88: Antimony

Antimony (Sb) and its compounds are among the oldest known remedies in the practice of medicine.^102,154 Because of a strong chemical similarity to arsenic, the features of antimony poisoning closely resemble arsenic poisoning (Chap. 89). Antimony poisoning also shares features common with other metal poisonings in the chapters that follow. Although relatively uncommon, antimony toxicity still occurs, usually as a complication of the treatment of visceral leishmanias.⁹² Acute overdose represents an even more rare, but potentially lethal event, often as a result of a nonconventional alcohol aversion treatment.^99,139

Objects discovered during exploration of ancient Mesopotamian life (third and fourth millennium b.c.) suggested that both the Sumerians and the Chaldeans were able to produce pure antimony.^102,154 The reference to eye paint in the Old Testament suggested the use of antimony.¹⁰² For several thousand years, Asian and Middle Eastern countries used antimony sulfide in the production of cosmetics, including rouge and black paint for eyebrows, also known as kohl or surma.^97,103 Because of the scarcity of antimony sulfide, lead replaced antimony as a main component in more modern cosmetic preparations.

One of the first monographs on metals, written in the 16th century, included a description of antimony.¹⁴⁶ The medicinal use of antimony for the treatment of syphilis, whooping cough, and gout dates to the medieval period. Paracelsus was credited with establishing antimony compounds as therapeutic agents and increasing their popularity. In spite of being aware of its toxic potential, many of the disciples of Paracelsus enthusiastically continued the use of antimony.¹⁰² Various antimony compounds were also used as topical preparations for the treatment of herpes, leprosy, mania, and epilepsy.¹⁵⁴ Orally administered tartar emetic (antimony potassium tartrate) was used for treatment of fever, pneumonia, inflammatory conditions, and as a decongestant, emetic, and sedative, but it was abandoned because of its significant toxicity.^22,47,66,81 The use of antimony as a homicidal agent¹⁴⁰ continued well into the 20th century (Chap. 1).

The current medical use of antimony is limited to the treatments of leishmaniasis and schistosomiasis, and to sporadic use as aversive therapy for substance abuse.^99,139 Pentavalent compounds are used because they are better tolerated. In the endemic regions of the world, generic pentavalent antimonials remain the mainstay of therapy because of their efficacy and low cost; however, the growing incidence of resistance may reduce future use.¹⁰⁷

Some contemporary homeopathic⁶⁰ and anthroposophical¹³³ practices still recommend use of antimonial compounds as home remedies; however, these practices are rare.^102,154 In spite of its anticancer effects in vitro⁴⁷ and remarkable therapeutic efficacy in patients with acute promyelocytic leukemia,¹²⁹ there is no current accepted oncologic use of antimony. When compared to suramin, a well-known antineoplastic compound, sodium stibogluconate appears to be a better inhibitor, giving a foundation for future research of antimony-based antineoplastics.¹²⁹

The elemental form of antimony has very few industrial uses because of its physical limitations, particularly the fact that it is not malleable. In contrast, its alloys with copper, lead, and tin have important applications. Various antimony compounds can be used in the production of textiles, enamels, ceramics, fireworks, and pigments, and as catalysts in chemical reactions. Industrial and occupational exposure to antimony occurs mainly by the inhalation of dust or fumes during the processing or packaging of antimony compounds.^14,71 Smelters can have occupational exposure to antimony as it is often present in arsenic-containing ore.⁵⁹ A time-weighted average over an 8 hour shift of permissible exposure limit for antimony and its compounds is established at 0.5 mg per cubic meter of air (mg/m³) by the Occupational Safety and Health Administration.¹⁴⁵ Antimony concentrations in cigarette smoke range from 10 to 60 mg/kg,^59,110 which may be responsible for a substantial percentage of antimony found in the lungs of smokers.⁵⁹

In developed countries, antimony poisoning rarely occurs following intentional ingestion of antimony preparations.^99,154 Most recent descriptions of antimony toxicity result from parenteral exposures during the treatment of schistosomiasis and leishmaniasis. Because of the infrequent use of therapeutic antimony preparations, health care providers in the United States may not be familiar with the standard dosing and administration procedures, placing their patients at risk for therapeutic misadventures.⁸⁷ One can expect an increase in cases of domestically treated leishmaniasis as a result of deployment of US troops to the Middle East.¹⁵⁵

Oral exposures usually occur following the use of antimony potassium tartrate–containing compounds.^99,139 Several cases were described after the use of old porcelain houseware or after use of antimony compounds as home remedies.^4,90,106,139

Antimony is located in the same group on the periodic table as arsenic (As), and as such it has many similar chemical, physical, and toxicologic properties. Because it can react as both a metal and a nonmetal, antimony is classified as a metalloid (Chap. 12).^14,135 Pure antimony is a lustrous, silver-white, brittle, hard metal that is easily pulverized.^105,154 It is extremely rare to find elemental antimony in nature because of its ability to rapidly convert to either antimony oxide or antimony trioxide.¹⁴ It has been suggested that even its name originates from anti monon (enmity to solitude) because antimony is almost always found with some other metal.¹⁰² Thus, for the purposes of this chapter, the term antimony refers to antimony ions.

In nature, antimony can be found in more than 100 different minerals,^83,102 including stibnite, cervantite, valentine, and kermesite.⁵³ The sulfide ore (stibnite) is the most abundant form,¹⁰² and Bolivia and South Africa are among the leading producers.¹⁵⁴ Like arsenic, antimony forms both organic and inorganic compounds with trivalent (3⁺) and pentavalent (5⁺) oxidation states. Common inorganic trivalent antimony compounds include antimony potassium tartrate (C₈H₄K₂O₁₂Sb₂), antimony trichloride (SbCl₃), antimony trioxide (SbO₃), antimony trisulfide (SbS₃), and stibine (SbH₃). Antimony pentasulfide (Sb₂S₅) and pentoxide (Sb₂O₅) are inorganic compounds that can act as oxidizing agents.⁶⁸ Antimony pentachloride (SbCl₅) is used as a chemical reagent with acidic properties. It reacts with water, forming hydrochloric acid that causes a direct corrosive effect on skin and mucous membranes.³⁷

Standard treatment of cutaneous leishmaniasis, recommended by the World Health Organization (WHO) and the Centers for Disease Control (CDC), is a 20 day course of 20 mg/kg/d of sodium stibogluconate.¹⁵⁵ Use of higher doses is associated with more side effects.¹⁵⁵ A recent new analytical approach measured a higher presence of trivalent antimony than previously reported in the pentavalent antimonial drug, suggesting that the pentavalent form acts as a carrier. It is postulated that trivalent antimony is released specifically in the acidic intracellular compartment targeting the Leishmania parasites. Released trivalent antimony could be responsible for the toxic effects of antiparasitic treatment.¹²⁸ The proposed mechanism of antimonial activity against the Leishmania parasites is inhibition of trypanothione reductase that is essential for the parasite survival and virulence.⁸

From an industrial perspective, the most important application of antimony is the use of antimony oxychloride (Sb₆O₆Cl₄) as a flame retardant.¹⁰² Investigation by the CDC of a possible antimony toxicity outbreak in US firefighters concluded that wearing uniforms made from fabric that contains antimony is safe.²⁹

Analysis of soil around firing ranges⁹⁵ and environmental examination around mines revealed elevated concentrations of antimony that can pose significant health risk.^70,157 A public health concern was raised after reports of elevated antimony concentrations in water containers and commercial juices due to leaching from the packaging material or flawed manufacturing process.^67,130

Tartar emetic (antimony potassium tartrate) is an odorless trivalent antimony compound with a sweet metallic taste⁶⁹ and a potent emetic effect.⁶⁸ Antimony potassium tartrate is considered to be one of the most toxic antimony compounds, with minimal lethal doses reported between 200 mg¹⁰⁶ and 1200 mg.¹⁰² There are large species variations of the LD₅₀ in experimental animals, with a reported range of 115 mg/kg in rabbits and rats to 600 mg/kg in mice. In comparison, because of low water solubility, antimony trioxide is considered to be nontoxic, with an LD₅₀ greater than 20,000 mg/kg.⁵⁷

The antiparasitic mechanisms action of antimony may result from the inhibition of phosphofructokinase, which is the rate-limiting step in the glycolytic pathway of schistosoma.³¹ Trivalent antimony compounds inhibit phosphofructokinase, leading to energy failure from impaired adenosine triphosphate (ATP) synthesis.^27,154 It is speculated that antimonial preparations exert their antiparasitic effect through selective targeting of guanosine diphosphate–mannose pyrophosphorylase, which interferes with nucleoside and mannose metabolism.⁵⁴ The result is that the parasites cannot synthesize purines and cannot survive without these mannose-containing glycoconjugates. The most recently proposed mechanism involves inhibition of trypanothione reductase.⁸ Even less is known about the effects of antimony in humans. It has been proposed that, like other metals, antimony inactivates thiol containing proteins and enzymes by binding to sulfhydryl groups.⁴² Pentavalent antimony may act as a prodrug that is converted in acidic intracellular compartment into active and more toxic trivalent antimony.¹²⁸

Absorption

Antimony is absorbed by inhalation, ingestion, or transcutaneously. Absorption from the gastrointestinal tract begins immediately following ingestion, and the oral bioavailability of antimony ranges from 15% to 50%.^58,147 It is suggested that antimony absorption might be a saturable process, given that several studies failed to demonstrate a dose-response relationship for absorption.^2,136 In fact, after a lethal ingestion of antimony tartrate, the total body antimony burden was only 5% of the ingested dose.⁹⁶ This poor gastrointestinal absorption in humans, in addition to the concomitant emesis, necessitates parenteral administration of many antimony based pharmaceuticals.

Pulmonary absorption of many inorganic antimony compounds is very slow and limited by low solubility.¹⁰² In contrast, animal data suggest that inhaled trivalent antimony is well absorbed from the lung, distributed to various organs, and subsequently excreted in the feces and urine.⁴⁶

Transcutaneous absorption of antimony trioxide and pentoxide was documented in studies with rabbits;¹⁰⁹ however, dermal absorption in humans of antimony trioxide is considered negligible.¹²⁵ The CDC, in its investigation of possible outbreak of antimony exposure in firefighters, did not measure significant transcutaneous absorption from the antimony containing uniforms.²⁹

Distribution

Distribution depends on the oxidation state of antimony. In animals, more than 95% of trivalent antimony is incorporated into the red blood cells within 2 hours of exposure, whereas in a similar time frame, 90% of pentavalent antimony remains in the serum.⁴⁸

When administered intravenously or orally, antimony is predominantly distributed among highly vascular organs, including the liver, kidneys, thyroid, and adrenals.^115,154 The antimony that is detected in the liver and spleen is predominantly in the pentavalent form, whereas the thyroid accumulates trivalent forms.¹³ Uptake by the liver occurs through the mechanisms of diffusion and saturable binding.¹³² In a hamster model, following a single injection of organic antimonials, the greatest concentration of antimony was found in the liver.⁵⁸ After inhalation, antimony accumulates predominantly in red blood cells and to a significantly lesser extent in liver and spleen.^46,48 It is possible that inhaled antimony is retained in the lungs for a prolonged period of time without significant systemic absorption and distribution.⁵⁹ Animal data also reported accumulation of antimony in the skeletal system and in fur.^50,51

After intramuscular (IM) administration of sodium stibogluconate, the antimony concentration time profile suggested the two-compartment open model, with rapid distribution phase and slower elimination half-life in the range of 10 hours.¹⁵⁹

Metabolism

Although antimony and arsenic share many toxicokinetic properties, unlike arsenic, inorganic trivalent antimony is not methylated in vivo.⁷ Some microorganisms, however, are capable of biomethylation of antimony.¹⁷ Instead, in humans, antimony is converted by binding to macromolecules, by incorporation into lipids,¹⁶ and by covalent interactions with sulfhydryl groups and phosphates. Pentavalent antimony may be converted to trivalent compounds in the liver¹⁵⁴ or it can release trivalent form into acidic intracellular environment of Leishmania infected cells.¹²⁸

Excretion

Trivalent antimony is excreted in the bile after conjugation with glutathione. A significant proportion of excreted antimony undergoes enterohepatic recirculation.⁷ The remainder is excreted in urine. The overall elimination is very slow, with only 10% of a given dose cleared in the first 24 hours and 30% in the first week;¹¹ some urinary antimony is still detected in the urine 100 days after administration.^98,154 Pentavalent antimony is much more rapidly excreted by the kidneys than trivalent antimony (50%–60% versus 10% over the first 24 hours).¹⁵⁴ In actuality, renal excretion of sodium stibogluconate can be as high as 90% within 6 hours of an IM administration.¹²² However, urine and serum antimony concentrations remain elevated for several years following therapeutic use.¹⁰¹ In workers, urine concentrations of pentavalent antimony correlate well with the extent of exposure.⁷

The clearance of tartar emetic has a biphasic pattern, with 90% being excreted within 24 hours after acute exposure, followed by a second slower phase with an estimated half-life of approximately 16 days.⁵⁰

The renal elimination half-life of inhaled stibine was estimated at approximately 4 days following occupational exposure.⁹¹

Antimony has no known biological functions and is considered to be potentially toxic even at very low concentrations.¹³¹ Like other toxic metals, antimony binds to sulfhydryl groups to inhibit a variety of metabolic functions.^32,42 Trivalent antimony compounds are more toxic than the pentavalent compounds because of their higher affinity for erythrocytes and sulfhydryl groups.⁹³ Tartar emetic and other antimony salts are also considered gastrointestinal irritants. One proposed mechanism for this local effect is the activation of enterochromaffin cells, which produce and secrete serotonin (5-HT₃). Released serotonin acts on the 5-HT₃ receptors, stimulating vagal sensory fibers and activating the vomiting center.^65,149 In addition, there is apparent direct central medullary action, particularly after administration of higher doses of antimony.¹⁵⁴

Data on human toxicity of antimony are very limited. They are largely extrapolated from occupationally exposed patients, adverse effects that have occurred during treatment of leishmaniasis and schistosomiasis, and very few case reports of intentional antimony exposures.¹⁰⁶ Serious adverse events and deaths resulting from the treatment with sodium stibogluconate are very rare, and if they occur, they are most often resulting from cardiac dysrhythmias or pancreatitis.¹⁵⁵ Patients older than 50 years may be at increased risk for more serious reactions to meglumine antimonate used for the treatment of visceral leishmaniasis.^45,112

Workers with occupational exposures usually present with subtle clinical symptoms as chronic toxicity develops slowly over time. It is important to recognize that antimony ore contains a small concentration of arsenic, making it difficult to determine whether the effects on workers are caused by contaminants such as arsenic or by the antimony. Therapeutic side effects of antiparasitic treatment may have acute and subacute clinical manifestations, as some patients with leishmaniasis require prolonged antimonial treatment to achieve cure,¹⁴³ exposing them, over time, to very large cumulative doses. Therapeutic misadventures are possible, particularly in the setting where antimony preparations are rarely used and health care providers are not familiar with the dosing regimen.⁸⁶

Patients with acute ingestions usually present with symptoms mimicking the toxicity of arsenic and other metal and metalloid salts.

Local Irritation

The most common manifestations of antimony toxicity involve local irritation. In sufficient concentration, antimony acts as an irritant to the eyes, skin, and mucosa. Ophthalmic exposure can cause conjunctivitis.^19,53,123 Irritation of the upper respiratory tract can lead to pharyngitis and frequent epistaxis.¹⁵²

Antimony pentachloride is very irritating and can cause local dermal and mucosal burns. It reacts with water, releasing hydrochloric acid, heat, and antimony pentoxide (Sb₂O₅). Following ingestion, contact with the water in saliva produces sufficient hydrochloric acid with the potential to result in consequential gastrointestinal burns.

Ocular exposure to Sb₂O₅ can cause typical caustic injury, resulting in blepharospasm, lacrimation, photophobia, and even corneal burns. Exposure to antimony trichloride fumes can cause similar ocular symptoms.⁶¹

Following systemic exposure ocular toxicity can manifest in optic atrophy, uveitis, and retinal hemorrhage with exudates resulting with diminished visual acuity.^34,89 Some of these changes can be permanent.⁸⁹

Thrombophlebitis is common after intravenous (IV) use of antimony but is also reported when poisoning occurs orally.⁹⁶

Gastrointestinal.

Following acute exposures, antimony can rapidly produce anorexia, nausea, vomiting, abdominal pain, and diarrhea.^96,99,150 Some patients may report a metallic taste in the mouth.^7,40 It is possible to sense a garlic odor on the breath, but this might be due to concomitant arsenic exposure. In severe overdose, gastrointestinal irritation can progress to hemorrhagic gastritis.⁹⁶ Workers chronically exposed to antimony dusts have a much higher incidence of gastrointestinal ulcers in comparison to controls (63 per 1000 versus 15 per 1000).²³ Many patients develop pancreatitis following treatment with pentavalent antimonial salts.^41,56,104 Because most cases improved despite continuation of treatment, a mechanism other than direct pancreatic toxicity is presumed. In another series, several patients with human immunodeficiency virus (HIV) who were treated with high doses of meglumine antimonate developed severe pancreatitis and died.⁴³

Cardiovascular.

In animals, antimony decreases myocardial contraction; lowers coronary vasomotor tone, producing decreased systolic pressure; and causes bradycardia.^39,154 The majority of reported human cardiac effects are related to the electrocardiographic (ECG) changes. Prolongation of the QT interval, inversion or flattening of T waves, and ST segment changes are frequently described during treatment of visceral leishmaniasis with pentavalent antimonial compounds (sodium stibogluconate and meglumine antimonate).^33,126,153 Torsade de pointes was described in patients treated with pentavalent antimonial preparations.^114,142 Prolongation of the cardiac action potential may be due to an increase in cardiac calcium currents.⁹⁴

In patients with underlying myocardial disease such as a cardiomyopathy, ECG changes can occur even at subtherapeutic antimony doses.⁶⁴ These changes are not necessarily associated with deterioration in cardiac function.^73,75 However, it is important to recognize that pentavalent antimonial drugs used for the treatment of leishmaniasis are associated with sudden death, probably as a result of the development of ventricular dysrhythmias.^30,138 Cardiomyopathy followed by congestive heart failure and death is rare but is a reported adverse effect attributed to antimony.^112,137 Pericarditis can present with chest pain and typical ECG changes during the treatment with antimony.⁴⁹

In regard to chronic antimony exposure, it appears that elevated concentrations of antimony in urine are associated with an increase in composite cardiovascular and cerebrovascular disease.¹

Respiratory.

Local irritation from antimony trioxide can produce laryngitis, tracheitis, and pneumonitis.^59,123,141 Pneumonitis is usually reversible after exposure ceases and can be followed radiologically.¹²³ Acute respiratory distress syndrome was reported after acute exposure to antimony pentachloride.^37,38

Although antimony oxides are capable of causing metal fume fever,^6,52 this is much less common in comparison to exposure to zinc oxide (Chaps. 103 and 124).^6,52 Antimony metal fume fever is reported to occur even with air concentrations below 5 mg/m³.³⁶

Workers chronically exposed to antimony compounds for many years may develop “antimony pneumoconiosis.”^35,103 Patients present with cough, wheezing, and exertional dyspnea that can progress to obstructive lung disease. Radiologically, antimony pneumoconiosis appears as diffuse, dense, punctate nonconfluent opacities with a predominant distribution in middle and lower lung lobes with or without pleural adhesions.¹¹⁹

Renal.

Patients treated with sodium stibogluconate can develop varied manifestations of nephrotoxicity ranging from renal cell casts, proteinuria, and increased blood urea nitrogen concentration³⁴ to acute kidney injury (AKI).^9,121 Some patients can also develop renal tubular acidosis⁸⁰ and acute tubular necrosis.¹²⁰ Older age and underlying chronic kidney disease are risk factors for development of AKI that can progress to death.¹¹² Hemodialysis may be helpful during oliguric phase in acute overdose.⁹⁹

Hepatic.

Acute exposure to antimony can result in severe acute liver injury.⁹⁹ Chronic therapeutic use of antimony compounds for the treatment of leishmaniasis can cause liver toxicity that can range from reversible elevations of aminotransferase concentrations to hepatic necrosis.^{76,78,127,154} Elderly patients are at an increased risk for development of significant hepatic ­failure.¹¹² Pediatric patients treated for leishmaniasis may develop fulminant hepatic failure after an initial positive response to antimony. The mechanism is unknown, but may be due to a direct antimony effect in combination with immunologically mediated liver injury.^10,44

Hematologic.

Severe anemia was reported in HIV positive patients during treatment with sodium stibogluconate. Bone marrow biopsy documented transient severe marrow dyserythropoiesis, followed by complete recovery on discontinuation of the therapy.^77,100

Patients treated with sodium stibogluconate for visceral leishmaniasis occasionally develop thrombocytopenia.^20,74,86 Rare cases of epistaxis are described during the treatment, and it is unclear if they are associated with thrombocytopenia.⁸⁸ Visceral leishmaniasis itself is known to be associated with pancytopenia, probably as a result of increased destruction of peripheral blood cells.¹¹⁸ It may be difficult to determine whether this phenomenon is caused by disease itself or is secondary to the treatment, although some authors suggested a drug-induced immune thrombocytopenia.¹¹⁸

Leukopenia is frequently observed in patients treated with antimonial compounds.^43,154,156 Some authors speculate that antimony-induced lymphopenia is associated with an increased frequency of herpes zoster in HIV infected patients.¹⁵⁶ It is suggested that pentavalent antimony can theoretically precipitate sickle cell crisis via common glutathione pathway.⁵⁵ A study with homeopathic antimony indicated procoagulant effect, and even some homeopathic practitioners use it in the treatment of bleeding disorder.⁷⁹

Dermatologic.

Antimony spots¹³⁴ are papules and pustules that develop around sweat and sebaceous glands and may resemble varicella. Chronically exposed patients can develop areas of eczema and lichenification that typically occur in the summer and are usually found on the arms, legs, and in the joint creases with sparing of the face, hands, and feet.^103,123 A similar skin rash was described in the 18th century after external application of antimony tartrate for medicinal use.¹⁰² Interestingly, these eruptions were usually interpreted as a sign of cure.⁶⁶ It is also suggested that antimony trioxide can cause contact dermatitis.¹⁰⁸ A very high incidence of severe cutaneous reactions (37%) was reported in patients who were treated with meglumine antimonate at 20 mg/kg/d.¹¹³ This high incidence was associated with high concentrations of other metals in the one particular drug lot. Herpes zoster was reported as a complication of antileishmaniasis treatment and it may be resulting from leukopenia.^113,156

Neurologic.

A patient with cutaneous leishmaniasis who was treated with sodium stibogluconate (pentavalent antimony) developed a reversible, peripheral sensory neuropathy in temporal association with treatment.²⁵

Musculoskeletal.

Therapeutic use of parenteral antimonials can be associated with diffuse muscle and joint pain.^{28,40,127,154} One of the most frequently reported clinical adverse effects of pentavalent antimonials was musculoskeletal pain.¹¹³ The symptoms can be so severe that they will require treatment interruption in about one third of the patients. Patients that are not candidates for the treatment with nonsteroidal antiinflammatory drug treatment can be managed with glucocorticoids.²⁴

Reproductive.

In animal studies, antimony causes ovarian atrophy, uterine metaplasia, and impaired conception.¹⁵ An association between spontaneous abortion and premature births reported in women who were occupationally exposed to antimony salts. Antimony was found in the blood, urine, placenta, amniotic fluid, and breast milk of these women.¹⁵

Carcinogenicity.

Female rats developed lung tumors after inhalation of antimony trioxide and antimony trisulfide.^18,63,148 A survey among antimony smelters suggested an excess of lung cancer, with a latency of 20 years, in comparison to a nonexposed population. However, concomitant exposure to arsenic and its effects could not be excluded, and the data were poorly or inadequately controlled for smoking habits.⁸⁵ In one group of workers who were exposed to antimony oxide over 9 to 31 years, there was no increased incidence of lung cancer.¹¹⁹ Patients with schistosomiasis have an increased incidence of bladder tumors, and antimony compounds are considered to be one potential cause.¹⁵⁴ The International Agency for Research on Cancer classified antimony trioxide as possibly ­carcinogenic to humans (group 2B).⁶²

Genotoxicity.

Both stibine and trimethylstibine are capable of damaging DNA, presumably by the generation of reactive oxygen species. Other forms of antimony tested, including potassium antimony tartrate, potassium hexahydroxyantimonate, and trimethylantimony dichloride, were found to not be genotoxic.⁵ Trivalent antimony interferes with proteins involved in nucleotide excision repair and partly impairs this pathway, pointing to an indirect mechanism in the genotoxicity of trivalent antimony.⁶²

Antimony compounds can react with nascent hydrogen, forming an extremely toxic gas, stibine (SbH₃), which resembles arsine (AsH₃) (Chap. 89). Stibine is probably the most toxic antimony compound. It is a colorless gas with a very unpleasant smell that rapidly decomposes at temperatures above 302°F (150°C).^72,154 Historically, stibine release was reported during charging of lead storage batteries.¹⁵⁴ In addition to gastrointestinal symptoms that include nausea, vomiting, and abdominal pain, stibine has strong oxidative properties that may result in massive hemolysis (Chap. 22). Similar to arsine,¹²⁴ severe stibine exposure may result in hematuria, rhabdomyolysis, and death. Maintenance workers are advised to avoid use of drain cleaners containing sodium hydroxide, which is capable of releasing hydrogen in situations where antimony may be present.¹¹⁶

Standard laboratory testing to help identify volume depletion and AKI is indicated for patients with acute antimony toxicity. A complete blood count, electrolytes, renal function studies, and a urinalysis should be obtained. When there is a known or suspected exposure to stibine, additional studies should include tests for hemolysis, such as determinations of bilirubin and haptoglobin. Blood should also be obtained for a blood type and cross-match, as transfusions are likely to be required.

An ECG should be obtained to evaluate for QT interval prolongation and dysrhythmias. Patients with known myocardial disease should have frequent evaluations of cardiac function,⁶⁴ and continuous ECG monitoring is recommended for all patients with significant symptoms or abnormal cardiovascular status. A chest radiograph should be performed in patients with respiratory symptoms and evidence of hypoxia after significant inhalation exposure. In addition, an abdominal radiograph should be considered in patients with ingestion to evaluate gastrointestinal antimony load and help guide decontamination.²⁶

Antimony concentration in a 24-hour urine collection can be used for assessment of the intensity of exposure to either trivalent or pentavalent antimony.⁷ A normal urinary antimony concentration in nonexposed patients is reported in the range of < 6.2 μg/L.^117,151 A serum antimony concentration cannot be determined in a timely fashion. The normal serum concentration of antimony is in the range of < 3 μg/L,¹⁰¹ although some laboratories use higher values.¹¹¹

Decontamination

Following a significant acute ingestion, the majority of patients develop vomiting. Induction of emesis is unlikely to offer any additional benefit. In contrast, gastric lavage may be beneficial, especially if performed before the onset of spontaneous emesis. Although it is unknown whether antimony is adsorbed to activated charcoal, based on experience with salts of arsenic, thallium, and mercury, administration of activated charcoal is appropriate. Additionally, because antimony has a documented enterohepatic circulation, multiple-dose activated charcoal may be of value.⁷ Limited data on arsenic decontamination suggested effectiveness of this method.⁸⁴ Based on experience with arsenic poisoning, the whole bowel irrigation (WBI) should be attempted in severe ingestions in patients who are able to tolerate it, especially if radiographs confirm radiopaque material.^3,26 One author suggested that WBI has no effectiveness after 48 hours from arsenic exposure.⁸⁴

For patients exposed to stibine, removal from the exposure should be followed by the administration of high-flow oxygen. Theoretically, patients with severe stibine exposures may require exchange transfusion for removal of the stibine–hemoglobin complex.¹²⁴ Dermal exposures, particularly to antimony tri- or pentachloride, may require decontamination with soap and water. Prompt removal from the contaminated area is important for patients exposed to stibine. Rescuers need to take appropriate precautions to ensure their own safety (Chap. 131).

Supportive Care

The mainstay of treatment for antimony poisoning is good supportive care. Clinicians should anticipate massive volume depletion and begin rehydration with isotonic crystalloid solutions. Electrolytes, urine output, and renal and liver function⁹⁹ should be followed closely. A central venous pressure monitor may be required in patients with cardiovascular instability. Antiemetics are indicated both for patient comfort and to facilitate the administration of activated charcoal. Following stibine exposure, the hemoglobin concentration should be followed closely and blood should be transfused based on standard criteria.

Chelation

Human experience with regard to chelation of antimony is rather limited because of the scarcity of serious toxicity and the rarity of instances when patients have received chelation. Most of the available data are based on animal experimentation. Dimercaprol, succimer, and dimercaptopropane–sulfonic acid (DMPS) all improve survival of experimental animals.^12,21,82,144 A group from Shanghai demonstrated the ability of the sodium salt of succimer to increase the murine LD₅₀ of tartar emetic 16-fold.¹⁵⁸ One animal study that compared survival after treatment with multiple chelators concluded that the most effective antidotes were DMPS and succimer.¹²

A single case series documented survival in three of four patients exposed to tartar emetic who were treated with intramuscular dimercaprol at a dose of 200 to 600 mg/d. All four patients had increased urinary excretion of antimony.⁹⁶ In another case report, a patient survived after chelation with dimercaprol but without evidence of enhanced urinary excretion of antimony.⁷ Although specific recommendations are difficult to make, it is reasonable to begin therapy with IM dimercaprol until it is certain that antimony is removed from the gastrointestinal tract, at which time the patient can be switched to oral succimer. If the patient experiences cardiac or respiratory symptoms with associated ECG changes during administration of dimercaprol, treatment should be stopped.⁹⁹ Because chelation doses for antimony poisoning are not established, chelators should be administered in doses and regimens that are determined to be safe and effective for other metals (Antidotes in Depth: A25 and A26).

• Antimony toxicity should be suspected in patients with unexplained profuse nausea, vomiting, diarrhea, and abdominal pain, particularly in the setting of alcohol aversion treatment.

• Most of the patients will require only supportive therapy with decontamination.

• Multiple doses of activated charcoal should be administered.

• WBI should be administered in the first 48 hours following oral ­exposure.

• Symptomatic patients should be admitted to telemetry for monitoring for cardiac dysrhythmias.

• Chelation should be considered in severe cases of acute overdose.

• Serious complications from treatment of leishmaniasis antimonial preparations are rare; they are mostly related to the heart and pancreas, with age and underlying diseases constituting known risk factors.

References