Acute Arsenic / Heavy Metal Poisoning

Overview

Arsenic is a metalloid found in nature in both inorganic and organic forms, and inorganic arsenic (especially arsenic trioxide, As2O3) represents the most toxic and clinically significant form of acute poisoning; organic arsenic compounds (for example arsenobetaine in seafood) are generally much less toxic and can cause falsely elevated urinary arsenic measurements. Arsenic covalently binds to sulfhydryl (–SH) groups within cells, inhibiting many mitochondrial enzymes, primarily the pyruvate dehydrogenase complex; this inhibition disrupts oxidative phosphorylation, halts cellular energy production, and causes damage in tissues with high metabolic demand (gastrointestinal mucosa, myocardium, peripheral nerves).

Acute inorganic arsenic poisoning can result from intentional ingestion (suicide attempt), occupational exposure (metallurgy, glass/pesticide manufacturing, semiconductor industry), or contaminated water/food sources; worldwide, the most common form of chronic exposure is through contaminated groundwater, but this protocol targets acute high-dose intake. EPIDEMIOLOGY:

Acute inorganic arsenic poisoning is relatively rare but a high-mortality toxicological emergency; case series indicate that intentional ingestions are associated with a more severe clinical picture and higher mortality than occupational/accidental exposures because the dose ingested is usually much higher. CLINICAL COURSE (phased): (1) Early/acute gastrointestinal phase — Within minutes to hours after ingestion, burning in the mouth and pharynx, metallic or garlic taste, intense thirst, severe abdominal pain, vomiting (often bloody), and cholera-like 'rice water' diarrhea (often bloody) develop. (2) Cardiovascular phase — Sinus tachycardia is an early finding; increased capillary permeability (fluid escape into the third space and vasodilation) combined with massive gastrointestinal fluid loss leads to hypovolemic shock.

Electrocardiography may show QT/QTc prolongation, ST depression, and flat T waves; torsades de pointes, polymorphic ventricular tachycardia, and ventricular fibrillation have been reported. The effect of arsenic trioxide on cardiac repolarization is well characterized: it blocks both the rapid (IKr) and slow (IKs) delayed rectifier potassium currents at clinically significant concentrations, resulting in prolonged action potential duration; this mechanism has been associated with acquired long QT syndrome and sudden cardiac death in patients receiving arsenic trioxide for acute promyelocytic leukemia treatment and forms the pathophysiological basis of arrhythmia risk in acute poisoning. (3) Neurological phase — In the acute period, headache, lethargy, delirium, hallucinations, seizures, and encephalopathy (due to cerebral edema) may develop and can result in coma; peripheral neuropathy classically begins in the subacute phase (days to weeks after exposure) and progresses in a painful, distal, sensory-motor, glove-and-sock pattern.

As a late finding, transverse white lines on the nails (Mees' lines) appear approximately 4-6 weeks after exposure and retrospectively support the diagnosis.

DIAGNOSIS AND DIAGNOSTIC THRESHOLDS

The diagnosis is made by combining the clinical picture and laboratory findings. The twenty-four-hour urinary arsenic is the most useful test; normal total urinary arsenic is below 50 micrograms/L, and a total value above 100 micrograms (in chelated or non-chelated samples) is generally considered abnormal, while in acute severe poisoning, 24-hour values can reach several thousand micrograms, and in spot urine, it can exceed 1000 micrograms/L.

Because seafood consumption can cause a false elevation due to organic arsenic, a history of seafood consumption in the previous 24-48 hours must be questioned before sampling. Blood arsenic decreases rapidly due to its short half-life (1-2 hours) (normal value is below 7 micrograms per 100 mL); therefore, a normal blood level does NOT EXCLUDE poisoning, and urinary arsenic is preferred for diagnosis.

Radio-opaque material may be seen on an abdominal X-ray and can help evaluate whether ingestion is ongoing. Additional laboratory evaluation should include complete blood count (anemia, basophilic stippling, cytopenia), kidney and liver function tests, electrolytes (potassium, magnesium, calcium — critical for QT), and electrocardiogram/QTc measurement.

SHOULD NOT BE CONFUSED WITH ARSIN GAS

Arsine gas (AsH3) produces a completely different clinical picture from inorganic arsenic intake and DOES NOT CREATE the classic arsenic toxidrome; arsine rapidly causes Coombs-negative, fulminant intravascular hemolysis through hemoglobin oxidation and depletion of erythrocyte glutathione stores, hemolysis can be delayed up to 24 hours after exposure, and acute kidney injury may not appear until 72 hours post-exposure. Therefore, in cases of suspected arsine exposure, the treatment approach (blood exchange, hemodialysis, hemolysis management) differs from the management of oral inorganic arsenic intake in this protocol and should be evaluated separately.

LETHAL DOSE

The estimated lethal intake dose for inorganic arsenic has been reported as approximately 0.6 mg/kg; for arsenic trioxide, a potentially fatal dose has been defined in the range of 1-2.5 mg/kg, and death usually occurs 1-4 days after ingestion. Because these values vary between sources, they should be used not as a strict threshold but as a reference to help predict clinical severity.

MANAGEMENT (key principles): (a) stabilization of airway, breathing, and circulation takes priority; (b) aggressive intravenous fluid resuscitation is applied — if systolic blood pressure is below 80 mmHg in adults, a bolus of 1000 mL isotonic NaCl or Ringer's lactate is given per hour, in children, a 20 mL/kg isotonic bolus is infused over 10-20 minutes; (c) continuous cardiac monitoring and serial electrocardiogram/QTc follow-up are carried out, potassium/magnesium/calcium levels are maintained within the normal range, other QT-prolonging drugs are avoided, and intravenous magnesium is given if torsades develop; (d) benzodiazepines are administered if seizures occur; (e) emesis is not induced for decontamination, gastric lavage may be considered within the first hour in life-threatening ingestion, routine use of activated charcoal is not recommended because it binds arsenic weakly; (f) chelation is initiated (detailed below); (g) the Poison Control Center (114) is contacted in the early phase of treatment. [numeric values preserved:

1] CHELATION

In patients with severe acute poisoning or who cannot take orally, dimercaprol (BAL) is started at 3-5 mg/kg intramuscularly every 4-6 hours; when the patient is hemodynamically stable and can tolerate orally, oral succimer (DMSA) 10 mg/kg three times daily (for 5 days), followed by twice daily (for 14 days) is continued. The chelation goal is to reduce 24-hour urinary arsenic to less than 50 micrograms/L.

DMPS (unithiol) is a water-soluble alternative chelator with a much higher therapeutic index compared to dimercaprol and can be preferred intravenously, especially in patients with renal failure requiring hemodialysis; its availability in our country varies. Chelation should be started as early as possible because efficacy significantly decreases as the time between exposure and chelation initiation increases; some sources emphasize that chelation started within four hours has the highest efficacy. [numeric values preserved:

3, 2]

Key considerations

• Thallium poisoning initially produces similar gastrointestinal symptoms and subacute painful peripheral neuropathy; however, in thallium, rapid and diffuse alopecia develops 1-3 weeks after exposure, which is characteristic and not typical in arsenic; thallium neuropathy predominantly affects small fibers (pain/temperature sensation) and is often accompanied by marked dysautonomia, whereas arsenic neuropathy predominantly affects motor function and shows slowing in nerve conduction studies.
• In mercury poisoning, the heavy metal toxidrome overlaps with arsenic; however, in inorganic mercury intake, corrosive gastrointestinal damage and acute renal failure are prominent, whereas in elemental or organic mercury exposure, neurological and behavioral findings (tremor, irritability, acrodynia) are dominant. The distinction is made through exposure history and urine/blood mercury levels; succimer and DMPS can be used as chelators in both poisonings.
• Lead poisoning is covered under a separate protocol; acute gastrointestinal findings and encephalopathy may overlap with arsenic, and anemia and basophilic stippling can be seen in both poisonings. Chelation thresholds and preferred agents for lead (calcium disodium EDTA, dimercaprol, succimer) are applied with different regimens; therefore, the lead protocol should be consulted separately.
• Cholera and other infectious gastroenteritis mimic arsenic with rice-water type diarrhea; however, in arsenic poisoning, metallic or garlic taste in the mouth, accompanying neurological findings, QT prolongation, and a known exposure history are distinguishing clues, and infectious causes can be ruled out with stool culture/toxin tests.
• Acute mesenteric ischemia causes abdominal pain disproportionately severe to physical findings and may not give early specific findings except for elevated lactate and a progressively worsening clinical picture; in arsenic, profuse watery diarrhea accompanying pain and systemic toxicity findings (QT prolongation, encephalopathy) are prominent.
• Distributive shock due to sepsis can mimic arsenic poisoning with hypotension and gastrointestinal symptoms; however, fever and a focus of infection are expected in sepsis, whereas in arsenic, there is typically no fever, and exposure history with metallic taste is prominent.
• Organophosphate/carbamate poisoning also causes vomiting, diarrhea, and abdominal pain; however, the distinguishing findings of cholinergic toxidrome such as miosis, bronchorrhea, bradycardia, and fasciculations are not seen in arsenic.
• Colchicine poisoning can also resemble arsenic clinically with severe gastrointestinal symptoms (vomiting, watery diarrhea), hypovolemic shock, and bone marrow suppression; the distinction is made with dose-exposure history and colchicine level, and in colchicine, multiorgan failure and alopecia typically develop 24–72 hours after intake (unlike arsenic, earlier, within days).
• Acute iron poisoning also produces a similar gastrointestinal-toxic picture with vomiting, bloody diarrhea, and hypovolemic shock; serum iron level and anion gap/metabolic acidosis depth are used in differential diagnosis.
• Exposure to arsine gas (AsH3) produces a toxidrome different from oral inorganic arsenic intake and is characterized by rapid, Coombs-negative, fulminant intravascular hemolysis; gastrointestinal corrosive signs and metallic taste are usually NOT PRESENT, hemolysis may be delayed up to 24 hours after exposure, and acute kidney injury may be delayed up to 72 hours, therefore it is differentiated from oral intake by occupational gas exposure history and laboratory findings of hemolysis (hemoglobinuria, elevated LDH, decreased haptoglobin).
• Paroxysmal nocturnal hemoglobinuria and other causes of hemolytic anemia (potassium chlorate, antimony exposure) can mimic arsine poisoning with acute hemolysis and dark urine; differentiation is made by exposure history, Coombs test, and hemolysis markers.

Why it matters

Source basis for critical doses/thresholds: (1) Chelation doses — dimercaprol (BAL) 3-5 mg/kg intramuscular every 4-6 hours, with a target of reducing 24-hour urine arsenic below 50 micrograms/L; this dose is consistent across at least three independent sources: ATSDR Medical Management Guidelines, StatPearls (Arsenic Toxicity), and the arsenic/mercury chelation review (Kosnett, J Med Toxicol 2013, PMC3846971) (the review gives a range of 4-5 mg/kg).

Succimer (DMSA) 10 mg/kg orally three times a day for 5 days, then twice daily for 14 days, a regimen confirmed with the CHEMET protocol in StatPearls and Goldfrank's Toxicologic Emergencies. Current reviews (Medscape/emedicine, ATSDR) emphasize that today the recommended first-line agents are actually water-soluble and less toxic DMPS or DMSA, and dimercaprol is used only as bridge therapy in severe patients/unable to take orally; therefore, the protocol's approach of "BAL in severe/patients unable to take orally, then switch to succimer once improved" is compatible with the current literature. (2) Diagnostic thresholds — 24-hour urine arsenic normally below 50 micrograms/L and total value above 100 micrograms considered abnormal are consistent in ATSDR and StatPearls sources. [numeric values preserved:

3, 2] The normal blood arsenic limit of 7 micrograms per 100 mL and its half-life of 1-2 hours are also sourced from ATSDR; this short half-life is the direct reason why blood levels are unreliable for diagnosis. (3) The threshold for fluid resuscitation — 1000 mL of isotonic fluid per hour for adults with a systolic blood pressure below 80 mmHg, 20 mL/kg bolus for children — is taken from ATSDR's official management guidelines. (4) The lethal dose range is reported differently: 0.6 mg/kg for inorganic arsenic in StatPearls, and 1-2.5 mg/kg for arsenic trioxide in ATSDR; this difference may depend on the compound (trioxide vs other inorganic salts), so both values are presented with references and are not given as a single definitive threshold. (5) The mechanistic basis of QT/electrolyte management is electrophysiological studies showing that arsenic trioxide blocks both rapid and slow delayed rectifier potassium currents (IKr and IKs) at clinically relevant concentrations (Circulation, Ficker et al.); this finding is an accepted mechanism explaining acquired long QT syndrome in patients with acute promyelocytic leukemia treated with arsenic trioxide and is directly associated with arrhythmia risk in acute poisoning (the study authors are Drolet, Simard, and Roden; the citation in the reference list has been corrected accordingly). (6) There is a CLEAR DISTINCTION among guidelines regarding the role of hemodialysis: hemodialysis only provides meaningful arsenic elimination if acute kidney failure coexists (dialysis clearance approximately 76-87 mL/min); there is NO evidence that hemodialysis changes clinical outcomes in patients with normal kidney function, and it is not routinely recommended — this distinction is supported by case series (PubMed 7449358, 1578049, PMC6796459). (7) The differential diagnosis of thallium/mercury is based on a review showing differences in alopecia and neuropathy patterns in thallium poisoning (PMC7994691).

NOTE: Since the dose_widget is multi-agent (BAL intramuscular and succimer oral have different units/routes/intervals), a single mg/kg value has not been provided; all doses should be confirmed at the bedside with Poison Control (114).

The "MUST BE CONFIRMED" markings are due to minor dose/regimen differences between sources (for example BAL 3-5 vs 4-5 mg/kg, DMPS regimens) and uncertainty regarding drug availability in our country. (8) OUTDATED/ABANDONED TEACHING — D-penicillamine: Although it has been suggested in some case reports for arsenic poisoning in the past, experimental studies have shown that D-penicillamine does not significantly reduce the arsenic load in tissues (Lack of effectiveness of D-penicillamine in experimental arsenic poisoning, PubMed 2540587); in the same study, DMSA provided almost complete protection against lethal effects, whereas BAL, DMPS, and DMSA substantially reduced tissue arsenic content, but D-penicillamine did not.

Therefore, D-penicillamine is NOT RECOMMENDED for current arsenic poisoning treatment and is not included in this protocol. (9) The electrolyte and QT thresholds defined in the FDA/EMA prescribing information for arsenic trioxide (the form used in acute promyelocytic leukemia treatment) also provide mechanistic support for QT monitoring in acute poisoning: during treatment, serum potassium should be maintained above 4 mEq/L and magnesium above 1.8 mg/dL, and if the absolute QT interval exceeds 500 milliseconds or the corrected QT exceeds 450 in males or 460 in females, the drug is stopped until electrolytes/risk factors are corrected (TRISENOX FDA prescribing information); similarly, targeting these thresholds (K+ >4 mEq/L, Mg2+ >1.8 mg/dL) in acute arsenic poisoning is a reasonable extrapolation, although these thresholds have not been additionally validated in the poisoning population.

Critical complications

• Hypovolemic shock develops as a result of massive gastrointestinal fluid loss and increased capillary permeability; it is managed with aggressive isotonic fluid resuscitation, and in unresponsive cases, vasopressor support and intensive care monitoring are required.
• Torsades de pointes and other polymorphic ventricular arrhythmias develop due to arsenic trioxide blocking cardiac potassium channels and prolonging the QT interval; they are managed with continuous cardiac monitoring, maintaining electrolytes (potassium, magnesium) within the normal range, intravenous magnesium sulfate administration for torsades if it develops, and overdrive pacing if necessary.
• Acute kidney injury can develop both due to a prerenal mechanism caused by hypovolemia and the direct tubular toxicity of arsenic; urine output and kidney functions are closely monitored, and if it develops, reconsideration of the dimercaprol dose and, if necessary, hemodialysis (both for kidney support and to aid arsenic elimination) is considered.
• Hemolysis due to dimercaprol treatment is observed, especially in patients with G6PD deficiency; if possible, G6PD screening should be done before treatment, and during treatment, early detection is achieved by monitoring hemogram and hemolysis markers (haptoglobin, LDH, indirect bilirubin), and if necessary, the drug is stopped and supportive therapy is given.
• Approximately half of dimercaprol injections cause systolic and diastolic hypertension, tachycardia, nausea-vomiting, chest pain, headache, and sterile abscess at the injection site; these reactions are dose-dependent, and in severe cases, dose reduction or discontinuation may be necessary.
• Subacute peripheral neuropathy appears days to weeks after exposure and progresses in a motor-predominant, distal, glove-and-sock pattern; evidence that chelation fully prevents this late neurological damage is limited, so even if early chelation has been initiated, the patient should be clearly informed about the risk of neuropathy and monitored with neurological examination.
• Bone marrow suppression (cytopenia) and non-hemolytic anemia may develop; they are recognized through serial hemogram monitoring, and transfusion support may be required in severe cases.
• Encephalopathy and seizure due to cerebral edema can occur in severe acute poisoning; if a seizure develops, it is treated with benzodiazepines and neuroimaging is performed to assess underlying cerebral edema.

Special considerations

• Dimercaprol is contraindicated in the first trimester of pregnancy because teratogenic effects have been reported in animal studies; however, in a pregnant patient with life-threatening severe poisoning and encephalopathy, chelation should be applied regardless of the trimester, and the decision must be made together with toxicology and high-risk pregnancy specialists.
• During breastfeeding, breastfeeding is contraindicated for a mother receiving dimercaprol because the drug passes into breast milk and can expose the nursing infant to heavy metals; breastfeeding should be discontinued for as long as the mother is receiving treatment.
• In pediatric patients, chelation doses are administered within the same mg/kg range as in adults; however, in fluid resuscitation, a child-specific bolus amount (20 mL/kg isotonic fluid over 10-20 minutes) is used, and early and frequent reassessment is necessary because dehydration and electrolyte disturbances in children can lead to much faster clinical deterioration compared to adults.
• In patients with renal failure, arsenic elimination is delayed, and dimercaprol should be used cautiously or discontinued if acute renal failure develops; in this patient group, hemodialysis becomes a treatment option providing both renal support and contributing to arsenic elimination, whereas there is no evidence that hemodialysis provides additional benefit in patients with normal renal function.
• In patients with G6PD deficiency, dimercaprol may cause hemolysis; screening should be performed before treatment if possible, but in life-threatening situations, treatment should not be delayed while waiting for screening results, and the blood count should be closely monitored.
• In elderly patients, underlying cardiac conduction disorders and limited electrolyte reserves may increase the risk of torsades de pointes due to arsenic-induced QT prolongation; therefore, in this group, electrolytes should be corrected and cardiac monitoring should be performed at shorter intervals.
• Due to its peanut oil-based formulation, dimercaprol carries a risk of anaphylaxis in patients with a known peanut allergy; allergy history should be definitely questioned before treatment, and as an alternative, the use of DMPS or early oral succimer transition should be considered.

Follow-up plan

In the acute phase, continuous cardiac monitoring and serial electrocardiogram/QTc measurement, serial electrolyte monitoring (potassium, magnesium, calcium), close monitoring of kidney function and urine output, as well as screening for hemolysis and cytopenia with a complete blood count should be performed. During chelation, treatment response is monitored with serial 24-hour urine arsenic measurement; the target value is for 24-hour urine arsenic to drop below 50 micrograms/L.

Transition from dimercaprol to oral succimer is done when hemodynamic stability is achieved and the patient tolerates oral intake. Patients with G6PD deficiency require close monitoring for hemolysis during dimercaprol treatment.

In the subacute-late period (days-weeks), regular neurological examination should be performed to assess for peripheral neuropathy, and electromyography should be used if necessary; alopecia (suggests thallium poisoning and is not expected in arsenic) and Mees lines on the nails, which appear approximately 4-6 weeks after exposure, should be checked. For discharge, the patient is expected to be asymptomatic, have normal vital signs, a normal electrocardiogram, and low/declining urine arsenic levels; it should be clearly explained to the patient that they must return immediately if they develop fever, abdominal pain, new numbness-tingling, or palpitations.

In cases of intentional ingestion, a psychiatric consultation must be requested before discharge; in occupational or environmental exposure, the source should be investigated, reported to public health authorities, and other individuals potentially exposed to the same source should be screened. Outpatient follow-up with neurology and toxicology should be planned, and all dosage and discharge decisions should be coordinated with the Poison Control Center (114).