This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). Neither the lethal dose nor the time required to kill someone are known with any confidence. Personality changes, hallucinations, and delusions are other examples of extreme cases.
- Eosinophils need bromide for fighting multicellular parasites.
- In a study by Trepanier et al. (27) addition of bromide made possible to discontinue barbiturate treatment (phenobarbital or primidone) in 19% of the dogs.
- Future prospective studies assessing bromide efficacy as monotherapy in epileptic dogs receiving a stable and uniform diet could help to better clarify its possible role as a possible first-line ASM and deepen our understanding of recommended serum therapeutic ranges.
- Bromide’s mechanism of action seems related to its preferential movement across neuronal chloride channels.
- Sodium bromide can be particularly useful in dogs with disease where administration of potassium might be undesirable (e.g., hypoadrenocorticism) but is contraindicated in case of hypertension, congestive heart failure or hepatic disease (28).
Dissociation of bromide salts
Bromide concentration in standard seawater (35 PSU) is about 65 mg/L, or around 0.2% of total dissolved salts. In contrast to the United States, where bromide has yet to be approved for use, it has been approved for distribution in other countries such as the United Kingdom and Australia. Bromide was originally used to treat refractory epileptics in combination with phenobarbital. Bromine is located in the periodic table’s halogens group, and its negatively charged form (Br) is an ion known as a bromide ion. Hypobromite is produced via eosinophil peroxidase, an enzyme that can use chloride but preferentially uses bromide.
Bromide: the good, the bad, and the ugly of the oldest antiseizure medication
Despite its widespread use, studies supporting the currently recommended serum therapeutic concentrations and its efficacy when used as monotherapy are still scarce. Due to the challenges presented in assessing serum bromide concentrations, clinicians should aim to work with a trusted laboratory and avoid comparing results obtained from different laboratories. Nonetheless, the noticeable variable sensitivity to bromide between different canine patients (40, 63), highlights the need for a tailored and individualized treatment plan, with the currently known therapeutic ranges and suggested doses to be used as an initial guide.
Final Thoughts on Bromide Detoxification
The end result of a loading dose can be assessed 1 week after the administration of a loading dose protocol. Resolution of cough occurs only after discontinuation of treatment, supporting a relationship with bromide treatment (41, 62). Onset of cough was reported between 2 weeks to 23 months after starting treatment (41), but was seen to developed as late as 8 years after initiation of treatment (62). Experimental studies in rats revealed that bromide can disturb the thyroid, testes and adrenal’s function (70, 71). Breakthrough seizures might occur during the treatment of bromism, which might increase the patient’s hospitalization time.
Bromide’s mechanism of action seems related to its preferential movement across neuronal chloride channels. The present research gaps and potential future developments in the use of this medication are also reviewed and discussed. This syndrome is caused by long-term therapeutic usage of ammonium, sodium, or potassium bromides as sedatives.
- Additionally, a 20–30% of epileptic dogs are refractory to treatment (23, 27, 93, 94), a phenomenon also observed in human medicine (95).
- Controversially, irritability and restlessness were also reported with potassium bromide treatment in dogs (64).
- Sir Charles Locock was the first to use it as an anticonvulsant on humans in 1857.
- Studies assessing the efficacy of bromide as an antiseizure medication in horses are currently lacking.
- Dermatologic adverse effects are only rarely reported in canine patients and do not appear to be a significant problem in patients receiving bromide therapy (63).
Potassium Bromide
Sodium bromide can be particularly useful in dogs with disease where administration of potassium might be undesirable (e.g., hypoadrenocorticism) but is contraindicated in case of hypertension, congestive heart failure or hepatic disease (28). Loop diuretics like furosemide might also increase bromide elimination by blocking chloride and bromide reabsorption (49, 50). Mercurial diuretics can increase bromide elimination, suggesting that bromide reabsorption might occur via the chloride channels in the thick ascending limb of Henle (47, 48). Chloride and bromide compete for tubular reabsorption, with bromide being naturally more easily reabsorbed and chloride more easily excreted (39, 45). After oral administration, bromide is easily absorbed in the gastrointestinal tract and has an estimated mean bioavailability of 46% (35), and maximal concentration in the cerebrospinal fluid occurs in about 2 h (36).
Intravenous loading can be performed with a NaBr solution and a protocol using a continuous rate infusion (CRI) during a 24-h period to administer a total of 900 mg/kg dose was previously suggested (51). A study by Gindiciosi et al. (14) described a loading protocol that consisted of the oral administration 600 mg/kg of KBr split into multiple doses and given over a 48-h period in association with a maintenance dose of 30 mg/kg/day. The previously described protocol can also be given rectally, in patients that are unable to take oral medication (56).
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Chronic bromide usage results in a number of neuropsychiatric changes, including the sedative and anticonvulsant effects found with acute dosage. It is used in the medical profession to purify various steroids used in the treatment of illnesses and the decrease of pain. Lithium bromide is often bromide detox used as a desiccant in air conditioning systems and is also utilized in absorption refrigerators on occasion. Their use in over-the-counter sleep aids and pain medications.
Rossmeisl and Inzana (68) found a mean bromide serum concentration of 3.7 mg/dL in dogs with clinical signs of bromism, compared to 1.7 mg/dL in control dogs. Panniculitis was reported in two dogs and resolved after discontinuation of bromide treatment (69). Vomiting and diarrhea (including bloody feces) were also described in dogs treated with potassium bromide or sodium bromide but are usually not severe and seldomly indicate discontinuation of treatment (63). Podell and Fenner (23) noted polyphagia in 7/23 dogs treated with a combination of phenobarbital and bromide once the last one was added to the antiseizure plan. Controversially, irritability and restlessness were also reported with potassium bromide treatment in dogs (64). Boothe et al. (41) reported that the use of bromide as monotherapy (4) or in association with phenobarbital (3) lead to the eradication of seizures in 7 of 15 treated cats.
Lithium Bromide
Bromine-based compounds are also used in water purification as biocides and disinfectants in swimming pools, spas, and industrial systems. Beyond the oceans, bromide is found in smaller quantities in some minerals, salt lakes, underground brines, and even trace amounts in freshwater. Bromide ions typically exist in compounds, such as salts, where they are bonded with other elements. The element bromine (Br₂) is a reddish-brown liquid at room temperature and is a member of the halogen group, which also includes elements like chlorine and iodine. Some enzymes use bromide as substrate or as a cofactor. Bromide is rarely mentioned in the biochemical context.
Given that loading doses may carry a higher risk of gastric irritation and vomiting, it is advisable to hospitalize patients during the loading dose period to enable better monitoring and control of these potential adverse effects. In canine patients, potassium bromide dosage as add-on therapy (e.g., in association with phenobarbital) is 20–40 mg/kg/day (11, 26, 28, 44, 51). For this reason, in canine patients, bromide steady-state concentrations are expected to take 2–3 months to achieve (44). Initially met with skepticism, bromide quickly gained enthusiasm within the medical field until being largely replaced by newer antiseizure medications with significantly fewer adverse effects in people. Continuous and accurate monitoring of bromide serum concentrations is necessary to maximize its therapeutic properties and ensure its safe use. The currently known challenges in measuring and monitoring bromide serum concentrations, make it difficult to tailor dosages to the individual patient and represent one of the downsides (or bad aspects) of its use.
Organobromine compounds are commonly used as brominated flame retardants. Bromide’s main commercial value is its use in producing organobromine compounds, which themselves are rather specialized. Balard and Löwig’s method can be used to extract bromine from seawater and certain brines. This reaction is analogous to the production of bleach, where chlorine is dissolved in the presence of sodium hydroxide.
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Seizures can also be a consequence of intracranial disease (structural epilepsy), metabolic disorders or intoxication (reactive seizures) (6). Idiopathic epilepsy (IE), which can be further subclassified into genetic epilepsy, suspected genetic epilepsy or IE of unknown cause, is the most common cause responsible for seizures in dogs (1, 4). In canine patients, epilepsy was found to be the most prevalent chronic neurological disorder (3, 4).
Managing epilepsy effectively in veterinary patients remains a challenging aspect of veterinary neurology since poorly controlled seizures can severely impact both the patient’s and the owner’s quality of life. Regular monitoring of the kidney function is therefore recommended in patients receiving bromide treatment (50). Since bromide is eliminated by the kidneys, renal disease can lead to an inappropriate rise in bromide serum concentration and consequent bromide toxicity (50). It is thought that dogs living close to the sea can be exposed to air with higher concentrations of salt in the form of aerosols (91, 92). The absence of known interactions between bromide and other antiseizure medications may be attributed to its lack of metabolism within the patient’s body (81). After precipitation of the proteins in the sample, tri-gold chloride is added to the serum leading to a color change that is related to the level of bromide present in the blood.
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Since its discovery in 1827, scientists have been keen to find out fresh uses for bromine. Bromide was the sole viable anticonvulsant on the market until the discovery of phenobarbital in 1912. Sir Charles Locock was the first to use it as an anticonvulsant on humans in 1857.
Reductions in phenobarbital dosage were possible in 35% (23) and 70% (58) of dogs, after the addition of bromide. Patients should be regularly assessed during loading dose protocols for monitoring of side effects that might occur, allowing adjustment or discontinuation of the protocol if necessary. After the end of the loading period, dogs should continue receiving the normal maintenance bromide dose. In horses, Raidal and Edwards (54) described the use of a loading dose of 120 mg/kg/day during a 5-day period and maintenance doses of 90–100 mg/kg of potassium bromide administered once daily.
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