Arsenic compounds can be classified into three major groups: inorganic, organic, and arsine gas (AsH₃). The latter is discussed separately. Arsenic compounds can also be classified by their valence state. The three most common valence states are the metalloid (elemental [0] oxidation state), arsenite (trivalent [+3] state), and arsenate (pentavalent [+5] state). In general, the arsenic compounds can be arranged in their order of decreasing toxicity: inorganic trivalent compounds, organic trivalent compounds, inorganic pentavalent compounds, organic pentavalent compounds, and elemental arsenic. Trivalent arsenic is generally two- to tenfold more toxic than pentavalent arsenic. The minimum oral lethal human dose of arsenic trioxide (trivalent) is probably between 10 and 300 mg. Some marine organisms and algae contain large amounts of organic arsenic in the form of arsenobetaine—a trimethylated arsenic compound—and arsenocholine. Arsenobetaine and arsenocholine are excreted unchanged in the urine, with total clearance in about 2 days, and exert no known toxic effects in humans.

The major routes of entry into the human body are ingestion and inhalation. Soluble forms of ingested arsenic are 60% to 90% absorbed from the gastrointestinal (GI) tract. The amount of arsenic absorbed by inhalation is also thought to be in this range. Toxic systemic effects have been reported from rare occupational accidents in which arsenic trichloride or arsenic acid was splashed on worker’s skin.

After absorption, arsenic is bound to proteins in the blood and redistributed to the liver, spleen, kidneys, lungs, and GI tract within 24 hours. Clearance from these tissues is dose dependent. Two to four weeks after exposure ceases, most of the arsenic remaining in the body is found in keratin-rich tissues (e.g., skin, hair, and nails).

Both forms of arsenic, arsenite and arsenate, undergo biomethylation in the liver to monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA). The methylation process may represent detoxification because the metabolites exert less acute toxicity in experimental lethality studies. The liver’s efficiency in methylation decreases with increasing arsenic dose. When the methylating capacity of the liver is exceeded, exposure to excess concentrations of inorganic arsenic results in increased retention of arsenic in soft tissues.

Arsenic is eliminated from the body primarily by renal excretion. Urinary arsenic excretion begins promptly after absorption, and depending on the amount of arsenic ingested, urinary arsenic excretion may remain elevated for 1 to 2 months. After acute intoxication by inorganic arsenic, arsenic is excreted in the urine as inorganic arsenic, MMA and DMA, but their proportion varies with time [5]. During the first 2 to 4 days after the intoxication, arsenic is excreted mainly in the inorganic form. This is followed by a progressive increase of the proportion excreted as MMA and DMA. The time at which arsenic is primarily excreted as its methylated metabolites depends on the severity and duration of the intoxication. Pentavalent arsenic is cleared more rapidly than trivalent arsenic. Because arsenic is quickly cleared from the blood, blood concentrations may be normal, while urine concentrations remain markedly elevated. Renal dysfunction may be a major impediment to normal elimination of arsenic compounds.

Inorganic arsenic can cross the human placenta. This was evident by the high arsenic concentrations found in a neonate following acute maternal arsenic intoxication [6].

There are two major mechanisms by which arsenic compounds appear to produce injury involving multiorgan systems. It is believed that arsenic’s overt toxicity is related to its reversible binding with sulfhydryl enzymes, leading to the inhibition of critical sulfhydryl-containing enzyme systems. Trivalent arsenite is particularly potent in this regard. The pyruvate and succinate oxidation pathways are particularly sensitive to arsenic inhibition. Dihydrolipoate, a sulfhydryl cofactor, appears to be a principal target. Normally, dihydrolipoate is oxidized to lipoate via a converting enzyme, dihydrolipoate dehydrogenase. Arsenic reacts with both dihydrolipoate and dihydrolipoate dehydrogenase, preventing the formation of lipoate. Lipoate is involved in the formation of key intermediates in the Krebs cycle. As a result of lipoate depletion, the Krebs cycle and oxidative phosphorylation are inhibited. Without oxidative phosphorylation, cellular energy stores (adenosine triphosphate [ATP]) are depleted, resulting in metabolic failure and cell death.

The other major mechanism by which arsenic is believed to produce cellular injury is termed arsenolysis. Pentavalent arsenate can competitively substitute for phosphate in biochemical reactions. During oxidative phosphorylation, energy is produced and stored in the form of ATP. The stable phosphate ester bond in ATP can be replaced by an arsenate ester bond. However, the high energy stored in the arsenate ester bond is wasted because it is unstable and rapidly hydrolyzed. Cellular respiration is stimulated in a futile attempt to restore this wasted energy. In effect, trivalent arsenic compounds inhibit critical enzymes in the Krebs cycle, leading to inhibition of oxidative phosphorylation, and pentavalent arsenic compounds uncouple oxidative phosphorylation by arsenolysis. This results in the disruption of cellular oxidative processes, leading to endothelial cellular damage. The fundamental lesion seen clinically is loss of capillary integrity, resulting in increased permeability of blood vessels and tissue hypoxia, leading to generalized vasodilation, transudation of plasma, hypovolemia, and shock.

In vitro, the effects of arsenic trioxide on repolarizing cardiac ion currents appear to be one of antagonism on both I_Kr and I_Ks as well as activation of I_{K – ATP}, which maintains normal repolarization [3]. In addition, arsenic trioxide increases cardiac calcium currents and reduces surface expression of the cardiac potassium channel human ether-a-go-go-related gene. The variability in QTc interval prolongation and the onset of ventricular dysrhythmias during arsenic therapy may represent these competing effects.

The most prominent clinical findings associated with acute arsenic poisoning are related to the GI tract. Some arsenic is corrosive. Acute ingestion may lead to oral irritation and a burning sensation in the mouth and throat. A metallic taste and/or a garlicky odor to the breath have been described, but often are not present. Nausea, vomiting, and abdominal pain are common. The toxic effects of arsenic on the GI tract are manifested as increased peristalsis and profuse watery stools and bleeding. In serious cases, hemorrhagic gastroenteritis may ensue within minutes to hours after acute ingestion. Nausea, vomiting, and severe hemorrhagic gastroenteritis can all lead to profound intravascular volume loss resulting in hypovolemia shock, which is the major cause of mortality and morbidity.

Noncardiogenic pulmonary edema may occur from increased capillary permeability, and cardiogenic pulmonary edema may occur from myocardial depression. Electrocardiogram (ECG) changes associated with arsenic poisoning consist of nonspecific ST- and T-wave changes, sometimes mimicking ischemia or hyperkalemia and QTc prolongation [7,8,9].
These ECG abnormalities are reported to occur in half the patients with arsenic poisoning, and these ECG changes may be evident from 4 to 30 hours postingestion, persisting for up to 8 weeks.

At least five cases of arsenic-induced polymorphic ventricular tachycardias consistent with torsades de pointes have been reported [8,9]. In all these cases, QTc prolongation was evident on the admission ECG. Except in the case of the patient who presented with cyanosis and cardiorespiratory arrest, peripheral neuropathy was a prominent finding on physical examination at the time of hospital admission, and the polymorphic ventricular tachydysrhythmias were ultimately self-limited. Although these cases were able to document as to when during the hospital course torsades de pointes were observed, the time between arsenic exposure and the onset of cardiac dysrhythmias can only be speculated.

Arsenic was abandoned 30 years ago as an anticancer medicinal, but has attracted renewed attention as a treatment for APL on the basis of impressive results from clinical studies in China and the United States [3]. Arsenic trioxide is licensed for use in patients with relapsed or refractory APL. Induction therapy in APL patients receiving daily median arsenic trioxide infusions of 0.15 mg per kg (range, 0.06 to 0.2 mg per kg) during 1 to 2 hours until bone marrow remission or for a maximum of 60 days has been associated with adverse drug events (Table 133.1) [3]. In patients receiving multiple courses of arsenic trioxide therapy, their QTc intervals returned to pretreatment values before their second course, signifying that arsenic trioxide may not permanently prolong the QTc interval.

Both acute and chronic arsenic poisoning may affect the hematopoietic system. A reversible bone marrow depression with pancytopenia, particularly leukopenia, may occur. However, it is the chronic form that is usually associated with severe hematopoietic derangements. A wide variety of hematologic abnormalities have been described with arsenic poisoning, including anemia, absolute neutropenia, thrombocytopenia, eosinophilia, and basophilic stippling [10]. Anemia is, in part, due to an increase in hemolysis and disturbed erythropoiesis/myelopoiesis with reticulocytosis and predominant normoblastic erythropoiesis. Accelerated pyknosis of the normoblast nucleus, karyorrhexis, is characteristic of arsenic poisoning, and the typical “cloverleaf” nuclei may be evident [11]. Hematologic findings may appear within 4 days after acute arsenic ingestion, and in the absence of any specific therapy, erythrocytes, leukocytes, and thrombocytes were reported to return to normal values within 2 to 3 weeks after discontinuing arsenic exposure.

Neurologic manifestations of arsenic poisoning have included confusion, delirium, convulsions, encephalopathy, and coma [12]. Neuropathy is usually not the initial complaint associated with acute arsenic poisoning. Arsenic-induced polyneuropathy has traditionally been described as an axonal-loss sensorimotor polyneuropathy (low-amplitude/unelicitable sensory and motor conduction responses, often with preserved motor conduction velocities). The first symptoms of neuropathy have been reported to appear 1 to 3 weeks after the presumptive arsenic exposure [12,13]. Clinical involvement spans the spectrum from mild paresthesia with preserved ambulation to distal weakness, quadriplegia, and respiratory muscle insufficiency. Arsenic neuropathy is a symmetrical sensorimotor neuropathy, with the sensory component being more prominent in a “stocking-and-glove” distribution [13,14]. This polyneuropathy may progress in an ascending fashion to involve proximal arms and legs. Dysesthesias begin in the lower extremities, with severe painful burning sensation occurring in the soles of the feet. There is loss of vibration and positional sense, followed by the loss of pinprick, light touch, and temperature sensation. Motor dysfunction is characterized by the loss of deep tendon reflexes and muscle weakness. In severe poisoning, ascending weakness and paralysis may occur and involve the respiratory muscles, resulting in neuromuscular respiratory failure [15,16]. It has been reported that many of the patients with arsenic neuropathy were initially thought to have Landry–Guillain–Barré disease [12,16].

Because the fundamental lesion in arsenic toxicity is the loss of capillary integrity, increased glomerular capillary permeability may result in proteinuria. However, the kidneys are relatively spared from the direct toxic effects of arsenic. Hypovolemic shock associated with the prominent GI symptoms may lead to hypoperfusion of the kidneys, resulting in oliguria, acute tubular necrosis, and renal insufficiency or failure. The kidneys are the main route of excretion for arsenic compounds. Normal-functioning kidneys can excrete more than 100 mg of arsenic in the first 24 hours [17]. Because of shock and decreased glomerular filtration rate and depending on the dose of arsenic ingested, peak urinary arsenic excretion may often be delayed by 2 to 3 days. Hemodialysis contributes minimally to arsenic clearance compared with the normal-functioning kidneys [18].

Dermal changes occurring most frequently in arsenic-exposed humans are hyperpigmentation, hyperkeratosis, and skin cancer [19]. The lesions usually appear 1 to 6 weeks after the onset of the illness. In most cases, a diffuse, branny desquamation develops over the trunk and extremities; it is dry, scaling, and nonpruritic. Patchy hyperpigmentation—dark-brown patches with scattered pale spots, sometimes described as “raindrops on a dusty road”—occurs particularly on the eyelids, temples, axillae, neck, nipples, and groin. Arsenic hyperkeratosis usually appears as cornlike elevations, less than 1 cm in diameter, occurring most frequently on the palms of the hands and on the soles of the feet. Most cases of arsenic keratoses remain morphologically benign for decades, and in other cases, marked atypia (precancerous) develops and appears indistinguishable from Bowen’s disease—an in situ squamous cell carcinoma. Skin lesions take several years to manifest the characteristic pigmented changes and hyperkeratoses, whereas it takes up to 40 years before skin cancer becomes evident. Brittle nails with transverse white bands (leukonychia striata arsenicalis transversus) appearing on the nails have been associated with arsenic poisoning and are known as Reynolds–Aldrich–Mees lines [20,21,22]. It reflects transient disruption of nail plate growth during acute poisoning. Leukonychia striata arsenicalis transversus takes about 5 to 6 weeks to appear over the lunulae after an acute poisoning. Thinning of the hair and patchy or diffuse alopecia are also associated with arsenic poisoning [12,23].

The temporal sequence of organ system injury may suggest acute arsenic intoxication. After a delay of minutes to hours, severe hemorrhagic gastroenteritis becomes evident, which may be accompanied by cardiovascular collapse or death. Bone marrow depression with leukopenia may appear within 4 days of arsenic ingestion and usually reaches a nadir at 1 to 2 weeks. Encephalopathy, congestive cardiomyopathy, noncardiogenic pulmonary edema, and cardiac conduction abnormalities may occur several days after improvement from the initial GI manifestation. Sensorimotor peripheral neuropathy may become apparent several weeks after resolution of the initial signs (gastroenteritis or shock) of intoxication resulting from ingestion.

The differentiation between arsenic neuropathy and Landry–Guillain–Barré disease is based on clinical and laboratory findings in that arsenic neuropathy rarely involves the cranial nerves, sensory manifestations are more prominent, weakness in the distal portions of the extremities is more severe, and the cerebrospinal fluid protein concentrations are usually less than 100 mg per dL [12,13].

Laboratory investigation should include complete blood count with peripheral smear, electrolytes, liver enzymes, creatine phosphokinase, arterial blood gas, renal profile with urine analysis, ECG, chest radiograph, and blood and urine arsenic concentrations. Nerve conduction velocity studies may be indicated if peripheral neurologic symptoms are present. Some arsenic compounds, particularly those of low solubility, are radiopaque, and if ingested, they may be visible on an abdominal radiograph.

The most important diagnostic test is urinary arsenic measurement. Urine arsenic concentrations may be measured as “spot,” that is, the concentration in a single-voided urine specimen, reported in μg per L. Urine arsenic concentrations may also be measured as a timed urine collection, or the concentration in urine collected during a 12- to 24-hour period, reported in micrograms per 12 or 24 hours. The quantitative 24-hour urine collection is considered the most reliable. In an emergency situation, the spot urine sample may be of value. Normal total urinary arsenic values are less than 50 μg per L or less than 25 μg per 24 hours. In the first 2 to 3 days following acute symptomatic intoxications, total 24-hour urinary arsenic excretion is typically in excess of several thousand micrograms, with spot urine concentration greater than 1,000 μg per L, and depending on the severity, it may not return to background for weeks. Recent ingestion of seafood may markedly elevate urinary arsenic values for the next 2 days. Therefore, it is important to take a careful dietary history of the past 48 hours when only total urinary arsenic is measured. Speciation of the urinary arsenic can be performed in some laboratories. Otherwise, the urinary arsenic test should be repeated in 2 to 3 days. Whole blood arsenic, normally less than 1 μg per dL, may be elevated early on in acute intoxication. However, blood concentrations decline rapidly to normal values despite elevated urinary arsenic excretion and continuing symptoms. Elevated arsenic content in hair and nail segments, normally less than 1 part per million, may persist for months after urinary arsenic values have returned to background. However, caution should be exercised when interpreting the arsenic content obtained from hair and nails because the arsenic content of these specimens may be increased by external exposure.

The management of acute arsenic poisoning relies on supportive care and chelation therapy. Treatment begins with eliminating further exposure to the toxin and providing basic and advanced life support. Anyone with arsenic intoxication necessitating hospitalization should initially be admitted to an intensive care unit (ICU).

Gastric lavage should be performed following an acute ingestion and should be considered if the ingestion has been within the past 24 hours, as some arsenic compounds of low solubility may be retained in the stomach for a prolonged period of time. Frequently, seriously poisoned patients will have already vomited, evacuating some of their stomach contents. Activated charcoal and cathartics may be used, but their efficacy is unclear [24]. When there is evidence of a heavy metal burden on an abdominal radiograph, whole-bowel irrigation (WBI) with a polyethylene glycol electrolyte solution may rapidly help clear the GI tract of the metallic load. However, the absence of radiopacities on the abdominal radiograph is nondiagnostic and WBI should still be considered when there is a definite history that a poorly soluble arsenic compound has been ingested.

Intravascular volume depletion may require aggressive replacement with crystalloids, colloids, and blood products. Vasopressors are recommended for refractory hypotension. Invasive monitoring of the patient’s hemodynamic status may be necessary.

In acute arsenic poisoning, extended cardiac monitoring for ventricular dysrhythmias is indicated for all patients who have prolonged QTc on their ECG. Electrolyte abnormalities—in particular, hypokalemia and hypomagnesemia—should be aggressively corrected, and concomitant QTc interval–prolonging drugs should be avoided. Serum potassium concentrations should be maintained at more than 4.0 mmol per L and magnesium concentrations at more than 1.8 mg per dL (0.74 mmol per L). There are no good data to indicate that suppression of ventricular dysrhythmias decreases mortality rates. If dysrhythmias occur, they should be treated according to current advanced cardiac life support guidelines. Type IA antidysrhythmic cardiac medications should be avoided because these drugs may themselves cause further QTc prolongation and worsen the polymorphic ventricular tachycardia. Lidocaine, magnesium, and isoproterenol have been used with limited success in the management of arsenic-induced torsades de pointes. A transvenous pacemaker for overdrive pacing may be necessary. Noncardiogenic and cardiogenic pulmonary edema should be managed according to current guidelines. In patients receiving arsenic trioxide induction therapy who develop prolonged QTc of more than 500 milliseconds on ECG, the risk/benefits of continuing therapy should be considered.

Hematologic effects of arsenic poisoning should be managed symptomatically with blood product transfusions and antibiotics as necessary for severe anemia, bleeding, or infections.

Patients with arsenic polyneuropathy should be given analgesics for pain and physical therapy for rehabilitation. Patients with polyneuropathy associated with severe arsenic poisoning should be observed closely for respiratory dysfunction. Neuromuscular respiratory failure may be delayed 1 to 2 months after the initial presentation. In cases in which there is progressive sensorimotor dysfunction, particularly ascending weakness, respiratory muscle function should be monitored carefully. When there is evidence of impending neuromuscular respiratory failure, aggressive supportive measures should be initiated in a timely fashion.

Patients with renal failure may benefit from hemodialysis. However, hemodialysis has limited use when normal renal function is present. Hemodialysis (initiated 24 to 96 hours postingestion) has been reported to remove about 4 mg of arsenic during a 4-hour period in patients with established renal failure [18]. It should not be surprising that only small amounts of arsenic are removed by dialysis as minimal amounts of arsenic are left in the central compartment once tissue distribution and equilibration is complete.

The principle behind chelation therapy is to increase excretion of the metal and decrease the target organ’s metal burden. A chelator is an organic compound that has a selective affinity for heavy metals. It competes with tissues and other compounds containing thiol groups for metal ions, removes metal ions that previously have been bound, and binds with the metal ion to form a stable complex (chelate), rendering the metal less reactive and less toxic. The metal–chelator complex is water soluble and can be excreted in the urine, bile, or both, and to some extent, it can be removed by hemodialysis.

Dimercaprol (2,3-dimercapto-1-propanol [British anti-Lewisite, BAL]) is the traditional chelating agent that has been used clinically in arsenic poisoning. In humans and animal models, the antidotal efficacy of BAL has been shown to be most effective when it was promptly administered (i.e., minutes to hours) after acute arsenic exposure [25]. In cases of suspected acute symptomatic intoxication, treatment should not be delayed while waiting for specific laboratory confirmation. BAL is administered parenterally as a deep intramuscular (IM) injection. The initial dose is 3 to 5 mg per kg every 4 hours, gradually tapering to every 12 hours during the next several days. As the patient improves, this may be switched to 2,3-dimercaptosuccinic acid (DMSA; succimer) (see section “Lead” of this chapter). In the United States, DMSA is available only in an oral formulation. This precludes its use in acute severe arsenic intoxication when shock, vomiting, gastroenteritis, and splanchnic edema limit GI absorption. For patients with stable GI and cardiovascular status, a dose regimen of 10 mg per kg every 8 hours for 5 days, reduced to every 12 hours for another 2 weeks, may be employed. D-Penicillamine has also been reported to be successful adjunct treatment in cases of acute pediatric arsenic toxicity [26]. Oral D-penicillamine, 25 mg per kg every 6 hours (maximum of 1 g per day), should be used if BAL or DMSA is unavailable or if the patient is unable to tolerate these medications. Disadvantages in using D-penicillamine include that it is administered only by the oral route, it is usually not well tolerated, it should be used with caution in patients who are allergic to penicillin, and it entails potential enhanced absorption of arsenic–chelate complex. Adverse drug events associated with long-term D-penicillamine treatment include fever, pruritus, leukopenia, thrombocytopenia, eosinophilia, and renal toxicity. A complete blood count and renal function tests should be monitored weekly during D-penicillamine therapy.

BAL and its metal chelate dissociate in an acid medium and maintenance of an alkaline urine may protect the kidneys during chelation therapy [27]. BAL should be administered with caution in patients with glucose-6-phosphate dehydrogenase deficiency because it may cause hemolysis. The adverse drug events of BAL appear to be dose dependent, with an incidence of greater than 50% at a dose of 5 mg per kg [28]. The reported adverse drug events include pain at the injection site; systolic and diastolic hypertension with tachycardia; nausea; vomiting; headache; burning or constricting sensation in the mouth, throat, and eyes; lacrimation; salivation; rhinorrhea; muscle aches; tingling of the extremities; pain in the teeth; sense of constriction in the chest; abdominal pain; sterile or pyogenic abscesses at the site of injection; and a feeling of anxiety or unrest. In addition to these adverse drug events, a febrile reaction may occur in children. These signs and symptoms are most severe within 30 minutes after administration of BAL and usually dissipate within 1 to 1.5 hours. The adverse drug events may be lessened by the use of epinephrine or by pretreatment with antihistamine or ephedrine [28].

The therapeutic end points of chelation are poorly defined. Usually 24-hour urinary arsenic excretion is followed before, during, and after chelation with continued chelation therapy until the urinary arsenic excretion is less than 25 μg per 24 hours. Alternatively, when it can be demonstrated that more than 90% of the total arsenic excreted in the urine is in the form of MMA and DMA, endogenous biomethylation and detoxification may obviate the need for continued chelation [5]. This is likely to occur during the recovery period when urinary inorganic arsenic concentration has declined to less than 100 μg per 24 hours or total blood arsenic concentration is less than 200 μg per L [5].

Chelation therapy may not reverse neuropathy [12,13,14,29]. Early treatment may prevent incipient peripheral neuropathy in some, but not all, patients. However, the value of chelation in the treatment of an established arsenic neuropathy has not been demonstrated. In cases of chronic symptomatic arsenic intoxication with high urinary arsenic excretion, an empiric course of chelation may be warranted.

Arsine binds to red blood cells (RBCs) causing a rapid and severe Coombs’ negative hemolytic anemia. The exact mechanism by which arsine is lytic to the RBC has not been definitively elucidated [31,32]. In vitro and animal studies indicate that hemolysis requires the presence of oxygen, there is a reduction in the RBCs’ glutathione concentration, which is time- and concentration dependent on arsine gas exposure, and there is an inverse correlation between the reduced glutathione concentration and the extent of hemolysis. These findings are consistent with a mechanism of oxidative stress-induced damages to the RBCs, resulting in hemolysis.

Toxic concentrations of arsine appear to have deleterious effect on the kidneys. Acute renal failure was often a common cause of death prior to advent of hemodialysis [31,33,34]. Postulated mechanisms of arsine-induced renal failure include direct toxic effects of arsine on renal tubular cell respiration, hypoxia due to the hemolytic anemia, and the massive release of the “arsenic–hemoglobin–haptoglobin complex” precipitating in the tubular lumen, resulting in a toxic effect on the nephron [35]. Depending on the severity, renal failure may be evident by 72 hours from the time of exposure [31].

The severity and time to manifestation of arsine poisoning depend on the concentration and duration of the exposure. After an acute massive exposure, death may occur without the classic signs and symptoms of arsine poisoning. It is believed that after low-concentration exposures, arsine is rapidly and efficiently cleared from plasma into the RBCs. However, high concentrations of arsine may exceed the binding capacity of the erythrocytes, and the gas may directly damage vital organs. In cases in which signs and symptoms of arsine poisoning develop over time, the associated morbidity and mortality is partly related to the consequences of its hematologic and renal effects. In general, after a significant exposure to arsine, there is usually
a delay of 2 to 24 hours before symptoms of arsine poisoning become apparent [31].

Initial complaints include dizziness, malaise, weakness, dyspnea, nausea, vomiting, diarrhea, headache, and abdominal pain [31,36]. Dark-red discoloration of the urine, hemoglobinuria, and/or hematuria frequently appear 4 to 12 hours after inhalation of arsine. Depending on the severity of the exposure, reddish staining of the conjunctiva and duskily bronzed skin may become apparent within 12 to 48 hours [36]. However, the sensitivity of this sign is unclear. The conjunctival and skin discoloration is due to the presence of hemoglobin. This should be distinguished from true jaundice due to the presence of bilirubin. The triad of abdominal pain, hematuria, and bronze-tinted skin is recognized as a characteristic clinical feature of arsine poisoning [31].

In one study, ECG changes associated with arsine poisoning included peaked T waves, particularly in the precordial leads [30]. The most pronounced T-wave changes occurred between the second and the twelfth day after exposure. The severity of illness did not correlate with the height of the T wave. There was no delay in atrioventricular or intraventricular conduction times. There was progressive normalization of the T-wave amplitude evident on the weekly follow-up ECG. The exact cause of the ECG change remains speculative.

All patients hospitalized for arsine poisoning should be admitted in the ICU. The management of arsine poisoning should be directed at preventing further exposure to the gas, restoring the intravascular RBC concentration, monitoring the serum potassium, preventing further renal insult, and providing aggressive supportive care. In cases of acute and severe arsine poisoning, exchange transfusion or plasma exchange may be an efficient and effective means of management [31,34,37]. It is important to maintain good urine output (2 to 3 mL per kg per hour) at all times. Alkalinization of the urine has been recommended to prevent deposition of RBC breakdown products in the kidneys. In situations in which there is evidence of renal insufficiency or failure, both exchange transfusion and hemodialysis may be required. There are practical and theoretic considerations for using exchange transfusion. It restores the intravascular RBC concentration and removes erythrocyte debris and arsenic–hemoglobin complexes [34]. Hemolysis due to arsine poisoning can be a dynamic process; there is one report of ongoing hemolysis for at least 4 days in patients not selected for exchange transfusion [38]. Theoretic support for the use of exchange transfusion came from animal studies where a large proportion of the fixed arsenic in the blood of animals poisoned with arsine was in a nondialyzable form, and adequate removal of arsine and its associated toxic complexes would be a problem with hemodialysis alone. It has been suggested that with early diagnosis of arsine poisoning and prompt institution of exchange transfusion, the incidence of renal damage and long-term renal insufficiency may be reduced [33,38].

The results of using BAL in the treatment of acute arsine poisoning have been disappointing [36,39]. BAL does not appear to afford protection against arsine-induced hemolysis. It remains speculative whether BAL would be of benefit in subacute or chronic arsine poisoning [31].