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BROMIDES

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Bromides includes inorganic and organic compounds, which release bromide ions in vivo.

Specific Substances

    A) INORGANIC BROMIDES
    1) Ammonium Bromide (synonym)
    2) Calcium Bromide (synonym)
    3) Potassium Bromide (synonym)
    4) Sodium Bromide (synonym)
    ORGANIC BROMIDES
    1) Acetylcarbromal (synonym)
    2) Bromdiphenhydramine (synonym)
    3) Bromisoval (synonym)
    4) Bromocriptine (synonym)
    5) Bromovalerylurea
    6) Brompheniramine (synonym)
    7) Bromural (synonym)
    8) Bromvaleryurea (synonym)
    9) Calcium bromogalactogluconate (synonym)
    10) Carbromal (synonym)
    11) Dexbrompheniramine (synonym)
    12) Dextromethorphan HBr (synonym)
    13) Halothane hydrobromide (synonym)
    14) Homatropine HBr (synonym)
    15) Neostigmine bromide (synonym)
    16) Pancuronium bromide (synonym)
    17) Propantheline bromide (synonym)
    18) Pyridostigmine bromide (synonym)
    19) Quinine HBr (synonym)
    20) Scopolamine HBr (synonym)
    21) Vecuronium Bromide (synonym)

Available Forms Sources

    A) SOURCES
    1) ORGANIC AND INORGANIC BROMIDES
    Generic NameAmount in mEqPercent of Bromide
    Acetylcarbromal3.6 mEq/g29
    Ammonium Bromide10 mEq/g80
    Bromdiphenhydramine3 mEq/g24
    Bromisovalum4.5 mEq/g36
    Bromocriptine1.5 mEq/g12
    Brompheniramine3 mEq/g25
    Calcium bromo- galactogluconate2.1 mEq/g16.7
    Carbromal4.3 mEq/g34
    Dexbrompheniramine3 mEq/g25
    Dextromethorphan HBr3 mEq/g23
    Halothane hydrobromide10 mEq/g81
    Homatropine HBr4 mEq/g29
    Neostigmine5 mEq/g38
    Pamabrom2.9 mEq/g23
    Pancuronium4 mEq/g37
    Potassium Bromide8 mEq/g67
    Propantheline2.2 mEq/g17.8
    Pyridostigmine4 mEq/g30.6
    Quinine HBr2 mEq/g17
    Scopolamine HBr3 mEq/g20.8
    Sodium Bromide10 mEq/g78
    Vecuronium Bromide2.9 mEq/g25

    a) (Fried & Malek-Ahmadi, 1975; Rothenberg et al, 1990; Bowers & Onoroski, 1990)
    2) DRUGS
    a) The most current preparations of Bromo-Seltzer(R) (after 1973) and of Nervine(R) (after October, 1975) no longer contain bromide. Old products, however, may be on market; check label. Bromide-containing medications are still widely prescribed in other countries.
    b) HALOTHANE slowly releases bromide ions, which may peak 2 to 3 days after anesthesia (Tinker et al, 1976).
    c) In the past bromides were widely used in the treatment of epilepsy, but have been largely replaced by safer alternatives. Bromides are currently being studied in the treatment of severe refractory seizure disorders (Oguni et al, 1994; Steinhoff & Kruse, 1992). Triple bromide elixir may still be used as an older therapy for the treatment of seizures. It contains 76% bromide ion (James et al, 1997).
    3) FUMIGANTS
    a) The major source of bromide exposure in humans in the United States is the presence of bromide residues in food commodities. Bromine containing fumigants, methyl bromide and ethylene dibromide, are extensively used in horticulture and in postharvest treatments (van Leeuwen & Sangster, 1987).
    b) METHYL BROMIDE is used in soil fumigation which can result in bromide levels as high as 380 mg/kg in vegetables such as lettuce, spinach, tomatoes, radishes, and cucumbers among others (van Leeuwen & Sangster, 1987).
    c) ETHYLENE DIBROMIDE is used in the postharvest fumigation of warehouses, ships' holds, and quarantine chambers effecting fruits, wheat, almonds, tobacco, and dried mushrooms; achieving levels as high as 300 mg/kg (van Leeuwen & Sangster, 1987).
    4) FOODS
    a) Most fruits and beverages contain bromide residues below 2 mg/kg. Most (root) vegetables, potatoes, milk and dairy products, meat, fish, and sugar contain bromide residues between 2 and 8 mg/kg.
    b) Some cereals and leafy vegetables can occasionally contain bromide residues higher than 200 mg/kg (van Leeuwen & Sangster, 1987).
    5) WATER
    a) Contaminated well water may be a source of bromide exposure (Brenner, 1978).
    b) The Dead Sea reportedly contains the greatest amount of bromide of any other large body of water in the world, with a bromide concentration of approximately 5 g/L. Hyperchloremia was reported in a patient who had consumed 3 to 4 tablespoonfuls of Dead Sea salt daily for several months for its purported holistic health benefits. His serum bromide concentration was 2540 mg/L (Taylor et al, 2010).

Overview

Life Support

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

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: In the past, bromides were widely used both as a sedative and an antiepileptic agent in the United States, and they are still used as sedatives in some areas of the world. It is still found as a bromide salt in many medications. The major source of bromide exposure in humans in the United States is the presence of bromide residues in food. Bromine-containing fumigants are extensively used in horticulture and in post-harvest treatments, but the amounts are too minimal to cause toxicity. Contaminated well water may be a source of bromide exposure.
    B) PHARMACOLOGY: Bromide ion causes secondary anion potentiation of gamma-aminobutyric acid (GABA) channels in the CNS. GABA receptors are complexed with chloride channels. Available bromide ions, due to their smaller hydrated diameter, diffuse more readily through cellular channels, producing a hyperpolarized post-synaptic membrane, which potentiates the action of GABA, an inhibitory neurotransmitter.
    C) TOXICOLOGY: With chronic exposure, the bromide ion displaces chloride from plasma, extracellular fluid, and, to some extent, from cells. The kidneys increase the elimination of chloride ions in an attempt to maintain a constant total halide concentration. Central nervous system function is progressively impaired, presumably through a membrane-stabilizing effect. A toxic concentration can be reached very rapidly when the intake of chloride is reduced.
    D) EPIDEMIOLOGY: Bromide poisoning is rare and, when it does occur, is generally secondary to chronic ingestion rather than acute overdose.
    E) WITH POISONING/EXPOSURE
    1) ACUTE: Bromide poisoning following acute ingestion is rare. Acute effects may include nausea, vomiting, gastric irritation, CNS depression, coma, hypotension, tachycardia, and respiratory distress.
    2) CHRONIC: Ingestion of chronic, excessive amounts may produce a toxic syndrome called "bromism", which is characterized by behavioral changes, hallucinations, psychosis, ataxia, irritability, headache, and confusion. Other symptoms of chronic bromide toxicity include: anorexia, weight loss, constipation, slurred speech, anemia, bromoderma (an erythematous, nodular, or acneiform rash over the face and possibly the entire body), bullous or pustular eruptions on the skin, toxic epidermal necrolysis, musculoskeletal pain, lethargy, and liver enzyme abnormalities. Fever may be seen in up to 25% of cases of chronic ingestion. Chronic intoxication usually develops over 2 to 4 weeks or longer.
    0.2.3) VITAL SIGNS
    A) Fever may occur with chronic intoxication.
    0.2.4) HEENT
    A) Pupils may be normal, miotic or mydriatic. Nystagmus is common.
    0.2.5) CARDIOVASCULAR
    A) WITH POISONING/EXPOSURE
    1) Tachycardia and hypotension have occurred with acute intoxication.
    0.2.7) NEUROLOGIC
    A) Acute intoxication can result in CNS depression and coma.
    B) Chronic effects may include behavioral changes, irritability, confusion, muscular weakness, anorexia, ataxia, lethargy, abnormal reflexes, and slurred speech.
    0.2.8) GASTROINTESTINAL
    A) Nausea and vomiting occur following acute or chronic ingestion. Anorexia and weight loss may occur with chronic intoxication.
    0.2.10) GENITOURINARY
    A) Acute renal failure is rare. Incontinence may develop with chronic intoxication.
    0.2.12) FLUID-ELECTROLYTE
    A) Spuriously elevated chloride level and low anion gap are characteristic of bromism, due to laboratory interference by the bromide ion.
    0.2.14) DERMATOLOGIC
    A) WITH POISONING/EXPOSURE
    1) Bromide toxicity is associated in about 25% of cases with the development of bromoderma, an erythematous, nodular or acneiform rash over the face and possibly the entire body. One case of toxic epidermal necrolysis has been reported.
    0.2.18) PSYCHIATRIC
    A) Chronic bromism has been associated with toxic psychosis resembling paranoid schizophrenia, personality changes, and mania with paranoid delusions.
    0.2.20) REPRODUCTIVE
    A) Bromides cross the placenta and may be detected in the milk of nursing mothers. Case reports suggest that prenatal exposure may cause growth retardation, craniofacial abnormalities and developmental delay.

Laboratory Monitoring

    A) Monitor serum electrolytes, renal function, and fluid status carefully. Spuriously elevated chloride level and low anion gap are characteristic of bromism due to laboratory interference by the bromide ion.
    B) Serum bromide concentrations should be monitored in patients with significant CNS effects.
    C) Consider abdominal x-ray as bromide is radiopaque. Abdominal x-ray may be helpful in confirming diagnosis of acute ingestion.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Care is symptomatic and supportive. Administer IV 0.9% sodium chloride to increase bromide elimination.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Care is symptomatic and supportive. Orotracheal intubation may be necessary if CNS depression develops. Aggressively hydrate patient with 0.9% sodium chloride to enhance bromide excretion. Diuretics such as furosemide may further enhance bromide excretion. Consider hemodialysis in patients with severe toxicity, and those with impaired renal function or in whom diuresis is not effective or is contraindicated.
    C) DECONTAMINATION
    1) Toxicity generally occurs with chronic ingestion. Consider activated charcoal only after large, recent ingestions in patients who are alert and can protect the airway. Gastric lavage is not indicated as acute ingestion is not life-threatening.
    D) AIRWAY MANAGEMENT
    1) Endotracheal intubation should be performed in patients with excessive drowsiness and the inability to protect their own airway.
    E) ANTIDOTE
    1) None
    F) INTRAVENOUS FLUIDS
    1) Infusion of 0.9% sodium chloride enhances urinary bromide excretion. Give initial bolus of 10 to 20 mg/kg as clinically indicated, followed by an infusion 2 to 3 times the maintenance fluid rate. Discontinue infusion when symptoms have improved and the serum bromide level is less than 100 to 150 mg/dL.
    G) DIURESIS
    1) Diuretics such as furosemide, ethacrynic acid, thiazides, or mannitol may be administered, in addition to intravenous sodium chloride, to obtain a urine flow of 3 to 6 mL/kg/hour. Administration may increase bromide clearance. Monitor fluid and electrolytes closely as hypernatremia may occur.
    H) ENHANCED ELIMINATION
    1) The addition of diuretics, such as furosemide, ethacrynic acid, thiazides, and mannitol, to intravenous chloride therapy has been shown to increase urinary bromide excretion. Hemodialysis greatly increases bromide clearance, and is indicated in patients with severe toxicity, underlying renal insufficiency, or when attempts at intravenous chloride administration have been unsuccessful or are contraindicated.
    I) PATIENT DISPOSITION
    1) HOME CRITERIA: Patients with inadvertent ingestions who are asymptomatic can be managed at home.
    2) OBSERVATION CRITERIA: Patients with deliberate overdose and symptomatic patients should be observed in a medical facility until free of symptoms.
    3) ADMISSION CRITERIA: All patients who are persistently symptomatic should be admitted.
    4) CONSULT CRITERIA: Consult a medical toxicologist or poison center for patients with significant toxicity or in whom the diagnosis is unclear.
    J) PITFALLS
    1) Failure to discern the difference between bromide intoxication and bromine gas intoxication, which primarily causes pulmonary and dermatologic manifestations. Failure to consider the possibility of bromide intoxication with drugs containing bromides as the salt form.
    K) PHARMACOKINETICS
    1) Bromide is well absorbed (95%). Volume of distribution is 0.35 to 0.48 L/kg and it is not protein bound. Eliminated renally, with a half-life of 12 days.
    L) TOXICOKINETICS
    1) Half-life is shortened by various treatment modalities: Intravenous sodium chloride: 65 hours; osmotic diuresis: 37 hours; ethacrynic acid plus mannitol: 1.65 hours; oral furosemide plus lactated ringers: 26 hours; hemodialysis: 0.8 to 2.1 hours.
    M) DIFFERENTIAL DIAGNOSIS
    1) Toxicologic and non-toxicologic causes of confusion and CNS depression (eg, barbiturates, benzodiazepines, lithium, phenytoin, carbamazepine, dementia, meningitis, CVA, CNS bleeding, tumor).

Range Of Toxicity

    A) TOXICITY: There is great interpatient variability in symptoms at a given serum bromide concentration. Most toxicity develops after chronic ingestion. Serum bromide concentrations of 50 to 100 mg/dL may be associated with symptoms; 200 mg/dL will produce toxic symptoms; 300 mg/dL may be fatal. Acute ingestion of 4500 mg bromovalerylurea caused lethargy and myoclonus in an adult. Chronic consumption of 0.5 to 1 g bromides/day may cause bromism.
    B) THERAPEUTIC DOSE: Adults: Acceptable daily intake: 1 mg/kg.

Clinical Effects

Summary Of Exposure

    A) USES: In the past, bromides were widely used both as a sedative and an antiepileptic agent in the United States, and they are still used as sedatives in some areas of the world. It is still found as a bromide salt in many medications. The major source of bromide exposure in humans in the United States is the presence of bromide residues in food. Bromine-containing fumigants are extensively used in horticulture and in post-harvest treatments, but the amounts are too minimal to cause toxicity. Contaminated well water may be a source of bromide exposure.
    B) PHARMACOLOGY: Bromide ion causes secondary anion potentiation of gamma-aminobutyric acid (GABA) channels in the CNS. GABA receptors are complexed with chloride channels. Available bromide ions, due to their smaller hydrated diameter, diffuse more readily through cellular channels, producing a hyperpolarized post-synaptic membrane, which potentiates the action of GABA, an inhibitory neurotransmitter.
    C) TOXICOLOGY: With chronic exposure, the bromide ion displaces chloride from plasma, extracellular fluid, and, to some extent, from cells. The kidneys increase the elimination of chloride ions in an attempt to maintain a constant total halide concentration. Central nervous system function is progressively impaired, presumably through a membrane-stabilizing effect. A toxic concentration can be reached very rapidly when the intake of chloride is reduced.
    D) EPIDEMIOLOGY: Bromide poisoning is rare and, when it does occur, is generally secondary to chronic ingestion rather than acute overdose.
    E) WITH POISONING/EXPOSURE
    1) ACUTE: Bromide poisoning following acute ingestion is rare. Acute effects may include nausea, vomiting, gastric irritation, CNS depression, coma, hypotension, tachycardia, and respiratory distress.
    2) CHRONIC: Ingestion of chronic, excessive amounts may produce a toxic syndrome called "bromism", which is characterized by behavioral changes, hallucinations, psychosis, ataxia, irritability, headache, and confusion. Other symptoms of chronic bromide toxicity include: anorexia, weight loss, constipation, slurred speech, anemia, bromoderma (an erythematous, nodular, or acneiform rash over the face and possibly the entire body), bullous or pustular eruptions on the skin, toxic epidermal necrolysis, musculoskeletal pain, lethargy, and liver enzyme abnormalities. Fever may be seen in up to 25% of cases of chronic ingestion. Chronic intoxication usually develops over 2 to 4 weeks or longer.

Vital Signs

    3.3.1) SUMMARY
    A) Fever may occur with chronic intoxication.
    3.3.3) TEMPERATURE
    A) Fever may be seen in up to 25% of cases of chronic ingestion (Hung, 2003; Sensenbach, 1944; Perkins, 1950; Blume et al, 1968; Trump & Hochberg, 1976; Stewart, 1973).

Heent

    3.4.1) SUMMARY
    A) Pupils may be normal, miotic or mydriatic. Nystagmus is common.
    3.4.3) EYES
    A) Pupils may be normal, miotic, or mydriatic and may be sluggishly reactive to light (Hanes & Yates, 1938; Harenko, 1967a).
    1) Anisocoria has been reported (Dax, 1946; Harenko, 1967a).
    B) Nystagmus is usually horizontal but may also be vertical (Harenko, 1967a; Isbell, 1972; Boyles & Martin, 1967).
    1) Ocular bobbing was described in a 44-year-old man with acute bromide intoxication (Paty & Sherr, 1972).
    2) INCIDENCE: Nystagmus is common with chronic intoxication, occurring in 35% of patients in some series (Harenko, 1967a).
    C) Diplopia, defective convergence and difficulty fixing the gaze are less common (Harenko, 1967a).
    D) Permanently decreased vision is an unusual complication of chronic poisoning (Harenko, 1967a; Kunze, 1976).
    E) Chronic exposure may result in blepharitis and conjunctivitis (Grant & Schuman, 1993).
    F) RETROBULBAR NEURITIS: Visual disturbances thought to be due to retrobulbar neuritis have been reported during chronic carbromal abuse (Grant & Schuman, 1993). Effects include visual reduction, scotoma, and pallor of the optic nerve.
    3.4.4) EARS
    A) HEARING LOSS: Hearing impairment, which may be permanent, is an uncommon effect of chronic or acute intoxication (Harenko, 1967; Mizukami et al, 1988).
    3.4.6) THROAT
    A) TONGUE: In patients with chronic bromism the tongue may have a furred or coated appearance (Blaylock, 1973; Nuki et al, 1966; Sensenbach, 1944) .
    B) DYSPHAGIA: Moderate oropharyngeal dysphagia, confirmed by a video fluoroscopic swallowing study (VFSS), was reported in a 73-year-old man with chronic bromism from ingesting bromvalerylurea (up to 3 g/day for 6 months). He was also experiencing dysarthria, psychosis with visual and auditory hallucinations, and cerebellar ataxia. Serum and urine bromide levels were 12.69 +/-0.24 mmol/L and 5.69 +/- 0.08 mmol/L, respectively. The patient's symptoms gradually resolved following forced diuresis with intravenous saline and intermittent boluses of furosemide. His serum bromide levels normalized and a repeat VFSS, 4 weeks later, indicated mild dysphagia (Yu et al, 2004).

Cardiovascular

    3.5.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Tachycardia and hypotension have occurred with acute intoxication.
    3.5.2) CLINICAL EFFECTS
    A) TACHYARRHYTHMIA
    1) WITH POISONING/EXPOSURE
    a) Tachycardia has occurred with acute and chronic bromide intoxication (Trump & Hochberg, 1976) van Essen et al, 1980; (Perkins, 1950).
    B) HYPOTENSIVE EPISODE
    1) WITH POISONING/EXPOSURE
    a) Hypotension has occasionally been reported with acute overdose of bromisoval, carbromal, brocarbamide, and sodium and potassium bromide (Schwabe, 1977; Maes et al, 1985; Mizukami et al, 1988).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) ACUTE LUNG INJURY
    1) ARDS may develop in patients with severe intoxication (Maes et al, 1985; Schwabe, 1977).
    B) BRONCHOSPASM
    1) Reactive airways dysfunction has been reported following inhalation of bromine and hydrobromic acid used as water disinfectants in a hot tub (Burns & Linden, 1997).

Neurologic

    3.7.1) SUMMARY
    A) Acute intoxication can result in CNS depression and coma.
    B) Chronic effects may include behavioral changes, irritability, confusion, muscular weakness, anorexia, ataxia, lethargy, abnormal reflexes, and slurred speech.
    3.7.2) CLINICAL EFFECTS
    A) CENTRAL NERVOUS SYSTEM DEFICIT
    1) WITH POISONING/EXPOSURE
    a) CNS depression is common after acute or chronic ingestion. Reported effects range from drowsiness to stupor to severe coma (Graham et al, 1968; Stewart, 1973; Sensenbach, 1944; Perkins, 1950; Maes et al, 1985; Ishiguro et al, 1982). Somnolence with increasing confusion has been reported following bromide poisoning (Taylor et al, 2010; Hung, 2003; Heckerling & Ammar, 1996; James et al, 1997).
    b) INCIDENCE: CNS depression occurred in 30% to 50% of cases with chronic intoxication in some series (Sensenbach, 1944; Perkins, 1950).
    c) CASE REPORT: A 23-year-old woman presented with drowsiness and myoclonic jerks in all extremities after ingesting 45 bromvalerylurea tablets (100 mg per tablet). Her serum bromide concentration was 81 mg/L (reference less than 10 mg/L). Following treatment with intravenous normal saline and furosemide, her symptoms resolved the next day (Lin et al, 2008).
    B) CEREBELLAR DISORDER
    1) SPEECH DISORDER
    a) Slurred speech is common with chronic toxicity (Taylor et al, 2010; Roy, 1975; Carney, 1971; Harenko, 1967a; Sensenbach, 1944; MacKay, 1969; Battin & Varkey, 1982; Blaylock, 1973; Morgan & Weaver, 1969; Stern, 1966; James et al, 1997). In some patients dysarthria is so severe that speech is incomprehensible(Harenko, 1967a). The pitch of the voice has been reported to increase (James et al, 1997).
    b) INCIDENCE: Slurred speech occurred in up to 79% of patients in some series (Harenko, 1967a; Sensenbach, 1944).
    2) ATAXIA
    a) Ataxia is common in chronic intoxication (Kuo et al, 2012; Yu et al, 2004; Perkins, 1950; Stewart, 1973; Wilkinson et al, 1969; Sensenbach, 1944; Carney, 1971; Battin & Varkey, 1982). Ataxia may be so severe that patients are unable to walk unaided without falling (Harenko, 1967a; Kunze, 1976).
    b) INCIDENCE: Ataxia occurred in 12% to 75% of patients in some series (Perkins, 1950; Stewart, 1973; Wilkinson et al, 1969; Sensenbach, 1944; Carney, 1971; Battin & Varkey, 1982).
    3) NYSTAGMUS
    a) Nystagmus is common in chronic overdose, occurring in 7% to 35% of patients in some series (Harenko, 1967a; Perkins, 1950). Nystagmus is usually horizontal but may also be vertical (Harenko, 1967a; Isbell, 1972; Boyles & Martin, 1967).
    4) IRREVERSIBLE CEREBELLO-BULBAR SYNDROME: A persistent cerebello-bulbar syndrome has been described following chronic bromisovalum intoxication. Effects include ataxia, dysarthria, tremor and hyperreflexia (Harenko, 1967b; van Balkom et al, 1985). Cerebellar atrophy may be evident on CT (van Balkom et al, 1985).
    C) TREMOR
    1) Tremor is common in patients with chronic bromide toxicity, occurring in 30% to 75% in some series (Perkins, 1950; Harenko, 1967a).
    D) HYPERREFLEXIA
    1) Deep tendon reflexes may be hyperactive or depressed in patients with chronic toxicity (Trump & Hochberg, 1976; Nuki et al, 1966; Perkins, 1950; Harenko, 1967). Reflexes may be asymmetrical or may change from day to day (Blaylock, 1973; Carney, 1971; Perkins, 1950; Harenko, 1967a; Trump & Hochberg, 1976).
    2) Babinski reflex may be positive (Isbell, 1972; Carney, 1971; Battin & Varkey, 1982; Blaylock, 1973). Clonus may develop (Palatucci, 1978).
    E) PSYCHOTIC DISORDER
    1) A toxic psychosis from chronic bromide poisoning has been well described. Patients may be agitated, delusional, disoriented, confused, paranoid, aggressive, or depressed (Hafiji et al, 2008; McDanal et al, 1974)(Abrams & Taylor, 1978; (Kunze, 1976; Fisher & Akhtar, 1970; Fried & Malek-Ahmadi, 1975; Raskind et al, 1978; Sayed, 1976; Stern, 1966; Vasuvattakul et al, 1995).
    2) HALLUCINATIONS: Auditory, visual or olfactory hallucinations may develop (Fried & Malek-Ahmadi, 1975; Fisher & Akhtar, 1970; Kunze, 1976).
    3) INCIDENCE: In one series some degree of psychiatric disturbance developed in 42 of 66 (64%) patients with chronic bromisovalum intoxication (Harenko, 1968).
    4) CASE REPORT: Psychosis with visual and auditory hallucinations and persecutory delusions were reported in a 73-year-old man with chronic bromism from ingesting bromvalerylurea (up to 3 g/day for 6 months). Serum and urine bromide levels were 12.69 +/- 0.24 mmol/L and 5.69 +/-0.08 mmol/L, respectively. The patient's psychosis gradually resolved and serum bromide levels normalized following administration of intravenous saline and intermittent boluses of furosemide (Yu et al, 2004).
    5) CASE REPORT: Long-term psychosis (persecutory delusion, psychomotor agitation and confusion) occurred in a 61-year-old man with a chronic history of pain who had been taken increasing doses of bromvalerylurea over a 3 month period (estimated dose 3g/day). Although a causal relationship cannot be determined, there is a temporal association with bromvalerylurea abuse and acute psychotic symptoms. Psychotic symptoms improved over a 2 week period with discontinuation of bromvalerylurea; however, the patient was lost to follow-up (Kuo et al, 2012).
    F) MYOCLONIA
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 23-year-old woman presented with drowsiness and myoclonic jerks in all extremities after ingesting 45 bromvalerylurea tablets (100 mg per tablet). Her serum bromide concentration was 81 mg/L (reference less than 10 mg/L). Following treatment with intravenous normal saline and furosemide, her symptoms resolved the next day (Lin et al, 2008).
    G) FATIGUE
    1) Weakness is common with chronic poisoning and may occasionally be severe (Wilkinson et al, 1969; Nuki et al, 1966; Trump & Hochberg, 1976). Rarely, weakness may be unilateral (Isbell, 1972; Perkins, 1950).
    2) INCIDENCE: Weakness has been reported in 12% to 26% of cases in some series (Perkins, 1950; Sensenbach, 1944).
    H) CEREBROSPINAL FLUID: PROTEIN - INCREASED +
    1) Elevation in CSF protein is common (Stern, 1966; Paty & Sherr, 1972; Palatucci, 1978). CSF protein elevation was found in 25% to 40% of bromide intoxications in some series (Thronton, 1977; Perkins, 1950). The clinical significance of this is unknown.
    I) MENINGEAL IRRITATION
    1) Neck stiffness, and positive Kernig and Brudzinski signs suggesting meningitis have occasionally been reported in chronic intoxication (Perkins, 1950)
    J) SEIZURE
    1) MYOCLONUS may develop in patients with severe chronic poisoning (Harenko, 1967)
    K) NEUROPATHY
    1) CRANIAL NERVE FINDINGS: Pupils may be normal, miotic, or mydriatic and may be sluggishly reactive to light (Hanes & Yates, 1938; Harenko, 1967a). Anisocoria has been reported (Dax, 1946; Harenko, 1967a).
    2) Diplopia, defective convergence and difficulty fixing the gaze are less common (Harenko, 1967a).
    3) Permanently decreased vision is an unusual complication of chronic poisoning (Harenko, 1967a; Kunze, 1976). Visual disturbances though to be due to retrobulbar neuritis has been reported during chronic carbromal abuse (Grant, 1993). Effects include visual reduction, scotoma and pallor of the optic nerve.
    4) Ptosis and a diminished gag reflex are rare findings (Blaylock, 1973).
    5) Hearing impairment, which may be permanent, is an uncommon effect of chronic or acute intoxication (Mizukami et al, 1988).
    L) HEADACHE
    1) Headache was reported in 9 of 40 patients in one series (Sensenbach, 1944).
    M) ELECTROENCEPHALOGRAM ABNORMAL
    1) EEG changes have developed following chronic bromide poisonings(Harenko & Huhmar, 1967). In pure bromide poisoning, paroxysmal and focal disturbance probably did not occur. With a serum bromide level of 260 mg/100 mL, delta waves as slow as 1 c.p.s. occurred. A significant EEG change was a generalized, diffuse slowing of the background activity.
    N) IMPAIRED COGNITION
    1) WITH THERAPEUTIC USE
    a) CASE REPORT/CHRONIC USE: A 25-year-old woman experienced mental status changes, including short-term memory loss, and unstable gait following long-term therapy (1 ampule every 2 weeks for 2 years, then 1 ampule every 2 days for 2 weeks) with an injectable analgesic for treatment of headaches and neck pain. Each 20 mL ampule contained sodium bromide 800 mg, sulpyrin 400 mg, sodium salicylate 400 mg, caffeine and sodium benzoate 100 mg, and glucose 2 mg. The patient's Mini-Mental Status Examination score was 22/30 (normal >/= 25/30), and she exhibited a widened stance deviating to each side. Impairment of tandem gait, finger-to-nose, and heel-to-knee tests were also observed, but deep tendon reflexes appeared to be normal. Laboratory analyses revealed hyperchloremia (171 mEq/L) with a negative anion gap (-48.7 mEq/L), and a serum bromide concentration of 2150 mg/L, indicating bromism. Following saline administration, the patient's serum chloride rapidly decreased to 110 mEq/L within the first day, with complete recovery within 3 days (Hsieh et al, 2007).
    3.7.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) MUSCLE WEAKNESS
    a) Bromide toxicosis in an epileptic dog due to renal insufficiency resulted in hind limb weakness, posterior paresis, ataxia and mild hypotonia. His medications consisted of phenobarbital and potassium bromide (29 mg/kg PO daily). Saline diuresis resulted in a decrease of serum bromide levels from 3,120 to 1,980 mg/liter (Nichols et al, 1996).

Gastrointestinal

    3.8.1) SUMMARY
    A) Nausea and vomiting occur following acute or chronic ingestion. Anorexia and weight loss may occur with chronic intoxication.
    3.8.2) CLINICAL EFFECTS
    A) VOMITING
    1) Nausea and vomiting frequently occur with acute ingestion. High concentrations are very irritating to the stomach (Reynolds, 1991).
    2) Nausea, vomiting and abdominal pain may develop with chronic intoxication(Harenko, 1967a; Sensenbach, 1944).
    B) LOSS OF APPETITE
    1) Anorexia, weight loss and malnutrition may develop with prolonged abuse (Dax, 1946; Harenko, 1967a; Kunze, 1976).
    C) SERUM AMYLASE RAISED
    1) WITH POISONING/EXPOSURE
    a) Hyperamylasemia developed in one patient after acute ingestion of a product containing carbromal, phenobarbital and diphenhydramine (Maes et al, 1985).
    D) CONSTIPATION
    1) Bromides may be constipating (Nuki et al, 1966).
    E) BEZOAR
    1) Bromide tablets may form a gastric bezoar, resulting in prolonged drug absorption (Iberti et al, 1984).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) LIVER ENZYMES ABNORMAL
    1) Mild elevations in transaminase levels (ALT 400 IU/L, AST 365 IU/L, Alkaline Phosphatase 88 IU/L) developed in a pregnant woman with bromoderma (Parish & Polin, 1974).

Genitourinary

    3.10.1) SUMMARY
    A) Acute renal failure is rare. Incontinence may develop with chronic intoxication.
    3.10.2) CLINICAL EFFECTS
    A) ACUTE RENAL FAILURE SYNDROME
    1) WITH POISONING/EXPOSURE
    a) Acute renal failure developed in a 22-year-old woman who developed hypotension (systolic blood pressure 70 mmHg) after overdose with approximately 10 g of sodium and potassium bromides and 50 mg of biperiden hydrochloride (Mizukami et al, 1988).
    2) Papillary necrosis and renal failure developed in 2 patients following the use of a 20% potassium bromide solution as a radiocontrast agent for retrograde pyelography (Joyce et al, 1985).
    B) IMPOTENCE
    1) Impotence and loss of libido have been reported with chronic intoxication (Hanes & Yates, 1938; Wilkinson et al, 1969).
    C) URINARY INCONTINENCE
    1) Incontinence may develop in patients with significant CNS effects from chronic intoxication (Sensenbach, 1944; Nuki et al, 1966; Perkins, 1950).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) ANEMIA
    1) Anemia may develop with chronic intoxication (Harenko, 1967a).
    B) ESR RAISED
    1) The erythrocyte sedimentation rate is commonly elevated (Harenko, 1967a; Stern, 1966).

Dermatologic

    3.14.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Bromide toxicity is associated in about 25% of cases with the development of bromoderma, an erythematous, nodular or acneiform rash over the face and possibly the entire body. One case of toxic epidermal necrolysis has been reported.
    3.14.2) CLINICAL EFFECTS
    A) ERUPTION
    1) BROMODERMA: A bromide rash occurs in less than 25% of cases following chronic ingestion and does not correlate with severity of intoxication or serum bromide levels (Hanes & Yates, 1938; Sensenbach, 1944).
    a) CASE REPORT: A 3-year-old girl with severe epilepsy had been treated with potassium bromide 0.5 g/day which was increased to 0.8 g/day. Approximately 1 month after the dose was increased she presented with grain-size, dark red, erythematous papules and pustules on her face and back. Biopsy revealed a massive infiltration of eosinophils and neutrophils forming an abscess in the dermis and epidermis (bromoderma tuberosum). Serum bromide levels were 114 mEq/L (normal 0 to 5 mEq/L). Potassium bromide was discontinued and she was treated with topical silver sulfadiazine. The eruption disappeared within 10 days (Anzai et al, 2003).
    b) CASE REPORT: A 56-year-old woman with polycythemia vera treated with piprobroman presented with pruritic symmetrical erythematous papulonodular eruptions with erosions and pustules on her forehead, upper trunk, and limbs after taking pipobroman, 75 mg daily, for several months. The patient was also exhibiting bizarre behavior initially diagnosed as psychotic depression. Laboratory analysis indicated a serum bromide concentration of 48.8 mg/L (upper limit of normal is less than 10 mg/L). Within 8 weeks after discontinuing pipobroman therapy and administration of fluids and topical corticosteroids, The skin eruption resolved and the patient's mental status returned to normal. Repeat lab analysis revealed a serum bromide concentration of 16.8 mg/L (Hafiji et al, 2008).
    B) ACNE
    1) The most commonly described rash is an acneiform eruption which may involve the face and trunk (Trump & Hochberg, 1976; Davis, 1978).
    2) CASE REPORT: A 30-year-old woman developed marked lethargy, mental confusion, fever, acneiform eruption on the face, hyperchloremia and a negative anion gap after taking a bromvalerylurea-containing nonprescription analgesic drug (200 mg/tablet) and dextromethorphan hydrobromide (20 mg/tablet) for several months. A serum bromide level of 19.7 mEq/L (normal range: 0.6 to 1.2 mEq/L) was reported (Hung, 2003).
    C) BULLOUS ERUPTION
    1) An erythematous bullous eruption may develop on the extremities (Trump & Hochberg, 1976).
    D) PUSTULE
    1) BROMODERMA TUBEROSUM: Pustular, vegetating, fungoid lesions may develop on the face or extremities with chronic use (Smith & Scheen, 1978) (Ziai et al 1967)(Hubner et al, 1976; Cordolini et al, 1991).
    2) In one patient, lesions had elevated bromide concentrations compared with areas of unaffected skin (Hubner et al, 1976)
    E) SKIN ULCER
    1) PYODERMA GANGRENOSUM: Purulent ulcerative lesions resembling pyoderma gangrenosum may develop with chronic bromide use (Smith & Scheen, 1978; Millns & Rogers, 1978; David et al, 1983).
    F) ERYTHEMA MULTIFORME
    1) An erythema multiforme like rash may develop with bromide use (Baer & Harris, 1967).
    G) LYELL'S TOXIC EPIDERMAL NECROLYSIS, SUBEPIDERMAL TYPE
    1) One case of toxic epidermal necrolysis has been reported in the literature. A 40-year-old man developed generalized erythematous lesions and erosions covering the trunk and extremities. Approximately 40% of the body surface was involved. The epithelization of the denuded area was complete within 2 weeks of discontinuing bromide ingestion and beginning intravenous betamethasone (Miyauchi, 1991).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) PAIN
    1) Patients with chronic poisoning may complain of severe musculoskeletal pain (Perkins, 1950).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) FINDING OF THYROID FUNCTION
    1) WITH POISONING/EXPOSURE
    a) Studies of bromide effects on human thyroid function have been inconclusive (Sangster et al, 1982; van Leeuwen & Sangster, 1987).
    b) Hyperthyroidism developed in a 22-year-old woman 13 days after overdose with approximately 10 g of sodium and potassium bromides and 50 mg of biperiden hydrochloride (Mizukami et al, 1988). After 30 days of treatment with mercazole, severe hypothyroidism developed.
    B) HYPERGLYCEMIA
    1) WITH POISONING/EXPOSURE
    a) Hyperamylasemia and hyperglycemia developed in one patient after acute ingestion of a product containing carbromal, phenobarbital and diphenhydramine (Maes et al, 1985).
    3.16.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) HYPOTHYROIDISM
    a) Bromide-induced hypothyroidism characterized by an increase in thyroid gland size and a decrease in serum thyroxine (T4) occurred in rats with bromide concentrations of 8 mmol/L and higher (van Leeuwen & Sangster, 1987).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) DISORDER OF IMMUNE FUNCTION
    1) MONOCLONAL GAMMOPATHY: A monoclonal gammopathy (IgG-kappa) was reported in a patient with bromoderma (Cordolini et al, 1991).

Reproductive

    3.20.1) SUMMARY
    A) Bromides cross the placenta and may be detected in the milk of nursing mothers. Case reports suggest that prenatal exposure may cause growth retardation, craniofacial abnormalities and developmental delay.
    3.20.2) TERATOGENICITY
    A) HYPOTONIA
    1) There is a single case report of a chronically exposed fetus who was born with hypotonia, macrocephaly, hypertelorism, and clinodactyly. The hypotonia was transient (Mangurten & Kaye, 1982).
    B) GROWTH RETARDED
    1) Two children born to a woman who ingested large amounts of bromides throughout both pregnancies had heights and head circumferences below the 5th percentile and a two year lag in bone ages when they were 7 and 8 years old (Opitz et al, 1972). Both children were of normal intelligence but the younger had enamel hypoplasia and malocclusion, and manifestations of congenital heart disease. Another sibling born after the mother stopped using bromides was normal.
    2) An infant born to a mother who ingested large amounts of bromides throughout her pregnancy was initially irritable with high pitched crying and difficulty feeding (Rossiter & Rendle-Short, 1972). At 2.5 years of age she was below the 10th percentile in height, weight and head circumference, with brisk reflexes and developmental delay.
    3.20.3) EFFECTS IN PREGNANCY
    A) PLACENTAL BARRIER
    1) Bromide crosses the placental barrier and may accumulate in the fetus (Pleasure & Blackburn, 1975; Finken & Robertson, 1963).
    2) A 27-year-old woman who was 34 weeks pregnant was admitted in a semicomatose state due to chronic bromism. The neonate, born five days after the mother's admission, demonstrated CNS depression, an elevated serum bromide level, marked hypoactivity, reduced cry and suck reflex, and hypotonia (Pleasure & Blackburn, 1975).
    a) The infant's bromide level was higher than a simultaneous maternal level (Pleasure & Blackburn, 1975).
    3) A neonate with transplacental bromism and a bromide level of 365 mg/dL (maternal level: 320 mg/dL) developed sedation, dilated pupils, depressed reflexes and decreased motor activity which resolved gradually (Finken & Robertson, 1963).
    4) Bromoderma was described in a neonate with a blood bromide level of 132 mg/dL. The mother, having ingested sodium bromide for the last 3 to 4 months of pregnancy, had a bromide level of 114 mg/dL; the levels of the mother and the neonate were done 4 days postpartum. The rash resolved by 8 days of age (Forster & Travis, 1951).
    5) An infant born to a woman who had used dextroamphetamine, chlorpromazine and ammonium and potassium bromide (6 grams/day) during her pregnancy was lethargic, with depressed reflexes and poor feeding (Mangurten & Ban, 1974). Five days after birth the infant's serum bromide level was 200 mg/dl and the mother's was 310 mg/dl. The child recovered completely.
    B) PREGNANCY CATEGORY
    BROMIDESD
    Reference: Briggs et al, 1998
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) Maternal ingestion of 5 grams/day has resulted in up to 66 mg/L in breast milk (Knowles, 1965).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor serum electrolytes, renal function, and fluid status carefully. Spuriously elevated chloride level and low anion gap are characteristic of bromism due to laboratory interference by the bromide ion.
    B) Serum bromide concentrations should be monitored in patients with significant CNS effects.
    C) Consider abdominal x-ray as bromide is radiopaque. Abdominal x-ray may be helpful in confirming diagnosis of acute ingestion.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Obtain serum electrolytes and bromide level. Spurious hyperchloremia may be caused by bromide interference when certain assays are used. Suspect bromism diagnosis in the presence of factitious hyperchloremia and a low to negative anion gap (Hsieh et al, 2007; James et al, 1997).
    B) LABORATORY INTERFERENCE
    1) The presence of bromide ion in serum interferes with commonly used methods of chloride determination and may result in falsely elevated chloride levels (Repplinger et al, 2015; Pressac et al, 1987; Ricci et al, 1982). Chloride determinations are generally done with indirect methods which do not distinguish between chloride and bromide ions (James et al, 1997). For specific methods, see method section.
    2) Bromide has also been shown to interfere with CO2 measurement on the Ektachem 700 analyzer (Komaiko et al, 1988).
    4.1.3) URINE
    A) OTHER
    1) Monitor urine output.

Radiographic Studies

    A) ABDOMINAL RADIOGRAPH
    1) Bromides are often radiopaque. Abdominal x-ray may be helpful in confirming diagnosis of acute ingestion (Maes et al, 1985) and detecting bezoar formation.

Methods

    A) MULTIPLE ANALYTICAL METHODS
    1) The presence of bromide ion in serum interferes with commonly used methods of chloride determination and may result in falsely elevated chloride levels (Pressac et al, 1987; Ricci et al, 1982).
    a) Bromide produces marked elevations in chloride measured by ion-selective electrode methods (PVA-4, Stat/Ion) or colorimetric mercuric thiocyanate methods (Autoanalyzer, RA 1000, SMAC) (Wenk et al, 1976; Baker et al, 1980; Elin et al, 1981; Pressac et al, 1987; Kan et al, 1986; Ng et al, 1992).
    b) Titration methods such as the coulometric system (ATSRA 8; chloride/carbon dioxide analyzer, CMT 10 chloride titrator) produce much less interference (Elin et al, 1981; Kan et al, 1986; Ng et al, 1992).
    c) CASE REPORT: Pseudo-hyperchloremia was reported in an 8-month-old boy who was receiving sodium bromide, 185 mg orally twice daily (total daily dose 71.2 mg/kg) for refractory seizures. His initial laboratory studies, analyzed via a Siemens Dimension Vista 1500, reported a chloride level of 179 mEq/L and an anion gap of negative 56. The results of a serum bromide concentration was unable to be obtained. The patient was administered sodium chloride and was discharged to home, following a neurology consult, with the same dose of sodium bromide because other anticonvulsants could not provide adequate seizure control. It is suspected that the reported elevated chloride level was a result of laboratory interference (Repplinger et al, 2015).
    2) Bromide was found to interfere with serum CO2 determination using a Kodak Ektachem 700 analyzer (Komaiko et al, 1988).
    3) Emancipator and Kroll (1990) propose a method to estimate serum bromide levels by comparing the differences in the amount of interference between two methods of measuring chloride.
    4) HPLC methods have been described for determining concentrations of bromisoval, carbromal, bromural, acecarbromal, bromisovalerylurea, and metabolites in biologic samples (Eichelbais et al, 1978) (Okamoto & Yamada, 1981)(Hobel & Bender, 1977; Miyauchi, 1991; Venizelos et al, 1992).
    5) A GLC method for determining concentrations of bromovalerylurea in plasma has been described (Kokatsu et al, 1992).
    6) A fluorescence test for detecting bromide in saliva has been described (Gaff et al, 1969).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) All patients who are persistently symptomatic should be admitted.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Patients with inadvertent ingestions who are asymptomatic can be managed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a medical toxicologist or poison center for patients with significant toxicity or in whom the diagnosis is unclear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with deliberate overdose and symptomatic patients should be observed in a medical facility until free of symptoms.

Monitoring

    A) Monitor serum electrolytes, renal function, and fluid status carefully. Spuriously elevated chloride level and low anion gap are characteristic of bromism due to laboratory interference by the bromide ion.
    B) Serum bromide concentrations should be monitored in patients with significant CNS effects.
    C) Consider abdominal x-ray as bromide is radiopaque. Abdominal x-ray may be helpful in confirming diagnosis of acute ingestion.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) SUMMARY
    1) Toxicity generally occurs with chronic ingestion. Gastric decontamination is only necessary after large ingestions in patients who are alert and can protect the airway.
    B) ACTIVATED CHARCOAL
    1) 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).
    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).
    6.5.2) PREVENTION OF ABSORPTION
    A) SUMMARY
    1) Toxicity generally occurs after chronic exposure and decontamination is often not necessary. Consider decontamination after recent large ingestions in patients who are alert and can protect the airway.
    B) 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).
    C) BEZOARS
    1) Bezoars may form due to intestinal bromides and are often radiopaque. Ongoing absorption may be occurring with visible tablets on abdominal radiograph. If clinical evidence suggests bromide bezoar, consider endoscopic removal or whole bowel irrigation.
    a) WHOLE BOWEL IRRIGATION/INDICATIONS: Whole bowel irrigation with a polyethylene glycol balanced electrolyte solution appears to be a safe means of gastrointestinal decontamination. It is particularly useful when sustained release or enteric coated formulations, substances not adsorbed by activated charcoal, or substances known to form concretions or bezoars are involved in the overdose.
    1) Volunteer studies have shown significant decreases in the bioavailability of ingested drugs after whole bowel irrigation (Tenenbein et al, 1987; Kirshenbaum et al, 1989; Smith et al, 1991). There are no controlled clinical trials evaluating the efficacy of whole bowel irrigation in overdose.
    b) CONTRAINDICATIONS: This procedure should not be used in patients who are currently or are at risk for rapidly becoming obtunded, comatose, or seizing until the airway is secured by endotracheal intubation. Whole bowel irrigation should not be used in patients with bowel obstruction, bowel perforation, megacolon, ileus, uncontrolled vomiting, significant gastrointestinal bleeding, hemodynamic instability or inability to protect the airway (Tenenbein et al, 1987).
    c) ADMINISTRATION: Polyethylene glycol balanced electrolyte solution (e.g. Colyte(R), Golytely(R)) is taken orally or by nasogastric tube. The patient should be seated and/or the head of the bed elevated to at least a 45 degree angle (Tenenbein et al, 1987). Optimum dose not established. ADULT: 2 liters initially followed by 1.5 to 2 liters per hour. CHILDREN 6 to 12 years: 1000 milliliters/hour. CHILDREN 9 months to 6 years: 500 milliliters/hour. Continue until rectal effluent is clear and there is no radiographic evidence of toxin in the gastrointestinal tract.
    d) ADVERSE EFFECTS: Include nausea, vomiting, abdominal cramping, and bloating. Fluid and electrolyte status should be monitored, although severe fluid and electrolyte abnormalities have not been reported, minor electrolyte abnormalities may develop. Prolonged periods of irrigation may produce a mild metabolic acidosis. Patients with compromised airway protection are at risk for aspiration.
    6.5.3) TREATMENT
    A) MONITORING OF PATIENT
    1) Monitor serum electrolytes, renal function, and fluid status carefully. Spuriously elevated chloride level and low anion gap are characteristic of bromism due to laboratory interference by the bromide ion.
    2) Serum bromide concentrations should be monitored in patients with significant CNS effects.
    3) Consider abdominal x-ray as bromide is radiopaque. Abdominal x-ray may be helpful in confirming diagnosis of acute ingestion.
    B) FLUID/ELECTROLYTE BALANCE REGULATION
    1) Infusion of 0.9% sodium chloride enhances urinary bromide excretion. Give an initial bolus of 10 to 20 mL/kg as clinically indicated, followed by an infusion two to three times the maintenance fluid rate. Discontinue infusion when symptoms have improved and the serum bromide level is less than 100 to 150 mg/dL.
    2) Intravenous administration of NaCl is more effective than oral chloride in increasing urinary bromide excretion (Hussar & Holley, 1956).
    C) DIURESIS
    1) Diuretics such as furosemide, ethacrynic acid, thiazides, or mannitol may be administered, in addition to intravenous chloride, to obtain a urine flow of 3 to 6 mL/kg/hour. Administration may increase bromide clearance.
    a) Furosemide 10 mg intravenously every 6 to 12 hours increases urinary bromide excretion beyond what is achieved with the administration of 0.9% sodium chloride alone. It is unknown whether diuresis improves clinical outcome, and dehydration is a potential complication if the fluid status is not carefully monitored.
    b) Monitor fluids and electrolytes closely as hypernatremia may occur.

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).

Enhanced Elimination

    A) DIURESIS
    1) The addition of diuretics such as furosemide (Millns & Rogers, 1978), ethacrynic acid (Adamson et al, 1966; Schmitt et al, 1966; Seliskar et al, 1966), thiazides (Wooster et al, 1967) and mannitol (Adamson et al, 1966) to intravenous chloride therapy has been shown to increase urinary bromide excretion.
    2) In a dog model of chronic bromide poisoning bromide clearance was 1.65 milliliters/minute in dogs treated with 0.9% NaCl infusion compared with 16 milliliters/minute in dogs treated with ethacrynic acid and 4.0 milliliters/minute in those treated with mannitol (Schmitt et al, 1966).
    B) HEMODIALYSIS
    1) Hemodialysis may greatly increase bromide clearance, and is indicated in patients with underlying renal insufficiency and when attempts at intravenous chloride administration have been unsuccessful or are contraindicated.
    2) Hemodialysis may be of value in severe cases when other treatment cannot be used. Hemodialysis has reduced the bromide half-life to 1 to 2 hours (Wieth & Funder, 1963; Schreiner, 1958).
    3) Hemodialysis increased bromide clearance from a baseline of 0.4 milliliters/minute to 99 milliliters/minute in a patient with chronic bromide intoxication (Schmitt et al, 1966).
    C) PERITONEAL DIALYSIS
    1) Peritoneal dialysis increased bromide clearance from a baseline of 0.4 milliliters/minute to 13.7 milliliters/minute in a patient with chronic bromide intoxication (Schmitt et al, 1966). This was comparable to the clearance obtained with 0.9% NaCl infusion and ethacrynic acid in the same patient.

Range Of Toxicity

Summary

    A) TOXICITY: There is great interpatient variability in symptoms at a given serum bromide concentration. Most toxicity develops after chronic ingestion. Serum bromide concentrations of 50 to 100 mg/dL may be associated with symptoms; 200 mg/dL will produce toxic symptoms; 300 mg/dL may be fatal. Acute ingestion of 4500 mg bromovalerylurea caused lethargy and myoclonus in an adult. Chronic consumption of 0.5 to 1 g bromides/day may cause bromism.
    B) THERAPEUTIC DOSE: Adults: Acceptable daily intake: 1 mg/kg.

Therapeutic Dose

    7.2.1) ADULT
    A) GENERAL
    1) Acceptable daily intake is 1 milligram/kilogram (van Gelderen et al, 1993).

Minimum Lethal Exposure

    A) SPECIFIC SUBSTANCE
    1) SODIUM BROMIDE
    a) Ingestion of 100 grams of sodium bromide in 36 hours was reported fatal in one adult patient (Sollmann, 1957).
    2) CARBROMAL
    a) Deaths have occurred in adults after ingestion of 10 grams (Baselt & Cravey, 1989).

Maximum Tolerated Exposure

    A) PEDIATRIC
    1) Based on a volume of distribution of 3.1 liters, a two-year-old child would reach a possibly toxic bromide level (72 milligrams/deciliter) following ingestion of 5.5 milliequivalents/day for 6 days (Torosian et al, 1973).
    B) ADULT
    1) In adult volunteers, chronic ingestion of 4 milligrams/kilogram/day of sodium bromide was considered a no observed effect level (van Gelderen et al, 1993).
    2) Chronic consumption of 0.5 to 1 g bromides/day may cause bromism (Dempsey, 2007).
    3) A 110 pound adult with a volume of distribution of 12 liters ingesting 16.5 milliequivalents/day would reach a possibly toxic serum bromide level of 72 milligrams/deciliter after 8 days and a definitely toxic level of 152 milligrams/deciliter after 25 days (Torosian et al, 1973).
    4) Increasing the daily dose of pyridostigmine bromide from 640 to 1380 milligrams for 2 days in a 59-year-old woman with myasthenia gravis resulted in a negative anion gap and an elevated bromide concentration of 5 millimoles/liter (Rothenberg et al, 1990).
    5) CASE REPORT: A 23-year-old woman presented with drowsiness and myoclonic jerks in all extremities after ingesting 45 bromovalerylurea tablet (100 mg per tablet). Her serum bromide concentration was 81 mg/L (reference range less than 10 mg/L). Following treatment with intravenous normal saline and furosemide, her symptoms resolved the next day (Lin et al, 2008).
    6) CASE REPORT: A 30-year-old woman developed marked lethargy, mental confusion, fever (38 degrees C), acneiform eruption on the face, hyperchloremia (serum chloride 171 mEq/L) and a negative anion gap (-53 mEq/L) after taking a bromovalerylurea-containing non-prescription analgesic drug (200 mg/tablet) and dextromethorphan hydrobromide (20 mg/tablet) for several months. A serum bromide level of 19.7 mEq/L (normal range: 0.6 to 1.2 mEq/L) was reported (Hung, 2003).

Serum Plasma Blood Concentrations

    7.5.1) THERAPEUTIC CONCENTRATIONS
    A) THERAPEUTIC CONCENTRATION LEVELS
    1) GENERAL
    a) Most "normal" bromide levels are in the range of 3 to 4 mg/L, but concentrations as high as 10 mg/L may result from normal dietary ingestion (Toseland, 1991).
    2) DISEASE STATE
    a) ANTICONVULSANT
    1) In years past, many epileptic patients have been treated with bromides with no evidence of deleterious effects as long as blood levels remained less than 60 to 80 mg/100 mL: the usual goal is serum levels less than 50 mg/100 mL (Woodbury et al, 1972).
    2) Recommended adult therapeutic ranges have been reported to range from 80 to 160 mg/dL to as high as 200 mg/dL (James et al, 1997).
    3) Levels in some epileptic patients taking bromides have reached 500 mg/L without an apparent clinical effect (Toseland, 1991).
    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) CONCENTRATION LEVEL
    a) A relationship between toxicity and serum bromide concentration exists. Levels of 50 to 100 mg/dL may be associated with symptoms (Hanes & Yates, 1938; Harenko, 1967); 200 mg/dL will produce toxic symptoms; 300 mg/dL may be fatal. Factors such as reduced salt intake, dehydration, diarrhea, vomiting, and renal failure may enhance bromide toxicity (James et al, 1997).
    b) A toxic concentration can be reached very rapidly if the intake of chloride is reduced (Woodbury et al, 1972).
    c) Serum concentration of 390.7 mg/dL was reported in a 17-year-old girl following chronic use (6 years) of triple bromide elixir for treatment of epilepsy. She was experiencing symptoms of bromism (James et al, 1997).
    d) In a series of 400 chronic bromide intoxication cases, 44% had blood bromide levels of 50 to 100 mg/dL (Hanes & Yates, 1938).
    e) Elevated serum bromide concentration may result from repetitive, short halothane exposures (Morrison & Friesen, 1990).
    f) A serum bromide level of 14.5 millimoles/liter (116 mg/dL) was reported in an 82-year-old female with resultant spurious hyperchloremia and a negative anion gap following chronic ingestion of high dose propantheline bromide (Heckerling & Ammar, 1996).
    g) A serum bromide concentration of 81 mg/L (reference range less than 10 mg/L) was reported in a 23-year-old woman who presented with drowsiness and myoclonic jerks in all extremities after ingesting 45 bromovalerylurea tablets (100 mg per tablet). Following treatment with intravenous normal saline and furosemide, her symptoms resolved the next day (Lin et al, 2008).
    h) CASE REPORT: A 56-year-old woman with polycythemia vera developed bromoderma and mental status changes after taking pipobroman, 75 mg daily, for several months. Her initial serum bromide concentration was 48.8 mg/L (upper limit of normal is less than 10 mg/L). Discontinuation of pipobroman therapy and administration of fluids and topical corticosteroids resulted in resolution of her bromoderma and a normalization of her mental state. Repeat lab analysis revealed a decrease in her serum bromide concentration to 16.8 mg/L (Hafiji et al, 2008).
    i) CASE REPORT: The serum bromide concentration of 2150 mg/L was reported in a 25-year-old woman who was on long-term therapy (1 ampule every 2 weeks for 2 years, then 1 ampule every 2 days for 2 weeks) with an injectable analgesic containing 800 mg of sodium bromide per ampule (Hsieh et al, 2007).
    j) CASE REPORT: A 57-year-old man, with Asperger syndrome, developed diffuse pain, malaise, confusion, slurred speech, and hyperchloremia (greater than 175 mEq/L) after consuming 3 to 4 tablespoonfuls of Dead Sea salt daily for several months. His serum bromide concentration was 2540 mg/L. The Dead Sea reportedly has the highest bromide concentration (5 g/L) of any other large body of water in the world (Taylor et al, 2010).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Bromide ion is thought to be effective for treatment of seizures due to secondary anion potentiation of gamma-aminobutyric acid (GABA) channels in the CNS. GABA receptors are complexed with chloride channels. Available bromide ions, due to their smaller hydrated diameter, diffuse more readily through cellular channels, producing a hyperpolarized postsynaptic membrane, which potentiates the action of GABA, an inhibitory neurotransmitter (James et al, 1997).

Toxicologic Mechanism

    A) Taken over a relatively prolonged period of time, the bromide ion displaces chloride from plasma, extracellular fluid and, to some extent, from cells. It has been reported that as much as 45% of the body's chloride stores may be replaced with bromide following significant exposures (James et al, 1997). In bromide poisoning, the kidneys increase the elimination of chloride ions in an attempt to maintain a constant total halide concentration.
    B) While osmolar equilibrium persists, central nervous system function is progressively impaired, presumably through a membrane-stabilizing effect. A toxic concentration can be reached very rapidly when the intake of chloride is reduced.
    C) Bromide is a gastrointestinal irritant when large quantities are ingested. For this reason, most toxicity is due to chronic rather than acute exposures (James et al, 1997).

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