Hydrogen Sulfide Toxicity

Etiology

Hydrogen sulfide toxicity typically results from gaseous exposure that initially acts as an irritant and later acts at the cellular level, inhibiting mitochondrial respiration. Inhalation is the most common route of exposure for the toxic substance to enter the bloodstream, although it can also be minimally absorbed through the skin.[2] Hydrogen sulfide is heavier than air and tends to accumulate and concentrate near the floors of poorly ventilated rooms rather than dispersing into the air.[1][10]

The bacterial decomposition of proteins, such as the decay of sulfur-containing fish, sewage, and manure, generates hydrogen sulfide. Environmental sources of hydrogen sulfide include volcanoes, caves, sulfur springs, and underground deposits associated with natural gas. The Maori people of Rotorua, New Zealand, live in an environment abundant with sulfur springs and geothermal sources of hydrogen sulfide and have been studied as a natural population of chronic low-level exposure to this gas.[8][9]

Hydrogen sulfide is the second most common cause of fatal gas inhalation in the workforce; carbon monoxide exposure is the most common.[8] There are several industries where exposure to hydrogen sulfide is a known risk, including pulp and paper mills, heavy-water production, roofing asphalt tanks, rubber vulcanization, viscose rayon production, and the leather industry. Agricultural workers in contact with livestock manure storage tanks and those working within sewers or sewer manholes are also at great risk of exposure and toxicity.[11][12] 

A distinctive characteristic of toxicity is its capacity to induce reversible unconsciousness, termed knockdown, if the patient is promptly rescued. Individuals who have undergone or experienced knockdown have been described as falling "as if letting the strings loose on a marionette."[8] Hydrogen sulfide presents a notable hazard to potential rescuers, as they frequently become affected themselves. Reports suggest that up to 25% of hydrogen sulfide toxicity fatalities involve rescuers.[13][14][15] 

The combustible nature of hydrogen sulfide gas increases the risk of explosions; hence, burns and traumatic injuries are additional concerns. All affected individuals should be assessed for acute traumatic injuries if they survive toxic exposure to ensure they receive proper medical attention. 

More recently, hydrogen cyanide has been used as a means of self-harm through chemical suicides and detergent suicides. This self-harming practice involves intentionally mixing common household chemicals and creating hydrogen sulfide gas. If performed within an enclosed space, such as a car, death can occur rapidly. As with occupational exposures, this method of suicide is a risk to rescuers and bystanders.

Hydrogen sulfide is also considered to have the ideal properties of a chemical weapon due to its lethality and ease of production. References to this can be found in terrorist training manuals, such as The Mujahideen Poisons Handbook.[16]

Epidemiology

There are more than 80 occupations where hydrogen sulfide can pose a health risk following acute incidents and chronic toxicity.[9] Second to carbon monoxide, hydrogen sulfide is the second most common cause of fatal gas inhalation in the workplace.[8] Despite this fact, acute hydrogen sulfide cases are sporadic, unpredictable, and relatively uncommon.

Two notable historical cases of industrial accidents highlight the danger of hydrogen sulfide. In 1950, a refinery explosion in Poza Rica, Mexico, hospitalized 320 people and resulted in 22 fatalities. The other occurred in Kaixian County, China, in 2003 following a gas pipe explosion resulting in 243 deaths.[9]

In addition to industrial exposure, it was popularized as a method of suicide in Japan in 2007. In Japan, 200 people died in 2008 through this method.[17] Suicides by this method increased significantly before strongly trending downward.[17][18][17] Approximately 80% of suicide attempts have resulted in the toxicity of first responders and civilians near the scene.[19] In the United States, from 1999 to 2007, 45 deaths were reported from chemical suicides involving hydrogen sulfide, with injuries also to first responders.[16] The majority of these deaths occurred in individuals greater than 20. Less than 1% of unintentional exposure to hydrogen sulfide results in death, whereas the mortality rate in intentional cases exceeds 50%.[14][20][21][22][23]

The 2022 annual report on the National Poison Data System (NPDS), sourced from America's poison centers, documents 779 exposures to hydrogen sulfide. Among these exposures, 762 were unintentional, with 323 individuals receiving treatment in a healthcare facility, resulting in3 fatalities. The report highlighted one case of intentional exposure with suicidal intent involving a female who was found unresponsive in her car with a bucket of chemicals. Unfortunately, she died on day 2 of hospitalization due to hypoxic-ischemic encephalopathy caused by hydrogen sulfide poisoning.[24]

Pathophysiology

In addition to its known exogenous sources, hydrogen sulfide is produced endogenously by cystathionine beta-synthase within the central nervous system. Hydrogen sulfide has a role in neuromodulation, smooth muscle relaxation, insulin regulation, inflammation, and responsiveness to oxidative stress.[16] 

Hydrogen sulfide has a distinctive odor of rotten eggs at low concentrations of 0.01 to 0.03 ppm, which is an excellent warning sign. However, at higher and more dangerous concentrations of around 100 ppm, neurotoxicity occurs with olfactory paralysis, and this warning signal of pending toxicity is lost.[9] Toxicity is concentration-dependent, with higher concentrations being more toxic even when considering a shorter exposure time. When inhaled, this irritation can lead to pulmonary injury, presenting as pulmonary edema.

Hydrogen sulfide poisoning mainly occurs by inhalation, but local irritation to mucus membranes can result in direct irritation, mainly to the eyes. Irritative conjunctivitis, known as gas eye, can be observed in individuals exposed to low levels of hydrogen sulfide for prolonged periods, approximately at 20 ppm. This superficial inflammation from the irritant effects is another warning property of the gas.

Hydrogen sulfide inhibits mitochondrial cytochrome C oxidase by making a complex bond to the ferric moiety of the protein, thereby arresting aerobic metabolism and blocking ATP synthesis.[9] This mechanism of toxicity is similar to hydrogen cyanide. Once aerobic metabolism is arrested, lactic acidosis and resultant oxidative stress develop, culminating in cell death. In addition, it reacts with iron to enhance the Fenton reaction, leading to free radical damage.[25] Once it enters the bloodstream and passes the blood-brain barrier, neurotoxic effects can be observed, including dizziness, seizure, coma, and, ultimately, death.[2][16][26] The cortex, basal ganglia, and brainstem are most sensitive to hydrogen sulfide. At concentrations above 1000 ppm, inhibition of the breathing center leads to apnea, even after a few breaths.[27]

Animal studies have reported marked disruption in the lung surfactant activity, increased lactate dehydrogenase activity, and increased total protein in the bronchoalveolar lavage fluid.[28][29]

Pathophysiological Effects of Hydrogen Sulfide Depending on Concentration [1] 

Toxicokinetics

Hydrogen sulfide is a gas, and human exposure and toxicity are most commonly through the inhalational route. Due to the gas' high lipid solubility, it is rapidly distributed into tissues. At physiological pH, two-thirds of hydrogen sulfide exists as hydrogen sulfide ion (HS-), and the remaining one-third is undissociated hydrogen sulfide (H₂S).[30] Hydrogen sulfide ions interact with metalloproteins, enzymes containing disulfide bonds, and thiol-S-methyltransferase. Upon absorption, it rapidly undergoes phase I oxidation, primarily through sulfide oxidation pathways located in the mitochondria. Sulfide quinone oxidoreductase (SQR), sulfide dioxygenase (SDO/ETHE1), and rhodanese are the main enzymes involved in detoxifying hydrogen sulfide. Hydrogen sulfide also undergoes phase II metabolism by thiol-S-methyltransferase within the liver and intestines, although at a rate 10,000 times slower compared to oxidation. The primary metabolite, thiosulfate, is excreted through the kidney.[9] 

Sulfhemoglobin is not found in the blood of patients, even in cases of high-concentration exposures.[8][31][32] 

History and Physical

Hydrogen sulfide toxicity should be considered in any individual found unconscious in an enclosed space or experiencing knockdown. Obtaining occupational history and recent local travel history is crucial, such as working in a petroleum plant, as a sewage inspector, or traveling to a natural hot spring or volcano. Patients may typically report a strong rotten egg smell before the onset of symptoms. However, it is essential to note that hydrogen sulfide rapidly paralyzes olfactory nerves, and after continued exposure, patients may fail to recall the malodorous scent. Lack of malodor should not be relied upon as a definitive exclusion of hydrogen sulfide toxicity.

Another potential key to diagnosis is the darkening of silver jewelry or coins. This reaction occurs due to the hydrogen sulfide's conversion of silver to silver sulfide, leading to a blackening of color.[33] 

Toxicity is dependent on the concentration of hydrogen sulfide exposure. Low-level exposure presents with irritation to mucous membranes, headache, insomnia, dizziness, and fatigue. High-level exposure presents with cough, dyspnea, hemoptysis, nausea, vomiting, and vertigo. Very high-level exposure presents myocardial infarction, rapid loss of consciousness (knockdown), seizures, and cardiopulmonary arrest. Clinical examination findings for low-dose exposure include conjunctivitis, a green-gray line on the gingiva, and pharyngitis. Clinical examination findings for high-level exposure include bradycardia, agitation, cyanosis, and acute lung injury. At higher doses, pulmonary edema, hemoptysis (hemorrhagic pulmonary edema), and delayed corneal injury may occur. Higher doses may also induce neurological symptoms of seizure, coma, and, ultimately, death.[2][6][7][16][26][34]

Toxic effects are also dependent on the duration of hydrogen sulfide exposure. Gas eye is a superficial inflammation of the cornea and conjunctiva that occurs in individuals exposed to low concentrations of hydrogen sulfide for a prolonged time. In addition to the irritation, reversible chromatic distortion and visual changes can be observed.[8] Halos around objects, blepharospasm, tearing, and photophobia are also observed. 

The tetrad of knockdown, pulmonary edema, conjunctivitis, and odor perception followed by olfactory paralysis is a unique toxidrome observed in hydrogen sulfide toxicity. 

Evaluation

No clinically available biological markers or direct measurements of hydrogen sulfide are useful in the medical setting. Confirmation of poisoning is impossible in the acute setting, although whole blood samples can be sent for analysis. A whole blood sulfide concentration above 0.05 mg/L is abnormal, but this sample must be obtained within 2 hours of exposure and analyzed immediately.[35]

Blood and urine thiosulfate concentrations reflect exposure to hydrogen sulfide in the acute setting. Still, these lab assays are not available in most institutions and, therefore, are unable to affect clinical management.[36] Urine thiosulfate is used in the workplace to monitor chronic low-level exposure. 

An arterial blood gas is expected to show acidemia with an elevated lactate level and can used as a surrogate marker of toxicity. However, this is nonspecific and can be observed in many clinical scenarios that do not involve hydrogen sulfide gas. Similar to cyanide, hydrogen sulfide inhibits oxygen utilization and is expected to have an elevated partial pressure of oxygen measured on a venous blood gas sample. 

Up to 20% of patients who undergo medical care are estimated to display some evidence of pulmonary edema.[37] A chest radiograph should be obtained. 

A thorough evaluation for trauma should be performed, with imaging such as computed tomography scans of the head and cervical spine, as many sustain traumatic brain injuries from the knockdown and fall.[8][38]

Treatment / Management

Initial treatment after exposure to hydrogen sulfide involves rapid removal from the source and decontamination. Rescuers must protect themselves and utilize personal protective equipment to prevent exposure and toxicity to themselves. Decontamination with water is required if ocular or skin irritation is present. Clothing should be removed and double-bagged. Hydrogen sulfide is poorly absorbed through the skin, but the clothing can emit further gas, which puts healthcare workers and other rescuers at risk of toxicity.[9] Supplemental oxygen should be provided as soon as safely possible. All patients who have experienced a fall, as in the case of a knockout, should be evaluated for signs of trauma, and Advanced Trauma Life Support (ATLS) protocol should be followed.

There is no antidote for hydrogen sulfide, and treatment involves aggressive supportive care. This treatment regimen encompasses administering crystalloids and vasopressors for hypotension, maximizing ventilation and oxygenation, and administering sodium bicarbonate according to arterial blood gas and serum bicarbonate concentrations.

There are multiple treatment modalities with inconsistent efficacy. One of these is the administration of 300 mg of sodium nitrite intravenously for 2 to 4 minutes. Sodium nitrite causes methemoglobin to accumulate at low levels. Hydrogen sulfide has a higher affinity for methemoglobin compared to what it does for cytochrome oxidase, and the theory is that it displaces and regenerates this enzyme to restore cellular respiration. Sulfmethemoglobin is generated in this process and excreted. This medication is most effective if given within minutes, as hydrogen sulfide toxicity escalates rapidly. After treatment with sodium nitrite, methemoglobin levels should be checked within 30 to 60 minutes, with ideal levels below 30%. If levels of methemoglobin become concerning, methylene blue may be administered. This treatment modality is not without risk, as it can potentiate the anoxia already present and can lead to further hypotension and hypoperfusion.[8][9][16] (B3)

Due to the similarities between hydrogen sulfide and cyanide toxicity, hydroxocobalamin and its analog cobinamide have been investigated as alternative therapies for hydrogen sulfide toxicity. As hydrogen sulfide has a high affinity for metalloproteinases, the goal of utilizing hydroxocobalamin is to bind the hydrogen sulfide in the blood and prevent free sulfide from reaching its target within the tissue, causing toxicity. Cobinamide has two binding sites for hydrogen sulfide, as opposed to the single site on hydroxocobalamin. Due to the rarity of toxicity, human studies are limited, but there is conflicting data in animal research on the efficacy of these treatment modalities. Due to the lethality of hydrogen sulfide toxicity, administering either sodium nitrite or hydroxocobalamin to seriously ill individuals is considered reasonable.[16][30]

Methylene blue is an antioxidant with the potential to oxidize sulfide, increase hydrogen sulfide trapping within the blood, restore the cell's redox potential, and restore normal mitochondrial function. Multiple animal models are being used to investigate its potential in treating humans.[9][16][39][40] (B2)

In addition to medical therapies for treating hydrogen sulfide toxicity, there is limited evidence to suggest that hyperbaric oxygen can help improve the delivery of oxygen to end organs. Oxygen therapy has been shown to reactivate oxidative phosphorylation competitively, enhance the detoxication of hydrogen sulfide, and improve oxygenation in patients with acute respiratory distress syndrome. There is no evidence that hyperbaric oxygen is superior to normobaric oxygen. Not every center can provide hyperbaric therapy; aggressive supportive care and normobaric oxygen delivery should not be delayed to provide hyperbaric oxygen.[16][26][30][26][41][42][43][44] (B3)

Differential Diagnosis

Other gaseous toxicities can present with symptoms similar to hydrogen sulfide toxicity. Context is critical when differentiating many of these toxic gases with overlapping symptoms. The following differentials should be considered when diagnosing a patient with hydrogen sulfide toxicity.

• Cyanide has a mechanism of action similar to hydrogen sulfide, and patients may also have an overlap of some symptoms, including seizures, tachypnea, and coma. Cyanide, however, is more likely to also present with headache, nausea, vomiting, arrhythmias, cyanosis, and renal and hepatic failure. Cyanide classically has the odor of bitter almonds rather than the rotten egg smell of hydrogen sulfide.[45]
• Patients with carbon monoxide poisoning and methemoglobinemia can also present with headache, dyspnea, and confusion but are also more likely to have symptoms of chest pain, nausea, and vomiting. Co-oximetry can help rule out carbon monoxide poisoning and methemoglobinemia.[46][47][48]
• Exposure to ammonia, chlorine, and sulfur mustard gases also causes mucus membrane irritation, accompanied by rapid clinic decompensation.
• Hydrocarbons commonly cause dyspnea and cough and may lead to respiratory distress. Infiltrates can be observed on a chest X-ray. Central nervous system depression and myocardial dysfunction can also occur.[49]
• Sudden unexpected death in epilepsy (SUDEP) can be mimicked by hydrogen sulfide toxicity, as it can induce a seizure, followed by death.[9] 

Prognosis

For individuals who have experienced knockdown due to high concentrations of hydrogen sulfide and are not removed from the source of exposure, death is rapid. Individuals who recover often appear to return to complete functional capacity. Still, there is evidence that they are at high risk for residual neurological impairment, which is further complicated by the potential for brain injury and anoxia due to trauma.[8][41][43] 

Data on the long-term effects of low-level exposure are conflicting. Studies on the population of Rotorua, New Zealand, who live near geothermal vents, found no correlation between their hydrogen sulfide exposure and cognitive function. However, they were at higher risk for respiratory illnesses such as chronic obstructive pulmonary disease, influenza, and pneumonia.[9] Data on these ecological studies are weak, as various confounding factors were not considered; for example, mercury and other sulfide levels were not measured.[8] Similarly, studies involving Egyptian sewer workers found higher levels of cognitive impairment, but the descriptions were very nonspecific, including lack of concentration, difficulty with memory, and headache. In addition, these symptoms could have nothing to do with hydrogen sulfide exposure and be due to job dissatisfaction and lower socioeconomic status, which these sewer workers were also experiencing.[8]

Complications

Complications of hydrogen sulfide toxicity typically occur with high-dose exposure. These include:

• Hyposmia and the decreased ability to perceive smell due to olfactory paralysis and neurotoxicity affecting the olfactory bulb and fibers [8]
• Conjunctivitis with reversible chromatic distortion and alterations to vision
• Pulmonary edema and acute respiratory distress syndrome
• Acute myocardial infarction
• Delayed neuropsychiatric sequelae with changes to personality, depression, and decreased cognitive ability [41][43][50]
• Death