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SULFITES

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Sulfites, metabisulfites, and bisulfites are strong reducing agents used as antioxidants in foods and drugs and as preservatives with antimicrobial activity. They are primary irritants and may produce hypersensitivity in asthmatics.

Specific Substances

    A) SODIUM BISULFITE
    1) Sodium acid sulfite
    2) Sodium hydrogen sulfite
    3) Sodium bisulphite
    4) Sodium sulfhydrate
    5) Sulfurous acid, monosodium salt
    6) Natrii bisulfis
    7) Bissulfito de sodio
    8) Natrii sulphis acidus
    9) Sodium bisulfite (1:1)
    10) Sodium bisulfite, solid
    11) Sodium bisulphite
    12) Sodium bisulfite solution
    13) Bisulfite de sodium (french)
    14) CAS 7631-90-5
    POTASSIUM BISULFITE
    1) Potassium acid sulfite
    SODIUM METABISULFITE
    1) Sodium pyrosulfite
    2) Disodium pyrosulfite
    3) Sodium metabisulphite
    4) Natrii pyrosulfis
    5) Natrium pyrosulfurosum
    6) Sodium metabisulfite
    7) Pyrosulfurous acid, disodium salt
    8) CAS 7757-74-6
    POTASSIUM METABISULFITE
    1) Potassium pyrosulfite
    2) Potassium metabisulphite
    3) Kalii metabisulfis
    4) Potasio metabisulfito
    5) Pyrosulfurous acid, dipotassium salt
    6) CAS 4429-42-9
    SODIUM SULFITE
    1) Sulfurous acid, disodium salt
    2) Sodium sulphite
    3) Sodii sulphis
    4) Sulfito de Sodio
    5) Anhydrous sodium sulfite
    6) Exsiccated sodium sulfite
    7) Disodium sulfite
    8) Natriumsulfid (German)
    9) CAS 7757-83-7
    POTASSIUM SULFITE
    1) Sulfurous acid, dipotassium salt
    2) CAS 7790-56-9
    CALCIUM SULFITE
    1) Sulfurous acid, calcium salt
    2) CAS 10257-55-3
    AMMONIUM SULFITE
    1) Sulfurous acid, diammonium salt
    2) CAS 10196-04-0
    GENERAL TERMS
    1) Uantax sbs
    2) Sulfite
    3) Hydrogen sulfite sodium
    4) Sulfurous acid, monosodium salt
    5) Sodium acid sulfite
    6) Leucogen
    7) Sodium hydrogen sulfite
    8) Sodium hydrogen sulfite, solid
    9) Sodium pyrosulfite
    10) Sodium hydrosulfide
    11) Sodium hydrogen sulfite, solution
    12) Sodium sulhydrate
    13) Monsodium sulfite

Available Forms Sources

    A) FORMS
    1) FOODS - Sulfiting agents are available in a wide variety of foods. Fruit drinks and soft drinks may contain 25 to 30 mg per serving, sausages up to 60 mg per serving and dehydrated fruits and vegetables up to 75 mg per serving. Wine or beer may contain 5 to 10 mg per ounce.
    2) Application of a food preservative as recommended in the label instructions resulted in 64 to 108 mg of sodium bisulfite per 3 oz of lettuce. In a double-blind, placebo-controlled study, ingestion of sulfite-treated lettuce produced a mean decrease in FEV(1) of 41% in 5 sulfite-sensitive asthmatics, accompanied by flushing, itching in the mouth, throat, and skin. Placebo-treated lettuce resulted in no significant decrease in FEV(1) (Howland & Simon, 1989).
    3) The FDA withdrew approval for use of sulfites with fresh vegetables as of August 1986, and appropriate labelling is required if sulfites are present in packaged foods at 10 ppm or more. Labelling must also be provided for sulfite-containing prescription drugs and alcoholic beverages (Ellenhorn & Barceloux, 1988).
    4) The Canadian Government also banned the use of sulfites on fresh fruit and vegetables in 1986 (CMA, 1988).
    5) PHARMACEUTICALS - Sulfites are used as antioxidants or preservatives in many pharmaceuticals including nebulizer sympathomimetic solutions (but not metered-dose inhalers), in concentrations of 0.3 to 0.75% (Koepke et al, 1983).
    a) Injectable preparations such as metoclopramide, epinephrine, and aminoglycosides may also contain sulfites. Infusion of gentamicin preserved with sulfites was reported to have caused dyspnea, chest and back pain attributed to sulfite sensitivity (Deziel-Evans & Hussey, 1989). Some local anesthetics contain sulfites (Schwartz et al, 1989; Dooms-Goossens et al, 1989). Adverse reactions to local anesthetics which contained sulfite have been reported in patients who subsequently tolerated sulfite-free local anesthetics (Fisher, 1989c).
    b) Parenteral amino acid solutions used in total parenteral nutrition may contain large amounts of sulfites, and was associated with tachycardia, central scotomas, night blindness, irritability, and coma in one patient (Abumrad et al, 1981).
    c) An ophthalmic solution containing sodium metabisulfite was associated with exacerbation of asthma. Sulfite-sensitivity was confirmed by ocular challenge with a metabisulfite solution (Schwartz & Sher, 1985).
    d) A list of sulfite-containing pharmaceuticals has been published (Dalton-Bunnow, 1985).
    B) USES
    1) Sulfites, metabisulfites, and bisulfites are strong reducing agents used as antioxidants in foods and drugs and as preservatives with antimicrobial activity.
    2) Ammonium sulfite is used in permanent wave solutions, photography and metal lubricants (Sax & Lewis, 1987).
    3) Calcium sulfite is used in bleaching textiles, in paper pulp cooking, and in cement (Budavari, 1989).
    4) Sodium bisulfite is used as a disinfectant or bleach, particularly for wool, in papermaking and tanning, in coagulating rubber latex, and in copper and brass plating (Budavari, 1989; Sax & Lewis, 1987).
    5) Sodium sulfite is used in the papermaking industry, as a reducing agent in dyes, as a photographic developer, as a textile bleach, and in silvering glass (Budavari, 1989).
    6) Potassium sulfite is used in photographic developers (Budavari, 1989).
    7) Potassium bisulfite is used as a tanning and bleaching agent (Sax & Lewis, 1987).
    8) Potassium metabisulfite is used in photographic developers, engraving and lithography, dyeing, and as a bleaching agent (Sax & Lewis, 1987).
    9) PHARMACEUTICALS - Sulfites are used as antioxidants or preservatives in many pharmaceuticals including nebulizer sympathomimetic solutions (but not metered-dose inhalers), in concentrations of 0.3 to 0.75% (Koepke et al, 1983).

Overview

Life Support

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

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) ACUTE TOXICITY may result in nausea, vomiting, diarrhea, abdominal pain, and gastric hemorrhage. Extremely large concentrations may produce CNS stimulation, seizures, hypotension, and cardiovascular collapse.
    B) HYPERSENSITIVITY reactions, occurring more frequently in asthmatics, may produce bronchoconstriction, diaphoresis, flushing, urticaria, tachycardia, hypotension, and anaphylaxis.
    1) ONSET - The onset of hypersensitivity reactions is immediate following inhalation, intravenous injection or ingestion of oral solutions. Ingestion of solids or food particles may delay the onset of symptoms, with a maximal effect 30 to 90 minutes after ingestion.
    0.2.4) HEENT
    A) Swelling of the tongue, angioedema, difficulty in swallowing, or upper airway obstruction may occur in sensitive individuals. Ocular injury may occur from exposure to high concentrations.
    0.2.5) CARDIOVASCULAR
    A) Hypotension and reflex tachycardia are common in hypersensitivity reactions. Anaphylaxis has been described.
    0.2.6) RESPIRATORY
    A) Bronchospasm, tachypnea, and dyspnea may occur, particularly in asthmatics, following inhalation of sulfite-preserved bronchodilator solutions, ingestion of prepared or restaurant foods preserved with sulfites.
    0.2.7) NEUROLOGIC
    A) CNS stimulation has been described in patients receiving bisulfite-containing peritoneal dialysis fluids. Neurotoxicity in the form of prolonged neural blockade has occurred after the inadvertent subarachnoid injection of sulfite-preserved anesthetic.
    0.2.8) GASTROINTESTINAL
    A) Acute ingestions of 3.5 mg/kg produce vomiting in most individuals. Larger doses may result in gastric irritation, abdominal pain, and gastric hemorrhage.
    0.2.14) DERMATOLOGIC
    A) Generalized urticaria and allergic eczematous dermatitis may be noted.
    0.2.20) REPRODUCTIVE
    A) No teratogenic effects have been observed in animal studies using sodium metabisulfite.

Laboratory Monitoring

    A) Skin test are not usually useful in screening for or diagnosis of sulfite sensitivity.
    B) Oral provocation challenge tests are recommended in patients with a history of sulfite sensitivity.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) In acute ingestions, treatment is aimed at reducing gastric irritation with appropriate dilution. In hypersensitivity or inhalation exposures, treatment is aimed at maintaining respirations and reversing bronchospasm and hypotension.
    B) DILUTION: If no respiratory compromise is present, administer milk or water as soon as possible after ingestion. Dilution may only be helpful if performed in the first seconds to minutes after ingestion. The ideal amount is unknown; no more than 8 ounces (240 mL) in adults and 4 ounces (120 mL) in children is recommended to minimize the risk of vomiting.
    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) 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.
    E) SEIZURES: Administer a benzodiazepine; DIAZEPAM (ADULT: 5 to 10 mg IV initially; repeat every 5 to 20 minutes as needed. CHILD: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed) or LORAZEPAM (ADULT: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist. CHILD: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue).
    1) Consider phenobarbital or propofol if seizures recur after diazepam 30 mg (adults) or 10 mg (children greater than 5 years).
    2) Monitor for hypotension, dysrhythmias, respiratory depression, and need for endotracheal intubation. Evaluate for hypoglycemia, electrolyte disturbances, and hypoxia.
    F) HYPERSENSITIVITY - Subcutaneous epinephrine, corticosteroids, non-sulfite-containing nebulized bronchodilators (ie, albuterol), and theophylline may be used to treat acute hypersensitivity reactions.
    G) PROPHYLAXIS - Inhaled sodium cromolyn 20 to 40 mg, nebulized atropine, oral sodium cromolyn, or oral cyanocobalamin 1 to 5 mg have prevented sensitivity reactions.
    0.4.3) INHALATION EXPOSURE
    A) In hypersensitivity or inhalation exposures, treatment is aimed at maintaining respirations and reversing bronchospasm and hypotension.
    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.
    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).

Range Of Toxicity

    A) Acute ingestions of 3.5 mg/kg or chronic ingestions of 4 to 6 gm/day produced GI effects. Asthmatic patients may exhibit hypersensitivity to as little as 10 mg in capsules or 5 mg in oral solutions.

Clinical Effects

Summary Of Exposure

    A) ACUTE TOXICITY may result in nausea, vomiting, diarrhea, abdominal pain, and gastric hemorrhage. Extremely large concentrations may produce CNS stimulation, seizures, hypotension, and cardiovascular collapse.
    B) HYPERSENSITIVITY reactions, occurring more frequently in asthmatics, may produce bronchoconstriction, diaphoresis, flushing, urticaria, tachycardia, hypotension, and anaphylaxis.
    1) ONSET - The onset of hypersensitivity reactions is immediate following inhalation, intravenous injection or ingestion of oral solutions. Ingestion of solids or food particles may delay the onset of symptoms, with a maximal effect 30 to 90 minutes after ingestion.

Vital Signs

    3.3.2) RESPIRATIONS
    A) TACHYPNEA may be noted.
    B) DYSPNEA may be noted.
    3.3.4) BLOOD PRESSURE
    A) HYPOTENSION - Dose related hypotension may be noted.
    3.3.5) PULSE
    A) TACHYCARDIA may be noted.

Heent

    3.4.1) SUMMARY
    A) Swelling of the tongue, angioedema, difficulty in swallowing, or upper airway obstruction may occur in sensitive individuals. Ocular injury may occur from exposure to high concentrations.
    3.4.3) EYES
    A) CONJUNCTIVITIS may be noted in sensitive individuals.
    B) EXCIPIENT EXPOSURE - Bisulfite-preserved epinephrine produced abnormal thickening of corneas, endothelial cell swelling and collapse, and loss of the normal mosaic of cell borders after exposure to 0.1% and 0.08% solutions, but not after exposure to 0.05% solutions (Grant, 1986).
    C) SCOTOMA - Central scotoma and night blindness were reported in a patient receiving sulfite - containing total parenteral nutrition (Abumrad et al, 1981).
    D) HYPERSENSITIVITY - Topical ophthalmic solutions containing sulfites can provoke asthma in sulfite-sensitive patients (Schwartz & Sher, 1985).
    3.4.5) NOSE
    A) NASAL PRURITUS and RHINORRHEA may be noted in sensitive individuals.
    3.4.6) THROAT
    A) ANGIOEDEMA - Swelling of the tongue, and difficulty with swallowing may occur in sensitive individuals (Prenner & Stevens, 1976).

Cardiovascular

    3.5.1) SUMMARY
    A) Hypotension and reflex tachycardia are common in hypersensitivity reactions. Anaphylaxis has been described.
    3.5.2) CLINICAL EFFECTS
    A) HYPOTENSIVE EPISODE
    1) Hypotension is commonly noted in hypersensitivity reactions, but also may be a dose related toxic effect. In animals, hypotension, cyanosis and cardiovascular collapse have been described with lethal doses (Lockett & Natoff, 1960).
    B) ANAPHYLACTOID REACTION
    1) Anaphylaxis has been described following ingestion of wine (Clayton & Busse, 1980), inhalation of sympathomimetics (Prenner & Stevens, 1976) and intravenous injection (Twarog & Leung, 1982; Riggs et al, 1986), and application of bisulfite-containing home permanent solution (Fisher, 1989a).
    C) TACHYARRHYTHMIA
    1) Reflex tachycardia may be noted in hypersensitivity reactions, secondary to hypotension.
    3.5.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) SHOCK
    a) In animals, hypotension, cyanosis and cardiovascular collapse have been described with lethal doses (Lockett & Natoff, 1960).

Respiratory

    3.6.1) SUMMARY
    A) Bronchospasm, tachypnea, and dyspnea may occur, particularly in asthmatics, following inhalation of sulfite-preserved bronchodilator solutions, ingestion of prepared or restaurant foods preserved with sulfites.
    3.6.2) CLINICAL EFFECTS
    A) BRONCHOSPASM
    1) SOURCES - Bronchospasm is the most common adverse effect in asthmatic patients who are sulfite-sensitive. Bronchospasm may occur following inhalation of sulfite-preserved bronchodilator solutions (Yarbrough et al, 1985), ingestion of restaurant foods preserved with sulfites (Wuthrich & Huwyler, 1989), or sulfite-containing derusting agents (Huber & Loving, 1991).
    2) INCIDENCE IN ADULT ASTHMATICS - It is estimated that 5 to 10% of asthmatics are sulfite sensitive (Freedman, 1977; Simon et al, 1982), however, these studies used oral capsule challenge doses. Studies using oral solution challenges have shown 60 to 66% of asthmatics were hypersensitive (Delohory et al, 1984; (Towns & Mellis, 1984). Single-blind oral capsule challenges in steroid-dependent asthmatics showed a prevalence of 19.3%, compared to 4.2% of non-steroid-dependent asthmatics, in a study of 203 patients (Bush et al, 1986).
    3) INCIDENCE IN CHILDREN - A single-blind study of 56 children with mild chronic asthma found a 20% decrease in FEV(1) in 4 (7.1%) after challenge with an MBS capsule of 200 mg. However, only 2 children (3.5%) had a positive response after ingestion of MBS solution containing a dose of 50 to 100 mg (Boner et al, 1990).
    4) DOSE-RESPONSE - Bronchospasm is more severe and occurs at lower doses when inhaled versus ingested. Ingestions of 10 to 50 mg in capsules, 5 to 25 mg in oral solutions and inhalation of nebulized solutions at 100th of the capsule dose have produced bronchospasm. Subcutaneous injection of 10 mg did not produce reactions and this appears to be an unlikely route of toxicity. Intravenous injections have produced bronchospasm (Baker et al, 1981; Goldfarb & Simon, 1984).
    5) NON-ASTHMATICS - Although most cases of bronchospasm have been reported in patients with pre-existing bronchoconstrictive airway disease, airway obstruction has been reported in non-asthmatic patients (Schwartz & Sher, 1986).

Neurologic

    3.7.1) SUMMARY
    A) CNS stimulation has been described in patients receiving bisulfite-containing peritoneal dialysis fluids. Neurotoxicity in the form of prolonged neural blockade has occurred after the inadvertent subarachnoid injection of sulfite-preserved anesthetic.
    3.7.2) CLINICAL EFFECTS
    A) SEIZURE
    1) CNS stimulation has been described in patients receiving bisulfite-containing peritoneal dialysis fluids (Halaby & Mattocks, 1965). In animals, restlessness and clonic seizures were observed.
    B) NEUROTOXICITY
    1) INTRATHECAL INJECTION - Inadvertant subarachnoid or intrathecal injection of chloroprocaine preserved with sodium bisulfite was associated with prolonged neural blockade (Moore et al, 1982; Reisner et al, 1980; Ravindran et al, 1980).
    3.7.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) NEUROPATHY
    a) Animal studies have shown that the bisulfite is neurotoxic (Seravalli & Lear, 1987; Hersh et al, 1990) and that the combination of chloroprocaine and bisulfite form an uncharged complex, which lowered the neurotoxic concentration of bisulfite (Ford & Raj, 1987).

Gastrointestinal

    3.8.1) SUMMARY
    A) Acute ingestions of 3.5 mg/kg produce vomiting in most individuals. Larger doses may result in gastric irritation, abdominal pain, and gastric hemorrhage.
    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) Doses of 4 to 6 grams per day predictably produce nausea, vomiting, gastric irritation, abdominal pain and occasional gastric hemorrhage (Rost & Franz, 1913). Single doses of 3.5 mg/kg produce vomiting in most individuals.
    2) Severe nausea and vomiting were reported in 10% of patients receiving oral challenges with 1500 to 2000 mg (Hosen, 1987).
    B) DIARRHEA
    1) Diarrhea may be noted.

Dermatologic

    3.14.1) SUMMARY
    A) Generalized urticaria and allergic eczematous dermatitis may be noted.
    3.14.2) CLINICAL EFFECTS
    A) URTICARIA
    1) Generalized urticaria has been described and may be accompanied by tingling and pruritus (Clayton & Busse, 1980; Prenner & Stevens, 1976).
    B) ECZEMA
    1) Hand eczema has been reported in a food handler who worked with sodium bisulfite (Fisher, 1975) or sodium metabisulfite (Fisher, 1989b). Allergic eczematous dermatitis of the head and neck area has occurred after exposure to sulfite-containing home permanent solutions in a patient who was patch test positive for bisulfite (Fisher, 1989a).
    C) CONTACT DERMATITIS
    1) Contact dermatitis has been reported following occupational exposure to sulfites (Apetato & Marques, 1986).
    D) EXCESSIVE SWEATING
    1) Diaphoresis may be noted in sensitive individuals.
    E) FLUSHING
    1) Flushing may be noted.

Reproductive

    3.20.1) SUMMARY
    A) No teratogenic effects have been observed in animal studies using sodium metabisulfite.
    3.20.2) TERATOGENICITY
    A) TESTIS DISORDER
    1) OTHER REPRODUCTIVE ORGAN EFFECTS - A study of the pathologic changes in sulfite oxidase-deficient rats with increased endogenously generated sulfite and S-sulfonates found severely atrophied testes devoid of spermatogenic cells (Gunnison et al, 1987).
    B) LACK OF EFFECT
    1) No teratogenic effects have been observed in animal studies using sodium metabisulfite (Dulak et al, 1984; Murray et al, 1979).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Skin test are not usually useful in screening for or diagnosis of sulfite sensitivity.
    B) Oral provocation challenge tests are recommended in patients with a history of sulfite sensitivity.
    4.1.2) SERUM/BLOOD
    A) No specific lab work (CBC, electrolytes) is needed unless otherwise clinically indicated.
    4.1.4) OTHER
    A) OTHER
    1) DERMAL
    a) Skin test are not usually useful in screening for or diagnosis of sulfite sensitivity.
    2) OTHER
    a) Oral provocation challenge tests are recommended in patients with a history of sulfite sensitivity. The standard protocol approved by the American Academy of Allergy and Immunology is presented below (Simon, 1987).
    1) Subsequent doses of metabisulfite of 0.1, 1, 5, 10, 15, 25, 50, 75, 100, 150, and 200 mg are administered in 20 mL of cold Minute-Maid Lemonade Crystals(R) solution.
    2) The solution is swished in the mouth for 10 to 15 seconds before swallowing. Challenge doses are given every 10 minutes, with pulmonary function tests measured before the challenge and preceeding each subsequent dose.
    b) A 20% drop in FEV1 is considered a positive challenge.
    c) A second double-blind placebo challenge, beginning at the previously established provoking dose, can be performed to confirm sulfite sensitivity.
    d) NOTE - Prior to conducting challenge testing resuscitative equipment, including supplies for intubation and ventilation should be made available.

Methods

    A) OTHER
    1) A colorimetric test strip is available OTC to detect unlabeled sulfites in foods (Sulfitest(R)) (Center Laboratories).
    2) These strips are not recommended by the FDA due to reports of false negative tests, which may have dire consequences in a sulfite-sensitive asthmatic. False negative tests were reported in 5 of 9 acidic foods in one study (Wanderer & Solomons, 1987).
    3) False negative results in one study occurred when sulfite was detected at levels greater than 10 ppm by the Monier-Williams method (Nordlee et al, 1988). False positive results were obtained with fin fish, poultry, and red meats (Nordlee et al, 1988).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Monitoring

    A) Skin test are not usually useful in screening for or diagnosis of sulfite sensitivity.
    B) Oral provocation challenge tests are recommended in patients with a history of sulfite sensitivity.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) DILUTION -
    1) DILUTION: If no respiratory compromise is present, administer milk or water as soon as possible after ingestion. Dilution may only be helpful if performed in the first seconds to minutes after ingestion. The ideal amount is unknown; no more than 8 ounces (240 mL) in adults and 4 ounces (120 mL) in children is recommended to minimize the risk of vomiting (Caravati, 2004).
    B) EMESIS -
    1) Emesis will be spontaneous in significant ingestions. Induced emesis is unlikely to be necessary.
    C) ACTIVATED CHARCOAL -
    1) Consider activated charcoal after large ingestions.
    2) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    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).
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) 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.
    2) 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) 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).
    B) SEIZURE
    1) SUMMARY
    a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
    b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
    c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).
    2) DIAZEPAM
    a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .
    3) NO INTRAVENOUS ACCESS
    a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
    b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).
    4) LORAZEPAM
    a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
    b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
    c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).
    5) PHENOBARBITAL
    a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
    b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
    c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
    d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
    e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
    f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).
    6) OTHER AGENTS
    a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):
    1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
    2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
    3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
    4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).
    C) ACUTE ALLERGIC REACTION
    1) Subcutaneous epinephrine, corticosteroids, non-sulfite-containing nebulized bronchodilators (ie: albuterol) and theophylline have all been used successfully to treat acute hypersensitivity reactions.
    D) ANAPHYLAXIS
    1) SUMMARY
    a) Mild to moderate allergic reactions may be treated with antihistamines with or without inhaled beta adrenergic agonists, corticosteroids or epinephrine. Treatment of severe anaphylaxis also includes oxygen supplementation, aggressive airway management, epinephrine, ECG monitoring, and IV fluids.
    2) BRONCHOSPASM
    a) ALBUTEROL
    1) ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007). CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 mg/kg (up to 10 mg) every 1 to 4 hours as needed, or 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).
    3) CORTICOSTEROIDS
    a) Consider systemic corticosteroids in patients with significant bronchospasm.
    b) PREDNISONE: ADULT: 40 to 80 milligrams/day. CHILD: 1 to 2 milligrams/kilogram/day (maximum 60 mg) in 1 to 2 divided doses divided twice daily (National Heart,Lung,and Blood Institute, 2007).
    4) MILD CASES
    a) DIPHENHYDRAMINE
    1) SUMMARY: Oral diphenhydramine, as well as other H1 antihistamines can be used as indicated (Lieberman et al, 2010).
    2) ADULT: 50 milligrams orally, or 10 to 50 mg intravenously at a rate not to exceed 25 mg/min or may be given by deep intramuscular injection. A total of 100 mg may be administered if needed. Maximum daily dosage is 400 mg (Prod Info diphenhydramine HCl intravenous injection solution, intramuscular injection solution, 2013).
    3) CHILD: 5 mg/kg/24 hours or 150 mg/m(2)/24 hours. Divided into 4 doses, administered intravenously at a rate not exceeding 25 mg/min or by deep intramuscular injection. Maximum daily dosage is 300 mg (Prod Info diphenhydramine HCl intravenous injection solution, intramuscular injection solution, 2013).
    5) MODERATE CASES
    a) EPINEPHRINE: INJECTABLE SOLUTION: It should be administered early in patients by IM injection. Using a 1:1000 (1 mg/mL) solution of epinephrine. Initial Dose: 0.01 mg/kg intramuscularly with a maximum dose of 0.5 mg in adults and 0.3 mg in children. The dose may be repeated every 5 to 15 minutes, if no clinical improvement. Most patients respond to 1 or 2 doses (Nowak & Macias, 2014).
    6) SEVERE CASES
    a) EPINEPHRINE
    1) INTRAVENOUS BOLUS: ADULT: 1 mg intravenously as a 1:10,000 (0.1 mg/mL) solution; CHILD: 0.01 mL/kg intravenously to a maximum single dose of 1 mg given as a 1:10,000 (0.1 mg/mL) solution. It can be repeated every 3 to 5 minutes as needed. The dose can also be given by the intraosseous route if IV access cannot be established (Lieberman et al, 2015). ALTERNATIVE ROUTE: ENDOTRACHEAL ADMINISTRATION: If IV/IO access is unavailable. DOSE: ADULT: Administer 2 to 2.5 mg of 1:1000 (1 mg/mL) solution diluted in 5 to 10 mL of sterile water via endotracheal tube. CHILD: DOSE: 0.1 mg/kg to a maximum of 2.5 mg administered as a 1:1000 (1 mg/mL) solution diluted in 5 to 10 mL of sterile water via endotracheal tube (Lieberman et al, 2015).
    2) INTRAVENOUS INFUSION: Intravenous administration may be considered in patients poorly responsive to IM or SubQ epinephrine. An epinephrine infusion may be prepared by adding 1 mg (1 mL of 1:1000 (1 mg/mL) solution) to 250 mL D5W, yielding a concentration of 4 mcg/mL, and infuse this solution IV at a rate of 1 mcg/min to 10 mcg/min (maximum rate). CHILD: A dosage of 0.01 mg/kg (0.1 mL/kg of a 1:10,000 (0.1 mg/mL) solution up to 10 mcg/min (maximum dose 0.3 mg) is recommended for children (Lieberman et al, 2010). Careful titration of a continuous infusion of IV epinephrine, based on the severity of the reaction, along with a crystalloid infusion can be considered in the treatment of anaphylactic shock. It appears to be a reasonable alternative to IV boluses, if the patient is not in cardiac arrest (Vanden Hoek,TL,et al).
    7) AIRWAY MANAGEMENT
    a) OXYGEN: 5 to 10 liters/minute via high flow mask.
    b) INTUBATION: Perform early if any stridor or signs of airway obstruction.
    c) CRICOTHYROTOMY: Use if unable to intubate with complete airway obstruction (Vanden Hoek,TL,et al).
    d) BRONCHODILATORS are recommended for mild to severe bronchospasm.
    e) ALBUTEROL: ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007).
    f) ALBUTEROL: CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 milligram/kilogram (maximum 10 milligrams) every 1 to 4 hours as needed OR administer 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).
    8) MONITORING
    a) CARDIAC MONITOR: All complicated cases.
    b) IV ACCESS: Routine in all complicated cases.
    9) HYPOTENSION
    a) If hypotensive give 500 to 2000 milliliters crystalloid initially (20 milliliters/kilogram in children) and titrate to desired effect (stabilization of vital signs, mentation, urine output); adults may require up to 6 to 10 L/24 hours. Central venous or pulmonary artery pressure monitoring is recommended in patients with persistent hypotension.
    1) VASOPRESSORS: Should be used in refractory cases unresponsive to repeated doses of epinephrine and after vigorous intravenous crystalloid rehydration (Lieberman et al, 2010).
    2) DOPAMINE: Initial Dose: 2 to 20 micrograms/kilogram/minute intravenously; titrate to maintain systolic blood pressure greater than 90 mm Hg (Lieberman et al, 2010).
    10) H1 and H2 ANTIHISTAMINES
    a) SUMMARY: Antihistamines are second-line therapy and are used as supportive therapy and should not be used in place of epinephrine (Lieberman et al, 2010).
    1) DIPHENHYDRAMINE: ADULT: 25 to 50 milligrams via a slow intravenous infusion or IM. PEDIATRIC: 1 milligram/kilogram via slow intravenous infusion or IM up to 50 mg in children (Lieberman et al, 2010).
    b) RANITIDINE: ADULT: 1 mg/kg parenterally; CHILD: 12.5 to 50 mg parenterally. If the intravenous route is used, ranitidine should be infused over 10 to 15 minutes or diluted in 5% dextrose to a volume of 20 mL and injected over 5 minutes (Lieberman et al, 2010).
    c) Oral diphenhydramine, as well as other H1 antihistamines, can also be used as indicated (Lieberman et al, 2010).
    11) DYSRHYTHMIAS
    a) Dysrhythmias and cardiac dysfunction may occur primarily or iatrogenically as a result of pharmacologic treatment (epinephrine) (Vanden Hoek,TL,et al). Monitor and correct serum electrolytes, oxygenation and tissue perfusion. Treat with antiarrhythmic agents as indicated.
    12) OTHER THERAPIES
    a) There have been a few reports of patients with anaphylaxis, with or without cardiac arrest, that have responded to vasopressin therapy that did not respond to standard therapy. Although there are no randomized controlled trials, other alternative vasoactive therapies (ie, vasopressin, norepinephrine, methoxamine, and metaraminol) may be considered in patients in cardiac arrest secondary to anaphylaxis that do not respond to epinephrine (Vanden Hoek,TL,et al).
    E) PREVENTIVE PROCEDURE
    1) Inhaled sodium cromolyn 20 to 40 mg has successfully blocked reactions when given 15 minutes prior to challenge doses of sulfites (Simon et al, 1984). Inhaled atropine 1 to 4 milligrams was protective in 3 of 6 patients (Simon et al, 1984).
    2) Oral cromolyn sodium 200 milligrams four times daily, one-half hour before meals and bedtime was reported effective in preventing sulfite-induced bronchoconstriction in an asthmatic patient (Schwartz & Sher, 1986).
    3) CYANOCOBALAMIN -
    a) Vitamin B12 - Cobalamins non-enzymatically catalyze oxidation of sulfite in the presence of oxygen. Administration of 1 to 5 mg orally may prevent sensitivity reactions from sulfite ingestion (Jacobsen et al, 1984).

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) 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).
    B) ACUTE ALLERGIC REACTION
    1) Subcutaneous epinephrine, corticosteroids, non-sulfite-containing nebulized bronchodilators (albuterol), and theophylline have all been used successfully to treat acute hypersensitivity reactions.
    2) Although sulfite-free epinephrine is available (Sus-phrine(R) from Forest; Epinephrine 1:1,000 from American Regent Laboratories), sulfite-preserved epinephrine should be used for severe, life-threatening reactions if the sulfite-free form cannot be readily obtained (Smolinske, 1992).
    C) PREVENTIVE PROCEDURE
    1) Inhaled sodium cromolyn 20 to 40 milligrams or nebulized atropine has successfully blocked reactions when given 15 minutes prior to challenge doses of sulfites.
    2) In one study of sulfite-sensitive patients, 9 out of 10 patients pre-treated with 20 milligrams of cromolyn sodium had a marked decrease in metabisulfite-induced bronchoconstriction (McClellan et al, 1990).
    3) Inhaled ipratropium (200 micrograms) had no effect on metabisulfite-induced bronchoconstriction (Nichol et al, 1989).
    D) 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).

Dermal Exposure

    6.9.1) DECONTAMINATION
    A) DERMAL DECONTAMINATION
    1) 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).

Abstracts

Case Reports

    A) ACUTE EFFECTS
    1) A 70-year-old female asthmatic had an attack of asthma, urticaria, and syncope after applying ammonium persulfate to her hair. She suffered a second similar attack after applying a home permanent with bisulfite. The patient was patch test positive to sodium sulfite (Fisher, 1989a).
    B) ADVERSE EFFECTS
    1) A 29-year-old nonatopic male developed eczema on both hands 3 months after beginning work as a baker. Patch testing was negative except for 5% metabisulfite. The dermatitis cleared after the patient stopped using flour containing metabisulfite (Fisher, 1989b).
    C) ROUTE OF EXPOSURE
    1) ORAL
    a) A 46-year-old female with a history of asthma had a severe attack of urticaria, asthma, and syncope during a dental procedure in which the ester-type local anesthetic, procaine, was injected. Epinephrine did not reverse the reaction, and her condition improved only after treatment with diphenhydramine and aminophylline. Subsequently she received an injection with an amide-type local anesthetic, mepivacaine, which produced the same symptom complex. Both of these local anesthetics contained sodium metabisulfite. The patient subsequently was given an injection of the amide-type local anesthetic, lidocaine, which does not contain sulfites, and tolerated it (Fisher, 1989c).
    D) ADULT
    1) A 24-year-old man experienced clammy skin, weakness, headaches, disassociation, chest tightness and tachycardia 10 minutes after eating a restaurant meal. Oral challenge demonstrated stomach tightness and lightheadedness after 10 mg of metabisulfite, abdominal distress, dizziness and mild hypotension after 25 mg, and prolonged hypotension after 50 mg (Schwartz, 1983).
    2) Pallor, coughing, and vomiting were reported within 2 minutes of a challenge dose of sodium bisulfite in a 7 year old boy with a history of allergic rhinitis, but no asthma (Wolf & Nicklas, 1985).

Range Of Toxicity

Summary

    A) Acute ingestions of 3.5 mg/kg or chronic ingestions of 4 to 6 gm/day produced GI effects. Asthmatic patients may exhibit hypersensitivity to as little as 10 mg in capsules or 5 mg in oral solutions.

Therapeutic Dose

    7.2.1) ADULT
    A) GENERAL
    1) ADULT - 0.3 to 2.0 grams have been used therapeutically as gastric antiseptics (Schwartz & Chester, 1984). In the United States, 2 to 3 milligrams/day (0.2 milligram/kilogram) is consumed in the normal diet, however, restaurant meals may contain 100 milligrams or more.

Minimum Lethal Exposure

    A) CASE REPORTS
    1) Sulfite-induced fatal hypersensitivity reactions are rare. Fourteen deaths were reported to the FDA prior to 1986 (FDA, 1986).
    2) An additional case of fatal anaphylaxis was reported in a 33-year-old man following ingestion of a few sips of wine containing sulfites 92 parts per million (Tsevat et al, 1987).

Maximum Tolerated Exposure

    A) ROUTE OF EXPOSURE
    1) ORAL -
    a) ACUTE OVERDOSE - Doses of 4 to 6 grams/day or 3.5 milligrams/kilogram acutely, produced nausea, vomiting, abdominal pain, gastric irritation and possibly gastric hemorrhage. Doses of 1 gram of sodium sulfite per day did not produce gastrointestinal symptoms (Rost & Franz, 1913).
    b) HYPERSENSITIVITY - Reactions in asthmatics occur at much lower doses than those producing toxic reactions. Challenge oral doses of 10 to 50 milligrams in capsules have produced toxicity and one-half that amount in solution may produce symptoms.
    c) CNS TOXICITY - The minimum toxic dose to produce CNS effects is 6 milligrams/kilogram in humans (Sax, 1979).
    2) INHALATION -
    a) METABISULFITE - In one study, inhalation of metabisulfite in doses from 0.1 to 12.8 micromoles resulted in a reproducible dose-response curve in 30 out of 30 asthmatics and in 1 out of 8 atopic, nonasthmatic subjects. A 20 percent decrease in FEV(1) occurred within 1 minute and most subjects recovered to within 10 percent of baseline after 30 to 40 minutes (Wright et al, 1990).
    3) PERITONEAL -
    a) Administration of intraperitoneal fluids containing sodium bisulfite 500 milligrams/liter produced CNS stimulation in patients receiving up to 10 to 12 liters/day in dialysis fluids (Halaby & Mattocks, 1965).
    4) PARENTERAL -
    a) Subcutaneous administration of 10 milligrams of sulfite was tolerated by six asthmatic patients. However, some highly sensitive subjects who reacted to 5 to 10 milligrams orally, also reacted to 1 to 10 milligrams subcutaneously (Smolinske, 1992).

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) GENERAL
    a) Serum levels of 700 to 1000 micromoles/liter were lethal to rabbits (Gunnison, 1981). Humans with severe deficiencies in sulfite oxidase have shown levels of 130 micromoles/liter following challenge with sulfur-containing amino acids.
    b) Plasma sulfite levels were done during a double-blind challenge with sulfite (200 milligram sodium metabisulfite capsule) and placebo in an atopic asthmatic. The baseline sulfite concentration was under 100 micrograms/milliliter. A 70 percent increase in plasma levels occurred 5 minutes after administration of the MBS capsule, but levels returned to baseline within 1 hour. There was an inverse correlation between plasma sulfite levels and central airway obstruction measured by pulmonary function tests (Acosta et al, 1989).

Toxicity Information

    7.7.1) TOXICITY VALUES

Pharmacology Toxicology

Toxicologic Mechanism

    A) Hypersensitivity reactions may be related to IgE-mediated mechanisms rarely, however, only 2 cases have documented positive skin tests and these were of anaphylactic reaction (Prenner & Stevens, 1976; Twarog & Leung, 1982).
    B) In a study of 13 patients with a history of sulfite sensitivity, serum samples were obtained before and after single-blind, placebo-controlled challenge with oral aqueous potassium metabisulfite. Six of 13 patients had positive challenges defined as a 20% decrease in FEV(1). In these 13 skin test-negative patients, mast cell degranulation, as measured by the release of neutrophil chemotactic factor of anaphylaxis, did not occur (Sprenger et al, 1989).
    C) A more likely cause of hypersensitivity is a cholinergic reflex mechanism. Inhaled sulfur dioxide from liquids, air pollution, aerosols or eructation from ingested capsules may activate tracheo-bronchial irritant receptors in the nose and upper airway which stimulate a cholinergic reflex response resulting in bronchoconstriction, peripheral vasodilation, diaphoresis, urticaria, angioedema and gastrointestinal effects.
    D) Another theory proposed that sulfite-sensitive asthmatics have a partial deficiency of the enzyme sulfite oxidase and have demonstrated that several sulfite sensitive asthmatics have decreased enzyme levels in fibroblast extracts.

Physicochemical

Physical Characteristics

    A) SULFUR DIOXIDE is a colorless, non-flammable gas with a strong, suffocating odor.
    B) SODIUM SULFITE is a white powder or crystal that has a saline, sulfurous taste (Sax & Lewis, 1987).
    C) SODIUM METABISULFITE has a sulfur dioxide odor and an acidic saline taste.
    D) SODIUM METABISULFITE is a white crystalline powder or colorless prismatic crystal (ACGIH, 1989).
    E) SODIUM BISULFITE does not exist in the solid state and preparations labeled as such usually consist of metabisulfite (Sax & Lewis, 1987).
    F) AMMONIUM SULFITE has an acrid sulfurous taste (Sax & Lewis, 1987).
    G) CALCIUM SULFITE exists as crystals or powder which oxidizes slowly in air to CALCIUM SULFATE. It is slightly soluble in water and alcohol (Sax & Lewis, 1987; Budavari, 1989).
    H) POTASSIUM SULFITE consists of white crystals, which are soluble in water and slightly soluble in alcohol (Sax & Lewis, 1989).
    I) POTASSIUM BISULFITE has a sulfur dioxide odor (Sax & Lewis, 1987).

Ph

    A) The particular form of sulfite present depends on the pH of the solution. At a pH of greater than 4, the primary form is the metabisulfite or sulfite. At a pH of 2, 25% is present as sulfur dioxide and another 25% as bisulfite.

Molecular Weight

    A) Varies

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