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Many bromide salts, including sodium bromide and potassium bromide, are colorless crystalline solids. This article clarifies what bromide is, where it naturally occurs, its common uses, and its impact on human health. Bromide is a chemical entity found in nature and used in many human applications.
Understanding Bromide Toxicity
Trace amounts of bromide are naturally present in the human body, with an average concentration in blood around 5.3 ± 1.4 milligrams per liter. Seawater contains significant concentrations of bromide, typically around 65 milligrams per liter, accounting for about 0.2% of all dissolved salts. The severity of adverse effects can be such that bromide was largely abandoned in human medicine and is currently contraindicated in cats.
- Although the exact point prevalence is not known, this was estimated to be between 0.6 and 0.75% in the general dog population (1).
- Trace amounts of bromide are naturally present in the human body, with an average concentration in blood around 5.3 ± 1.4 milligrams per liter.
- Dr. Hulda Clark, a naturopath whose work has gained attention in alternative health circles, has developed a distinctive theory about cancer causation that differs markedly from conventional medical understanding.
- Despite the lack of any randomized studies at that time, the available clinical data is considered enough to name bromide as the first effective ASM, marking the beginning of the modern treatment of human epilepsy (19).
- This syndrome is caused by long-term therapeutic usage of ammonium, sodium, or potassium bromides as sedatives.
- This reaction is analogous to the production of bleach, where chlorine is dissolved in the presence of sodium hydroxide.
Dissociation of bromide salts
Neurological and behavioral signs were the most reported adverse effects among different veterinary species (63). Studies assessing the efficacy of bromide as an antiseizure medication in horses are currently lacking. According to Podell et al. (11), bromide receives a moderate recommendation for its’ use in monotherapy and this medication is “most likely” expected to provide an effective treatment. The use of bromide in monotherapy, as a first-line antiseizure treatment in alternative to phenobarbital, was also previously described (28).
- Doses between 30 and 40 mg/kg/day can be adequate when using bromide in monotherapy (11, 51, 52).
- This leads to spurious hyperchloremia (or pseudohyperchloremia) to be frequently recorded when assessing the serum, whole blood or plasma of patients receiving bromide treatment (77, 78).
- Bromide was originally used to treat refractory epileptics in combination with phenobarbital.
- Bromide dose reduction, intravenous fluid therapy and induction of diuresis with saline solution (0.9% NaCl) can lead to a quicker improvement in a matter of hours (63, 68).
- Bromide follows phenobarbital and imepitoin (for idiopathic epilepsy) as the ASM with “moderate recommendation and most likely to be effective treatment” when used in monotherapy (11).
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Despite this, the impact of bromide in contributing to hypertriglyceridemia is currently unknown and evidence to support a clear causal relationship between bromide treatment and pancreatitis also seems to still be lacking. Phenobarbital alone or in combination with bromide can also lead to the development of hypertriglyceridemia in dogs, a known risk factor for pancreatitis (67). Based on anecdotal reports regarding the gastric irritant effect of bromide salts (28), administration in divided smaller doses or in association with food might help preventing vomiting (44, 63). Although weight variations in patients treated with bromide are currently not clear, eating habits and body weight should be closely monitored (63). Royaux et al. (61) described possible benefits of the addition of bromide to epileptic dogs receiving imepitoin.
Efficacy and comparative analysis with other antiseizure medications
Bromargyrite—natural, crystalline silver bromide—is the most common bromide mineral known but is still very rare. Although uncommon, chronic toxicity from bromide can result in bromism, a syndrome with multiple neurological symptoms.
Improvement of initially witnessed side effects was reported with both medications, but phenobarbital still appeared to be better tolerated, with 20% of the patients receiving bromide continuing to experience vomiting by the end of the study (16). Despite this, therapeutic serum concentrations can still be achieved before reaching steady-state concentrations, what can justify the administration of initial loading doses in selected patients (35). In addition to phenobarbital, imepitoin and potassium bromide are the only approved ASM for the treatment of canine epilepsy in Europe (11).
Following its initial use as an add-on therapy in association with phenobarbital, reports on the use of bromide as an effective alternative first-line antiepileptic also became available (16, 28). Bromide continued to be the only effective ASM used in human medicine until 1912, when the antiseizure properties of phenobarbital were discovered (18). Reckless use of this medication with excessively high doses and lack of adequate follow-up were also one of the suspected reasons behind the development of unacceptable mental dullness and apathy in people (21).
Subsequently, another assessment should be performed one-month post-loading to determine the appropriate ongoing maintenance dose (51, 52). Adequate monitoring allows individualization and optimization of treatment due to the narrow therapeutic ranges and known pharmacokinetic variability between individuals (52). In horses, bromide has also a sedative and calming effect that can lead to its misuse in competition animals (73). Bromide dose reduction, intravenous fluid therapy and induction of diuresis with saline solution (0.9% NaCl) can lead to a quicker improvement in a matter of hours (63, 68). Throughout different species, severe bromide toxicity results in manifestations such as depression, alterations in behavior, ataxia, hind limbs paresis, mydriasis, stupor, and coma (63).
What Is Bromide? Its Natural Presence and Common Uses
Despite this, clinical studies evaluating the safety and efficacy of intravenous bromide administration in veterinary patients are still lacking. In contrast with other antiseizure medications, bromide does not go through hepatic biotransformation and has no hepatotoxic effects (29). Medications like barbiturates (e.g., phenobarbital), which boost chloride conductance through GABA-ergic activity, may work together with bromide to elevate the seizure threshold (29).
In this study, bromide led to an improvement in seizure control in 11 of the 22 dogs that composed the cohort, 4 become seizure free and 7 had a reduction of seizure frequency of at least 50% (26). Despite having a currently more limited role in human epilepsy, bromide can still be considered and have an important role in the treatment of refractory pediatric epilepsy (24, 25). Neither of the attempted alternatives revealed increased efficacy in the control of seizures or decreased adverse effects, which became one of the main drawbacks of bromide therapy (21). The information presented in this review aims to enhance the understanding of primary practitioners and veterinary neurologists regarding the current insights into the use of bromide in epileptic patients. International veterinary epilepsy task force (IVETF) current indications to recommend maintenance ASM treatment (9).
A study by Lichtenauer et al. (90) evaluated a possible relationship between the proximity of a dog’s residential area to the coast and the dose of potassium bromide required to maintain adequate serum bromide concentrations (90). Dogs with adequate seizure control can experience recurrence of seizures after a sudden increase in chloride intake through a diet change and consequent drop in serum bromide concentrations (89). For this reason, there is a general recommendation for the ingestion of chloride to be maintained constant in human and veterinary patients receiving treatment with bromide (87, 88).
Potassium Bromide
Nodular pulmonary lesions and endogenous lipid pneumonia with secondary pneumothorax were also previously described (62). Bromide should not be used in pregnant or lactating animals since its safety is yet to be assessed in these bromide detox patients. Cutaneous lesions included nonsuppurative white macules with scales and pustular dermatitis (63).
Peer-reviewed journal articles for bromine (Br)
Bromoethane, sometimes known as ethyl bromide, is a haloalkane chemical compound. Potassium bromide (KBr) is a common salt used as an anticonvulsant and sedative. Bromargyrite, a natural, crystalline silver bromide that is still fairly rare, is the most prevalent bromide mineral. Bromide was first offered to dogs in 1907, but its promise as an anticonvulsant was not found until 1986. By the twentieth century, the term “bromide” had come to be used figuratively to refer to anything or someone so monotonous or commonplace that it may put someone to sleep.
The dose for NaBr is approximately 15% less of that of KBr, since potassium has a higher molecular weight than sodium, making 1 g of NaBr to contain more bromide than 1 g of KBr (28, 44, 51). After glomerular filtration, bromide suffers extensive tubular reabsorption leading to its long elimination half-life (39). Canine thyroid function also does not seem to become affected by the chronic use of bromide (37, 38). Although an active transport system in the choroid plexus can remove accumulation of bromide from the CSF and CNS, this system can be overwhelmed if administration of bromide is high enough (33).
Additionally, this method is laborious and nowadays most laboratories prefer the use of mass spectrometry. This method carries a risk of falsely record elevated bromide levels due to the presence of other iodides (78). This assessment should be anticipated if seizure frequency increases with more than 3 seizures before the next scheduled assessment or if toxicity is suspected (11).
Methyl bromide is a colorless, odorless gas that is used as a fumigant for insect management in agriculture and transportation. At normal temperature and pressure, potassium bromide is a white crystalline powder. The use of methyl dibromide and ethylene dibromide in soil fumigation can leave traces of these chemicals in harvested crops.
Despite this, when compared to bromide, phenobarbital revealed a higher efficacy, leading to the eradication of seizures in 85% of dogs. Currently there is only one study evaluating bromide’s efficacy in monotherapy for the treatment of epilepsy in dogs and comparing it with phenobarbital (16). 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.