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SODIUM CACODYLATE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Sodium cacodylate is an organic pentavalent arsenical compound.

Specific Substances

    A) No Synonyms were found in group or single elements
    1.2.1) MOLECULAR FORMULA
    1) C2-H6-As-O2.Na

Available Forms Sources

    A) USES
    1) Sodium Cacodylate is used as a non-selective herbicide, dofoliant, and silvicide and in medication (Budavari, 1996a; HSDB , 1997; Lewis, 1993a; Morgan, 1993)

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) Sodium cacodylate is an organic, pentavalent arsenical compound. It is a white or yellow, amorphous powder or crystalline solid which may be odorless or have a faint odor. It is advisable to treat all arsenic compounds as highly toxic.
    B) Organic arsenic compounds are better absorbed by the dermal route than are inorganic arsenic compounds. The dust is irritating and corrosive to the skin, eyes, and mucous membranes. Anorexia, nausea, abdominal pain, and elevated urinary arsenic levels have been observed after dermal contact. Organic arsenicals may be more toxic by mouth than injection due to the rapid release of inorganic arsenic by gastric acid. Chronic laryngitis and dermatitis may occur after chronic exposure.
    C) In experimental animals, sodium cacodylate has caused fetal deaths and fetotoxicity. Sodium cacodylate is regarded as a human carcinogen.
    D) Acute arsenic ingestion generally produces symptoms within 30 to 60 minutes, but onset may be delayed for several hours if ingested with food. A metallic or garlic taste, vomiting, abdominal pain, dysphagia, and profuse watery (rice-water-like) and sometimes bloody diarrhea may occur. Dehydration, intense thirst, and fluid-electrolyte disturbances are common. Hypovolemia from capillary leaking ("third spacing" of fluids) is a common early sign.
    E) Systemic arsenic poisoning from occupational exposure is uncommon. Arsenic workers have developed a hoarse voice, nasal irritation and possibly perforation of the nasal septum, irritation of eyes, skin, and mucous membranes, and rarely, cirrhosis of the liver. Nausea and vomiting are infrequent. Painful ulceration of the wrist and scrotal skin, lips, and nostrils may develop with dust exposure.
    F) The primary target organs initially are the gastrointestinal tract, heart, brain, and kidneys. Eventually, the skin, bone marrow, and peripheral nervous system may be significantly damaged. The peripheral neuropathy appears to be similar regardless of the route of exposure.
    0.2.3) VITAL SIGNS
    A) Patients may rapidly become hypotensive. Tachycardia may develop secondary to pain, hypovolemia, cardiac effects of arsenic, or anxiety.
    0.2.4) HEENT
    A) Headache, conjunctivitis, photophobia, dimness of vision, diplopia, and lacrimation may occur. This material is irritating and corrosive to the eyes and mucous membranes. A garlic-like odor may be detected on the breath.
    0.2.5) CARDIOVASCULAR
    A) Ventricular tachycardia and ventricular fibrillation (with QT prolongation) have been described after acute arsenic ingestion.
    0.2.6) RESPIRATORY
    A) Acute respiratory failure was seen in a patient with severe arsenic poisoning. Pulmonary edema may occur and be life-threatening. Adult respiratory distress syndrome (ARDS) has been reported.
    0.2.7) NEUROLOGIC
    A) Toxic delirium and encephalopathy are possible complications. Peripheral neuropathy is common.
    0.2.8) GASTROINTESTINAL
    A) Early symptoms within hours following arsenic ingestion include abdominal pain, vomiting, profuse bloody or watery ("rice-water-like") diarrhea, pain in the extremities and muscles, weakness, and flushing of the skin.
    0.2.9) HEPATIC
    A) Hepatocellular damage may occur, but is not common. A common post-mortem finding is mitotic activity of hepatocytes.
    0.2.10) GENITOURINARY
    A) Anuria, hematuria, proteinuria, acute tubular necrosis, renal failure, and chronic renal insufficiency from cortical necrosis have been described.
    0.2.12) FLUID-ELECTROLYTE
    A) Electrolyte imbalances may occur.
    0.2.13) HEMATOLOGIC
    A) Hemolysis, pancytopenia, isolated leukopenia, or anemia may occur.
    0.2.14) DERMATOLOGIC
    A) Sodium cacodylate dust is irritating and corrosive to the skin; common skin findings may include flushing, diaphoresis, palmar hyperkeratosis, peripheral edema, hyperpigmentation, brawny desquamation, and exfoliative dermatitis. Transverse white striae of the nails may occur. Shingles (Herpes Zoster) may also be a complication.
    0.2.20) REPRODUCTIVE
    A) In general, arsenic is likely fetotoxic in humans, however at permissible occupational exposure limits arsenic is NOT likely to be a significant risk to human reproduction. Fertility does not seem to be effected in either males or females.
    B) Arsenic is excreted in human breast milk.
    C) ANIMAL STUDIES - Prenatal mortality and gross malformations have been observed in the offspring of exposed experimental animals.
    D) ANIMAL STUDIES - Systemic toxicity was present before any effects were noted on the testes in rats.
    0.2.21) CARCINOGENICITY
    A) Sodium cacodylate is a confirmed human carcinogen. An IARC review linked arsenic to skin cancer and a greater risk of lung cancer. OSHA has linked arsenic to cancer of the skin, lungs, lymph glands, and bone marrow. Bladder, kidney, prostate, liver, breast and colon cancer have also been linked with arsenic exposure.

Laboratory Monitoring

    A) Quantitative 24 hour urine collections are the most reliable laboratory measure of arsenic poisoning. Urinary concentrations between 700 and 1000 mcg/L (0.7 to 1.0 mg/L) may indicate potentially harmful exposure.
    B) This agent may cause nephrotoxicity. Monitor renal function tests and urinalysis in patients with significant exposure.
    C) Arsenic is radiopaque and an abdominal film should be obtained whenever arsenic ingestion is suspected.
    D) This agent may produce abnormalities of the hematopoietic system. Monitor the complete blood count in patients with significant exposure.
    E) This agent may cause hepatotoxicity. Monitor liver function tests in patients with significant exposure.
    F) Monitor arterial blood gases and chest x-ray in patients who develop pulmonary edema.
    G) Monitor serum electrolytes in patients with significant vomiting, diarrhea, or hypotension from fluid "third spacing."

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) Do NOT induce emesis.
    B) GASTRIC LAVAGE: Consider after ingestion of a potentially life-threatening amount of poison if it can be performed soon after ingestion (generally within 1 hour). Protect airway by placement in the head down left lateral decubitus position or by endotracheal intubation. Control any seizures first.
    1) CONTRAINDICATIONS: Loss of airway protective reflexes or decreased level of consciousness in unintubated patients; following ingestion of corrosives; hydrocarbons (high aspiration potential); patients at risk of hemorrhage or gastrointestinal perforation; and trivial or non-toxic ingestion.
    C) ACTIVATED CHARCOAL: Administer charcoal as a slurry (240 mL water/30 g charcoal). Usual dose: 25 to 100 g in adults/adolescents, 25 to 50 g in children (1 to 12 years), and 1 g/kg in infants less than 1 year old.
    D) The primary threats to life from acute exposure are hypovolemia and cardiac toxicity resulting in dysrhythmias or cardiogenic shock. In chronic arsenic poisoning, the most important step is removing the patient from the source of exposure.
    E) HYPOTENSION: Infuse 10 to 20 mL/kg isotonic fluid. If hypotension persists, administer dopamine (5 to 20 mcg/kg/min) or norepinephrine (ADULT: begin infusion at 0.5 to 1 mcg/min; CHILD: begin infusion at 0.1 mcg/kg/min); titrate to desired response.
    F) Tachycardia may be a response to hypovolemia and should be treated initially with fluid replacement as clinically warranted.
    G) Ventricular tachycardia or ventricular fibrillation may occur after acute arsenic poisoning and should be treated with DC countershock and standard antiarrhythmic agents (LIDOCAINE, PROCAINAMIDE, AMIODARONE). Refer to TREATMENT/ORAL EXPOSURE section in the main body of this document for more information. Monitor serum electrolytes and administer replacement therapy as indicated.
    H) Alkalinization of the urine may prevent deposition of red cell breakdown products from hemolysis in renal tubular cells.
    1) URINE ALKALINIZATION
    a) Administer 1 to 2 mEq/kg sodium bicarbonate bolus. Add 132 milliequivalents (3 ampules) sodium bicarbonate and 20 to 40 milliequivalents potassium chloride (as needed) to one liter of dextrose 5 percent in water and infuse at approximately 1.5 times the maintenance fluid rate. Adjust as needed to achieve a urine pH of at least 7.5 and a urine output of 1 to 3 mL/kg/hr.
    b) Assure adequate hydration and renal function. Monitor fluid balance, serum electrolytes, and blood pH. Obtain hourly intake/output and urine pH.
    I) Chelation therapy may be indicated at a urine arsenic level of 200 mcg/liter or higher. Dimercaprol (BAL), D-PENICILLAMINE and DMSA are effective arsenic chelators.
    1) DIMERCAPROL (BAL): Usual dosage range is 3 to 5 milligrams/kilogram intramuscularly every 4 to 12 hours until symptoms resolve or another chelator is substituted. The dose and frequency used depend on the degree of toxicity seen. Dose dependent side effects include hypertension, tachycardia, anorexia, restlessness, vomiting, pain, salivation, fever, convulsions, "leukotoxic effect," and reducing substances in the urine. Early administration (within 18 hours of acute exposure) of BAL may be effective in preventing arsenical neuropathy in some cases.
    2) D-PENICILLAMINE: The usual dose is 25 milligrams/kilogram/dose given four times daily up to one gram per day, adults may require larger doses (i.e., up to 2 grams/day).
    3) DMSA: 2,3-Dimercaptosuccinic acid (DMSA) is an investigational drug. It has the advantage of being an oral agent as well as being relatively non-toxic.
    4) N-acetylcysteine (NAC) cannot presently be recommended for the treatment of arsenic poisoning.
    5) THERAPEUTIC END-POINT: Repeat five-day courses of chelation therapy should be prescribed in severe poisonings until the 24-hour urine arsenic level falls below 50 micrograms/liter.
    J) A MOBILIZATION TEST has been suggested to aid the diagnosis of mild or chronic exposure. Its usefulness has been questioned because of the relatively rapid excretion of absorbed arsenic. Refer to TREATMENT/ORAL EXPOSURE section in the main body of this document for more information.
    K) Physical therapy may be helpful for patients with established arsenical neuropathies.
    L) ACUTE LUNG INJURY: Maintain ventilation and oxygenation and evaluate with frequent arterial blood gases and/or pulse oximetry monitoring. Early use of PEEP and mechanical ventilation may be needed.
    M) HEMODIALYSIS should be performed in the presence of any degree of renal failure.
    N) NOTE: See treatment of oral exposure in the main body of this document for complete information.
    0.4.3) INHALATION EXPOSURE
    A) INHALATION: Move patient to fresh air. Monitor for respiratory distress. If cough or difficulty breathing develops, evaluate for respiratory tract irritation, bronchitis, or pneumonitis. Administer oxygen and assist ventilation as required. Treat bronchospasm with an inhaled beta2-adrenergic agonist. Consider systemic corticosteroids in patients with significant bronchospasm.
    B) Alkalinization of the urine may prevent deposition of red cell breakdown products from hemolysis in renal tubular cells.
    1) URINE ALKALINIZATION
    a) Administer 1 to 2 mEq/kg sodium bicarbonate bolus. Add 132 milliequivalents (3 ampules) sodium bicarbonate and 20 to 40 milliequivalents potassium chloride (as needed) to one liter of dextrose 5 percent in water and infuse at approximately 1.5 times the maintenance fluid rate. Adjust as needed to achieve a urine pH of at least 7.5 and a urine output of 1 to 3 mL/kg/hr.
    b) Assure adequate hydration and renal function. Monitor fluid balance, serum electrolytes, and blood pH. Obtain hourly intake/output and urine pH.
    C) Chelation therapy may be indicated at a urine arsenic level of 200 mcg/liter or higher. Dimercaprol (BAL), D-PENICILLAMINE and DMSA are effective arsenic chelators.
    1) DIMERCAPROL (BAL): Usual dosage range is 3 to 5 milligrams/kilogram intramuscularly every 4 to 12 hours until symptoms resolve or another chelator is substituted. The dose and frequency used depend on the degree of toxicity seen. Dose dependent side effects include hypertension, tachycardia, anorexia, restlessness, vomiting, pain, salivation, fever, convulsions, "leukotoxic effect," and reducing substances in the urine. Early administration (within 18 hours of acute exposure) of BAL may be effective in preventing arsenical neuropathy in some cases.
    2) D-PENICILLAMINE: The usual dose is 25 milligrams/kilogram/dose given four times daily up to one gram per day, adults may require larger doses (i.e., up to 2 grams/day).
    3) DMSA: 2,3-Dimercaptosuccinic acid (DMSA) is an investigational drug. It has the advantage of being an oral agent as well as being relatively non-toxic.
    4) N-acetylcysteine (NAC) cannot presently be recommended for the treatment of arsenic poisoning.
    5) THERAPEUTIC END-POINT: Repeat five-day courses of chelation therapy should be prescribed in severe poisonings until the 24-hour urine arsenic level falls below 50 micrograms/liter.
    D) A MOBILIZATION TEST has been suggested to aid the diagnosis of mild or chronic exposure. Its usefulness has been questioned because of the relatively rapid excretion of absorbed arsenic. Refer to TREATMENT/INHALATION EXPOSURE section in the main body of this document for more information.
    E) Physical therapy may be helpful for patients with established arsenical neuropathies.
    F) ACUTE LUNG INJURY: Maintain ventilation and oxygenation and evaluate with frequent arterial blood gases and/or pulse oximetry monitoring. Early use of PEEP and mechanical ventilation may be needed.
    G) HEMODIALYSIS should be performed in the presence of any degree of renal failure.
    H) HYPOTENSION: Infuse 10 to 20 mL/kg isotonic fluid. If hypotension persists, administer dopamine (5 to 20 mcg/kg/min) or norepinephrine (ADULT: begin infusion at 0.5 to 1 mcg/min; CHILD: begin infusion at 0.1 mcg/kg/min); titrate to desired response.
    I) NOTE: See treatment of inhalation exposure in the main body of this document for complete information.
    0.4.4) EYE EXPOSURE
    A) DECONTAMINATION: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, the patient should be seen in a healthcare facility.
    B) No cases of systemic arsenic poisoning following only eye exposure have been reported.
    C) If significant eye irritation is present, prolonged initial flushing and early ophthalmologic consultation are advisable.
    D) NOTE: See treatment of eye exposure in the main body of this document for complete information.
    0.4.5) DERMAL EXPOSURE
    A) OVERVIEW
    1) DECONTAMINATION: Remove contaminated clothing and jewelry and place them in plastic bags. Wash exposed areas with soap and water for 10 to 15 minutes with gentle sponging to avoid skin breakdown. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).
    2) Alkalinization of the urine may prevent deposition of red cell breakdown products from hemolysis in renal tubular cells.
    a) URINE ALKALINIZATION
    1) Administer 1 to 2 mEq/kg sodium bicarbonate bolus. Add 132 milliequivalents (3 ampules) sodium bicarbonate and 20 to 40 milliequivalents potassium chloride (as needed) to one liter of dextrose 5 percent in water and infuse at approximately 1.5 times the maintenance fluid rate. Adjust as needed to achieve a urine pH of at least 7.5 and a urine output of 1 to 3 mL/kg/hr.
    2) Assure adequate hydration and renal function. Monitor fluid balance, serum electrolytes, and blood pH. Obtain hourly intake/output and urine pH.
    3) Chelation therapy may be indicated at a urine arsenic level of 200 mcg/liter or higher. Dimercaprol (BAL), D-PENICILLAMINE and DMSA are effective arsenic chelators.
    a) DIMERCAPROL (BAL): Usual dosage range is 3 to 5 milligrams/kilogram intramuscularly every 4 to 12 hours until symptoms resolve or another chelator is substituted. The dose and frequency used depend on the degree of toxicity seen. Dose dependent side effects include hypertension, tachycardia, anorexia, restlessness, vomiting, pain, salivation, fever, convulsions, "leukotoxic effect," and reducing substances in the urine. Early administration (within 18 hours of acute exposure) of BAL may be effective in preventing arsenical neuropathy in some cases.
    b) D-PENICILLAMINE: The usual dose is 25 milligrams/kilogram/dose given four times daily up to one gram per day, adults may require larger doses (i.e., up to 2 grams/day).
    c) DMSA: 2,3-Dimercaptosuccinic acid (DMSA) is an investigational drug. It has the advantage of being an oral agent as well as being relatively non-toxic.
    d) N-acetylcysteine (NAC) cannot presently be recommended for the treatment of arsenic poisoning.
    e) THERAPEUTIC END-POINT: Repeat five-day courses of chelation therapy should be prescribed in severe poisonings until the 24-hour urine arsenic level falls below 50 micrograms/liter.
    4) A MOBILIZATION TEST has been suggested to aid the diagnosis of mild or chronic exposure. Its usefulness has been questioned because of the relatively rapid excretion of absorbed arsenic. Refer to TREATMENT/DERMAL EXPOSURE section in the main body of this document for more information.
    5) Physical therapy may be helpful for patients with established arsenical neuropathies.
    6) ACUTE LUNG INJURY: Maintain ventilation and oxygenation and evaluate with frequent arterial blood gases and/or pulse oximetry monitoring. Early use of PEEP and mechanical ventilation may be needed.
    7) HEMODIALYSIS should be performed in the presence of any degree of renal failure.
    8) Treat dermal irritation or burns with standard topical therapy. Patients developing dermal hypersensitivity reactions may require treatment with systemic or topical corticosteroids or antihistamines.
    9) Restriction from further exposure may be necessary for workers with significant arsenical dermatitis, ulcerations, or dermatoses.
    10) HYPOTENSION: Infuse 10 to 20 mL/kg isotonic fluid. If hypotension persists, administer dopamine (5 to 20 mcg/kg/min) or norepinephrine (ADULT: begin infusion at 0.5 to 1 mcg/min; CHILD: begin infusion at 0.1 mcg/kg/min); titrate to desired response.
    11) NOTE: See treatment of dermal exposure in the main body of this document for complete information.

Range Of Toxicity

    A) One milligram/kilogram of ingested arsenic may be lethal in a child. An oral dose of 120 mg of arsenic trioxide may be fatal.
    B) As little as 20 milligrams of arsenic may produce life-threatening toxicity. Estimates of acute oral toxic doses of various arsenic compounds range from 1 milligram to 10 grams.
    C) Trivalent arsenic (arsenite) is more toxic in animals than the pentavalent form (arsenate). However, significant toxicity may occur with large amounts of pentavalent salts in humans. Pentavalent arsenic may be converted in vivo to trivalent arsenic.

Clinical Effects

Summary Of Exposure

    A) Sodium cacodylate is an organic, pentavalent arsenical compound. It is a white or yellow, amorphous powder or crystalline solid which may be odorless or have a faint odor. It is advisable to treat all arsenic compounds as highly toxic.
    B) Organic arsenic compounds are better absorbed by the dermal route than are inorganic arsenic compounds. The dust is irritating and corrosive to the skin, eyes, and mucous membranes. Anorexia, nausea, abdominal pain, and elevated urinary arsenic levels have been observed after dermal contact. Organic arsenicals may be more toxic by mouth than injection due to the rapid release of inorganic arsenic by gastric acid. Chronic laryngitis and dermatitis may occur after chronic exposure.
    C) In experimental animals, sodium cacodylate has caused fetal deaths and fetotoxicity. Sodium cacodylate is regarded as a human carcinogen.
    D) Acute arsenic ingestion generally produces symptoms within 30 to 60 minutes, but onset may be delayed for several hours if ingested with food. A metallic or garlic taste, vomiting, abdominal pain, dysphagia, and profuse watery (rice-water-like) and sometimes bloody diarrhea may occur. Dehydration, intense thirst, and fluid-electrolyte disturbances are common. Hypovolemia from capillary leaking ("third spacing" of fluids) is a common early sign.
    E) Systemic arsenic poisoning from occupational exposure is uncommon. Arsenic workers have developed a hoarse voice, nasal irritation and possibly perforation of the nasal septum, irritation of eyes, skin, and mucous membranes, and rarely, cirrhosis of the liver. Nausea and vomiting are infrequent. Painful ulceration of the wrist and scrotal skin, lips, and nostrils may develop with dust exposure.
    F) The primary target organs initially are the gastrointestinal tract, heart, brain, and kidneys. Eventually, the skin, bone marrow, and peripheral nervous system may be significantly damaged. The peripheral neuropathy appears to be similar regardless of the route of exposure.

Vital Signs

    3.3.1) SUMMARY
    A) Patients may rapidly become hypotensive. Tachycardia may develop secondary to pain, hypovolemia, cardiac effects of arsenic, or anxiety.
    3.3.4) BLOOD PRESSURE
    A) HYPOTENSION - Patients may rapidly become hypotensive after acute arsenic poisoning from "third spacing" of fluids, diarrhea, or blood loss into the GI tract (Schoolmeester & White, 1980; Sittig, 1991).
    3.3.5) PULSE
    A) TACHYCARDIA - Patients may become tachycardic secondary to pain, hypovolemia, cardiac effects of arsenic, or anxiety (Morgan, 1989; HSDB , 1997).

Heent

    3.4.1) SUMMARY
    A) Headache, conjunctivitis, photophobia, dimness of vision, diplopia, and lacrimation may occur. This material is irritating and corrosive to the eyes and mucous membranes. A garlic-like odor may be detected on the breath.
    3.4.2) HEAD
    A) HEADACHE - Headache may occur (Sittig, 1991).
    B) ALOPECIA - Hair loss may occur with chronic exposure (Finkel, 1983).
    3.4.3) EYES
    A) CONJUNCTIVITIS - Conjunctivitis, photophobia, dimness of vision, diplopia, optic neuritis, optic atrophy, and lacrimation may occur (Heyman et al, 1956; Grant, 1993). Sodium cacodylate dust is irritating and corrosive to the eyes (CHRIS, 1997; (HSDB , 1997; Sittig, 1991).
    3.4.5) NOSE
    A) BURNING - A sensation of burning, dryness and constriction of the oral and nasal cavities may occur (Finkel, 1983) Hathaway et al, 1996).
    3.4.6) THROAT
    A) BREATH ODOR - A garlic-like odor may be detected on the breath (HSDB , 1997) Morgan, 1993; (Sittig, 1991).
    B) LARYNGITIS - One laboratory worker using sodium cacodylate as an electron microscopy reagent developed chronic laryngitis, although it was unclear whether or not the arsenic compound was the etiologic agent (Weakley, 1977).
    C) INTENSE THIRST - Intense thirst may occur (Sittig, 1991).

Cardiovascular

    3.5.1) SUMMARY
    A) Ventricular tachycardia and ventricular fibrillation (with QT prolongation) have been described after acute arsenic ingestion.
    3.5.2) CLINICAL EFFECTS
    A) CONDUCTION DISORDER OF THE HEART
    1) Particularly ventricular tachycardia and ventricular fibrillation (with QT prolongation) have been described after acute arsenic ingestion (Peterson & Rumack, 1977; Goldsmith, 1980; St Peter et al, 1970; Sittig, 1991).
    2) These dysrhythmias may be secondary to electrolyte imbalances rather than a direct toxic effect of arsenic on the myocardium (Sittig, 1991).
    B) ELECTROCARDIOGRAM ABNORMAL
    1) ECG changes have included QT prolongation, left axis deviation, peaked T waves, and also deeply inverted T waves (Gousios & Adelson, 1959; Heyman et al, 1956).
    2) These ECG changes may be secondary to electrolyte imbalances rather than a direct toxic effect of arsenic on the myocardium (Sittig, 1991), although a direct, reversible effect on the myocardium has been postulated from animal experiments (Massmann & Opitz, 1954).

Respiratory

    3.6.1) SUMMARY
    A) Acute respiratory failure was seen in a patient with severe arsenic poisoning. Pulmonary edema may occur and be life-threatening. Adult respiratory distress syndrome (ARDS) has been reported.
    3.6.2) CLINICAL EFFECTS
    A) RESPIRATORY FAILURE
    1) Acute respiratory failure presumably from severe weakness of respiratory muscles has been seen in a patient with severe arsenic poisoning (Greenberg et al, 1979). The condition progressed despite dimercaprol therapy and required ventilatory assistance for one month.
    B) ACUTE LUNG INJURY
    1) Either noncardiogenic from capillary leaking, or cardiogenic from myocardial depression, may occur and be life-threatening (Morgan, 1989; Sittig, 1991).
    C) ACUTE LUNG INJURY
    1) Adult respiratory distress syndrome (ARDS) has been reported (Zaloga et al, 1970; Schoolmeester & White, 1980).

Neurologic

    3.7.1) SUMMARY
    A) Toxic delirium and encephalopathy are possible complications. Peripheral neuropathy is common.
    3.7.2) CLINICAL EFFECTS
    A) TOXIC ENCEPHALOPATHY
    1) Toxic delirium and encephalopathy are complications of acute arsenic poisoning (Jenkins, 1966; Sittig, 1991).
    2) The encephalopathy may be permanent and result in cortical atrophy one to six months after exposure (Fincher & Koerker, 1987). Early institution of chelation therapy may not be successful in preventing arsenic encephalopathy (Fincher & Koerker, 1987).
    B) SECONDARY PERIPHERAL NEUROPATHY
    1) Peripheral neuropathy commonly begins 1 to 3 weeks after acute exposure to inorganic arsenicals (Heyman et al, 1956; HSDB , 1997; Le Quesne & McLeod, 1977). It usually begins as paresthesias of the soles of the feet, then the hands, progressing proximally over the next few days (Heyman et al, 1956).
    2) Severe muscle weakness and wasting then develops, causing severe disability (Le Quesne & McLeod, 1977; Sittig, 1991). It may initially be confused with Guillain-Barre syndrome (Donofrio et al, 1987). The paresthesias may be painful and are frequently described as severe burning pain in a stocking and glove distribution.
    3) PHYSICAL FINDINGS of arsenic neuropathy usually include prominently decreased sensation to touch, pinprick, and temperature, frequently in a stocking and glove distribution (Heyman et al, 1956). Loss of vibration sense is also common. Profound muscle weakness and wasting, distal more so than proximal, also occurs (Donofrio et al, 1987; Heyman et al, 1956; Sittig, 1991). Wrist drop, foot drop, and fasciculations may occur (Heyman et al, 1956).
    4) ELECTRODIAGNOSTIC STUDIES of arsenic neuropathy have shown a reduction of motor conduction velocity and marked abnormalities of sensory nerve action potentials (Le Quesne & McLeod, 1977).
    5) NERVE BIOPSY may demonstrate various stages of axonal degeneration without demyelination (Le Quesne & McLeod, 1977) or with demyelination (Donofrio et al, 1987).
    6) DIMERCAPROL (BAL) does not seem to be able to reverse arsenic neuropathy (Donofrio et al, 1987; Heyman et al, 1956; Le Quesne & McLeod, 1977); recovery is usually very slow and incomplete. It has been claimed that if BAL is administered within hours of ingestion, however, that neuropathy may be prevented (Jenkins, 1966), although this may not always be true (Marcus, 1987).
    a) Early and prolonged chelation therapy with BAL followed by d-penicillamine did not prevent development of a mild peripheral neuropathy in a patient who injected sodium arsenite and potassium cyanide intravenously in a suicide attempt (DiNapoli et al, 1989).

Gastrointestinal

    3.8.1) SUMMARY
    A) Early symptoms within hours following arsenic ingestion include abdominal pain, vomiting, profuse bloody or watery ("rice-water-like") diarrhea, pain in the extremities and muscles, weakness, and flushing of the skin.
    3.8.2) CLINICAL EFFECTS
    A) GASTROENTERITIS
    1) Early symptoms within hours following arsenic ingestion include abdominal pain, vomiting, profuse bloody or watery diarrhea (sometimes described as "rice-water-like"), pain in the extremities and muscles, weakness, and flushing of the skin (CHRIS, 1997; (Finkel, 1983; Gilman et al, 1985; HSDB , 1997; Sittig, 1991).

Hepatic

    3.9.1) SUMMARY
    A) Hepatocellular damage may occur, but is not common. A common post-mortem finding is mitotic activity of hepatocytes.
    3.9.2) CLINICAL EFFECTS
    A) LIVER DAMAGE
    1) Hepatocellular damage may occur after acute arsenic poisoning, but is not common (Donofrio et al, 1987). Mitotic activity of hepatocytes may be a common post-mortem finding in arsenic poisoning (Mackell et al, 1985).

Genitourinary

    3.10.1) SUMMARY
    A) Anuria, hematuria, proteinuria, acute tubular necrosis, renal failure, and chronic renal insufficiency from cortical necrosis have been described.
    3.10.2) CLINICAL EFFECTS
    A) RENAL FAILURE SYNDROME
    1) Anuria, hematuria, proteinuria (Zaloga et al, 1970; Schoolmeester & White, 1980), acute tubular necrosis, renal failure (Giberson et al, 1976; Vaziri et al, 1980), and chronic renal insufficiency from cortical necrosis have been described (Gerhardt et al, 1978).

Hematologic

    3.13.1) SUMMARY
    A) Hemolysis, pancytopenia, isolated leukopenia, or anemia may occur.
    3.13.2) CLINICAL EFFECTS
    A) HEMOLYSIS
    1) Hemolysis may occur after acute arsenic poisoning (Kyle & Pease, 1965).
    B) PANCYTOPENIA
    1) After either acute or chronic arsenic exposure, pancytopenia may occur (Kyle & Pease, 1965; Kjeldsberg & Ward, 1972). However, isolated leukopenia or anemia may also occur. The anemia is usually normochromic and normocytic, but may be hypochromic and microcytic (Kyle & Pease, 1965).
    2) Bone marrow aspirate may demonstrate pronounced erythroid hyperplasia similar to that seen with pernicious anemia (Selzer & Ancel, 1983). Basophilic stippling and rouleau formation of red cells may also occur (Kyle & Pease, 1965).

Dermatologic

    3.14.1) SUMMARY
    A) Sodium cacodylate dust is irritating and corrosive to the skin; common skin findings may include flushing, diaphoresis, palmar hyperkeratosis, peripheral edema, hyperpigmentation, brawny desquamation, and exfoliative dermatitis. Transverse white striae of the nails may occur. Shingles (Herpes Zoster) may also be a complication.
    3.14.2) CLINICAL EFFECTS
    A) SKIN IRRITATION
    1) Sodium cacodylate dust is irritating and corrosive to the skin (CHRIS, 1997; (HSDB , 1997; Sittig, 1991).
    B) SKIN FINDING
    1) Common skin findings after either acute or chronic arsenic poisoning may include flushing, diaphoresis, palmar hyperkeratosis, peripheral edema, hyperpigmentation, brawny desquamation, and exfoliative dermatitis (Heyman et al, 1956; Hutton & Christians, 1983; Schoolmeester & White, 1980; Zaloga et al, 1970).
    C) MEE'S LINE
    1) Transverse white striae of the nails may occur after acute exposure. Mee's lines commonly take 5 weeks to appear above the cuticle and advance 1 mm per week afterwards, allowing an approximation of the time of acute exposure (Heyman et al, 1956).
    D) HERPES ZOSTER
    1) Shingles may also be a complication of arsenic poisoning (Jenkins, 1966).

Reproductive

    3.20.1) SUMMARY
    A) In general, arsenic is likely fetotoxic in humans, however at permissible occupational exposure limits arsenic is NOT likely to be a significant risk to human reproduction. Fertility does not seem to be effected in either males or females.
    B) Arsenic is excreted in human breast milk.
    C) ANIMAL STUDIES - Prenatal mortality and gross malformations have been observed in the offspring of exposed experimental animals.
    D) ANIMAL STUDIES - Systemic toxicity was present before any effects were noted on the testes in rats.
    3.20.2) TERATOGENICITY
    A) LACK OF EFFECT
    1) RELATED COMPOUND-
    a) HUMAN RISK - Arsenic is NOT likely to be a significant risk to human reproduction at permissible occupational exposure limits (Council on Scientific Affairs, 1985).
    b) While arsenic is likely fetotoxic in humans, data are currently inadequate to determine whether or not such effects could occur in the absence of maternal toxicity (Council on Scientific Affairs, 1985).
    B) ANIMAL STUDIES
    1) Administration of 900 mg/kg of sodium cacodylate intraperitoneally to pregnant hamsters on one day during the period of days 8 through 12 of gestation caused both prenatal mortality and gross malformations in the offspring (Hood & Harrison, 1982; RTECS , 1997).
    a) Observed fetal abnormalities included cleft lip and palate, micromelia, fused ribs, talipes, syndactyly, and exencephaly (Hood & Harrison, 1982).
    b) Parenteral administration of high arsenic doses caused exencephaly, skeletal defects, and abnormalities of the genitourinary system. At lower doses in drinking water, only minimal fetal effects have been seen (Hathaway et al, 1996).
    3.20.3) EFFECTS IN PREGNANCY
    A) CASE REPORTS
    1) ACUTE TOXICITY
    a) NEONATAL DEATH - Acute ingestion of arsenic by a female with a 30 week pregnancy has been reported to result in the death of the infant born 4 days after the poisoning (Lugo et al, 1969). The child apparently died of hyaline membrane disease, but did have elevated tissue levels of arsenic. It seems apparent that arsenic can cross the placenta.
    B) CASE REPORTS
    1) LACK OF EFFECT
    a) Six women developing arsenical encephalopathy during the fourth to eighth months of pregnancy delivered normal children (Schardein, 1993).
    C) CASE SERIES
    1) ABORTION
    a) EPIDEMIOLOGICAL STUDIES - Increased rates of spontaneous abortions and decreased birth weights were found in a study of women living near a smelter in Sweden, which emitted lead, sulfur dioxide, and arsenic (Schardein, 1993). There was no increased incidence of congenital malformations in this group (Schardein, 1993).
    D) OCCUPATIONAL EXPOSURE
    1) AMA COUNCIL ON SCIENTIFIC AFFAIRS -
    a) Although arsenic compounds are likely fetotoxic in humans, exposure at permissible occupational levels is not likely to present a significant risk to human reproduction (Council on Scientific Affairs, 1985).
    E) ANIMAL STUDIES
    1) FERTILITY
    a) Continuous dietary administration of up to 215 mg/kg of arsenic did not have adverse effects on fertility in female rats (Barlow & Sullivan, 1982).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) Arsenic is excreted in the breast milk in both experimental animals and humans (Barlow & Sullivan, 1982).
    B) ANIMAL STUDIES
    1) BREAST MILK
    a) Arsenic is excreted in the breast milk in experimental animals (Barlow & Sullivan, 1982).

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS124-65-2 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) IARC Classification
    a) Listed as: Sodium cacodylate
    b) Carcinogen Rating: 1
    1) The agent (mixture) is carcinogenic to humans. The exposure circumstance entails exposures that are carcinogenic to humans. This category is used when there is sufficient evidence of carcinogenicity in humans. Exceptionally, an agent (mixture) may be placed in this category when evidence of carcinogenicity in humans is less than sufficient but there is sufficient evidence of carcinogenicity in experimental animals and strong evidence in exposed humans that the agent (mixture) acts through a relevant mechanism of carcinogenicity.
    3.21.2) SUMMARY/HUMAN
    A) Sodium cacodylate is a confirmed human carcinogen. An IARC review linked arsenic to skin cancer and a greater risk of lung cancer. OSHA has linked arsenic to cancer of the skin, lungs, lymph glands, and bone marrow. Bladder, kidney, prostate, liver, breast and colon cancer have also been linked with arsenic exposure.
    3.21.3) HUMAN STUDIES
    A) CARCINOMA
    1) IARC REVIEW - An IARC review found that there is a causal relationship between medicinal, drinking water, or occupational heavy arsenic exposure and skin cancer (IARC, 1973). There is also a clearly increased risk of lung cancer in workers inhaling high levels of arsenic trioxide (IARC, 1973).
    a) Arsenic and arsenic compounds are in IARC Group 1 (carcinogenic to humans) (HSDB , 1997; RTECS , 1997):
    1) -Evidence in humans - sufficient
    2) -Evidence in animals - limited
    3) -Evidence for activity in short term tests - limited
    2) Sodium cacodylate is in USEPA classification D (not classifiable as to human carcinogenicity) based on no human data and inadequate data in animals (HSDB , 1997).
    3) Sodium cacodylate is a confirmed human carcinogen (Lewis, 1996).
    4) CARCINOMAS - Basal cell and squamous cell carcinomas of the skin have been described after both acute and chronic arsenic exposure (Clayton & Clayton, 1994; Jackson & Grainge, 1975; Renwick et al, 1981; Sittig, 1991; Wagner et al, 1979).
    5) The Occupational Safety and Health Administration (OSHA) has linked arsenic to cancer of the skin, lungs, lymph glands, and bone marrow (Anon, 1979). A study of a population in Taiwan drinking high-arsenic concentration artesian well water found a dose-response relationship between the amount of arsenic in the water and the incidence of mortality from bladder, kidney, skin, prostate, lung, and liver cancer (Chen et al, 1988).
    6) CASE REPORTS - Two patients with arsenic-induced basal cell carcinomas of the skin also developed malignancies of other organs (breast and colon) (Jackson & Grainge, 1975).
    7) CASE REPORT - One worker who was exposed to arsenious oxide and sodium arsenite for 20 years developed cirrhosis of the liver and primary liver carcinoma (Finkel, 1983).

Genotoxicity

    A) Limited data are available regarding sodium cacodylate and its free acid (dimethylarsenic acid) which exists in equilibrium with the sodium salt. Single strand DNA breakage, tetraploidy, and micronuclei have been reported.

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Quantitative 24 hour urine collections are the most reliable laboratory measure of arsenic poisoning. Urinary concentrations between 700 and 1000 mcg/L (0.7 to 1.0 mg/L) may indicate potentially harmful exposure.
    B) This agent may cause nephrotoxicity. Monitor renal function tests and urinalysis in patients with significant exposure.
    C) Arsenic is radiopaque and an abdominal film should be obtained whenever arsenic ingestion is suspected.
    D) This agent may produce abnormalities of the hematopoietic system. Monitor the complete blood count in patients with significant exposure.
    E) This agent may cause hepatotoxicity. Monitor liver function tests in patients with significant exposure.
    F) Monitor arterial blood gases and chest x-ray in patients who develop pulmonary edema.
    G) Monitor serum electrolytes in patients with significant vomiting, diarrhea, or hypotension from fluid "third spacing."
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) An arsenic blood level below 7 mcg/100 mL is considered in the normal range. Blood levels are highly variable and may be useful only after acute exposure to confirm the diagnosis; they may become undetectable following acute poisoning at times when urinary arsenic excretion remains substantial (Fesmire et al, 1988).
    2) This agent may cause hepatotoxicity. Monitor liver function tests in patients with significant exposure.
    3) This agent may cause nephrotoxicity. Monitor renal function tests and urinalysis in patients with significant exposure.
    4) Monitor serum electrolytes in patients with significant vomiting, diarrhea, or hypotension from fluid "third spacing."
    B) ACID/BASE
    1) Monitor arterial blood gases in patients who develop pulmonary edema.
    C) HEMATOLOGIC
    1) This agent may produce abnormalities of the hematopoietic system. Monitor the complete blood count in patients with significant exposure.
    4.1.3) URINE
    A) URINARY LEVELS
    1) 24-hour urine collections for total arsenic excretion or spot specimens measured as concentration of arsenic (in micrograms or milligrams) per gram of urinary creatinine are generally the preferred samples, as they balance out the effects of varying urine volume and concentration.
    2) A method for a quick urine spot test (Reinsch test) has been described (Grande et al, 1987) but its clinical utility is uncertain. Even with chelation, an unexposed individual should not have more than 100 mcg of arsenic per 24 hour total urine output. Urinary arsenic may be elevated up to 200 to 1700 mcg/L within 4 hours after eating some seafoods (Baselt & Cravey, 1989; Baselt, 1988) Hathaway et al, 1996).
    a) Urinary concentrations between 700 and 1000 mcg/L (0.7 to 1.0 mg/L) may indicate potentially harmful exposure (Hathaway et al, 1996).
    b) Urine levels are generally below 100 mcg/gram of creatinine in unexposed individuals with no seafood intake for two days, and generally below 20 mcg/gram of creatinine using the hydride-generation atomic absorption spectrophotometry method of measurement (Hathaway et al, 1996).
    4.1.4) OTHER
    A) OTHER
    1) HAIR
    a) Arsenic has been demonstrated in hair and nails within hours after exposure (Lander et al, 1965). Normal concentration of arsenic in hair and nails is less than 1 mcg/gram (Baselt & Cravey, 1989; Baselt, 1988).
    1) However, many commercial laboratories performing hair analyses for consumers have not been shown to yield consistent and reliable results (Barrett, 1985), and such levels cannot be interpreted in individual patients. Hair or nail analysis is only useful in epidemiologic studies to distinguish potentially exposed from unexposed groups.
    2) OTHER
    a) Periodic sputum cytology examinations have been recommended for workers with chronic arsenic exposure (HSDB , 1991).

Radiographic Studies

    A) ABDOMINAL RADIOGRAPH
    1) Arsenic is radiopaque and an abdominal film should be obtained whenever arsenic ingestion is suspected (Hilfer & Mendel, 1962; Gousios & Adelson, 1959).
    B) CHEST RADIOGRAPH
    1) Monitor the chest x-ray in patients who develop pulmonary edema.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Monitoring

    A) Quantitative 24 hour urine collections are the most reliable laboratory measure of arsenic poisoning. Urinary concentrations between 700 and 1000 mcg/L (0.7 to 1.0 mg/L) may indicate potentially harmful exposure.
    B) This agent may cause nephrotoxicity. Monitor renal function tests and urinalysis in patients with significant exposure.
    C) Arsenic is radiopaque and an abdominal film should be obtained whenever arsenic ingestion is suspected.
    D) This agent may produce abnormalities of the hematopoietic system. Monitor the complete blood count in patients with significant exposure.
    E) This agent may cause hepatotoxicity. Monitor liver function tests in patients with significant exposure.
    F) Monitor arterial blood gases and chest x-ray in patients who develop pulmonary edema.
    G) Monitor serum electrolytes in patients with significant vomiting, diarrhea, or hypotension from fluid "third spacing."

Oral Exposure

    6.5.2) PREVENTION OF ABSORPTION
    A) EMESIS
    1) Do NOT induce emesis.
    B) GASTRIC LAVAGE
    1) INDICATIONS: Consider gastric lavage with a large-bore orogastric tube (ADULT: 36 to 40 French or 30 English gauge tube {external diameter 12 to 13.3 mm}; CHILD: 24 to 28 French {diameter 7.8 to 9.3 mm}) after a potentially life threatening ingestion if it can be performed soon after ingestion (generally within 60 minutes).
    a) Consider lavage more than 60 minutes after ingestion of sustained-release formulations and substances known to form bezoars or concretions.
    2) PRECAUTIONS:
    a) SEIZURE CONTROL: Is mandatory prior to gastric lavage.
    b) AIRWAY PROTECTION: Place patients in the head down left lateral decubitus position, with suction available. Patients with depressed mental status should be intubated with a cuffed endotracheal tube prior to lavage.
    3) LAVAGE FLUID:
    a) Use small aliquots of liquid. Lavage with 200 to 300 milliliters warm tap water (preferably 38 degrees Celsius) or saline per wash (in older children or adults) and 10 milliliters/kilogram body weight of normal saline in young children(Vale et al, 2004) and repeat until lavage return is clear.
    b) The volume of lavage return should approximate amount of fluid given to avoid fluid-electrolyte imbalance.
    c) CAUTION: Water should be avoided in young children because of the risk of electrolyte imbalance and water intoxication. Warm fluids avoid the risk of hypothermia in very young children and the elderly.
    4) COMPLICATIONS:
    a) Complications of gastric lavage have included: aspiration pneumonia, hypoxia, hypercapnia, mechanical injury to the throat, esophagus, or stomach, fluid and electrolyte imbalance (Vale, 1997). Combative patients may be at greater risk for complications (Caravati et al, 2001).
    b) Gastric lavage can cause significant morbidity; it should NOT be performed routinely in all poisoned patients (Vale, 1997).
    5) CONTRAINDICATIONS:
    a) Loss of airway protective reflexes or decreased level of consciousness if patient is not intubated, following ingestion of corrosive substances, hydrocarbons (high aspiration potential), patients at risk of hemorrhage or gastrointestinal perforation, or trivial or non-toxic ingestion.
    C) ACTIVATED CHARCOAL
    1) Although arsenic is commonly listed as being effectively adsorbed to charcoal, data are lacking.
    2) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    3) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) HYPOTENSIVE EPISODE
    1) Hypotension from acute arsenic ingestion is likely due to intravascular volume depletion from vomiting, diarrhea, or "third spacing" of fluids.
    2) The initial treatment should consist of adequate volume replacement with crystalloid solutions. Placing the patient in Trendelenburg position and using MAST trousers may also be useful. Blood products should only be used if significant bleeding or hemolysis are present.
    3) Aggressive monitoring of volume status should be undertaken, even in the absence of hypotension initially. Bladder catheterization to monitor hourly urine output and a central venous or Swan-Ganz catheter should be used as clinically warranted.
    4) Vasopressors should be used only if volume replacement does not reverse the hypotension.
    5) DOPAMINE
    a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    6) NOREPINEPHRINE
    a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
    b) DOSE
    1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
    2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
    3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).
    B) CONDUCTION DISORDER OF THE HEART
    1) Tachycardia may be a response to hypovolemia and should be treated initially with fluid replacement as clinically warranted.
    2) Ventricular tachycardia or ventricular fibrillation may occur after acute arsenic poisoning and should be treated with DC countershock and standard antiarrhythmic agents. Monitor serum electrolytes and administer replacement therapy as indicated.
    C) LIDOCAINE
    1) LIDOCAINE/DOSE
    a) ADULT: 1 to 1.5 milligrams/kilogram via intravenous push. For refractory VT/VF an additional bolus of 0.5 to 0.75 milligram/kilogram can be given at 5 to 10 minute intervals to a maximum dose of 3 milligrams/kilogram (Neumar et al, 2010). Only bolus therapy is recommended during cardiac arrest.
    1) Once circulation has been restored begin a maintenance infusion of 1 to 4 milligrams per minute. If dysrhythmias recur during infusion repeat 0.5 milligram/kilogram bolus and increase the infusion rate incrementally (maximal infusion rate is 4 milligrams/minute) (Neumar et al, 2010).
    b) CHILD: 1 milligram/kilogram initial bolus IV/IO; followed by a continuous infusion of 20 to 50 micrograms/kilogram/minute (de Caen et al, 2015).
    2) LIDOCAINE/MAJOR ADVERSE REACTIONS
    a) Paresthesias; muscle twitching; confusion; slurred speech; seizures; respiratory depression or arrest; bradycardia; coma. May cause significant AV block or worsen pre-existing block. Prophylactic pacemaker may be required in the face of bifascicular, second degree, or third degree heart block (Prod Info Lidocaine HCl intravenous injection solution, 2006; Neumar et al, 2010).
    3) LIDOCAINE/MONITORING PARAMETERS
    a) Monitor ECG continuously; plasma concentrations as indicated (Prod Info Lidocaine HCl intravenous injection solution, 2006).
    D) PROCAINAMIDE
    1) PROCAINAMIDE/ADULT LOADING DOSE
    a) 20 to 50 milligrams/minute IV until dysrhythmia is suppressed or toxicity develops from procainamide (hypotension develops or the QRS is widened by 50%), or a total dose of 17 milligrams/kilogram is given (1.2 grams for a 70 kilogram person) (Neumar et al, 2010).
    b) ALTERNATIVE DOSING: 100 mg every 5 minutes until dysrhythmia is controlled, or toxicity develops from procainamide (hypotension develops or the QRS is widened by 50%) or 17 mg/kg have been given (Neumar et al, 2010).
    c) MAXIMUM DOSE: 17 milligrams/kilogram (Neumar et al, 2010).
    2) PROCAINAMIDE/CONTROLLED INFUSION
    a) In conscious patients, procainamide should be administered as a controlled infusion (20 milligrams/minute) because of the risk of QT prolongation and its hypotensive effects (Link et al, 2015)
    3) PROCAINAMIDE/ADULT MAINTENANCE DOSE
    a) 1 to 4 milligrams/minute via an intravenous infusion (Neumar et al, 2010).
    4) PROCAINAMIDE/PEDIATRIC LOADING DOSE
    a) 15 milligrams/kilogram IV/Intraosseously over 30 to 60 minutes; discontinue if hypotension develops or the QRS widens by 50% (Kleinman et al, 2010).
    5) PROCAINAMIDE/PEDIATRIC MAINTENANCE DOSE
    a) Initiate at 20 mcg/kg/minute and increase in 10 mcg/kg/minute increments every 15 to 30 minutes until desired effect is achieved; up to 80 mcg/kg/minute (Bouhouch et al, 2008; Ratnasamy et al, 2008; Mandapati et al, 2000; Luedtke et al, 1997; Walsh et al, 1997).
    6) PROCAINAMIDE/PEDIATRIC MAXIMUM DOSE
    a) 2 grams/day (Bouhouch et al, 2008; Ratnasamy et al, 2008; Mandapati et al, 2000; Luedtke et al, 1997; Walsh et al, 1997).
    7) MONITORING PARAMETERS
    a) ECG, blood pressure, and blood concentrations (Prod Info procainamide HCl IV, IM injection solution, 2011). Procainamide can produce hypotension and QT prolongation (Link et al, 2015).
    8) AVOID
    a) Avoid in patients with QT prolongation and CHF (Neumar et al, 2010).
    E) AMIODARONE
    1) AMIODARONE/INDICATIONS
    a) Effective for the control of hemodynamically stable monomorphic ventricular tachycardia. Also recommended for pulseless ventricular tachycardia or ventricular fibrillation in cardiac arrest unresponsive to CPR, defibrillation and vasopressor therapy (Link et al, 2015; Neumar et al, 2010). It should be used with caution when the ingestion involves agents known to cause QTc prolongation, such as fluoroquinolones, macrolide antibiotics or azoles, and when ECG reveals QT prolongation suspected to be secondary to overdose (Prod Info Cordarone(R) oral tablets, 2015).
    2) AMIODARONE/ADULT DOSE
    a) For ventricular fibrillation or pulseless VT unresponsive to CPR, defibrillation, and a vasopressor therapy give an initial dose of 300 mg IV followed by 1 dose of 150 mg IV. For stable ventricular tachycardias: Infuse 150 milligrams over 10 minutes, and repeat if necessary. Follow by a 1 milligram/minute infusion for 6 hours, then a 0.5 milligram/minute. Maximum total dose over 24 hours is 2.2 grams (Neumar et al, 2010).
    3) AMIODARONE/PEDIATRIC DOSE
    a) Infuse 5 milligrams/kilogram as a bolus for pulseless ventricular tachycardia or ventricular fibrillation; may repeat twice up to 15 mg/kg. Infuse 5 milligrams/kilogram over 20 to 60 minutes for perfusing tachycardias. Maximum single dose is 300 mg. Routine use with other drugs that prolong the QT interval is NOT recommended (Kleinman et al, 2010).
    4) ADVERSE EFFECTS
    a) Hypotension and bradycardia are the most common adverse effects (Neumar et al, 2010).
    F) ALKALINE DIURESIS
    1) Alkalinization of the urine may help prevent deposition of red cell breakdown products in renal tubular cells if hemolysis is occurring.
    2) SODIUM BICARBONATE/INITIAL DOSE
    a) Administer 1 to 2 milliequivalents/kilogram of sodium bicarbonate as an intravenous bolus. Add 132 milliequivalents (3 ampules) sodium bicarbonate and 20 to 40 milliequivalents potassium chloride (as needed) to one liter of dextrose 5 percent in water and infuse at approximately 1.5 times the maintenance fluid rate. In patients with underlying dehydration additional administration of 0.9% saline may be needed to maintain adequate urine output (1 to 2 milliliters/kilogram/hour). Manipulate bicarbonate infusion to maintain a urine pH of at least 7.5.
    3) SODIUM BICARBONATE/REPEAT DOSES
    a) Additional sodium bicarbonate (1 to 2 milliequivalents per kilogram) and potassium chloride (20 to 40 milliequivalents per liter) may be needed to achieve an alkaline urine.
    4) CAUTION
    a) Obtain hourly intake/output and urine pH. Assure adequate hydration and renal function prior to alkalinization. Do not administer potassium to an oliguric or anuric patient. Monitor fluid and electrolyte balance carefully. Monitor blood pH, especially in intubated patients, to avoid severe alkalemia.
    G) CHELATION THERAPY
    1) INDICATIONS
    a) The urine arsenic level which should prompt chelation in an asymptomatic patient has been said to be 200 micrograms/liter (Kersjes et al, 1987).
    2) THERAPEUTIC END-POINT
    a) Repeat five-day courses of chelation therapy should be prescribed in severe poisonings until the 24-hour urine arsenic level falls below 50 micrograms/liter (Goldfrank et al, 1986; AMA, 1986).
    3) MOBILIZATION TEST
    a) Diagnosis for mild or chronic exposure can be aided by the following procedure, although some authorities doubt its usefulness because of the relatively rapid excretion of absorbed arsenic:
    1) Collect a 24 hour urine for baseline arsenic excretion (normal less than 100 micrograms/24 hours).
    2) Following the baseline 24 hour collection, a second 24 hour urine collection should be performed while the patient receives 4 doses, every 6 hours of D-penicillamine (25 milligrams/kilogram/dose up to 250 milligrams/dose). This cannot be given to patients allergic to penicillin.
    3) Either urine collection showing arsenic excretion greater than 100 micrograms/24 hours is diagnostic and should be followed by a 5 day course of D-penicillamine. 24 hour urine collections to measure arsenic excretion during chelation are recommended. When urine arsenic falls below 50 micrograms/24 hours, chelation may be terminated. Observation for return of symptoms and a repeat of the mobilization test 1 to 2 weeks following initial therapy are strongly recommended.
    4) During the mobilization test, the patient should avoid eating seafood. Ingestion of seafood, particularly shellfish, may transiently increase urinary arsenic levels to 200 to 1700 micrograms/liter (Baselt & Cravey, 1989; Baselt, 1988).
    5) In epidemiologic studies, blood arsenic, pubic hair arsenic, and nail arsenic may be helpful to define potentially exposed versus unexposed populations, but such results cannot be interpreted in individual patients.
    H) DIMERCAPROL
    1) EFFICACY: Dimercaprol (BAL) is an effective arsenic chelator, but has the disadvantages of requiring painful intramuscular injections and having numerous side effects. BAL has been reported to result in clinical improvement and decrease in hospital days in children poisoned with arsenic (Woody & Kometani, 1948).
    2) ADVERSE EFFECTS: Typical side effects which are dose related include hypertension, tachycardia, anorexia, restlessness, vomiting, pain, salivation, fever, convulsions, "leukotoxic effect," and reducing substances in the urine (Woody & Kometani, 1948).
    3) DOSE: Usual dosage range is 3 to 5 milligrams/kilogram intramuscularly every 4 to 12 hours until symptoms resolve or another chelator is substituted. The dose used is dependent on the severity of symptoms and urinary arsenic levels.
    I) PENICILLAMINE
    1) EFFICACY: D-penicillamine has been successfully used in acute arsenic poisoning in children (Peterson & Rumack, 1977) Kuravilla et al, 1975; (Watson et al, 1981). It has the advantage of being an oral agent, but the disadvantages of not being able to be given to patients allergic to penicillin, not being retained well if patients are vomiting, and the theoretical problem of enhancing absorption of the arsenic-chelator complex. It does not appear to result in depletion of zinc and copper when given for several weeks (Peterson & Rumack, 1977).
    2) ADVERSE EFFECTS: Long term therapy for the treatment of arthritis or Wilson's disease has resulted in fever, pruritus, leukopenia, thrombocytopenia, eosinophilia, and renal toxicity; these effects have not been reported when the drug is used for short-term heavy metal chelation (Gilman et al, 1985).
    3) DOSE: The usual dose is 25 milligrams/kilogram/dose given four times daily up to one gram per day (Peterson & Rumack, 1977), but larger doses (i.e., up to 2 grams/day) may be required in adults.
    4) In an experimental animal model, d-penicillamine was found to lack effectiveness in trivalent arsenic-poisoned mice and guinea pigs (Kreppel et al, 1989).
    J) SUCCIMER
    1) EFFICACY: 2,3-Dimercaptosuccinic acid (DMSA) is an investigational drug which appears to be a very effective arsenic chelator in experimental animals (Graziano et al, 1978) and man (Lenz et al, 1981; Kosnett & Becker, 1987; Fournier et al, 1988). In a patient treated with DMSA (30 milligrams/kilogram/day for 5 days) for long-term ingestion of arsenic, plasma concentrations were unchanged after treatment and renal arsenic excretion increased 1.5 fold (Fournier et al, 1988). DMSA has the advantage of being an oral agent as well as being relatively non-toxic.
    K) ACETYLCYSTEINE
    1) EFFICACY: N-acetylcysteine (NAC) has been shown to increase the LD50 of sodium arsenite in mice (Shum et al, 1981). NAC has the advantage of being both an oral and an intravenous agent, but has not been studied for this indication in humans and cannot presently be recommended for the treatment of arsenic poisoning.
    L) NEUROPATHY
    1) Early administration (within 18 hours of acute exposure) of BAL may be effective in preventing arsenical neuropathy in some cases (Jenkins, 1966). However, once neuropathy has developed (usually 1 to 3 weeks after acute exposure), chelation with BAL may not be effective in reversing it (Heyman et al, 1956; Donofrio et al, 1987; Le Quesne & McLeod, 1977).
    2) Physical therapy may be helpful for patients with established arsenical neuropathies.
    M) ACUTE LUNG INJURY
    1) ONSET: Onset of acute lung injury after toxic exposure may be delayed up to 24 to 72 hours after exposure in some cases.
    2) NON-PHARMACOLOGIC TREATMENT: The treatment of acute lung injury is primarily supportive (Cataletto, 2012). Maintain adequate ventilation and oxygenation with frequent monitoring of arterial blood gases and/or pulse oximetry. If a high FIO2 is required to maintain adequate oxygenation, mechanical ventilation and positive-end-expiratory pressure (PEEP) may be required; ventilation with small tidal volumes (6 mL/kg) is preferred if ARDS develops (Haas, 2011; Stolbach & Hoffman, 2011).
    a) To minimize barotrauma and other complications, use the lowest amount of PEEP possible while maintaining adequate oxygenation. Use of smaller tidal volumes (6 mL/kg) and lower plateau pressures (30 cm water or less) has been associated with decreased mortality and more rapid weaning from mechanical ventilation in patients with ARDS (Brower et al, 2000). More treatment information may be obtained from ARDS Clinical Network website, NIH NHLBI ARDS Clinical Network Mechanical Ventilation Protocol Summary, http://www.ardsnet.org/node/77791 (NHLBI ARDS Network, 2008)
    3) FLUIDS: Crystalloid solutions must be administered judiciously. Pulmonary artery monitoring may help. In general the pulmonary artery wedge pressure should be kept relatively low while still maintaining adequate cardiac output, blood pressure and urine output (Stolbach & Hoffman, 2011).
    4) ANTIBIOTICS: Indicated only when there is evidence of infection (Artigas et al, 1998).
    5) EXPERIMENTAL THERAPY: Partial liquid ventilation has shown promise in preliminary studies (Kollef & Schuster, 1995).
    6) CALFACTANT: In a multicenter, randomized, blinded trial, endotracheal instillation of 2 doses of 80 mL/m(2) calfactant (35 mg/mL of phospholipid suspension in saline) in infants, children, and adolescents with acute lung injury resulted in acute improvement in oxygenation and lower mortality; however, no significant decrease in the course of respiratory failure measured by duration of ventilator therapy, intensive care unit, or hospital stay was noted. Adverse effects (transient hypoxia and hypotension) were more frequent in calfactant patients, but these effects were mild and did not require withdrawal from the study (Wilson et al, 2005).
    7) However, in a multicenter, randomized, controlled, and masked trial, endotracheal instillation of up to 3 doses of calfactant (30 mg) in adults only with acute lung injury/ARDS due to direct lung injury was not associated with improved oxygenation and longer term benefits compared to the placebo group. It was also associated with significant increases in hypoxia and hypotension (Willson et al, 2015).
    N) HEMODIALYSIS
    1) Should be performed in the presence of any degree of renal failure, as the main route of excretion will be inhibited if this occurs. As the serum creatinine falls, urinary arsenic may increase (Giberson et al, 1976). Dialysance of arsenic in two patients was 76 and 87 milliliters/minute (Vaziri et al, 1980). This may be greater than renal clearance in the presence of oliguria or renal failure.
    2) Hemodialysis was instituted 4-hours postadmission in a 30-year-old male who ingested 6 ounces of a rodenticide containing 1.5 percent arsenous oxide (equivalent to 2,150 milligrams metallic arsenic), although the patient exhibited no evidence of renal impairment (Fesmire et al, 1988). Additional studies are needed to evaluate this regimen for safety and efficacy before it can be routinely recommended (Fesmire et al, 1988).

Inhalation Exposure

    6.7.1) DECONTAMINATION
    A) Move patient from the toxic environment to fresh air. Monitor for respiratory distress. If cough or difficulty in breathing develops, evaluate for hypoxia, respiratory tract irritation, bronchitis, or pneumonitis.
    B) OBSERVATION: Carefully observe patients with inhalation exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.
    C) INITIAL TREATMENT: Administer 100% humidified supplemental oxygen, perform endotracheal intubation and provide assisted ventilation as required. Administer inhaled beta-2 adrenergic agonists, if bronchospasm develops. Consider systemic corticosteroids in patients with significant bronchospasm (National Heart,Lung,and Blood Institute, 2007). Exposed skin and eyes should be flushed with copious amounts of water.
    6.7.2) TREATMENT
    A) ALKALINE DIURESIS
    1) Alkalinization of the urine may help prevent deposition of red cell breakdown products in renal tubular cells if hemolysis is occurring.
    2) SODIUM BICARBONATE/INITIAL DOSE
    a) Administer 1 to 2 milliequivalents/kilogram of sodium bicarbonate as an intravenous bolus. Add 132 milliequivalents (3 ampules) sodium bicarbonate and 20 to 40 milliequivalents potassium chloride (as needed) to one liter of dextrose 5 percent in water and infuse at approximately 1.5 times the maintenance fluid rate. In patients with underlying dehydration additional administration of 0.9% saline may be needed to maintain adequate urine output (1 to 2 milliliters/kilogram/hour). Manipulate bicarbonate infusion to maintain a urine pH of at least 7.5.
    3) SODIUM BICARBONATE/REPEAT DOSES
    a) Additional sodium bicarbonate (1 to 2 milliequivalents per kilogram) and potassium chloride (20 to 40 milliequivalents per liter) may be needed to achieve an alkaline urine.
    4) CAUTION
    a) Obtain hourly intake/output and urine pH. Assure adequate hydration and renal function prior to alkalinization. Do not administer potassium to an oliguric or anuric patient. Monitor fluid and electrolyte balance carefully. Monitor blood pH, especially in intubated patients, to avoid severe alkalemia.
    B) CHELATION THERAPY
    1) INDICATIONS
    a) The urine arsenic level which should prompt chelation in an asymptomatic patient has been said to be 200 micrograms/liter (Kersjes et al, 1987).
    2) THERAPEUTIC END-POINT
    a) Repeat five-day courses of chelation therapy should be prescribed in severe poisonings until the 24-hour urine arsenic level falls below 50 micrograms/liter (Goldfrank et al, 1986; AMA, 1986).
    3) MOBILIZATION TEST
    a) Diagnosis for mild or chronic exposure can be aided by the following procedure, although some authorities doubt its usefulness because of the relatively rapid excretion of absorbed arsenic:
    1) Collect a 24 hour urine for baseline arsenic excretion (normal less than 100 micrograms/24 hours).
    2) Following the baseline 24 hour collection, a second 24 hour urine collection should be performed while the patient receives 4 doses, every 6 hours, of D-penicillamine (25 milligrams/kilogram/dose up to 250 milligrams/dose). This cannot be given to patients allergic to penicillin.
    3) Either urine collection showing arsenic excretion greater than 100 micrograms/24 hours is diagnostic and should be followed by a 5 day course of D-penicillamine. 24 hour urine collections to measure arsenic excretion during chelation are recommended. When urine arsenic falls below 50 micrograms/24 hours, chelation may be terminated. Observation for return of symptoms and a repeat of the mobilization test 1 to 2 weeks following initial therapy are strongly recommended.
    4) During the mobilization test, the patient should avoid eating seafood. Ingestion of seafood, particularly shellfish, may transiently increase urinary arsenic levels to 200 to 1700 micrograms/liter (Baselt & Cravey, 1989; Baselt, 1988).
    5) In epidemiologic studies, blood arsenic, pubic hair arsenic, and nail arsenic may be helpful to define potentially exposed versus unexposed populations, but such results cannot be interpreted in individual patients.
    C) DIMERCAPROL
    1) EFFICACY: Dimercaprol (BAL) is an effective arsenic chelator, but has the disadvantages of requiring painful intramuscular injections and having numerous side effects. BAL has been reported to result in clinical improvement and decrease in hospital days in children poisoned with arsenic (Woody & Kometani, 1948).
    2) ADVERSE EFFECTS: Typical side effects which are dose related include hypertension, tachycardia, anorexia, restlessness, vomiting, pain, salivation, fever, convulsions, "leukotoxic effect," and reducing substances in the urine (Woody & Kometani, 1948).
    3) DOSE: Usual dosage range is 3 to 5 milligrams/kilogram intramuscularly every 4 to 12 hours until symptoms resolve or another chelator is substituted. The dose used is dependent on the severity of symptoms and urinary arsenic levels.
    D) PENICILLAMINE
    1) EFFICACY: D-penicillamine has been successfully used in acute arsenic poisoning in children (Peterson & Rumack, 1977) Kuravilla et al, 1975; (Watson et al, 1981). It has the advantage of being an oral agent, but the disadvantages of not being able to be given to patients allergic to penicillin, not being retained well if patients are vomiting, and the theoretical problem of enhancing absorption of the arsenic-chelator complex. It does not appear to result in depletion of zinc and copper when given for several weeks (Peterson & Rumack, 1977).
    2) ADVERSE EFFECTS: Long term therapy for the treatment of arthritis or Wilson's disease has resulted in fever, pruritus, leukopenia, thrombocytopenia, eosinophilia, and renal toxicity; these effects have not been reported when the drug is used for short-term heavy metal chelation (Gilman et al, 1985).
    3) DOSE: The usual dose is 25 milligrams/kilogram/dose given four times daily up to one gram per day (Peterson & Rumack, 1977), but larger doses (i.e., up to 2 grams/day) may be required in adults.
    4) In an experimental animal model, d-penicillamine was found to lack effectiveness in trivalent arsenic-poisoned mice and guinea pigs (Kreppel et al, 1989).
    E) SUCCIMER
    1) EFFICACY: 2,3-Dimercaptosuccinic acid (DMSA) is an investigational drug which appears to be a very effective arsenic chelator in experimental animals (Graziano et al, 1978) and man (Lenz et al, 1981; Kosnett & Becker, 1987; Fournier et al, 1988). In a patient treated with DMSA (30 milligrams/kilogram/day for 5 days) for long-term ingestion of arsenic, plasma concentrations were unchanged after treatment and renal arsenic excretion increased 1.5 fold (Fournier et al, 1988). DMSA has the advantage of being an oral agent as well as being relatively non-toxic.
    F) ACETYLCYSTEINE
    1) EFFICACY: N-acetylcysteine (NAC) has been shown to increase the LD50 of sodium arsenite in mice (Shum et al, 1981). NAC has the advantage of being both an oral and an intravenous agent, but has not been studied for this indication in humans and cannot presently be recommended for the treatment of arsenic poisoning.
    G) NEUROPATHY
    1) Early administration (within 18 hours of acute exposure) of BAL may be effective in preventing arsenical neuropathy in some cases (Jenkins, 1966). However, once neuropathy has developed (usually 1 to 3 weeks after acute exposure), chelation with BAL may not be effective in reversing it (Heyman et al, 1956; Donofrio et al, 1987; Le Quesne & McLeod, 1977).
    2) Physical therapy may be helpful for patients with established arsenical neuropathies.
    H) ACUTE LUNG INJURY
    1) ONSET: Onset of acute lung injury after toxic exposure may be delayed up to 24 to 72 hours after exposure in some cases.
    2) NON-PHARMACOLOGIC TREATMENT: The treatment of acute lung injury is primarily supportive (Cataletto, 2012). Maintain adequate ventilation and oxygenation with frequent monitoring of arterial blood gases and/or pulse oximetry. If a high FIO2 is required to maintain adequate oxygenation, mechanical ventilation and positive-end-expiratory pressure (PEEP) may be required; ventilation with small tidal volumes (6 mL/kg) is preferred if ARDS develops (Haas, 2011; Stolbach & Hoffman, 2011).
    a) To minimize barotrauma and other complications, use the lowest amount of PEEP possible while maintaining adequate oxygenation. Use of smaller tidal volumes (6 mL/kg) and lower plateau pressures (30 cm water or less) has been associated with decreased mortality and more rapid weaning from mechanical ventilation in patients with ARDS (Brower et al, 2000). More treatment information may be obtained from ARDS Clinical Network website, NIH NHLBI ARDS Clinical Network Mechanical Ventilation Protocol Summary, http://www.ardsnet.org/node/77791 (NHLBI ARDS Network, 2008)
    3) FLUIDS: Crystalloid solutions must be administered judiciously. Pulmonary artery monitoring may help. In general the pulmonary artery wedge pressure should be kept relatively low while still maintaining adequate cardiac output, blood pressure and urine output (Stolbach & Hoffman, 2011).
    4) ANTIBIOTICS: Indicated only when there is evidence of infection (Artigas et al, 1998).
    5) EXPERIMENTAL THERAPY: Partial liquid ventilation has shown promise in preliminary studies (Kollef & Schuster, 1995).
    6) CALFACTANT: In a multicenter, randomized, blinded trial, endotracheal instillation of 2 doses of 80 mL/m(2) calfactant (35 mg/mL of phospholipid suspension in saline) in infants, children, and adolescents with acute lung injury resulted in acute improvement in oxygenation and lower mortality; however, no significant decrease in the course of respiratory failure measured by duration of ventilator therapy, intensive care unit, or hospital stay was noted. Adverse effects (transient hypoxia and hypotension) were more frequent in calfactant patients, but these effects were mild and did not require withdrawal from the study (Wilson et al, 2005).
    7) However, in a multicenter, randomized, controlled, and masked trial, endotracheal instillation of up to 3 doses of calfactant (30 mg) in adults only with acute lung injury/ARDS due to direct lung injury was not associated with improved oxygenation and longer term benefits compared to the placebo group. It was also associated with significant increases in hypoxia and hypotension (Willson et al, 2015).
    I) HEMODIALYSIS
    1) Should be performed in the presence of any degree of renal failure, as the main route of excretion will be inhibited if this occurs. As the serum creatinine falls, urinary arsenic may increase (Giberson et al, 1976). Dialysance of arsenic in two patients was 76 and 87 milliliters/minute (Vaziri et al, 1980). This may be greater than renal clearance in the presence of oliguria or renal failure.
    2) Hemodialysis was instituted 4-hours postadmission in a 30-year-old male who ingested 6 ounces of a rodenticide containing 1.5 percent arsenous oxide (equivalent to 2,150 milligrams metallic arsenic), although the patient exhibited no evidence of renal impairment (Fesmire et al, 1988). Additional studies are needed to evaluate this regimen for safety and efficacy before it can be routinely recommended (Fesmire et al, 1988).
    J) HYPOTENSIVE EPISODE
    1) SUMMARY
    a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.
    2) DOPAMINE
    a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    3) NOREPINEPHRINE
    a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
    b) DOSE
    1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
    2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
    3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).
    K) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Eye Exposure

    6.8.1) DECONTAMINATION
    A) EYE IRRIGATION, ROUTINE: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, an ophthalmologic examination should be performed (Peate, 2007; Naradzay & Barish, 2006).
    6.8.2) TREATMENT
    A) OCULAR ABSORPTION
    1) No cases of systemic arsenic poisoning following only eye exposure have been reported.
    B) CONSULTATION
    1) If significant eye irritation is present, prolonged initial flushing and early ophthalmologic consultation are advisable.
    C) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Dermal Exposure

    6.9.1) DECONTAMINATION
    A) DECONTAMINATION: Remove contaminated clothing and wash exposed area thoroughly with soap and water for 10 to 15 minutes. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).
    6.9.2) TREATMENT
    A) ALKALINE DIURESIS
    1) Alkalinization of the urine may help prevent deposition of red cell breakdown products in renal tubular cells if hemolysis is occurring.
    2) SODIUM BICARBONATE/INITIAL DOSE
    a) Administer 1 to 2 milliequivalents/kilogram of sodium bicarbonate as an intravenous bolus. Add 132 milliequivalents (3 ampules) sodium bicarbonate and 20 to 40 milliequivalents potassium chloride (as needed) to one liter of dextrose 5 percent in water and infuse at approximately 1.5 times the maintenance fluid rate. In patients with underlying dehydration additional administration of 0.9% saline may be needed to maintain adequate urine output (1 to 2 milliliters/kilogram/hour). Manipulate bicarbonate infusion to maintain a urine pH of at least 7.5.
    3) SODIUM BICARBONATE/REPEAT DOSES
    a) Additional sodium bicarbonate (1 to 2 milliequivalents per kilogram) and potassium chloride (20 to 40 milliequivalents per liter) may be needed to achieve an alkaline urine.
    4) CAUTION
    a) Obtain hourly intake/output and urine pH. Assure adequate hydration and renal function prior to alkalinization. Do not administer potassium to an oliguric or anuric patient. Monitor fluid and electrolyte balance carefully. Monitor blood pH, especially in intubated patients, to avoid severe alkalemia.
    B) CHELATION THERAPY
    1) INDICATIONS
    a) The urine arsenic level which should prompt chelation in an asymptomatic patient has been said to be 200 micrograms/liter (Kersjes et al, 1987).
    2) THERAPEUTIC END-POINT
    a) Repeat five-day courses of chelation therapy should be prescribed in severe poisonings until the 24-hour urine arsenic level falls below 50 micrograms/liter (Goldfrank et al, 1986; AMA, 1986).
    3) MOBILIZATION TEST
    a) Diagnosis for mild or chronic exposure can be aided by the following procedure, although some authorities doubt its usefulness because of the relatively rapid excretion of absorbed arsenic:
    1) Collect a 24 hour urine for baseline arsenic excretion (normal less than 100 micrograms/24 hours).
    2) Following the baseline 24 hour collection, a second 24 hour urine collection should be performed while the patient receives 4 doses, every 6 hours, of D-penicillamine (25 milligrams/kilogram/dose up to 250 milligrams/dose). This cannot be given to patients allergic to penicillin.
    3) Either urine collection showing arsenic excretion greater than 100 micrograms/24 hours is diagnostic and should be followed by a 5 day course of D-penicillamine. 24 hour urine collections to measure arsenic excretion during chelation are recommended. When urine arsenic falls below 50 micrograms/24 hours, chelation may be terminated. Observation for return of symptoms and a repeat of the mobilization test 1 to 2 weeks following initial therapy are strongly recommended.
    4) During the mobilization test, the patient should avoid eating seafood. Ingestion of seafood, particularly shellfish, may transiently increase urinary arsenic levels to 200 to 1700 micrograms/liter (Baselt & Cravey, 1989; Baselt, 1988).
    5) In epidemiologic studies, blood arsenic, pubic hair arsenic, and nail arsenic may be helpful to define potentially exposed versus unexposed populations, but such results cannot be interpreted in individual patients.
    C) DIMERCAPROL
    1) EFFICACY: Dimercaprol (BAL) is an effective arsenic chelator, but has the disadvantages of requiring painful intramuscular injections and having numerous side effects. BAL has been reported to result in clinical improvement and decrease in hospital days in children poisoned with arsenic (Woody & Kometani, 1948).
    2) ADVERSE EFFECTS: Typical side effects which are dose related include hypertension, tachycardia, anorexia, restlessness, vomiting, pain, salivation, fever, convulsions, "leukotoxic effect," and reducing substances in the urine (Woody & Kometani, 1948).
    3) DOSE: Usual dosage range is 3 to 5 milligrams/kilogram intramuscularly every 4 to 12 hours until symptoms resolve or another chelator is substituted. The dose used is dependent on the severity of symptoms and urinary arsenic levels.
    D) PENICILLAMINE
    1) EFFICACY: D-penicillamine has been successfully used in acute arsenic poisoning in children (Peterson & Rumack, 1977) Kuravilla et al, 1975; (Watson et al, 1981). It has the advantage of being an oral agent, but the disadvantages of not being able to be given to patients allergic to penicillin, not being retained well if patients are vomiting, and the theoretical problem of enhancing absorption of the arsenic-chelator complex. It does not appear to result in depletion of zinc and copper when given for several weeks (Peterson & Rumack, 1977).
    2) ADVERSE EFFECTS: Long term therapy for the treatment of arthritis or Wilson's disease has resulted in fever, pruritus, leukopenia, thrombocytopenia, eosinophilia, and renal toxicity; these effects have not been reported when the drug is used for short-term heavy metal chelation (Gilman et al, 1985).
    3) DOSE: The usual dose is 25 milligrams/kilogram/dose given four times daily up to one gram per day (Peterson & Rumack, 1977), but larger doses (i.e., up to 2 grams/day) may be required in adults.
    4) In an experimental animal model, d-penicillamine was found to lack effectiveness in trivalent arsenic-poisoned mice and guinea pigs (Kreppel et al, 1989).
    E) SUCCIMER
    1) EFFICACY: 2,3-Dimercaptosuccinic acid (DMSA) is an investigational drug which appears to be a very effective arsenic chelator in experimental animals (Graziano et al, 1978) and man (Lenz et al, 1981; Kosnett & Becker, 1987; Fournier et al, 1988). In a patient treated with DMSA (30 milligrams/kilogram/day for 5 days) for long-term ingestion of arsenic, plasma concentrations were unchanged after treatment and renal arsenic excretion increased 1.5 fold (Fournier et al, 1988). DMSA has the advantage of being an oral agent as well as being relatively non-toxic.
    F) ACETYLCYSTEINE
    1) EFFICACY: N-acetylcysteine (NAC) has been shown to increase the LD50 of sodium arsenite in mice (Shum et al, 1981). NAC has the advantage of being both an oral and an intravenous agent, but has not been studied for this indication in humans and cannot presently be recommended for the treatment of arsenic poisoning.
    G) NEUROPATHY
    1) Early administration (within 18 hours of acute exposure) of BAL may be effective in preventing arsenical neuropathy in some cases (Jenkins, 1966). However, once neuropathy has developed (usually 1 to 3 weeks after acute exposure), chelation with BAL may not be effective in reversing it (Heyman et al, 1956; Donofrio et al, 1987; Le Quesne & McLeod, 1977).
    2) Physical therapy may be helpful for patients with established arsenical neuropathies.
    H) ACUTE LUNG INJURY
    1) ONSET: Onset of acute lung injury after toxic exposure may be delayed up to 24 to 72 hours after exposure in some cases.
    2) NON-PHARMACOLOGIC TREATMENT: The treatment of acute lung injury is primarily supportive (Cataletto, 2012). Maintain adequate ventilation and oxygenation with frequent monitoring of arterial blood gases and/or pulse oximetry. If a high FIO2 is required to maintain adequate oxygenation, mechanical ventilation and positive-end-expiratory pressure (PEEP) may be required; ventilation with small tidal volumes (6 mL/kg) is preferred if ARDS develops (Haas, 2011; Stolbach & Hoffman, 2011).
    a) To minimize barotrauma and other complications, use the lowest amount of PEEP possible while maintaining adequate oxygenation. Use of smaller tidal volumes (6 mL/kg) and lower plateau pressures (30 cm water or less) has been associated with decreased mortality and more rapid weaning from mechanical ventilation in patients with ARDS (Brower et al, 2000). More treatment information may be obtained from ARDS Clinical Network website, NIH NHLBI ARDS Clinical Network Mechanical Ventilation Protocol Summary, http://www.ardsnet.org/node/77791 (NHLBI ARDS Network, 2008)
    3) FLUIDS: Crystalloid solutions must be administered judiciously. Pulmonary artery monitoring may help. In general the pulmonary artery wedge pressure should be kept relatively low while still maintaining adequate cardiac output, blood pressure and urine output (Stolbach & Hoffman, 2011).
    4) ANTIBIOTICS: Indicated only when there is evidence of infection (Artigas et al, 1998).
    5) EXPERIMENTAL THERAPY: Partial liquid ventilation has shown promise in preliminary studies (Kollef & Schuster, 1995).
    6) CALFACTANT: In a multicenter, randomized, blinded trial, endotracheal instillation of 2 doses of 80 mL/m(2) calfactant (35 mg/mL of phospholipid suspension in saline) in infants, children, and adolescents with acute lung injury resulted in acute improvement in oxygenation and lower mortality; however, no significant decrease in the course of respiratory failure measured by duration of ventilator therapy, intensive care unit, or hospital stay was noted. Adverse effects (transient hypoxia and hypotension) were more frequent in calfactant patients, but these effects were mild and did not require withdrawal from the study (Wilson et al, 2005).
    7) However, in a multicenter, randomized, controlled, and masked trial, endotracheal instillation of up to 3 doses of calfactant (30 mg) in adults only with acute lung injury/ARDS due to direct lung injury was not associated with improved oxygenation and longer term benefits compared to the placebo group. It was also associated with significant increases in hypoxia and hypotension (Willson et al, 2015).
    I) HEMODIALYSIS
    1) Should be performed in the presence of any degree of renal failure, as the main route of excretion will be inhibited if this occurs. As the serum creatinine falls, urinary arsenic may increase (Giberson et al, 1976). Dialysance of arsenic in two patients was 76 and 87 milliliters/minute (Vaziri et al, 1980). This may be greater than renal clearance in the presence of oliguria or renal failure.
    2) Hemodialysis was instituted 4-hours postadmission in a 30-year-old male who ingested 6 ounces of a rodenticide containing 1.5 percent arsenous oxide (equivalent to 2,150 milligrams metallic arsenic), although the patient exhibited no evidence of renal impairment (Fesmire et al, 1988). Additional studies are needed to evaluate this regimen for safety and efficacy before it can be routinely recommended (Fesmire et al, 1988).
    J) IRRITATION SYMPTOM
    1) Treat dermal irritation or burns with standard topical therapy. Patients developing dermal hypersensitivity reactions may require treatment with systemic or topical corticosteroids or antihistamines.
    2) Workers with significant arsenical dermatitis, ulcerations, or dermatoses may be overexposed and may need to be precluded from further exposure.
    K) HYPOTENSIVE EPISODE
    1) SUMMARY
    a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.
    2) DOPAMINE
    a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    3) NOREPINEPHRINE
    a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
    b) DOSE
    1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
    2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
    3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).
    L) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Range Of Toxicity

Summary

    A) One milligram/kilogram of ingested arsenic may be lethal in a child. An oral dose of 120 mg of arsenic trioxide may be fatal.
    B) As little as 20 milligrams of arsenic may produce life-threatening toxicity. Estimates of acute oral toxic doses of various arsenic compounds range from 1 milligram to 10 grams.
    C) Trivalent arsenic (arsenite) is more toxic in animals than the pentavalent form (arsenate). However, significant toxicity may occur with large amounts of pentavalent salts in humans. Pentavalent arsenic may be converted in vivo to trivalent arsenic.

Minimum Lethal Exposure

    A) One milligram/kilogram of ingested arsenic may be lethal in a child (Woody & Komentani, 1948).
    B) As little as 20 milligrams of arsenic may produce life- threatening toxicity (Zaloga et al, 1970; Schoolmeester & White, 1980) Huttone & Christians, 1983).
    C) An oral dose of 120 mg of arsenic trioxide may be fatal (Finkel, 1983).
    D) Published Values (RTECS , 1997):
    1) LDLo: (Subcutaneous) RABBIT - 300 mg/kg
    2) LDLo: (Subcutaneous) GUINEA PIG - 300 mg/kg
    3) LDLo: (IP) GUINEA PIG - 10 mg/kg

Maximum Tolerated Exposure

    A) Chronic dermal and possibly inhalation exposure to sodium cacodylate was associated with development of chronic laryngitis in one laboratory technician and chronic dermatitis in another. However, the exposures were not quantitated and it was questionable whether or not the arsenic compound was the etiologic agent (Weakley, 1977).
    B) Estimates of acute oral toxic doses of various arsenic compounds range from one milligram to 10 grams.
    C) Arsenic trioxide in a solubilized form becomes sodium arsenite, which is more toxic than in an unsolubilized form.
    1) 200 milligrams of arsenic trioxide ingestion by an adult may be lethal (Baselt & Cravey, 1989; Baselt, 1988). The probable oral lethal dose in humans is said to be .5 to 5 g/kg (Sittig, 1991).
    2) Acute ingestion of 9 to 14 milligrams of arsenic trioxide by a 16-month-old child produced classic gastrointestinal symptoms of arsenic poisoning (Watson et al, 1981).
    3) A 30-year-old man survived an ingestion of 6 ounces of "Blue Ball Rat Killer" containing 1.5% arsenous oxide (2,150 milligrams, metallic arsenic per 6 ounces) with aggressive therapy (fluid resuscitation, chelation and hemodialysis) (Fesmire et al, 1988).
    D) Trivalent arsenic (arsenite) is more toxic in animals than the pentavalent form (arsenate) (ACGIH, 1996a; Morgan, 1993).
    1) However, significant toxicity may occur with large amounts of pentavalent salts in humans.
    2) Pentavalent arsenic may be converted in vitro to trivalent arsenic.

Workplace Standards

    A) ACGIH TLV Values for CAS124-65-2 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    B) NIOSH REL and IDLH Values for CAS124-65-2 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    C) Carcinogenicity Ratings for CAS124-65-2 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): 1 ; Listed as: Sodium cacodylate
    a) 1 : The agent (mixture) is carcinogenic to humans. The exposure circumstance entails exposures that are carcinogenic to humans. This category is used when there is sufficient evidence of carcinogenicity in humans. Exceptionally, an agent (mixture) may be placed in this category when evidence of carcinogenicity in humans is less than sufficient but there is sufficient evidence of carcinogenicity in experimental animals and strong evidence in exposed humans that the agent (mixture) acts through a relevant mechanism of carcinogenicity.
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    D) OSHA PEL Values for CAS124-65-2 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) References: RTECS, 2003
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 1 g/kg
    2) LD50- (ORAL)MOUSE:
    a) 5 mg/kg
    3) LD50- (ORAL)RAT:
    a) 2600 mg/kg

Physicochemical

Physical Characteristics

    A) Sodium cacodylate is a colorless or white to light yellow amorphous powder with a slight odor. It can also be in the form of trihydrate crystals or granules (Budavari, 1996; HSDB , 1997; Lewis, 1993).
    B) Deliquescent: Sodium cacodylate liquefies in its water of hydration at 60 degrees C and it becomes anhydrous at 120 degrees C (Budavari, 1996; Lewis, 1993).
    C) Sodium cacodylate, when burned, emits a garlic-like odor and a bluish flame (Budavari, 1996).
    D) Sodium cacodylate contains approximately 35% arsenic (47% in anhydrous form) (HSDB , 1997).
    E) The commercial product contains 22-28% sodium cacodylate, 3-5% cacodylic acid, and the balance inert solids (or water) (CHRIS, 1997; (HSDB , 1997).

Ph

    A) 8-9 (Budavari, 1996)

Molecular Weight

    A) 159.98 (Budavari, 1996)

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