JAVMA, Vol 240, No. 6, March 15, 2012 Scientific Reports 705

A systematic review of the safety 

of potassium bromide in dogs

Hope E. Baird-Heinz, dvm; A’ndrea L. Van Schoick, dvm; Francis R. Pelsor, pharmd; 

D. Lauren Ranivand, mph; Laura L. Hungerford, dvm, mph, phd

Objective—To critically evaluate and summarize available information on the safety of potassium bromide in dogs.

Design—Systematic review.

Sample—111 references reporting safety information relevant to potassium bromide published between 1938 and 2011.

Procedures—PubMed searches without date limitations were conducted with the terms 

“potassium bromide” and “sodium bromide” in December 2009 and October 2011. Additional articles were identified through examination of article reference lists and book chapters on seizures in dogs and pharmacology.

Results—Reversible neurologic signs were the most consistently reported toxicoses and 

were generally associated with adjunctive potassium bromide treatment or high serum 

bromide concentrations. Dermatologic and respiratory abnormalities were rare in dogs. Insufficient information was available to assess the effects of potassium bromide on behavior 

or to determine the incidence of vomiting, weight gain, polyphagia, pancreatitis, polyuria, 

polydipsia, or reproductive abnormalities associated with potassium bromide administration. Evidence suggested that administration of potassium bromide with food may alleviate 

gastrointestinal irritation and that monitoring for polyphagia, thyroid hormone abnormalities, 

and high serum bromide concentrations may be beneficial.

Conclusions and Clinical Relevance—Results suggested that potassium bromide is not 

an appropriate choice for treatment of every dog with seizures and that practitioners should 

tailor therapeutic regimens and clinical monitoring to each dog. Abrupt dietary changes or 

fluid therapy may compromise seizure control or increase the likelihood of adverse events. 

Availability of an appropriately labeled, approved potassium bromide product could provide 

better assurance for veterinarians and their clients of the quality, safety, and effectiveness 

of the product for veterinary use. (J Am Vet Med Assoc 2012;240:705–715)

Potassium bromide was first reported as a treatment for epilepsy in people in 18571 and was described as an animal treatment before 1876.2

 The drug was widely available 

over the counter during the early part of the 20th century, 

and in 1938, sales of products containing bromide in the 

United States were second only to sales of products containing acetylsalicylic acid.3

 Although bromide salts are still 

used to treat specific types of refractory seizures in children,4,5 the use of KBr in humans has decreased throughout 

the 20th century owing to the availability of other antiseizure medications that have fewer toxic effects.6

 Undesirable 

effects of bromides in humans include lethargy, sleepiness, 

confusion, hallucinations, muscle pain, ataxia, nausea, 

vomiting, anorexia, acneiform and erythematous rashes, 

nodular and pustular skin lesions, stupor, and coma.3,7

From the Center for Veterinary Medicine, US FDA, 7519 Standish Pl, 

Rockville, MD 20855 (Baird-Heinz, Van Schoick, Pelsor, Ranivand, 

Hungerford); and the Department of Epidemiology and Public 

Health, University of Maryland School of Medicine, Baltimore, MD 

21201 (Hungerford). Dr. Baird-Heinz’s present address is Veterinary 

Relief Services, 3308 Westclarke Dr, Plano, TX 75093.

The authors thank Susan Marsh, Julie Bailey, Evgenij Evdokimov, Vitolis 

Vengris, Thomas Modric, Amey Adams, and John Mussman for technical assistance and Elizabeth Luddy for review of the manuscript. 

Address correspondence to Dr. Hungerford (laura.hungerford@fda.hhs.gov).

Abbreviations

ADE Adverse drug event

GI Gastrointestinal

KBr Potassium bromide 

NaBr Sodium bromide

PB Phenobarbital

PD Polydipsia

PU Polyuria

In

treatm

with i

disord

veteri

zures i

combi

gle ag

been r

dogs 

seriou

and h

dispen

substa

for sei

 dogs, PB and KBr are still considered the standard 

ent for long-term management of seizures associated 

diopathic epilepsy,8–10 the most common neurologic 

er in dogs.9 In a recent Australian survey,11 80% of 

narians reported that they used KBr to manage sein dogs. Although KBr has traditionally been used in 

nation with PB, it is increasingly being used as a sinent for treatment of dogs with seizures12–14 and it has 

ecommended as a first-line anticonvulsant in some 

with newly diagnosed epilepsy.8,14 Concern regarding 

s ADEs associated with PB, such as pancytopenia15

epatotoxicosis,16 and the restrictions associated with 

sing PB related to its classification as a controlled 

nce also make KBr a more convenient choice than PB 

zure management.17
706 Scientific Reports JAVMA, Vol 240, No. 6, March 15, 2012

SMALL ANIMALS

Potassium bromide and, to a lesser extent, NaBr are 

compounded and marketed in the United States as a solution or in capsules. Potassium bromide, NaBr, and PB have 

not been approved by the US FDA for use in humans or 

animals in the United States. This means that these drugs 

have not been reviewed by the FDA to determine whether 

they are safe and effective or to show that they are produced 

in a consistent manner according to recognized quality 

standards. For unapproved drugs, there is no mandatory 

requirement for reporting of ADEs by drug manufacturers; therefore, the FDA Center for Veterinary Medicine receives relatively few ADE reports related to these products. 

Without FDA approval and mandatory ADE reporting, the 

safety, effectiveness, and quality of KBr products available 

to practitioners and patients in the United States cannot be 

ensured, potentially leaving veterinarians and pet owners 

unaware of adverse effects and other risks involved with 

the use of KBr. Because KBr is commonly used in the veterinary community, it is important that veterinarians have 

the information necessary to prescribe it in the safest manner possible. The purpose of the study reported here was to 

systematically review and critically evaluate the published 

literature on the safety of KBr in dogs.

Materials and Methods

A PubMed search was conducted in December 2009

with the term “potassium bromide” to identify articles 

related to the safety of bromide. Additional articles were 

identified through manually searching reference lists in 

the identified publications, in other relevant articles, and 

in book chapters on seizures in dogs and pharmacology. The literature search was repeated in October 2011, 

adding the term “sodium bromide,” to identify articles 

that had been published following the original PubMed 

search and to more completely encompass potential adverse effects expected with KBr treatment because the 

initial search identified information relevant to KBr safety in articles reporting results of studies that used NaBr.

Published reports that did not involve systemic administration of bromides to humans or animals or did 

not assess physiologic effects were excluded because they 

were not applicable to this review. Individual reports were 

not excluded on the basis of study design, species of interest, condition being treated, or language of publication. 

Foreign language references were evaluated first on the 

basis of the title and then on the basis of a review of the abstract; references that appeared potentially relevant on the 

basis of the title or abstract were translated into English.

Potentially relevant publications were reviewed to determine the physiologic systems involved and the strength 

of evidence linking each reported ADE to KBr or NaBr. 

Review and historical articles with no original data and reports of bromide use in humans or dogs in which toxicity was not examined were excluded. Relationships among 

treatment groups were examined, the evidence was evaluated for causality of adverse events, and it was determined 

whether findings were statistically significant. Articles were 

classified as providing primary, supportive, or anecdotal 

evidence on the basis of an evaluation of the strength of evidence presented in the article, as described.18 Publications 

that contained quantitative or descriptive data investigating 

adverse effects of bromide treatment in mammals were considered to provide primary evidence. Publications reporting 

studies in which safety monitoring was conducted but no 

ADEs were seen were also considered to provide primary 

evidence. Publications in which ADEs were described in 

the context of a study, but without data, and publications 

that discussed important ADEs but lacked sufficient case 

detail to definitively attribute the reported ADEs to KBr or 

NaBr administration were considered to provide supportive 

evidence. Publications were classified as providing anecdotal evidence if they contained opinions or observations 

by experts rather than objective, supportive safety data. 

The strength of evidence available in each article was summarized, and spreadsheet templates were used to organize 

reports of bromide-associated toxicoses by specific body 

systems. Findings were summarized by system; additional 

literature on physiologic mechanisms was incorporated to 

provide interpretive context.

Results

The PubMed searches retrieved 843 publications. 

Searches of reference lists in these articles and in book 

chapters and additional targeted searches yielded 93 additional publications, resulting in a total database of 936 

publications. Of these, 703 were eliminated because they 

did not discuss systemic use of KBr or did not contain 

physiologic information or because bromide was used 

only to measure the extracellular water compartment. 

Of the 233 remaining publications, 38 were in a foreign 

language. Of these, 20 had English titles or abstracts that 

appeared relevant and were translated. Eight of these 20 

were included in the systematic review.19–26 Twelve translated articles and 12 other foreign-language publications 

that could be evaluated without translation on the basis of 

their titles, abstracts, tables, or figures were found to lack 

sufficient specific data on ADEs associated with bromides. 

Six other foreign-language publications were not translated because they were judged to provide information similar to information that had already been reviewed. These 

30 publications were not included in the review. 

Publications that discussed the use of bromide as a 

treatment in humans or animals included 42 historical or 

review articles that contained only descriptive summaries 

and no original data. Another group of publications discussed use of bromides in humans (n = 14), horses (2), 

rats (4), or chicks (1), but no ADEs were reported. It 

was unclear in these 21 publications whether ADEs were 

not evaluated, were not reported, or were truly not observed. In 22 other publications, KBr was used in dogs 

but no ADEs could be directly attributed to bromide administration. In these publications, there was insufficient 

description to determine whether ADEs were evaluated 

at all or were not observed, affected animals had other 

treatments or conditions likely to produce observed signs, 

physiologic measurements were described but no clinical 

changes were observed, or the provided information was 

vague and the types of ADEs described were documented 

in other references containing data. Seven publications reported findings only in nonmammalian species, including 

flies, fish, and birds. Although these 92 publications did 

not provide data for assessing bromide toxicity, some of 

them provided background and contextual information 

that was used in the descriptive review.

The 111 publications that provided data on drug 

safety included those in which KBr or NaBr was used 
JAVMA, Vol 240, No. 6, March 15, 2012 Scientific Reports 707

as a monotherapy or as a part of combination treatment 

(usually with PB). There were few controlled trials 

involving dogs that evaluated the safety of KBr when 

used alone; however, there were many reports of observational studies. On the basis of our critical review, 

38 publications provided primary evidence relevant to 

KBr safety (Table 1); these publications contained data 

related to dogs,15,27–37,a cats,38,39 rats,40–49 mice,50,51 catTable 1—Characteristics of 38 publications that provided primary evidence regarding adverse effects of KBr relevant for dogs.

Author Year Species No. treated Drug Study design Body system affected and signs

Bel et al54

Boothea

Boothe et al38

Boothe et al38

Buchberger et al40 

2001 

2002 

2002 

2002 

1990 

Humans 

Dogs 

Cats 

Cats 

Rats 

1 NaBr 

23 KBr 

 

 

 

17 KBr 

 

 

7 KBr 

36 NaBr 

 

 

 

 

 

Case report 

Randomized controlled trial 

Cross-sectional study 

Experimental study 

Experimental study 

Dermatologic (vegetative skin lesions)

Neurologic (ataxia, obtundation, 

 hyperactivity, and abnormal behaviors), 

 GI (vomiting, polyphagia, and 10% weight 

 increase), and PU and PD

GI (vomiting and weight gain), PU and PD, and 

 respiratory (coughing and bronchial 

 asthmatic changes)

No ADEs reported during observation period

Neurologic (hypoactivity), GI (decreased 

 weight and anorexia), dermatologic (ruffled 

 fur), endocrine (decreased thyroxine 

 and triiodothyronine and increased thyroid-

 stimulating hormone concentrations), and 

 death

Chang et al27

Diener et al55

2006 

1998 

Dogs 

Humans 

4 KBr 

 

 

5 KBr 

 

 

 

Cross-sectional survey 

Case series 

Neurologic (lethargy, ataxia, and 

 restlessness), GI (vomiting, diarrhea, and 

 polyphagia), and dermatologic (pruritus)

GI (vomiting and diarrhea), pancreatitis, 

 dermatologic (folliculitis, subcutaneous 

 nodules, and necrotizing panniculitis), and 

 fever

Disse et al41

Genicot et al19

Goldstein50

Hafiji et al56

1996 

1991 

1979 

2008 

Rats 

Cattle 

Mice 

Humans 

18 NaBr 

 

 

 

11 KBr 

 

30 NaBr 

 

1 Pipobroman 

 (bromide- 

 containing 

 drug) 

Experimental study 

Experimental study 

Experimental study 

 Case report 

Reproductive (in offspring of treated dams: 

 lower body and brain weight, delayed 

 behavioral development, and modified 

 neuroplasticity)

GI (polyphagia and lower weight gain 

 compared with controls)

Neurologic (sedation, loss of righting reflex, 

 and ataxia) and death

Neurologic (delusions, hallucinations, and 

 depression) and dermatologic 

 (erythematous, papulonodular eruption with 

 erosions, pustules, and necrosis)

 

Hanes and Yates3

Hansen and Hubner51

Harned et al42

Harris and Derian28

Jacobs et al15

1938 

1983 

1944 

1949 

1998 

Humans 

Mice 

Rats 

Dogs 

Dogs 

400 Bromide 

 

 

 

100 NaBr 

 

97 NaBr 

 

 

3 NaBr 

 

 

1 KBr and 

 clorazepate 

 dipotassium

2 PB 

Case series 

Experimental study 

Experimental study 

Experimental study 

Case series 

Neurologic (headache, delusions, emotional 

 changes, lethargy, memory loss, and ataxia), 

 dermatologic (rash and papules), and 

 reproductive (loss of libido)

Neurologic (restlessness and behavioral 

 changes) and GI (weight loss)

Reproductive (in offspring of treated dams: 

 stillbirths, neonatal deaths, delayed growth, 

 and slower maze learning)

Neurologic (lethargy and incoordination), GI 

 (diarrhea and oral ulceration), and 

 dermatologic (pustular dermatitis)

No ADEs reported during 8-week follow-up 

 period

Kagitani-Shimono 

 et al57

Kantrowitz et al29

2005 

1999 

Humans 

Dogs 

4 NaBr 

 

8 KBr 

15 KBr and PB 

55 PB 

Case series 

Cross-sectional study 

No ADEs reported during 2- to 5-year follow-

 up period

Endocrine (no thyroid hormone changes 

 among dogs treated with KBr alone)

Knight and 

 Reina-Guerra52

1977 Cattle 14 NaBr Experimental study Neurologic (ataxia)

Loeber et al43 1983 Rats 50 NaBr 

 

Experimental study Endocrine (decreased thyroxine and growth 

 hormone concentrations and decreased 

March et al30

Millikan and Paul58

Newsome et al44

Palmer and Clarke31

Paull et al32

2002 

1946 

1978 

1933 

2003 

Dogs 

Humans 

Rats 

Dogs 

Dogs 

 

 

6 KBr 

 

36 NaBr 

 

 

20 NaBr 

 

 

2 NaBr 

5 KBr 

 

 

Experimental study 

Uncontrolled clinical trial 

Experimental study 

Experimental study 

Experimental study 

 growth) and reproductive (decreased 

 spermatogenesis)

Neurologic (caudal paresis, ataxia, 

 hyporeflexia, and agitation)

Neurologic (sleepiness, ataxia, slurred 

 speech, grogginess, disorientation, and 

 hallucinations) and GI (nausea and vomiting) 

Endocrine (increased thyroxine 

 concentration) and GI (no anorexia and 

 possibly decreased growth)

No ADEs reported during observation period

Endocrine (no thyroid hormone changes); no 

 ADEs reported during 6-month follow-up 

 period
708 Scientific Reports JAVMA, Vol 240, No. 6, March 15, 2012

SMALL ANIMALS

Table 1 continued—Characteristics of 38 publications that provided primary evidence regarding adverse effects of KBr relevant for dogs.

Author Year Species No. treated Drug Study design Body system affected and signs

Perkins59

Raidal and 

 Edwards53

Rosenblum33

Rossmeisl 

 and Inzana34

Sangster60

Steiner et al35

Schwartz et al36

van Leeuwen 

 et al45

van Logten et al46

van Logten et al47

Velický et al48

Vobecký et al49

Wagner39

Yohn et al37

1950 

2008 

1958 

2009 

 

 

1983 

2008 

2011 

1983 

1973 

1974 

1997 

2005 

2001 

1992 

Humans 

Horses 

Dogs 

Dogs 

Humans 

Dogs 

Dogs 

Rats 

Rats 

Rats 

Rats 

Rats 

Cats 

Dogs 

27 Various 

 bromides 

 

 

 

 

 

 

12 KBr 

 

24 NaBr 

 

 

 

31 KBr or KBr 

 and PB 

52 None 

(epileptic

 controls)

24 KBr 

 

 

 

98 KBr 

118 PB 

121 KBr and PB 

1 KBr 

 

500 NaBr 

 

 

 

 

16 NaBr 

 

100 NaBr 

 

 

 

120 KBr 

 

 

 

10 dams KBr 

and 80 pups 

 

 

26 KBr 

 

1 KBr 

 

Case reports 

 

Experimental study 

Experimental study 

Case-control study 

Experimental study 

Cross-sectional study 

Case report 

Experimental study 

Experimental study 

Experimental study 

Experimental study 

Experimental study 

Cohort study 

Case report 

Neurologic (paresis, ataxia, tremor, 

 hallucinations, disorientation, sleepiness, 

 headache, muscle pain, hyporeflexia or 

 hyperreflexia, anisocoria, depression, 

 irritability, stupor, coma, and increased CSF 

 total protein concentration), GI (stomach 

 cramps, foul breath), dermatologic (rash), 

 fever, and death

Neurologic (ataxia and proprioceptive 

 deficits)

Neurologic (ataxia, stupor, shivering, and 

 coma), GI (salivation, weight loss, vomiting, 

 and diarrhea), dermatologic (nonsuppurative, 

 macular, and scaly dermatitis), and death

Neurologic (paresis, ataxia, mydriasis,

 aggression, stupor, and coma) and GI 

 (regurgitation and megaesophagus)

Neurologic (sleepiness and grogginess), GI 

 (nausea), and endocrine (increased 

 thyroxine and triiodothyronine 

 concentrations)

Pancreatitis (no evidence for ADEs on the 

 basis of canine pancreatic lipase

 immunoreativity)

No ADEs reported during 8-week follow-up 

 period

Reproductive (male and female infertility, 

 fewer offspring, and postnatal death) and 

 endocrine (decreased thyroxine and 

 increased thyroid-stimulating hormone 

 concentrations) 

Neurologic (incoordination and decreased 

 grooming)

Neurologic (incoordination and decreased 

 grooming), endocrine (growth retardation), 

 and reproductive (decreased 

 spermatogenesis and fewer corpora lutea)

Endocrine (decreased thyroxine and 

 triiodothyronine concentrations and 

 parenchymatous goiter-like changes in 

 thyroid gland)

Reproductive (decreased survival of young, 

 retarded growth, and decreased milk 

 production) and GI (anorexia and weight 

 loss)

Respiratory (cough and severe dyspnea) and 

 death

Neurologic (depression, stupor, hyporeflexia, 

 anisocoria, paresis, and muscle pain)

tle,19,52 horses,53 and humans.54–60 Among these 38 publications providing primary evidence, there were 22 experimental studies (5 involving dogs and 17 involving 

other species), 2 clinical trials (1 involving dogs and 

1 involving humans), 1 cohort study involving cats, 

1 case-control study involving dogs, 4 cross-sectional 

studies (3 involving dogs and 1 involving cats), and 9 

case reports or case series (3 involving dogs and 6 involving other species). One publication included data 

from 2 types of studies.

Sixty publications were classified as providing supportive evidence, such as descriptive information that supported ADEs documented in the primary evidence publications. These publications involved dogs,13,17,20,61–74,b,c cats,21

rabbits,22,61 rats,75–82 mice,83 cattle,84 goats,84,85 horses,84,86

and humans.5,7,23,24,87–109 These publications described 

important ADEs, but were limited in their ability to 

clearly attribute ADEs to bromide administration. 

Some publications evaluated KBr only when administered in combination with PB or other anticonvulsant 

drugs. Some patients had concurrent diseases or complex medical histories, making it difficult to determine 

whether clinical signs could be attributed to bromide 

administration. Other publications loosely described 

bromism or general signs, but did not provide quantitative data.

Thirteen publications were considered to provide 

anecdotal evidence. These included 5 letters to the editor discussing publications that had already been examined,26,110–113 5 brief reports that provided comments about 

adverse effects but did not provide data,25,114–117 and 3 abstracts of presentations that described preliminary results 

from small studies involving KBr administration but did 

not mention whether adverse events were identified.d–f

On the basis of the identified publications, body 

systems for which ADEs were reported included the 

neurologic (including behavioral), GI (including pancreatitis), reproductive, endocrine, dermatologic, and 

respiratory systems. Additionally, PU and PD were frequently mentioned; however, these were considered to 

be relatively nonspecific signs and were not associated 

with a single body system.
JAVMA, Vol 240, No. 6, March 15, 2012 Scientific Reports 709

Discussion

Evaluation of the safety of a new animal drug is a critical part of the FDA drug approval process. Preapproval 

assessment of potential ADEs is generally based on preliminary data about the structure and pharmacology of the 

compound, experimental studies, and observations from 

clinical trials.118 This information is used to predict 

safety for the larger population of animals that will 

be treated if the drug is approved and marketed. For 

drugs such as KBr, which have already been widely 

used in animal populations, information on health effects with clinical use can be directly observed, rather 

than relying solely on inference from experimental 

studies. However, the number of published articles 

that directly address safety questions may be limited. 

In the present study, we identified a considerable body 

of pharmacological, primary, and supportive evidence 

regarding the in vivo safety of KBr. 

Potassium bromide is a halide salt that is thought 

to exert its antiepileptic activity by passing through 

neuronal chloride ion channels, thereby hyperpolarizing neuronal membranes, raising the seizure threshold, 

and stabilizing neurons against excitatory input from 

epileptic foci.12 Bromide ions have a smaller hydrated 

diameter than chloride ions do and therefore passively 

cross these neuronal channels more readily.7 Bromide 

distributes into the CSF and interstitial tissues of the 

brain and is actively transported out of the CNS via the 

choroid plexus. At pharmacological doses, the active 

transport mechanism is overwhelmed and bromide accumulates in the brain and CSF.12

When given orally as NaBr, the estimated bioavailability of bromide in dogs is 46%,119 but bioavailability 

may differ considerably among individuals. Generally, 

KBr and NaBr solutions would be expected to have 

similar GI absorption, although because of molecular 

weight differences, a solution of 250 mg of KBr/mL 

would be equivalent to a solution of 211 mg of NaBr/

mL. The prandial state of the animal would not be expected to affect bromide absorption because bromide is 

water soluble and absorbed along the entire GI tract.120

Corn syrup or flavored sweeteners have been added to 

compounded bromide solutions to improve palatability.121 The addition of low-digestible carbohydrates, 

such as mannitol and sorbitol, may alter the osmolarity 

of intestinal fluids and result in changes to the rate of 

GI transit.122

Bromide is not subject to hepatic metabolism, making it suitable for use in dogs with hepatic disease.9,123 It 

is excreted unchanged by the kidneys, where it is freely 

filtered by the glomeruli and then undergoes tubular 

reabsorption in competition with chloride.62 Bromide is 

reabsorbed more readily than is chloride119 and distributes throughout the body, essentially replacing chloride 

in body fluids.120 Therefore, the reported mean volume 

of distribution of 0.45 L/kg (0.20 L/lb) approximates 

the extracellular fluid space.12 The mean elimination 

half-life of bromide when KBr is orally administered to 

dogs has been estimated to be from 24.9124 to 46 days.119

Dietary chloride has been shown to be a key variable 

affecting the elimination half-life of bromide.125 Generally, regular administration of KBr for 4 to 5 half-lives 

is required for serum bromide concentrations to reach 

steady state. Therapeutic serum bromide concentrations may be achieved more quickly by administration 

of loading doses of KBr. 

Animals with decreased renal function may be predisposed to bromide toxicosis owing to a decreased ability to eliminate bromide as a result of reduced glomerular filtration rate.34,65 Increased chloride intake leads to 

increased urinary elimination of bromide,9 likely as a 

result of competition for tubular reabsorption between 

chloride and bromide.125 Trepanier and Babish125 found 

that an increase in dietary chloride content from 0.2% 

to 1.3% led to a decrease in serum bromide half-life 

from 69 to 24 days. They also found that, among 11 

commercial dry dog foods, chloride content ranged 

from 0.33% to 1.32% on a dry-matter basis. Abrupt diet 

changes in dogs receiving KBr could either compromise 

seizure control or raise safety concerns.72 Use of IV fluids containing chloride could also reduce serum bromide concentration to subtherapeutic concentrations 

during fluid therapy.10 Loop diuretics, such as ethacrynic acid and presumably furosemide, may also increase 

bromide elimination by blocking chloride and bromide 

reuptake.65 It has also been suggested, albeit anecdotally, that NaBr rather than KBr should be used in patients 

with adrenal insufficiency because these patients may 

have difficulty maintaining potassium homeostasis.123

Because of factors affecting the dose-response relationships for KBr, treatment is generally titrated to effect for 

individual dogs.69

Given the pharmacological properties of bromide 

and specific information in the 111 publications identified in the present study, the effects of KBr could be 

summarized for multiple physiologic systems. Bromide 

toxicosis in dogs was most frequently associated with 

high serum bromide concentrations; however, authors 

have reported that toxicoses can be seen at low concentration in unusually sensitive dogs.30,33 One study126

found that most dogs that develop signs of toxicoses 

with bromide monotherapy had serum bromide concentrations in the range of 2.4 to 4 mg/mL but also 

found that dogs were successfully treated without signs 

of toxicoses at serum concentrations as high as 4 to 4.8 

mg/mL. Another publication30 reported clinical signs of 

toxicosis at serum bromide concentrations of approximately 4 mg/mL, but no signs of toxicoses at concentrations of 1.78 to 2.7 mg/mL.30 In a laboratory study,33 unspecified minimal signs of toxicosis were found in dogs 

given 100 mg of NaBr/kg/d (45.5 mg/lb/d) for 6 weeks; 

mean serum concentration was 2.7 mg/mL. However, 

in the same study, 3 deaths occurred between weeks 4 

and 6 in another group of dogs treated with 200 mg 

of NaBr/kg/d (90.9 mg/lb/d). The importance of monitoring clinical signs for individual animals should be 

emphasized because effective and toxic serum bromide 

concentrations have been reported to differ between 

dogs34 and an overlap in toxic versus nontoxic serum 

concentrations has been demonstrated. In fact, the use 

of clinical signs to judge appropriateness of treatment 

may be more important than monitoring serum bromide concentration alone.

Neurologic and behavioral signs were the most 

commonly reported ADEs associated with bromide ad-
710 Scientific Reports JAVMA, Vol 240, No. 6, March 15, 2012

SMALL ANIMALS

ministration in dogs and other species in clinical and 

experimental studies reviewed in the present study. 

Sedation and, conversely, irritability and restlessness 

have been reported in dogs3,8,27–31,a,c and humans.3,22

A sedative, calming effect has also been reported in 

horses.127 Cattle treated with KBr had a decrease in 

aggressive behavior, compared with untreated controls.19 Signs of more severe bromism were also similar across species and included signs of depression,56

behavioral changes,40,50,51,58 ataxia,27,28,33,34,50,52,53,58,a,c

hind limb paresis,30,31,35 mydriasis,34,35,37,59 stupor,59 and 

coma.33,34,59,65,69 In humans, headache,3,59 sleepiness,58–60

muscle pain,37,59 and hallucinations56,58 have also been 

reported. Neurologic signs have been described when 

KBr was used alone or in addition to PB.30,34,37,65,b In 

clinical studies, observed behavioral changes could also 

stem from the prodromal or postictal phases of seizure 

activity rather than from bromide toxicosis.128 Adverse 

neurologic effects are reversible and may be alleviated 

within several days by decreasing the PB dose by 10% to 

30% (when bromide is given in combination with PB) 

and within hours by treating with saline (0.9% NaCl) 

solution IV.12,37,65,113,121

Gastrointestinal ADEs have also been reported. Vomiting has been commonly described as an adverse effect 

of both KBr and NaBr administration, but a large number 

of the reports identified in the present study were anecdotal and lacked supportive data. Vomiting was seen in 2 

of 20 dogs receiving 400 to 500 mg of NaBr/kg/d (181.8 

to 227.3 mg/lb/d) with food.33 The vomiting in one of 

those dogs was so severe that drug administration was 

discontinued. Another study30 found that KBr at dosages 

as high as 30 mg/kg (13.6 mg/lb), PO, every 12 hours 

for 115 days with food did not result in vomiting. Occasional vomiting was reported in the medical histories 

of 2 of 22 dogs following KBr treatment; however, these 

dogs were also receiving PB.74 Vomiting was reported in 

1 of 17 cats receiving KBr.38 Nausea and vomiting have 

also been reported occasionally for human patients being 

treated with bromides.55,58–60 In dogs, transient diarrhea 

and bloody feces were seen in an experimental study33

when serum bromide concentrations were 1.8 to 4 mg/

mL, but it was unclear how frequently and in how many 

dogs diarrhea occurred. Three dogs treated with 0.2 g 

of NaBr/kg/d (0.09 g/lb/d) developed severe, intermittently bloody diarrhea, of which 2 developed oral ulcerations.28 Diarrhea has also been occasionally reported 

with clinical use in dogs27 and humans,4,55 as have other 

GI problems. Two reviews anecdotally mentioned megaesophagus as a potential adverse effect of KBr treatment 

in dogs.9,34 These adverse GI effects have rarely been severe enough to require cessation of KBr treatment in any 

species. Potassium bromide and NaBr have long been reported, albeit anecdotally, as gastric irritants, and vomiting has been attributed to this irritant effect.12,33,34,38,63,121

Administration with food or as a divided dose may be 

effective in preventing GI irritation.12,30,58,121 For publications identified in the present study, adverse GI effects 

could not be clearly attributed to KBr administration, although there was anecdotal support. 

Weight loss leading to emaciation has been seen 

experimentally in rodents40,49,51,57 and in 10 of 20 dogs 

receiving large doses of NaBr with controlled caloric intake.33 Weight gain was seen in 1 of 17 client-owned 

cats being treated with KBr.38 In a 221-day study of 22 

Belgian White and Blue Cattle (11 of which were treated with KBr), average daily gain was significantly less in 

KBr-treated animals, compared with untreated animals, 

in the first 53 days, but time spent eating was significantly increased in the treated animals from days 168 to 

221.19 Polyphagia, a commonly reported adverse effect 

of both PB and KBr, has been suggested to be a result of 

increased caloric need or a behavioral effect and may be 

involved in these weight changes. In most publications 

that reported polyphagia in the present study, it was difficult to distinguish whether this was actually related 

to KBr treatment because there was concurrent administration of other drugs. In 1 study,69 polyphagia was 

reported in 7 of 23 dogs following the addition of KBr 

to PB treatment. Given that all of these dogs continued 

to receive PB, it was unclear whether the polyphagia 

was due to KBr alone or to the combination of drugs. 

In a small study,27 polyphagia was reported by owners 

of 1 of 4 dogs receiving KBr monotherapy, 6 of 11 dogs 

receiving PB monotherapy, and 8 of 10 dogs receiving 

both KBr and PB. On the basis of publications identified in the present study, monitoring food consumption 

and weight patterns may be warranted in dogs receiving KBr treatment, particularly because polyphagia can 

lead to garbage ingestion and other complications.69

Most KBr-related studies in dogs have not assessed 

pancreatic outcomes; however, several small studies 

have explored a possible association between pancreatitis and treatment with a combination of PB and KBr. 

Schwartz-Porsche and Jurgens20 reported clinical signs 

of pancreatitis in 2 of 22 dogs and pancreatic fibrosis at 

necropsy in 2 of 7 dogs receiving KBr. However, there 

was no comparison group of untreated dogs and all 

dogs had previously been treated with maximal doses of 

either PB or primidone. Hess et al129 reported pancreatitis to be more common in dogs with epilepsy, although 

no treatments were compared. Gaskill and Cribb63 reported that pancreatitis developed in 3 of 6 dogs after 

KBr was added to PB treatment. They also found, using 

serum samples from private practices submitted for KBr 

or PB testing to a diagnostic laboratory, that a higher 

percentage of dogs with measurable serum concentrations of bromide and PB (10/17) also had high serum 

amylase or lipase activities, compared with dogs with 

only measurable PB concentrations (8/88). A history 

supportive of pancreatitis was reported for a higher 

percentage of the dogs with measurable serum bromide 

and PB concentrations (5/17), compared with dogs 

with only PB concentrations (2/88). Steiner et al35 used 

a similar approach with 121 serum samples submitted 

for KBr or PB testing to relate serum and PB concentrations and canine pancreatic lipase immunoreactivity. 

There were no significant differences in proportions of 

dogs with canine pancreatic lipase immunoreactivity 

> 102.1 μg/L (ie, dogs with canine pancreatic lipase immunoreactivity greater than the upper reference limit) 

or > 199.9 μ/L (ie, dogs with canine pancreatic lipase 

immunoreactivity diagnostic for pancreatitis) for dogs 

with measurable serum concentrations of only bromide, 

only PB, or both bromide and PB. Interpretation of results from studies that use diagnostic laboratory sub-
JAVMA, Vol 240, No. 6, March 15, 2012 Scientific Reports 711

missions is difficult because of biases associated with 

ascertaining exposure and disease status for this type 

of convenience sample. Additionally, practitioners may 

be more likely to submit samples from dogs with poor 

seizure control, signs of toxicosis, or health problems 

than from otherwise healthy dogs with well-regulated 

epilepsy. Pancreatitis has been associated with a large 

number of other drugs in humans, but not with KBr 

or PB,130 although it has been mentioned in some case 

reports.55 However, pancreatitis in dogs has been associated with abnormal food consumption131 and polyphagia has been reported for dogs treated with PB, KBr, 

or a combination of both.27 Two dogs with pancreatitis 

were described in a study69 of 23 dogs, but pancreatitis 

was attributed to polyphagia and garbage ingestion. Additionally, the clinical signs of pancreatitis (vomiting, 

lethargy, diarrhea, and signs of abdominal pain)129 have 

been individually reported as ADEs, making identification of pancreatitis more complicated. On the basis of 

our literature review, there was not enough evidence to 

determine whether dogs receiving KBr were at higher 

risk of developing pancreatitis.

None of the identified publications in the present 

study directly assessed the safety of bromide in reproductively active dogs. In humans, reversible impotence 

and loss of libido were among the first recognized effects of bromides.1,3 Reversible decreases in fertility 

have been reported in both female and male rats at 

NaBr doses ≥ 4,800 mg/kg (2,181.8 mg/lb),43,45,47 but 

fetal viability was not affected at dosages of up to 1,200 

mg of NaBr/kg/d (545.5 mg/lb/d). Bromide crosses the 

placenta and is excreted in milk.49 In rats, gestational 

treatment of dams led to decreased survival time, lower 

weight gain, and postnatal developmental delays in offspring.41,49 Even at lower dosages of 120 mg of NaBr/

kg/d (54.5 mg/lb/d) during gestation, offspring had a 

slower rate of maze learning than did controls.42 Given 

the variety of reproductive effects seen in other species, 

more research is needed to determine whether KBr can 

be safely used in reproductively active dogs. In general, 

reproductive effects may be of lesser concern because it 

is usually recommended that dogs with idiopathic epilepsy be neutered. 

Delayed growth was also reported in studies41–43,47,49

of rats that were exposed as juveniles, but not in utero, 

and small studies reported other effects potentially related to cellular replication. Six dogs treated with NaBr 

were described as having delayed callus formation following induced fractures, compared with controls in a 

Russian study25 in the 1950s. A study on rabbits22 and 

another on rats47 reported that animals treated with 

NaBr had lower erythrocyte counts than did controls. 

These effects have not been reported in other studies; 

further information is needed to determine whether 

these findings have relevance for clinical use of KBr.

Therapeutic administration of KBr in dogs was not 

found to affect thyroid weight or serum total thyroxine, 

free thyroxine, triiodothyronine, and thyroid-stimulating 

hormone concentrations or to cause histologic changes.29,32 In rats and humans, effects have not been reported 

at therapeutic doses,43,60 but the thyroid has been identified as a target organ at higher doses. Changes in goitrogenic cellular amounts, identified on the basis of light 

and electron microscopic evaluation of thyroid tissue, 

were reported in rats receiving 10, 50, 100, 200, and 400 

mg of bromide (as KBr) for various durations.48,80–82 At 

very high doses (19,200 mg of NaBr/kg of feed [8,727.3 

mg/lb of feed]), histologic changes in rat thyroid tissue (eg, increased number of smaller follicles, higher 

amounts of follicular epithelium, decreased amounts of 

colloid, and a more granular appearance) and reduced 

thyroxine concentration indicated decreased thyroid activity.43 A statistically significant decrease in total thyroxine concentration was also identified in animals 

treated in another study45 with similar design at doses 

≥ 4,800 mg/kg. In humans, a bromide intake of 9 mg/

kg (4.1 mg/lb) led to increases in serum thyroxine and 

triiodothyronine concentrations in females, although 

individual serum concentrations remained within reference limits for the duration of the study.60 Similar 

changes were not observed in male subjects or in any 

subjects treated with 4 mg of bromide/kg (1.8 mg/lb). 

No precise mechanism of action has been identified; 

however, effects on transport and perhaps synthesis of 

thyroid hormones caused by bromide inhibition of active iodide absorption by the thyroid gland have been 

suggested.32 Although no effects of KBr on the thyroid 

gland have been reported for dogs, monitoring serum 

thyroid hormone concentrations and evaluating thyroid tissues at necropsy would be helpful because available dog studies were small in size.

Polyuria and PD have been reported with clinical 

use of KBr in dogs. Polyuria and PD were documented in 13 of 23 dogs when KBr was added to PB treatment.69 In a randomized, controlled triala

 of 43 epileptic 

dogs treated with either KBr or PB monotherapy, dogs 

in both groups developed PU and PD after 1 month of 

treatment. By 6 months, dogs treated with PB reportedly no longer had PU or PD; none of the dogs treated with KBr had PU, but PD was still present in 4% 

of these dogs.a In a cross-sectional client survey,27 PU 

and PD were not described by owners of the 4 dogs 

receiving KBr monotherapy, but were reported for more 

than half of the 11 dogs treated with PB and for all 10 

dogs treated with both KBr and PB. Polydipsia has also 

been reported in a cat treated with KBr.38 This limited 

and conflicting information makes it difficult to draw 

conclusions about the relationship between KBr administration and PU and PD.

Skin lesions were rarely reported in experimental 

overdose studies or in summaries of clinical cases of 

bromide intoxication in dogs identified in the present 

study. When reported, skin lesions in dogs were described as nonsuppurative white macules with scales33

or as pustular dermatitis.28 Pruritic skin lesions were 

anecdotally listed as an occasional adverse effect in 

dogs in 2 reviews.9,121 In a survey, owners reported 

pruritus in 1 of 4 dogs treated with KBr; however, no 

skin changes were described.27 Skin lesions were not 

commonly reported in rats but, when observed, were 

ascribed to poor grooming secondary to neurologic effects.46,47 In a report3

 of 400 human cases of bromism, 

cutaneous lesions were a relatively common adverse effect and have been reported in other studies.5,54–56,59,95

Lesions reported in human cases include acne, bromoderma tuberosum, bromoderma nodosum, and necro-
712 Scientific Reports JAVMA, Vol 240, No. 6, March 15, 2012

SMALL ANIMALS

tizing panniculitis. These lesions may be accompanied 

by fever, joint and muscle pain, and atrophy of subcutaneous fat.55 The mechanisms are unknown, but dermatologic lesions have been attributed to both allergic 

and toxic reactions to accumulated bromide.56 Overall, 

dermatologic reactions are not expected to be a problem with clinical KBr use in dogs because of the very 

small number of cases reported to date.

Respiratory problems were not reported in clinical or toxicity studies in dogs or humans identified in 

the present study. One author62 mentioned, as part of a 

review chapter, that he had encountered several cases 

of coughing in dogs being treated with KBr. In cats, 

coughing and dyspnea are a major concern and have 

been reported following KBr treatment. In 1 study,38 6 

of 17 cats developed coughing during KBr treatment 

and 1 had a severe bronchial lung pattern on thoracic 

radiographs. Sarkisov,21 in the 1950s, reported that 14 

cats treated with NaBr recovered less completely from 

experimentally induced bacterial pneumonia than did 

15 control cats. Treated cats had a clinically prolonged 

course and developed histologic changes, including 

thickened bronchiolar walls, alveolar exudate, and 

emphysema. In another study,39 11 of 26 cats treated 

clinically with KBr developed coughing and dyspnea. 

Two of these cats treated continuously with KBr had 

severe signs for several months and subsequently died. 

High eosinophil counts were present in bronchoalveolar lavage samples collected from 2 of the 11 cats. Feline bronchial asthma, one of the most commonly diagnosed respiratory conditions of cats, is traditionally 

associated with eosinophilic infiltration.132 Eosinophils 

preferentially use bromide to form oxidants that can 

cause cytotoxicosis, despite low serum bromide concentrations.133 Studies have not examined the effects 

of high serum bromide concentrations on eosinophil 

function. Although the literature supports a concern 

for KBr administration and respiratory disease in cats, 

adverse respiratory effects are not expected in dogs on 

the basis of publications reviewed in the present study.

In the present study, we were able to identify a substantial number of publications providing information 

relevant to evaluation of the safety of KBr in dogs. The 

publications that provided primary evidence for this 

review followed > 170 dogs treated with KBr or NaBr 

and > 210 dogs treated with KBr combined with PB. 

However, many of these studies were relatively small, 

and there was a lack of large randomized, experimental 

or clinical trials that compared KBr administered alone 

with a placebo or an active control. Generally, randomized controlled trials and experimental laboratory 

studies provide the strongest evidence of drug effects.18

In these types of studies, individuals are randomly assigned to treatment groups to minimize bias and subjects are more intensively monitored for adverse events 

during the study period.134 This makes attribution 

of effectiveness and ADEs of a particular drug much 

clearer. Randomized trials may also provide information about the frequency of particular ADEs and their 

relative importance in the study population. However, a 

limitation of these studies is that results may not reflect 

or predict how the drug will behave in a more diverse 

or less healthy general population.135 Additionally, adverse events that are rare or do not develop in the short 

period of the clinical trial may not be recognized.134

Drawing on a full range of publications and including 

smaller nonrandomized or observational studies may 

avoid information loss and biases that occur in systematic reviews that use strict exclusion criteria.136 A number of reviews of human drugs have found that case 

reports and spontaneous reporting systems provide 

better information than do clinical trials about new 

and unexpected ADEs.137,138 Therefore, the consistency, 

quality, and quantity of the evidence were evaluated in 

each article that dealt with safety issues related to KBr, 

rather than excluding studies on the basis of the type of 

study design. Important safety information was found 

in studies of all types. Case studies,7,13,15,36,37,63,65,84 for 

example, provided valuable specifics for several kinds 

of ADEs not reported in other study types.

The present systematic literature review differed 

from the laboratory-based studies more traditionally 

used to determine safety of new animal drugs (ie, evaluation of clinical and pathological changes in 4 groups 

of healthy laboratory dogs, with each group receiving 

either 0, 1, 3, or 5 times the therapeutic dose).118 Although data were available from several studies28,30,32,33

on bromide overdose, results in other publications provided summary information rather than the detailed individual data that are generally submitted for new animal 

drug approval. Much of the available literature was from 

client-owned pets with idiopathic epilepsy that were 

treated with KBr or PB under conditions of clinical use. 

Although the amount of detail for each animal was more 

limited, these pet owner reports included adverse events 

that were subtle and occurred after longer periods of administration (eg, PU and PD or behavioral signs). These 

may not be as readily noted in a laboratory setting or in a 

short-term clinical trial involving a selected population. 

Furthermore, the present systematic review allowed the 

evaluation of > 50 years of literature on the use of KBr 

in dogs, providing a volume and variety of evidence that 

far exceeded the data traditionally available to determine 

the safety of new animal drugs. Related findings in laboratory animals and humans that supported the available 

information for dogs could also be integrated. If KBr 

becomes more frequently used as monotherapy, future 

analyses may allow more complete systematic reviews 

and meta-analyses as well as further information on the 

safety questions raised in the present review.

On the basis of known pharmacological properties 

of bromides and specific information in the 111 publications identified in the present study, safety concerns 

for KBr could be evaluated and summarized for multiple physiologic systems. Bromide toxicosis in dogs was 

most frequently associated with high serum bromide 

concentrations; however, unusually sensitive dogs 

may also develop signs of toxicosis. The importance of 

monitoring clinical signs for individual animals should 

be emphasized because clinical signs may be a more 

useful measure of successful treatment than serum bromide concentration. Considerations that may affect the 

safety of KBr in individual animals include kidney and 

adrenal function, the amount of chloride in the diet, 

and the administration of IV fluids. Most adverse effects appeared to be reversible, but specific estimates of 
JAVMA, Vol 240, No. 6, March 15, 2012 Scientific Reports 713

incidence and comparative frequency of ADEs would 

provide a more thorough safety profile of KBr. 

Neurologic signs were the most common type of 

ADE identified in the present study. Signs included sedation, irritability, restlessness, depression, behavioral 

changes, ataxia, hind limb paresis, mydriasis, stupor, 

and coma. Adverse neurologic effects were reported to be 

reversible and alleviated within several days by decreasing the PB dose or within hours by IV administration 

of saline solution. Adverse GI effects such as vomiting, 

transient diarrhea, and bloody feces have been reported 

in dogs but do not appear to require cessation of KBr 

treatment for resolution. Polyphagia and anorexia have 

been commonly reported for dogs receiving PB or KBr. 

Eating patterns and weight should be monitored in dogs 

receiving KBr, particularly because polyphagia can lead 

to garbage ingestion and other complications. There was 

not enough evidence at this time to conclude that dogs 

receiving KBr were at higher risk of developing pancreatitis than were dogs receiving other treatments. Pancreatitis may be related to polyphagia and garbage ingestion 

as well as to KBr treatment. Use of KBr in reproductively 

active dogs is of concern owing to the variety of reproductive effects reported in other species.

Results of the present review suggested that potential effects of KBr on thyroid function do not appear to be 

clinically important in dogs; however, more research is 

needed. Dermatologic reactions are not of concern with 

clinical KBr use in dogs, and respiratory disease in dogs 

is unlikely, considering the large amount of literature 

available and the very small number of cases reported.

Practitioners should use this information on KBr safety to tailor dosing and monitoring regimens specifically to 

individual dogs. Potassium bromide is not an appropriate 

therapeutic choice for every dog, which magnifies the importance of a valid veterinarian-client-patient relationship 

when determining whether an individual dog is a candidate for KBr treatment. Communication of the spectrum 

of potential adverse effects to owners and encouragement 

of close home monitoring for ADEs, especially for dogs 

on concurrent medications and with concurrent diseases, 

are important safety measures. Ultimately, availability of 

an FDA-approved KBr product with appropriate labeling 

information would provide better assurance for veterinarians and their clients of the quality, safety, and effectiveness of this product for animal use. 

a. Boothe D. Comparison of phenobarbitol and bromide as first 

choice anticonvulsant therapy in the canine epileptic (abstr), in 

Proceedings. 20th Annu Am Coll Vet Intern Med Forum 2002;369.

b. Dewey CW, Ducote JM, Coates JR, et al. Intrarectally administered potassium bromide loading in normal dogs (abstr), in Proceedings. 17th Annu Am Coll Vet Intern Med Forum 1999;238.

c. Mason MF. Halide distribution in body fluids in chronic bromide 

intoxication. PhD dissertation, Graduate School of Arts and Sciences, Duke University, 1935;61–74. 

d. Dreifuss FE, Bertram EH. Bromide therapy for intractable seizures (abstr). Epilepsia 1986;27:593.

e. George K, Boothe DM, Nguyen J, et al. Disposition of bromide 

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1996;757.

f. Trepanier LA. Pharmacokinetics and clinical use of bromide 

(abstr), in Proceedings. 11th Annu Am Coll Vet Intern Med Forum 1993;878–880.

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