AUTHOR AND EDITOR INFORMATION
Section 1 of 11  
Author: Kermit D Huebner, MD, FACEP, Research Director, Carl R Darnall Army Medical Center
Kermit D Huebner is a member of the following medical societies: Alpha Omega Alpha, American Academy of Emergency Medicine, Association of Military Surgeons of the US, Society for Academic Emergency Medicine, and Society of USAF Flight Surgeons
Coauthor(s):
Ren M Kinoshita, DO, PGY-1 Resident Physician, Department of Emergency Medicine, Carl R Darnall Army Medical Center
Editors: Fred Henretig, MD, Medical Director, Delaware Valley Regional Poison Control Center, Departments of Emergency Medicine and Pediatrics, Director, Section of Clinical Toxicology, Professor, University of Pennsylvania School of Medicine, Children's Hospital; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Rick Kulkarni, MD, Medical Director, Assistant Professor of Surgery, Section of Emergency Medicine, Yale-New Haven Hospital; John D Halamka, MD, MS, Associate Professor of Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center; Chief Information Officer, CareGroup Healthcare System and Harvard Medical School; Attending Physician, Division of Emergency Medicine, Beth Israel Deaconess Medical Center; Robert G Darling, MD, FACEP, Clinical Assistant Professor of Military and Emergency Medicine, Uniformed Services University of the Health Sciences, F Edward Hebert School of Medicine; Director, Center for Disaster and Humanitarian Assistance Medicine
Author and Editor Disclosure
Synonyms and related keywords:
AsH3, arsine gas, arsine exposure, arseniuretted hydrogen, arsenous hydride, arsenic trihydride, hydrogen arsenide, arsenic, chemical warfare, CW, chemical warfare agent, arsine-derived organoarsenic compounds, lewisite, beta-chlorovinyldichloroarsine, adamsite, diphenylaminearsine, Clark I, diphenylchlorarsine, Clark II, diphenylcyanoarsine, global cellular hypoxia, acute renal tubular necrosis, oliguric renal failure, anuric renal failure, arsine-induced renal failure, acute respiratory distress syndrome, ARDS, arsenicals, terrorism
Background
Arsine, the most toxic form of arsenic, has some properties that may make it useful as a chemical warfare (CW) agent; it is a colorless, odorless, nonirritating gas that is 2.5 times denser than air. At concentrations above 0.5 ppm, a garliclike odor may be noted; however, arsine is toxic at much lower concentrations. Arsine is often produced from the reduction of inorganic arsenic salts with the use of acids and metal cofactors such as zinc. Once in the body arsenic is readily distributed where peak serum levels occurs in approximately 60 minutes. The majority of arsenic is excreted by the kidneys, with some excretion in sweat, feces, and bile in small amounts.
Although it has been investigated as a CW agent, no battlefield use has been documented. During and prior to World War II, the British studied this agent and rejected its use in the field. They concluded that arsine was more than 10 times less toxic than phosgene (CG) and was both difficult to manufacture and highly flammable. Although arsine was determined not to be useful as a battlefield CW agent, concern exists that it may be useful as a small-scale weapon of assassination or terror. In contrast, several arsine-derived organoarsenic compounds have been developed and used as CW agents, including lewisite (beta-chlorovinyldichloroarsine), adamsite (diphenylaminearsine), Clark I (diphenylchlorarsine), and Clark II (diphenylcyanoarsine). Possible sources of occupational exposure are many, including microchip production in the semiconductor industry and other industries in which workers are involved in galvanizing, soldering, etching, and lead plating. It may also be produced inadvertently by mixing arsenic-containing insecticides and acids.
Pathophysiology
Inhaled arsine gas is distributed rapidly and causes massive red blood cell hemolysis that can potentially lead to global cellular hypoxia. The exact mechanisms leading to hemolysis have not been fully elucidated, but oxidative cell lysis has been suggested.
A study of mice exposed to moderate-to-high levels of arsine for 90 days revealed a significant decrease in hemoglobin and hematocrit along with an increase in mean corpuscular hemoglobins and mean corpuscular hemoglobin concentrations after 5 days of exposure.1 Blood collected at 15 and 90 days showed a less severe anemia but a greater increase in mean corpuscular volumes and absolute reticulocyte count indicating a regenerative response. At 90 days, the concentration of methemoglobin was increased along with an increase in intracellular denatured proteins, or Heinz bodies. In vitro studies have shown that arsine gas significantly depletes reduced intracellular glutathione. These studies further support the oxidative toxicity of the gas.
Other mechanisms of hemolysis may include the inhibition of catalase and the formation of reactive oxidative species (ROS), such as hydrogen peroxide, within the cell. The release of free heme from hemoglobin may also produce hemolysis by a colloid-osmotic mechanism, and denaturing of hemoglobin can lead to an abnormal association of hemoglobin with erythrocyte membrane proteins that increase fragility of the erythrocyte membrane. Many researchers believe that hemolysis is a direct result of an arsenic dihydride intermediate and elemental arsenic produced from oxidized arsine. While there is disagreement of the reactive species involved and the mechanism of destruction, it is plausible that arsine causes cellular destruction by multiple mechanisms and the oxidative pathophysiology of arsine is well supported.
Renal failure due to tubular destruction is an important sequelae of arsine toxicity. Although arsine may have direct effects on the renal system, most of the damage is believed to result indirectly from the breakdown of red blood cells and the increased load of hemoglobin. As in rhabdomyolysis, this destroys the tubular network leading to renal failure and is further complicated by renal hypoxia secondary to the decreased oxygen capacity of the blood.
Mortality/Morbidity
Arsine has been reported to cause immediate death at 150-250 ppm. In addition to absolute concentration, the duration of exposure is another factor that determines toxicity. Exposure to 25-50 ppm for 30 minutes or 100 ppm for less than 30 minutes may also result in massive red blood cell hemolysis and ultimately death. Symptoms may be noticed with concentrations as low as 0.15 ppm, and delirium may be seen at 10 ppm.
Most of the reported deaths are believed to have been secondary to acute renal failure. Of arsine-induced renal failure cases, 100% were fatal prior to the advent of hemodialysis. More recent mortality rates for patients with acute arsine toxicity report death in approximately 25% or less of reported cases.
History
Most patients report little or no discomfort at the time of exposure. According to the Centers for Disease Control and Prevention (CDC), signs and symptoms generally occur 2-24 hours after exposure and are a result of massive hemolysis. Signs and symptoms include generalized weakness, dark urine, jaundice, and dyspnea. Oliguria and renal failure often occur 1-3 days after exposure.
A case series documenting comprehensive descriptions of the symptoms and clinical course of arsine toxicity was published in 1975.2 Eight sailors were exposed to arsine gas that had escaped from a cylinder in the cargo hold of the Asiafreighter. Four sailors were exposed from 1 hour 5 minutes to 3 hours 45 minutes (cases 1-4). Four other sailors were exposed for approximately 15 minutes or less (cases 5-8).
All 8 sailors developed fever, headache, myalgia, epigastric pain, nausea, and vomiting between 1 and 12 hours of exposure. Cases 1-4 each developed intravascular hemolysis, renal failure, and marrow suppression with poor reticulocyte response and thrombocytopenia. Case 1 was exposed for the longest amount of time and suffered from anoxia and encephalopathy and was anuric for 5 weeks. Long-term complications for cases 1-4 included peripheral neuropathies, and case 1 was still severely disabled 6 months after the incident. Cases 5-8 developed much milder symptoms. All 8 sailors survived. The CDC case definition of arsine poisoning includes the following:3 - Suspected: A case in which a potentially exposed person is being evaluated by health care worker or public health officials for poisoning by a particular chemical agent, but no specific credible threat exists.
- Probable: A clinically compatible case in which a high index of suspicion (credible threat or patient history regarding location and time) exists for arsine exposure, or an epidemiologic link exists between this case and a laboratory-confirmed case.
- Confirmed: A clinically compatible case in which laboratory tests have confirmed exposure.
The classic triad of symptoms in sublethal arsine exposures includes abdominal pain, hematuria, and jaundice. Symptoms by organ system are as follows: - General - Fever, chills, shivering, thirst, malaise
- Cardiovascular - Long QT syndrome, hypovolemic shock, tachycardia, dysrhythmias
- Neurologic - Headache; dizziness; sensorimotor peripheral neuropathy (usually 1-3 wk after exposure); neuropsychological symptoms (several days after exposure) including memory loss, restlessness, and confusion
- Pulmonary - Dyspnea
- Gastrointestinal - Nausea, vomiting, abdominal pain, anorexia, jaundice
- Genitourinary - Red or dark-colored urine, flank pain, decreased urine output
- Muscle - Weakness, cramping
Physical
Physical signs and their severity depend on the concentration of arsine gas and the duration of the patient's exposure.
- Vital signs - Hyperthermia, tachypnea, tachycardia, hypotension
- Head, ears, eyes, nose, and throat (HEENT) - Discoloration of conjunctivae (red, orange, brown, or brassy; reportedly distinct from hyperbilirubinemia), scleral icterus, garlic odor to breath (possible)
- Pulmonary - Rales from acute respiratory distress syndrome (ARDS) in severe exposure
- Gastrointestinal - Abdominal tenderness, hepatomegaly
- Genitourinary - Costovertebral angle tenderness, colored urine (red, brown, or green from hemoglobinuria and/or methemoglobinuria)
- Extremities - Possible paresthesias and Mees lines with chronic arsenic toxicity from arsine exposure
Causes
- Arsine gas is used in the semiconductor industry when depositing arsenic on microchips. Exposure also may occur from producing, cleaning, or reclaiming gallium arsenide wafers.
- Arsine is released during the (usually accidental) production of hydrogen in an acid medium in contact with arsenic-contaminated metals.
- Arsine may potentially be used as a chemical warfare agent.
- Suspect arsine exposure if multiple victims present in a delayed fashion with hematuria, abdominal or flank pain, and jaundice.
- Severe acute arsine exposure may result in sudden death.
Anemia, Acute
CBRNE - Chemical Warfare Mass Casualty Management
CBRNE - Cyanides, Hydrogen
CBRNE - Evaluation of a Chemical Warfare Victim
Cholecystitis and Biliary Colic
Cholelithiasis
Colchicine
Copper sulfate
Dinitrophenols
Envenomations (snake or spider)
Hemolytic Uremic Syndrome
Hepatitis
Hyperkalemia
Lead
Leptospirosis in Humans
Malaria
Methemoglobinemia
Naphthalene
Phosphine
Renal Calculi
Renal Failure, Acute
Rhabdomyolysis
Smoke Inhalation
Thallium
Toxicity, Arsenic
Urinary Tract Infection, Female
Urinary Tract Infection, Male
Other Problems to be Considered
Cold agglutinin disease
Paroxysmal nocturnal hemoglobinuria
Pyrogallic acid toxicity
Stibine gas toxicity
Lab Studies
No specific test is available for arsine exposure; however, arsine exposure may lead to detection of elevated arsenic levels in urine (>50 mcg/L for a spot test or >50 mcg for a 24-hour urine test) and signs of hemolysis (eg, hemoglobinuria, anemia, or low haptoglobin). In addition, arsine may be detected in environmental samples. The following tests may aid in the diagnosis: - Complete blood cell count
- Hemolytic anemia: Coombs test results are negative; this may be severe and rapidly developing, with pink serum resulting from free hemoglobin, and decreased haptoglobin.
- Elevated white blood cell count: This may be seen early.
- Methemoglobinemia
- Urinalysis
- Hemoglobinuria (possible methemoglobinuria)
- Proteinuria (with possible tubular casts)
- Serum chemistry panel
- Hemolysis can cause hyperkalemia, elevated lactate dehydrogenase level, and hyperbilirubinemia.
- Renal failure can cause elevated creatinine and BUN levels.
- Hepatic transaminase levels may be elevated.
- Arsenic levels
- Blood and urine arsenic levels are elevated acutely, but these findings are not necessarily helpful in treatment decisions.
- A 24-hour urine arsenic test may help in monitoring chronic, low-level arsine exposures.
- Electrocardiography
- Peaked T waves from hyperkalemia may be seen.
- Nonspecific ST-segment and T-wave abnormalities have been reported.
- QT-interval prolongation is possible from arsenic toxicity.
Imaging Studies
- No routine imaging studies are indicated.
- Chest radiography is indicated to detect ARDS in patients with pulmonary symptoms.
Prehospital Care
Hot zone
Rescuers must be appropriately trained and attired before entering the hot zone. If training or equipment availability is questionable, assistance should be obtained from local or regional HAZMAT team or other equipped response organization. Positive pressure, self-contained breathing apparatus (SCBA) is highly recommended. Chemical protective clothing is usually not required since arsine gas is not directly absorbed through the skin. The exception is exposure to compressed liquid gas that may cause frostbite injury to the skin or eyes. Maintain victims' airway, breathing, and circulation and transport them out of the hot zone.
Decontamination zone
Victims who have exposure only to arsine gas do not need decontamination. They may be transferred immediately to the support zone.
Support zone
Support zone personnel require no protective gear if the victim has been exposed only to arsine gas. Support personnel should always continue to manage ABCs, which includes supplementary oxygen and venous access. The patient should be intubated if the airway is not patent or protected. Hypotension should be addressed with infusion of normal saline or lactated Ringer solution. If available, the victim's electrolytes status, mainly potassium, and oxygenation status with ABG should be obtained. The victim is transported to a medical facility as soon as possible.
Emergency Department Care
The main goal of the emergency medicine physician is to support vascular, renal, hematologic, and cardiorespiratory function.
- Airway: Ensure the airway is patent and protected.
- Breathing: Administer supplementary oxygen or intubation as necessary. Consider using bronchodilators in patients with bronchospasm or racemic epinephrine aerosol in children with wheezing.
- Circulation: Treat hypotension with normal saline (NS) or lactated Ringer solution. Consider dopamine for hypotension or oliguria. Norepinephrine should be considered in cases of resistant shock.
- Disability: Assess the patient's neurological status.
- Exposure: Necessary with exposure to liquid compressed arsine gas. Frostbite injuries may be irrigated with lukewarm water according to standard treatment. A thorough eye examination should be performed along with an ophthalmologist consultation if needed in patients with eye injuries.
- Several case reports have demonstrated the efficacy and benefits of exchange transfusion, to include both red blood cell exchange (RBC-E) and plasma exchange (PE).4, 5, 6, 7, 8 RBC-E and PE may have a synergistic effect with better outcome than RBC-E alone. Exchange transfusion is the treatment of choice for patients with severe hemolysis. This treatment is believed to have the following benefits:
- Supports oxygen-carrying capacity of the blood
- Removes free hemoglobin
- Removes arsine and arsenic dihydride residues
- Initiate diuresis to avoid heme-pigment nephropathy. Both intravenous mannitol and urinary alkalinization have anecdotal value.
- Chelating agents (eg, 2,3-dimercaptopropanol, British antilewisite [BAL]) have not been shown to be of benefit in acute arsine toxicity.
Consultations
- Contact the blood bank and hematologist regarding exchange transfusion.
- Consult a nephrologist for hemodialysis in patients with acute renal failure.
- Follow local emergency management plan and protocols if intentional release of arsine is suspected.
Diuresis with intravenous mannitol and urinary alkalinization with sodium bicarbonate may be of benefit prior to the onset of renal failure.
Drug Category: Diuretics
These agents promote urine flow.
| Drug Name | Mannitol (Osmitrol, Resectisol) |
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| Description | Increases osmotic pressure of glomerular filtrate, inducing an osmotic gradient that inhibits tubular resorption of water and electrolytes, resulting in increased urinary output. |
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| Adult Dose | Usual loading dose is 0.5-1 g/kg body weight IV, followed by 0.25-0.5 g/kg q4-6h to maintain diuresis |
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| Pediatric Dose | Administer as in adults |
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| Contraindications | Documented hypersensitivity; anuria; severe pulmonary congestion; progressive renal damage; severe dehydration; active intracranial bleeding; progressive heart failure |
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| Interactions | May enhance renal excretion of lithium |
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| Pregnancy | C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
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| Precautions | Carefully evaluate cardiovascular status before rapid administration of mannitol, since a sudden increase in extracellular fluid may lead to fulminating CHF; avoid pseudoagglutination; when blood is given simultaneously, add at least 20 mEq of sodium chloride to each liter of mannitol solution; do not give electrolyte-free mannitol solutions with blood |
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Drug Category: Urinary alkalinization agents
These agents decrease risk of heme-pigment–induced renal injury from arsine-related hemolysis.
| Drug Name | Sodium bicarbonate (Neut) |
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| Description | Dosing of sodium bicarbonate to induce urinary alkalinization not standardized; urinary alkalinization may prevent heme-pigment nephropathy by decreasing hemoglobin crystallization in renal tubules and/or by decreasing iron uptake by tubular epithelium. |
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| Adult Dose | 1 mEq/kg IV as bolus, followed by continuous IV maintenance infusion of sodium bicarbonate-containing fluids; examples of infusate include D5W with 3 ampules of sodium bicarbonate (132-150 mEq) per liter or D5-1/2NS with 2 ampules of sodium bicarbonate (88-100 mEq) per liter |
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| Pediatric Dose | Administer as in adults |
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| Contraindications | Alkalosis, hypernatremia, hypocalcemia, severe pulmonary edema, and unknown abdominal pain |
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| Interactions | Urinary alkalinization induced by increased sodium bicarbonate concentrations may cause decreased levels of lithium, tetracyclines, chlorpropamide, methotrexate, and salicylates; increases levels of amphetamines, pseudoephedrine, flecainide, anorexiants, mecamylamine, ephedrine, quinidine, and quinine |
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| Pregnancy | C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
|
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| Precautions | Establish urinary flow with intravascular volume repletion prior to alkalinizing urine; administering bicarbonate may induce hypokalemia and other electrolyte disorders |
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Further Inpatient Care
- All patients who have suspected arsine exposure should be carefully observed for 24 hours.
- Monitor renal function; initiate hemodialysis as necessary for acute renal failure.
- Monitor hemoglobin levels; perform transfusions to maintain oxygen-carrying capacity of the blood.
Further Outpatient Care
- Monitor the patient for signs of chronic arsenic toxicity.
In/Out Patient Meds
- Chelating agents (eg, BAL) may be used to treat chronic arsenic toxicity.
- Chronic arsenic toxicity from arsine exposure is treated no differently than exposure from other sources.
- See Toxicity, Arsenic for more information.
Deterrence/Prevention
- Train workers in high-risk industries to avoid toxic arsine exposures.
- Screen workers in the same environment as those persons already exposed to acute arsine poison.
Complications
- Hemolytic anemia
- Renal failure
- Hyperkalemia
- Death
- Overwhelming exposures cause rapid death from massive hemolysis.
- In those who survive acute exposures, most deaths occur from renal failure.
- Chronic arsenic toxicity: Patients who survive acute arsine exposure may develop chronic arsenic toxicity, including anemia and peripheral neuropathy.
Prognosis
- Patients who reach medical attention should survive with modern, supportive medical care.
- Historically, patients who developed renal failure had 100% mortality. More recent (but still dated) studies report a mortality rate from arsine poisoning of approximately 25%.
Patient Education
Medical/Legal Pitfalls
- A multiple casualty arsine exposure incident may overwhelm hospital resources to perform exchange transfusions.
- Monitor persons who have been exposed to arsine serially until the possibility of chronic arsenic toxicity has been ruled out.
The authors and editors of eMedicine gratefully acknowledge the contributions of previous author, Jeffrey R Suchard, MD, to the development and writing of this article.
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CBRNE - Arsenicals, Arsine excerpt Article Last Updated: Jan 17, 2008
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