These occur in a dose–response fashion (Table 2). Hydrogen sulfide reacts with water to form irritating acid sulfides. Mucous membranes are especially susceptible to the effects of H₂S because of their moisture and anatomic proximity to the environment. The irritant effects of H₂S to the face are sensed by the trigeminal nerve and the olfactory nerve detects its odor, although there may be significant overlap between these two domains.

Table 2 Range of toxicity of hydrogen sulfide (Adapted from references [11, 23, 24])

Membrane irritation begins to occur with H₂S exposures in the range of 2–5 ppm. Mild nausea, vomiting, and lacrimation tend to occur in the range of 80–100 ppm. Higher concentrations, in the range of 500 ppm, typically are required to cause immediate respiratory symptoms. Obvious signs of systemic toxicity tend not to occur until H₂S concentrations of approximately 250 ppm have been attained. Findings at these concentrations may include cough, tachypnea, chest pain, headache, dizziness, lethargy, and confusion. At still higher concentrations, seizures and coma occur. Concentrations of 1,000 to 3,000 ppm were fatal to dogs; death occurred within 15–20 min at 1,000 ppm. At the higher concentration, respiration ceased after a few breaths [21]. The most common clinical findings after H₂S exposures are headache, nausea, vomiting, dyspnea, disequilibrium, conjunctivitis, sore throat, and unconsciousness [25]. A toxidrome for hydrogen sulfide poisoning has been proposed by Guidotti, consisting of any one or combination of the following effects:

• Odor perception (followed by olfactory paralysis)

• Conjunctivitis

• Pulmonary edema

• Acute central neurotoxicity (“knockdown”) [2].

Ocular Effects

The eyes react first to the irritant effects of H₂S. As levels increase, the conjunctivae may become inflamed and swollen. After major exposures, the cornea may develop erosions and ulcerations. Associated signs and symptoms include photophobia, lacrimation, and pain. Because both the cornea and the conjunctivae are affected, the term keratoconjunctivitis is used to describe the eye effects. This is known in industry as “gas eye .” Visual impairment lasting for days has been reported. The possibility of permanent blindness after hydrogen sulfide exposure remains controversial [26].

Knockdown Effects

Hydrogen sulfide is known for its rapid “knockdown” capability. At ambient concentrations of 700–1,000 ppm H₂S, exposed persons may suddenly collapse. If the exposure is terminated promptly, this situation may result in no residual effects [27]. Frequently, workers in the oil fields report this effect; after recovering, they resume their work [5]. If exposure is not terminated, respiratory arrest may occur rapidly.

Pulmonary Effects

Inhaled irritants tend to increase the respiratory rate and decrease the minute volume. Hydrogen sulfide directly produces an increase in ventilation mediated by carotid arterial chemoreceptors at doses below those sufficient to cause central apnea [28]. Significant H₂S exposure may result in redness, inflammation, sloughing, or exfoliation of the airways as H₂S reacts with the moisture of the mucosal surfaces. Hemorrhagic bronchitis has been reported and may require ventilatory support [29].

Due to the moderate water solubility of H₂S, the gas can penetrate the deep airways of the lung and injure alveoli, causing pulmonary edema. The prevalence of pulmonary edema in H₂S-poisoned patients reaching the emergency department has been reported from 4% to 20% [2, 27]. Pulmonary edema appears to make a small contribution to mortality in H₂S poisoning, presumably because respiratory arrest occurs so rapidly in those severely poisoned. Cases of interstitial pulmonary fibrosis following hydrogen sulfide poisoning have also been reported, but appear to be exceptionally rare [30].

Cardiovascular Effects

Typical and atypical chest pain, dysrhythmias, and acute myocardial infarction with heart failure are reported after H₂S exposure [31]. Cardiovascular effects are most likely due to cellular anoxia, rather than direct toxic effects of H₂S on cardiac myocytes. In fact, recent literature describes protective effects of low levels of H₂S against myocardial ischemia/reperfusion injury, infarction, and cardiac dysrhythmias in animal and in vitro models [32, 33].

Neurologic Effects

Early-onset neurologic symptoms (dizziness, ataxia, headache, “knockdown”) are believed to be due to direct toxic effects of hydrogen sulfide. Coma, seizures, or signs of increased intracranial pressure from edema may occur in the setting of cerebral anoxia. Those who survive acute exposures to high levels of H₂S frequently make a complete neurologic recovery. However, some H₂S poisonings with loss of consciousness have been associated with long-term neurological dysfunction, including headaches, memory problems, motor dysfunction, and neuropsychiatric effects [24]. These are proposed to result from secondary anoxic brain injury caused by respiratory arrest, seizures, or other hypoxia resulting from H₂S poisoning (i.e., pulmonary edema) [2]. Trauma may also accompany acute H₂S exposures due to knockdown effects, confounding the causality assessment of neurological sequelae [34, 35]. Although acute high-level exposures may result in altered neurological function, quality evidence that chronic low-level exposures cause long-term harm is lacking.

Metabolic Acidosis

Metabolic acidosis, with elevated lactate concentration, may occur in individuals with serious H₂S poisoning due to impairment of oxidative phosphorylation , ATP consumption exceeding production, and the resulting shift to anaerobic metabolism.

Death

Twenty-nine deaths from 5,563 H₂S exposures in the United States were reported to the American Association of Poison Control Centers over a 9-year period [23]. Most fatal cases involved exposures occurring in confined spaces, such as sewer s, animal-handling and processing plants, waste dumps, sludge plants, tanks and cesspools, pulp mills, and other confined environments. In case reports of deaths occurring after acute H₂S exposure, individuals lost consciousness after only one or two breaths; this is known as the “slaughterhouse sledgehammer” effect [23, 36–39]. In these fatal cases, patients seemed to succumb from respiratory failure, acute pulmonary edema, or coma. Patients exposed to only H₂S gas do not have a substantial risk of secondary contamination to personnel outside the so-called hot zone. Rescuers should be trained and attired properly with positive-pressure, self-contained breathing apparatus before entering the hot zone.

Diagnosis

The exposure history and clinical presentation are the keys to making the diagnosis of acute hydrogen sulfide poisoning. A rotten egg odor on a patient or their belongings is suggestive of H₂S, though other agents have a similar smell, including sulfur compounds such as mercaptans, carbon disulfide, and trimethylamine. Historically, dark discoloration of a patient’s coins and jewelry has been suggested as a clue to H₂S poisoning.

Important toxicologic differential diagnoses with presentation similar to H₂S poisoning include other cellular asphyxiants , such as carbon monoxide, cyanide, azide, and cyanide-related substances.

The presence of metabolic acidosis can be further evaluated by assessment of arterial blood gases with co-oximetry, electrolytes, and lactate concentrations. If the diagnosis of H₂S poisoning is not immediately obvious, cyanide, toxic alcohols (ethylene glycol, methanol), salicylate, and carboxyhemoglobin concentrations should be obtained, if indicated by the clinical history.

Sulfide ion levels can be measured on whole blood. However, lack of specificity, difficulty in performing the test accurately, and limited availability make sulfide levels useless in initial diagnosis [18]. One case series found urine thiosulfate concentrations elevated in nonfatal H₂S poisoning, despite undetectable blood sulfide levels. Urine thiosulfate may therefore be a useful means of confirming H₂S poisoning in patients who survive exposure [40]. Industrial hygienists, hazardous materials responders, and firefighters can measure H₂S concentrations in the ambient atmosphere around the site of an incident. In the case of an identified H₂S release or exposure, it is critical that H₂S concentrations are directly communicated with the individuals on site, so that appropriate precautions can be taken and secondary casualties prevented.

Treatment

Supportive care is the mainstay of therapy for exposures to H₂S. This includes removal from exposure, administration of supplemental oxygen, and decontamination of the eyes and skin. Decontamination can be accomplished by copiously irrigating exposed skin and eyes with normal saline or water. Ventilatory support, administration of anticonvulsants if there is seizure activity, intravenous fluids, and vasopressors may be necessary. Cycloplegics and antibiotics may be needed for eye injuries. Systemic antibiotics may be indicated if there is evidence of superinfected aspirated pulmonary secretions.

Indications for ICU Admission in Hydrogen Sulfide Poisoning

Respiratory distress, respiratory failure, or signs of airway injury

Unconsciousness

Seizures or persistent neurological impairment

Electrocardiogram changes

Methemoglobin Induction

One possible antidotal therapy is induction of methemoglobinemia. Hydrogen sulfide poisoning causes lactic acidosis by the inhibition of cytochrome c oxidase and depletion of ATP. The formation of methemoglobinemia by nitrites creates a large pool of ferric iron, which has a greater affinity than cytochrome c oxidase for H₂S. Methemoglobin may therefore serve as a sink, allowing cytochrome c to be reactivated and reestablishing aerobic metabolism [41–43]. However, the period during which H₂S is available in blood after removal from exposure is short-lived. One animal model found no benefit to infusion of a methemoglobin solution 90 s after termination of a toxic H₂S exposure [44]. Future research is needed to determine if antidotes that propose to work by binding diffusible H₂S, including methemoglobin induction, are truly effective.

One method of inducing methemoglobinemia is by use of sodium nitrite, which may be found as a component of a cyanide antidote kit. The use of nitrites in H₂S poisoning is supported by animal studies and human case reports (Grade III evidence) [45, 46]. Intravenous (IV) access should be established as soon as possible and IV sodium nitrite administered once the decision is made to induce methemoglobinemia. The generally accepted adult dose of sodium nitrite is 10 mL of a 3% solution; the pediatric dose is 0.33 mL/kg up to 10 mL but may be adjusted based on hemoglobin level. Because sodium nitrite is a potent vasodilator, it should not be administered rapidly, but given over 2–5 min. The thiosulfate portion of the cyanide antidote kit is not useful in H₂S poisoning. Sulfide is present in the blood only transiently, and methemoglobin therapy is not indicated in most patients. If a patient has persistent acidosis, shock, cardiotoxicity, or coma despite optimal supportive care, the authors recommend induction of methemoglobinemia given the above animal and case-based human evidence supporting possible benefit.

Hydroxocobalamin and Cobinamide

Hydroxocobalamin, a precursor of Vitamin B₁₂, and cobinamide, a Vitamin B₁₂ analog, both have a high affinity for sulfides and have been investigated as possible antidotes for H₂S poisoning. Animal models suggest a reduction in lethality and amelioration of cardiac depression with hydroxocobalamin treatment [47, 48]. A single fatal human case report notes a reduction in blood sulfide levels after hydroxocobalamin treatment [49]. One rabbit model shows increased survival and binding of sulfide to cobinamide [50]. However, in these animal models, sulfide is continuously infused, generating a constant supply of H₂S that may complex with an antidote before entering cells. Neither hydroxocobalamin nor cobinamide has yet proven clinically useful in human H₂S poisoning. Again, this may be due to the extreme rapidity with which free hydrogen sulfide leaves the circulation and enters tissues, once victims are removed from exposure. Any complex-forming antidote that cannot be administered almost immediately is likely to be of limited value [51–53]. Given the current absence of evidence supporting antidotal effects of hydroxocobalamin and cobinamide in humans, the authors recommend against their use in hydrogen sulfide poisoning (Grade III Evidence).

Hyperbaric Oxygen

Hyperbaric oxygen is a theoretical therapy for H₂S poisoning. A few case reports and retrospective series have described using hyperbaric oxygen for H₂S poisoning. In these cases, positive outcomes were reported (Grade III Evidence) [54, 55]. However, these data are uncontrolled and subject to publication bias. The pillar of evidence-based treatment for human hydrogen sulfide poisoning remains supportive care, once the patient has been removed from the source of exposure. Hyperbaric oxygen therapy is rarely immediately available and logistically often interferes with the provision of supportive care. It is therefore the authors’ opinion that hyperbaric oxygen should not be used in human H₂S poisoning. Current evidence that does not demonstrate a clear benefit and there is a high likelihood that hyperbaric oxygen treatment will delay other beneficial aspects of care.

Prehospital Treatment

A study of 250 cases of exposure to H₂S in the Alberta oil fields found that with increased awareness and improved prehospital treatment, the fatality rate was reduced from 6% to 2.8%, unconsciousness on hospital arrival decreased from 13% to 2%, and hospital admission rates decreased from 51% to 22%. Prehospital treatment also resulted in an overall decrease in workers’ compensation claims [34].

Prevention

Safety officers, industrial hygienists, and workers in those industries should learn the hazards of H₂S and the proper response in the event of an accident. Safe evacuation and prompt medical attention are important. Real-time gas detecting devices are available and should be used to monitor levels of H₂S before entry into a potentially contaminated zone.

Common Errors in Hydrogen Sulfide Poisoning

Failure to consider hydrogen sulfide in cases of rapid knockdown, multiple victim poisonings at a single site, or unexplained poisoning in a confined space

Failure to account for olfactory fatigue to hydrogen sulfide gas

Failure to protect emergency personnel during attempted rescue of poisoned patients

Failure to consider hydrogen sulfide in cases of seizure, coma, or metabolic acidosis

Failure to assess for trauma secondary to sudden unconsciousness

Failure to treat on the basis of clinical presentation rather than reported or suspected exposure

Failure to perform ocular decontamination

Evidence-Based Recommendations for Practice

Clinical Recommendation	Evidence rating
Supportive care should include decontamination and oxygen supplementation	III
Methemoglobin induction with sodium nitrite may be considered for severely poisoned patients that remain symptomatic in medical care	III
Patients severely poisoned by H2S should be evaluated for concomitant trauma	III

Key Points in Hydrogen Sulfide Poisoning

• 1. Hydrogen sulfide causes a rapid knockdown effect.

• 2. Decontamination is essential.

• 3. Safe removal from exposure and supportive care is the mainstay of therapy.

• 4. Trauma frequently accompanies H₂S poisoning and must be evaluated and treated.

• 5. Induction of methemoglobinemia with IV sodium nitrite may be antidotal.

• 6. Vitamin B₁₂ and its analogs currently lack human evidence for effectiveness.

• 7. Hyperbaric oxygen therapy currently lacks human evidence for effectiveness.

Grading System for Levels of Evidence Supporting Recommendations in Critical Care Toxicology, 2nd Edition

• I Evidence obtained from at least one properly randomized controlled trial.

• II-1 Evidence obtained from well-designed controlled trials without randomization.

• II-2 Evidence obtained from well-designed cohort or case–control analytic studies, preferably from more than one center or research group.

• II-3 Evidence obtained from multiple time series with or without the intervention. Dramatic results in uncontrolled experiments (such as the results of the introduction of penicillin treatment in the 1940s) could also be regarded as this type of evidence.

• III Opinions of respected authorities, based on clinical experience, descriptive studies and case reports, or reports of expert committees.