- 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. 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. 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. EPIDEMIOLOGY: Bromide poisoning is rare and, when it does occur, is generally secondary to chronic ingestion rather than acute overdose. TOXICITY: ACUTE: Bromide poisoning following acute ingestion is rare. Acute effects may include nausea, vomiting, gastric irritation, CNS depression, coma, hypotension, tachycardia, and respiratory distress. 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.
- USES: Used as a cough suppressant. It is often sold in combination preparations with acetaminophen, chlorpheniramine, doxylamine, diphenhydramine, and other medications. It lacks analgesic properties, but is prescribed in combination with morphine to enhance the analgesic effects of morphine. PHARMACOLOGY: Structurally similar to opioids, but has no analgesic properties. Acts centrally on the medulla oblongata to suppress cough. TOXICOLOGY: Binds to opioid receptors at high doses causing miosis, respiratory depression, and CNS depression. Binds to PCP site on NMDA receptors, causing sedation. Inhibits serotonin re-uptake. Alteration of dopaminergic transmission may be responsible for movement disorders. EPIDEMIOLOGY: Dextromethorphan is available over the counter. It is frequently abused, especially by adolescents, in an attempt to experience euphoria and/or hallucinations. “DXM”, “DEX”, and “roboshots” are commonly used street names. OVERDOSE: MILD TO MODERATE: CNS effects are most prevalent and include sedation, dysphoria, ataxia, nystagmus, hyperexcitability, dystonia, and changes in muscle reflexes. Other effects have included miosis, tachycardia, hypertension, and nausea and vomiting. SEVERE: Can cause toxic psychosis and delirium, seizures, coma, hypotension, and respiratory depression. May cause serotonin syndrome after overdose or therapeutic use if taken with other serotonergic agents. ADVERSE EVENTS: Adverse effects following recommended doses are mild and infrequent, but may include drowsiness, fatigue, dizziness, and fixed drug eruption.
Range of Toxicity:
- 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. THERAPEUTIC DOSE: Adults: Acceptable daily intake: 1 mg/kg.
- TOXICITY: In patients 6 years of age and older, mild toxicity was reported with acute ingestions in the range of 2.2 mg/kg to 7.7 mg/kg. More severe toxicity (ie, seizures, hallucinations, altered mental status, tachycardia, hypertension, hyperthermia, agitation, respiratory depression) was reported with acute dextromethorphan ingestions of 7.8 mg/kg or greater. In patients less than 6 years of age, moderate to severe toxicity (ie, nystagmus, mydriasis, ataxia, dizziness, dystonia, lethargy, and coma) was reported following acute dextromethorphan ingestions ranging from 5 to 38 mg/kg. CASE REPORTS: Coma was reported in an adult who ingested 720 mg over 36 hours. Long-acting preparations and combination products may have greater potential for toxicity in children. Adults have tolerated up to 960 mg/day with minor adverse effects (14 mg/kg assuming 70 kg body weight). THERAPEUTIC DOSE: ADULT: 20 mg orally every 4 hours or 30 mg orally every 6 to 8 hours; maximum: 120 mg/day. PEDIATRIC: Children (2 to 6 yrs): 5 mg orally every 4 hours or 7.5 mg orally every 6 to 8 hours; maximum: 30 mg/day. Children (6 to 12 yrs): 10 mg orally every 4 hours or 15 mg orally every 6 to 8 hours; maximum: 60 mg/day.
- Support: MANAGEMENT OF MILD TO MODERATE TOXICITY: Care is symptomatic and supportive. Administer IV 0.9% sodium chloride to increase bromide elimination. MANAGEMENT OF SEVERE TOXICITY: 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.
- Decontamination: 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.
- Airway management: Endotracheal intubation should be performed in patients with excessive drowsiness and the inability to protect their own airway.
- Antidote: None
- Fluid/electrolyte balance regulation: 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.
- Diuresis: 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.
- Monitoring of patient: 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. Serum bromide concentrations should be monitored in patients with significant CNS effects. Consider abdominal x-ray as bromide is radiopaque. Abdominal x-ray may be helpful in confirming diagnosis of acute ingestion.
- Enhanced elimination procedure: 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.
- Patient disposition: HOME CRITERIA: Patients with inadvertent ingestions who are asymptomatic can be managed at home. OBSERVATION CRITERIA: Patients with deliberate overdose and symptomatic patients should be observed in a medical facility until free of symptoms. ADMISSION CRITERIA: All patients who are persistently symptomatic should be admitted. CONSULT CRITERIA: Consult a medical toxicologist or poison center for patients with significant toxicity or in whom the diagnosis is unclear.
- Support: MANAGEMENT OF MILD TO MODERATE TOXICITY: Treatment is symptomatic and supportive. For mild/moderate asymptomatic hypertension (no end organ damage), pharmacologic treatment is generally not necessary. Control agitation and confusion with benzodiazepines. MANAGEMENT OF SEVERE TOXICITY: Treatment is symptomatic and supportive. Treat agitation with benzodiazepines. Treat seizures with IV benzodiazepines; barbiturates or propofol may be needed if seizures persist or recur. For severe hypertension, nitroprusside is preferred. Labetalol, nitroglycerin, and phentolamine are alternatives. Treat serotonin toxicity with benzodiazepines, and consider cyproheptadine, if symptoms persist. Severe cases may require neuromuscular paralysis. For respiratory and CNS depression, successful reversal with naloxone has been reported, but is not consistent. Orotracheal intubation may be necessary.
- Decontamination: PREHOSPITAL: Generally not indicated because of the risk of CNS depression and seizures. Emergency medical personnel can consider activated charcoal in the patient who is alert and cooperative with ingestion within the last hour and in whom a long transport time is anticipated. HOSPITAL: Consider activated charcoal if the patient presents soon after the ingestion and has a protected airway. Seizures and/or CNS depression have occurred within 30 minutes after dextromethorphan ingestion.
- Airway management: Ensure adequate ventilation and perform endotracheal intubation early in patients with significant CNS or respiratory depression.
- Antidote: There is no specific antidote.
- Serotonin syndrome: IV benzodiazepines, cooling measures. Cyproheptadine may be considered (ADULT – 12 mg initially followed by 2 mg every 2 hours if symptoms persist, up to a maximum of 32 milligrams in 24 hours. CHILD – 0.25 milligram/kilogram/day divided every 6 hours, maximum dose 12 milligrams/day). Severe cases have been managed with benzodiazepine sedation and neuromuscular paralysis with non-depolarizing agents.
- Monitoring of patient: Monitor for signs of respiratory depression. Monitor for signs of CNS hyperactivity or depression. Obtain an ECG. Consider obtaining acetaminophen concentrations, as these drugs may be sold in combination preparations. No other specific lab work (CBC, urinalysis, electrolyte) is needed unless otherwise indicated. Plasma dextromethorphan levels are not clinically useful in overdose, but may be useful in determining metabolizer phenotype.
- Enhanced elimination procedure: It is unknown if hemodialysis would be effective in overdose.
- Patient disposition: HOME CRITERIA: Patients who are asymptomatic (other than mild drowsiness or infrequent vomiting) with acute inadvertent ingestions of 7.5 mg/kg or less, and who have not ingested other potentially toxic substances, can be managed at home. Poison center telephone follow-up is suggested every 2 hours for up to 4 hours in patients ingesting 5 mg/kg to 7.5 mg/kg. For patients taking other medications that may interact with dextromethorphan (eg, tricyclic antidepressants, selective serotonin reuptake inhibitors, monoamine oxidase inhibitors, lithium) poison center-initiated follow-up every 2 hours for 8 hours is suggested. Observation at home is appropriate for asymptomatic patients if they are greater than 4 hours postexposure. OBSERVATION CRITERIA: Patients with deliberate overdose or abuse, patients exhibiting more than mild symptoms (eg, infrequent vomiting, mild drowsiness), or those who have ingested greater than 7.5 mg/kg should be sent to a healthcare facility for evaluation. Observe patients until severe CNS symptoms resolve. Tachycardia may be persistent and patients should be observed until tachycardia resolves. Patients ingesting regular release products should be observed 4 to 6 hours; those ingesting sustained release or long acting preparations should be observed 8 to 12 hours. ADMISSION CRITERIA: Patients with persistent CNS effects should be admitted. CONSULT CRITERIA: Consult a medical toxicologist for patients with severe toxicity or in whom the diagnosis is unclear. Refer patients for substance abuse counseling as appropriate.