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PAPER
Serum bromide concentrations following loading dose in epileptic dogs B. Gindiciosi, V. Palus, S. Eminaga, E. Villiers and G. Bruto Cherubini Dick White Referrals, Cambridgeshire CB8 0UH
OBJECTIVE: To determine serum bromide concentrations following an oral loading dose in dogs. METHODS: Retrospective review of clinical records of dogs suffering from seizures that were treated with bromide. A loading dose of 600 mg/kg potassium bromide was administered orally in 17 to 48 hours together with a maintenance dose of 30 mg/kg/day. Blood samples were collected within 24 hours after completing the protocol and serum bromide concentrations were determined by ultra-violet gold chloride colorimetric assay. RESULTS: Thirty-eight dogs were included in the study. The median age was 3 (range, 0·2 to 10) years and bodyweight 21·8 (3·45 to 46·2) kg. The median serum bromide concentration was 1·26 (0·74 to 3·6) mg/mL. Thirty-two dogs (84·2%) had serum bromide concentrations within the therapeutic interval (1 to 3 mg/mL). The serum concentration in five dogs (13·2%) was just under the minimal therapeutic value and in one dog (2·6%) it exceeded the maximal therapeutic value (3·6 mg/mL). CLINICAL RELEVANCE: Following this oral loading dose protocol, serum bromide concentrations reach the therapeutic range in the majority of dogs. This indicates that the suggested protocol is effective in achieving therapeutic concentrations rapidly in epileptic dogs.
Journal of Small Animal Practice (2014) 55, 108–111 DOI: 10.1111/jsap.12173 Accepted: 18 November 2013; Published online: 16 January 2014
INTRODUCTION Bromide is a negatively charged bromine ion with anticonvulsant properties, used in treatment of canine epilepsy administered as a potassium or sodium salt (Schwartz-Porsche et al. 1990). It has been successfully used for more than two decades as sole treatment or in combination with phenobarbital (Pearce 1990, Schwartz-Porsche et al. 1990, Podell & Fenner 1993). Although it has been recently suggested that phenobarbital has better efficacy for controlling seizures (Boothe et al. 2012), bromide remains a reasonable first choice for the treatment of canine epilepsy, mainly because of the lack of hepatic metabolism (Soremark 1960). Reported bromide half life in dogs varies between 15 and 46 days (Schwartz-Porsche et al. 1990, Trepanier & Babish 1995, March et al. 2002). Due to this long serum half-life a loading protocol has been suggested in order to achieve therapeutic concentrations faster in dogs with seizures (Trepanier 1995, Trepanier & Babish 1995, Sisson 1997). Because of the linear pharmacokinetics of bromide, the serum bromide concentrations at steady state can be simply derived from a single dose administered (Rauws 108
1983). Therefore, in order to target the lower end of the therapeutic interval (1 mg/mL), 450 mg/mL should be given as the loading dose (Trepanier & Babish 1995). This has been tested previously where a loading dose protocol of 600 mg/kg potassium bromide (KBr) was administered intrarectally and as an intravenous (iv) constant rate infusion (Dewey et al. 1999). The average serum bromide concentration after intrarectal dosing was 0·92 mg/mL (range: 0·81 to 1·11 mg/mL) and after iv infusion 1·18 mg/mL (range: 1·13 to 1·22 mg/mL). While pharmacokinetic properties of bromide are well established, to the authors’ knowledge an oral KBr loading protocol has not been evaluated in a clinical setting and serum bromide concentrations after an oral KBr loading dose protocol in dogs suffering from seizures have not yet been reported. The objective of this study was to determine the serum bromide concentrations following a 24-hour oral loading dose protocol in dogs and to assess if the dose is effective in reaching therapeutic concentrations in a clinical setting. A secondary goal was to assess the safety of the KBr loading protocol described and report any significant adverse effects that would interrupt or delay the completion of the loading dose protocol.
Journal of Small Animal Practice
•
Vol 55
•
February 2014
•
© 2014 British Small Animal Veterinary Association
Serum bromide following loading dose
MATERIALS AND METHODS Case selection Clinical records of client-owned dogs examined at Dick White Referrals (Cambridgeshire, UK) for seizure investigations between April 2009 and May 2012 were reviewed. Dogs that were treated with an oral KBr loading dose protocol were included in the study. A dose of 600 mg/kg KBr was administered orally together with 30 mg/kg/day maintenance dose. The full loading dose was administered in 5 to 10 equally divided smaller doses and given in a 17 to 48-hour interval. Dogs were included in the study whether they received KBr loading dose as monotherapy or in combination with another antiepileptic drug. All dogs had haematology and biochemistry results within their respective reference intervals on admission. In addition, all dogs had magnetic resonance imaging of the brain performed and samples of cerebrospinal fluid collected for analysis. Following these investigations all dogs were suspected to have idiopathic epilepsy. The dogs were hospitalised during the treatment protocol and monitored for 24 hours a day during the hospitalisation. Dogs were fed on a commercially prepared tinned diet with chloride content between 0·8 and 1·0% per 100 g dry matter (Royal Canin canned canine Sensitivity Control diet. Crown Pet Foods Ltd., Canned canine i/d diet, Hill’s Pet Nutrition Ltd.). Blood samples for serum bromide concentrations were collected between 1 and 24 hours after completing the loading dose protocol. Dogs that did not have serum bromide concentrations determined within 24 hours after completing the protocol, had KBr administered via other routes than oral or received the loading dose in a longer period than 48 hours were excluded from the study. Dogs that underwent the above mentioned loading dose protocol but vomited during the loading dose protocol were excluded from the statistical analysis.
for normal distribution. Because the majority of these variables were not normally distributed, data is represented as median and range. Percentages were calculated for dogs that had serum bromide concentrations within the therapeutic interval and for those that had values below or above this interval.
RESULTS The records of 76 dogs that had an oral loading dose of KBr were identified. The records of 38 dogs were excluded from the study because 34 dogs did not have serum bromide concentrations determined within 24 hours, 1 dog received the loading dose rectally, 1 dog completed the loading dose protocol in 56 hours and 2 dogs vomited during the protocol. A total of 38 dogs were included in the statistical analysis. Breeds most commonly represented were Labrador retriever (n=5), crossbreed (n=5), Jack Russell terrier (n=3), Border collie (n=3), Border terrier (n=3), boxer (n=3), German shepherd dog (n=2), Staffordshire bull terrier (n=2), Dalmatian (n=2), cocker spaniel (n=2). These dogs had a median bodyweight of 21·8 kg (range: 3·45 to 46·2 kg). The age range was 0·2 to 10 years (median, 3 years). The median post loading serum bromide concentration was 1·27 mg/mL (range: 0·74 to 3·6 mg/mL; Fig 1). Serum bromide concentrations of individual dogs arranged from lowest to highest and compared to the therapeutic interval are represented in Fig 2. A total of 32 dogs (84·2%) had serum bromide concentrations within the therapeutic interval (1 to 3 mg/mL). The serum concentrations in five dogs (13·2%) were under the minimal therapeutic value at 0·74, 0·78, 0·91, 0·94 and 0·95 mg/mL, respectively. In one dog (2·6%) the result exceeded the maximal therapeutic value (3·6 mg/mL). The two dogs that vomited had serum bromide concentrations after the loading dose of 0·73 mg/mL and 0·99 mg/mL. Apart from vomiting,
Clinical records review The collected data included breed, age, bodyweight, total loading and maintenance dose of bromide administered, serum bromide concentrations after the loading dose and the incidence of vomiting during the loading dose protocol. The serum bromide concentrations were compared to the therapeutic interval of 1 to 3 mg/mL. Blood sample analysis Serum was separated immediately and analysed promptly or if collected overnight refrigerated until the next morning. The collected samples were analysed in the in-house laboratory. Serum bromide concentrations were determined by an ultraviolet gold chloride colorimetric assay using Olympus AU400 Chemistry analyzer (Beckman Coulter International S.A.) and reagents provided by Cathachem Inc. Statistical analysis Single variable descriptive statistics were calculated for bodyweight, age and serum bromide concentrations. Due to the small sample size, the Shapiro-Wilk test of normality was used to test Journal of Small Animal Practice
•
Vol 55
•
February 2014
•
FIG 1. Serum bromide concentrations following oral KBr loading dose protocol. Centre line in box – median concentration, box – interquartile range (middle 50% of the population), whiskers – minimum and maximum range excluding the outliers (dogs 37 and 38)
© 2014 British Small Animal Veterinary Association
109
B. Gindiciosi et al.
FIG 2. Serum bromide concentrations of individual dogs arranged from lowest to highest and compared to the therapeutic range (1 to 3 mg/mL)
other adverse effects included sedation, ataxia and polyphagia, however, it was not possible to quantify the occurrence of these adverse effects.
DISCUSSION The main aim of this study was to evaluate the efficacy of an oral KBr loading dose protocol in reaching therapeutic concentrations in serum. Clinical records of dogs that suffered from seizures and had KBr administered orally at the dose of 600 mg/ kg together with 30 mg/kg/day maintenance dose and given within a 48-hour period were reviewed. The results have shown that serum bromide concentrations reach a median of 1·27 mg/ mL (range: 0·74 to 3·6 mg/mL) and that the majority of dogs (>80%) had serum bromide concentrations within the therapeutic interval. Serum bromide therapeutic intervals vary among different reports and also whether bromide is given alone or together with a barbiturate (Trepanier 1995, Trepanier et al. 1998). Initially, a therapeutic interval of 1 to 2 mg/mL was extrapolated from human medicine (Podell & Fenner 1993). More recently, therapeutic intervals for dogs have been established by correlating serum bromide concentrations and therapeutic outcome and found to be 0·88 to 3 mg/mL. (Trepanier et al. 1998). The therapeutic interval used in this study with a minimal therapeutic value of 1 mg/mL and maximal of 3 mg/mL was adopted from Boothe et al. (2012). Bromide has few interactions with other substances within the body. However, one is the competition with chloride ions for reabsorption by the kidneys (Rauws & Van Logten 1975). It has been demonstrated that excretion of bromide varies with dietary chloride intake and this influences the serum bromide concentration (Trepanier & Babish 1995). The dogs in this study were fed a commercially prepared diet with a constant chloride content. However, given the high dose of KBr administered over a short period of time, the effect of changes in dietary chloride content on serum bromide concentration are expected to be minimal. In addition to dietary chloride content, renal function is another factor that could influence serum bromide 110
concentrations in this study. All dogs were screened for renal insufficiency by measuring serum urea and creatinine concentrations, which were all within their respective reference intervals. The use of more sensitive measures of kidney function, such as creatinine clearance was not performed, and as such dogs with kidney dysfunction may have been missed skewing the results. However, it is unlikely that this would represent a major limitation. Neurological and behavioural signs are the most commonly reported adverse effects with KBr administration. In this study sedation, ataxia and also polyphagia were observed as the most frequent adverse effects. Unfortunately, due to the lack of complete data collected from medical records, the incidence of these adverse effects could not be quantified. Furthermore, adverse gastrointestinal events have been previously described for dogs receiving high oral doses of KBr (Rosenblum 1958, Baird-Heinz et al. 2012). Vomiting is thought to be induced by direct irritation of gastric mucosa by KBr. In this study, measures were taken to try to avoid these adverse effects by dividing the total loading dose in 5 to 10 smaller doses and administering each with a small meal. Despite these precautions 2 of the 40 dogs, accounting for 5% of the dogs studied, experienced vomiting during the protocol. Both dogs continued to finish the full loading dose protocol but with a delay. Their serum bromide concentrations after the protocol were slightly under the minimum therapeutic value. In addition, it should be noted that vomiting cannot be solely attributed to KBr administration in one case, due to the use of other medications. One of the study limitations is the small sample size. In addition there are limitations that are inherent to all retrospective studies, such as relying on accurate and complete record-keeping. Furthermore, the 1 to 24 hour post loading interval for the collection of blood samples might influence the results. However, it should be noted that peak serum bromide concentrations after oral administration are reached between 30 and 45 minutes (Trepanier & Babish 1995). In conclusion, the results of this study demonstrate the KBr loading dose protocol is efficient in reaching the therapeutic serum bromide concentrations in dogs suffering from seizures in the clinical setting.
Journal of Small Animal Practice
•
Vol 55
•
February 2014
•
© 2014 British Small Animal Veterinary Association
Serum bromide following loading dose
Conflict of interest None of the authors of this article has a financial or personal relationship with other people or organisations that could inappropriately influence or bias the content of the paper. References Baird-Heinz, H. E., Van Schoick, A. L., Pelsor, F. R., et al. (2012) A systematic review of the safety of potassium bromide in dogs. Journal of American Veterinary Medical Association 240, 705-715 Boothe, D. M. (2012) Anticonvulsants and other neurologic therapies in small animals. Bromide. In: Small Animal Clinical Pharmacology and Therapeutics. 2nd edn. Ed D. M. Boothe. Elsevier Saunders, St. Louis, MO, USA. pp 960-964 Boothe, D. M., Dewey, C. & Carpenter, D. M. (2012) Comparison of phenobarbital with bromide as a first-choice antiepileptic drug for treatment of epilepsy in dogs. Journal of American Veterinary Medical Association 240, 1073-1083 Dewey, C. W., Ducoté, J. M., Coates, J. R., et al. (1999) Intrarectally administered potassium bromide loading in normal dogs. Journal of Veterinary Internal Medicine 13, 238 March, P. A., Podell, M. & Sams, R. A. (2002) Pharmacokinetics and toxicity of bromide following high-dose oral potassium bromide administration in healthy Beagles. Journal of Veterinary Pharmacology and Therapeutics 25, 425-432 Pearce, L. K. (1990) Potassium bromide as an adjunct to phenobarbital for the management of uncontrolled seizures in dogs. Progress in Veterinary Neurology 1, 95-101 Podell, M. & Fenner, W. R. (1993) Bromide therapy in refractory canine idiopathic epilepsy. Journal of Veterinary Internal Medicine 7, 318-327
Journal of Small Animal Practice
•
Vol 55
•
February 2014
•
Rauws, A. G., (1983) Pharmacokinetics of bromide ion - an overview. Food and Chemical Toxicology 4, 379-382 Rauws, A. G. & Van Logten, M. J. (1975) The influence of dietary chloride on bromide excretion in the rat. Toxicology 3, 29-32 Rosenblum, I. (1958) Bromide intoxication. I. Production of experimental intoxication in dogs. Journal of Pharmacology and Experimental Therapeutics 122, 379-385 Schwartz-Porsche, D., Jurgens, N., May, T., et al. (1990) Pharmacokinetics of bromide and bromide therapy in canine epilepsy. Proceedings of the 4th Annual Symposium of the European Society of Veterinary Neurology. Bern, Switzerland, October 19 to 20. pp 32-34 Sisson, A. (1997) Current experiences with anticonvulsants in dogs and cats. Proceedings of the fifteenth annual veterinary medical forum. Lakewood, CO, USA. American College of Veterinary Internal Medicine, pp 596-598 Soremark, R. (1960) Distribution and kinetics of bromide ions in the mammalian body. Acta Radiologica. Supplementum 190, 114 Trepanier, L. A. (1995) Use of bromide as an anticonvulsant for dogs with epilepsy. Journal of American Veterinary Medical Association 207, 163-166 Trepanier, L. A. & Babish, J. G. (1995) Effect of dietary chloride content on the elimination of bromide by dogs. Research in Veterinary Science 58, 252-255 Trepanier, L. A. & Babish, J. G., (1995) Pharmacokinetic properties of bromide in dogs after the intravenous and oral administration of single doses. Research in Veterinary Science 58, 248-251 Trepanier, L. A., Van Schoick, A., Schwark, W. S., et al. (1998) Therapeutic serum drug concentrations in epileptic dogs treated with potassium bromide alone or in combination with other anticonvulsants: 122 cases. Journal of American Veterinary Medical Association 213, 1449-1453
© 2014 British Small Animal Veterinary Association
111
PAPER
Serum bromide concentrations following loading dose in epileptic dogs B. Gindiciosi, V. Palus, S. Eminaga, E. Villiers and G. Bruto Cherubini Dick White Referrals, Cambridgeshire CB8 0UH
OBJECTIVE: To determine serum bromide concentrations following an oral loading dose in dogs. METHODS: Retrospective review of clinical records of dogs suffering from seizures that were treated with bromide. A loading dose of 600 mg/kg potassium bromide was administered orally in 17 to 48 hours together with a maintenance dose of 30 mg/kg/day. Blood samples were collected within 24 hours after completing the protocol and serum bromide concentrations were determined by ultra-violet gold chloride colorimetric assay. RESULTS: Thirty-eight dogs were included in the study. The median age was 3 (range, 0·2 to 10) years and bodyweight 21·8 (3·45 to 46·2) kg. The median serum bromide concentration was 1·26 (0·74 to 3·6) mg/mL. Thirty-two dogs (84·2%) had serum bromide concentrations within the therapeutic interval (1 to 3 mg/mL). The serum concentration in five dogs (13·2%) was just under the minimal therapeutic value and in one dog (2·6%) it exceeded the maximal therapeutic value (3·6 mg/mL). CLINICAL RELEVANCE: Following this oral loading dose protocol, serum bromide concentrations reach the therapeutic range in the majority of dogs. This indicates that the suggested protocol is effective in achieving therapeutic concentrations rapidly in epileptic dogs.
Journal of Small Animal Practice (2014) 55, 108–111 DOI: 10.1111/jsap.12173 Accepted: 18 November 2013; Published online: 16 January 2014
INTRODUCTION Bromide is a negatively charged bromine ion with anticonvulsant properties, used in treatment of canine epilepsy administered as a potassium or sodium salt (Schwartz-Porsche et al. 1990). It has been successfully used for more than two decades as sole treatment or in combination with phenobarbital (Pearce 1990, Schwartz-Porsche et al. 1990, Podell & Fenner 1993). Although it has been recently suggested that phenobarbital has better efficacy for controlling seizures (Boothe et al. 2012), bromide remains a reasonable first choice for the treatment of canine epilepsy, mainly because of the lack of hepatic metabolism (Soremark 1960). Reported bromide half life in dogs varies between 15 and 46 days (Schwartz-Porsche et al. 1990, Trepanier & Babish 1995, March et al. 2002). Due to this long serum half-life a loading protocol has been suggested in order to achieve therapeutic concentrations faster in dogs with seizures (Trepanier 1995, Trepanier & Babish 1995, Sisson 1997). Because of the linear pharmacokinetics of bromide, the serum bromide concentrations at steady state can be simply derived from a single dose administered (Rauws 108
1983). Therefore, in order to target the lower end of the therapeutic interval (1 mg/mL), 450 mg/mL should be given as the loading dose (Trepanier & Babish 1995). This has been tested previously where a loading dose protocol of 600 mg/kg potassium bromide (KBr) was administered intrarectally and as an intravenous (iv) constant rate infusion (Dewey et al. 1999). The average serum bromide concentration after intrarectal dosing was 0·92 mg/mL (range: 0·81 to 1·11 mg/mL) and after iv infusion 1·18 mg/mL (range: 1·13 to 1·22 mg/mL). While pharmacokinetic properties of bromide are well established, to the authors’ knowledge an oral KBr loading protocol has not been evaluated in a clinical setting and serum bromide concentrations after an oral KBr loading dose protocol in dogs suffering from seizures have not yet been reported. The objective of this study was to determine the serum bromide concentrations following a 24-hour oral loading dose protocol in dogs and to assess if the dose is effective in reaching therapeutic concentrations in a clinical setting. A secondary goal was to assess the safety of the KBr loading protocol described and report any significant adverse effects that would interrupt or delay the completion of the loading dose protocol.
Journal of Small Animal Practice
•
Vol 55
•
February 2014
•
© 2014 British Small Animal Veterinary Association
Serum bromide following loading dose
MATERIALS AND METHODS Case selection Clinical records of client-owned dogs examined at Dick White Referrals (Cambridgeshire, UK) for seizure investigations between April 2009 and May 2012 were reviewed. Dogs that were treated with an oral KBr loading dose protocol were included in the study. A dose of 600 mg/kg KBr was administered orally together with 30 mg/kg/day maintenance dose. The full loading dose was administered in 5 to 10 equally divided smaller doses and given in a 17 to 48-hour interval. Dogs were included in the study whether they received KBr loading dose as monotherapy or in combination with another antiepileptic drug. All dogs had haematology and biochemistry results within their respective reference intervals on admission. In addition, all dogs had magnetic resonance imaging of the brain performed and samples of cerebrospinal fluid collected for analysis. Following these investigations all dogs were suspected to have idiopathic epilepsy. The dogs were hospitalised during the treatment protocol and monitored for 24 hours a day during the hospitalisation. Dogs were fed on a commercially prepared tinned diet with chloride content between 0·8 and 1·0% per 100 g dry matter (Royal Canin canned canine Sensitivity Control diet. Crown Pet Foods Ltd., Canned canine i/d diet, Hill’s Pet Nutrition Ltd.). Blood samples for serum bromide concentrations were collected between 1 and 24 hours after completing the loading dose protocol. Dogs that did not have serum bromide concentrations determined within 24 hours after completing the protocol, had KBr administered via other routes than oral or received the loading dose in a longer period than 48 hours were excluded from the study. Dogs that underwent the above mentioned loading dose protocol but vomited during the loading dose protocol were excluded from the statistical analysis.
for normal distribution. Because the majority of these variables were not normally distributed, data is represented as median and range. Percentages were calculated for dogs that had serum bromide concentrations within the therapeutic interval and for those that had values below or above this interval.
RESULTS The records of 76 dogs that had an oral loading dose of KBr were identified. The records of 38 dogs were excluded from the study because 34 dogs did not have serum bromide concentrations determined within 24 hours, 1 dog received the loading dose rectally, 1 dog completed the loading dose protocol in 56 hours and 2 dogs vomited during the protocol. A total of 38 dogs were included in the statistical analysis. Breeds most commonly represented were Labrador retriever (n=5), crossbreed (n=5), Jack Russell terrier (n=3), Border collie (n=3), Border terrier (n=3), boxer (n=3), German shepherd dog (n=2), Staffordshire bull terrier (n=2), Dalmatian (n=2), cocker spaniel (n=2). These dogs had a median bodyweight of 21·8 kg (range: 3·45 to 46·2 kg). The age range was 0·2 to 10 years (median, 3 years). The median post loading serum bromide concentration was 1·27 mg/mL (range: 0·74 to 3·6 mg/mL; Fig 1). Serum bromide concentrations of individual dogs arranged from lowest to highest and compared to the therapeutic interval are represented in Fig 2. A total of 32 dogs (84·2%) had serum bromide concentrations within the therapeutic interval (1 to 3 mg/mL). The serum concentrations in five dogs (13·2%) were under the minimal therapeutic value at 0·74, 0·78, 0·91, 0·94 and 0·95 mg/mL, respectively. In one dog (2·6%) the result exceeded the maximal therapeutic value (3·6 mg/mL). The two dogs that vomited had serum bromide concentrations after the loading dose of 0·73 mg/mL and 0·99 mg/mL. Apart from vomiting,
Clinical records review The collected data included breed, age, bodyweight, total loading and maintenance dose of bromide administered, serum bromide concentrations after the loading dose and the incidence of vomiting during the loading dose protocol. The serum bromide concentrations were compared to the therapeutic interval of 1 to 3 mg/mL. Blood sample analysis Serum was separated immediately and analysed promptly or if collected overnight refrigerated until the next morning. The collected samples were analysed in the in-house laboratory. Serum bromide concentrations were determined by an ultraviolet gold chloride colorimetric assay using Olympus AU400 Chemistry analyzer (Beckman Coulter International S.A.) and reagents provided by Cathachem Inc. Statistical analysis Single variable descriptive statistics were calculated for bodyweight, age and serum bromide concentrations. Due to the small sample size, the Shapiro-Wilk test of normality was used to test Journal of Small Animal Practice
•
Vol 55
•
February 2014
•
FIG 1. Serum bromide concentrations following oral KBr loading dose protocol. Centre line in box – median concentration, box – interquartile range (middle 50% of the population), whiskers – minimum and maximum range excluding the outliers (dogs 37 and 38)
© 2014 British Small Animal Veterinary Association
109
B. Gindiciosi et al.
FIG 2. Serum bromide concentrations of individual dogs arranged from lowest to highest and compared to the therapeutic range (1 to 3 mg/mL)
other adverse effects included sedation, ataxia and polyphagia, however, it was not possible to quantify the occurrence of these adverse effects.
DISCUSSION The main aim of this study was to evaluate the efficacy of an oral KBr loading dose protocol in reaching therapeutic concentrations in serum. Clinical records of dogs that suffered from seizures and had KBr administered orally at the dose of 600 mg/ kg together with 30 mg/kg/day maintenance dose and given within a 48-hour period were reviewed. The results have shown that serum bromide concentrations reach a median of 1·27 mg/ mL (range: 0·74 to 3·6 mg/mL) and that the majority of dogs (>80%) had serum bromide concentrations within the therapeutic interval. Serum bromide therapeutic intervals vary among different reports and also whether bromide is given alone or together with a barbiturate (Trepanier 1995, Trepanier et al. 1998). Initially, a therapeutic interval of 1 to 2 mg/mL was extrapolated from human medicine (Podell & Fenner 1993). More recently, therapeutic intervals for dogs have been established by correlating serum bromide concentrations and therapeutic outcome and found to be 0·88 to 3 mg/mL. (Trepanier et al. 1998). The therapeutic interval used in this study with a minimal therapeutic value of 1 mg/mL and maximal of 3 mg/mL was adopted from Boothe et al. (2012). Bromide has few interactions with other substances within the body. However, one is the competition with chloride ions for reabsorption by the kidneys (Rauws & Van Logten 1975). It has been demonstrated that excretion of bromide varies with dietary chloride intake and this influences the serum bromide concentration (Trepanier & Babish 1995). The dogs in this study were fed a commercially prepared diet with a constant chloride content. However, given the high dose of KBr administered over a short period of time, the effect of changes in dietary chloride content on serum bromide concentration are expected to be minimal. In addition to dietary chloride content, renal function is another factor that could influence serum bromide 110
concentrations in this study. All dogs were screened for renal insufficiency by measuring serum urea and creatinine concentrations, which were all within their respective reference intervals. The use of more sensitive measures of kidney function, such as creatinine clearance was not performed, and as such dogs with kidney dysfunction may have been missed skewing the results. However, it is unlikely that this would represent a major limitation. Neurological and behavioural signs are the most commonly reported adverse effects with KBr administration. In this study sedation, ataxia and also polyphagia were observed as the most frequent adverse effects. Unfortunately, due to the lack of complete data collected from medical records, the incidence of these adverse effects could not be quantified. Furthermore, adverse gastrointestinal events have been previously described for dogs receiving high oral doses of KBr (Rosenblum 1958, Baird-Heinz et al. 2012). Vomiting is thought to be induced by direct irritation of gastric mucosa by KBr. In this study, measures were taken to try to avoid these adverse effects by dividing the total loading dose in 5 to 10 smaller doses and administering each with a small meal. Despite these precautions 2 of the 40 dogs, accounting for 5% of the dogs studied, experienced vomiting during the protocol. Both dogs continued to finish the full loading dose protocol but with a delay. Their serum bromide concentrations after the protocol were slightly under the minimum therapeutic value. In addition, it should be noted that vomiting cannot be solely attributed to KBr administration in one case, due to the use of other medications. One of the study limitations is the small sample size. In addition there are limitations that are inherent to all retrospective studies, such as relying on accurate and complete record-keeping. Furthermore, the 1 to 24 hour post loading interval for the collection of blood samples might influence the results. However, it should be noted that peak serum bromide concentrations after oral administration are reached between 30 and 45 minutes (Trepanier & Babish 1995). In conclusion, the results of this study demonstrate the KBr loading dose protocol is efficient in reaching the therapeutic serum bromide concentrations in dogs suffering from seizures in the clinical setting.
Journal of Small Animal Practice
•
Vol 55
•
February 2014
•
© 2014 British Small Animal Veterinary Association
Serum bromide following loading dose
Conflict of interest None of the authors of this article has a financial or personal relationship with other people or organisations that could inappropriately influence or bias the content of the paper. References Baird-Heinz, H. E., Van Schoick, A. L., Pelsor, F. R., et al. (2012) A systematic review of the safety of potassium bromide in dogs. Journal of American Veterinary Medical Association 240, 705-715 Boothe, D. M. (2012) Anticonvulsants and other neurologic therapies in small animals. Bromide. In: Small Animal Clinical Pharmacology and Therapeutics. 2nd edn. Ed D. M. Boothe. Elsevier Saunders, St. Louis, MO, USA. pp 960-964 Boothe, D. M., Dewey, C. & Carpenter, D. M. (2012) Comparison of phenobarbital with bromide as a first-choice antiepileptic drug for treatment of epilepsy in dogs. Journal of American Veterinary Medical Association 240, 1073-1083 Dewey, C. W., Ducoté, J. M., Coates, J. R., et al. (1999) Intrarectally administered potassium bromide loading in normal dogs. Journal of Veterinary Internal Medicine 13, 238 March, P. A., Podell, M. & Sams, R. A. (2002) Pharmacokinetics and toxicity of bromide following high-dose oral potassium bromide administration in healthy Beagles. Journal of Veterinary Pharmacology and Therapeutics 25, 425-432 Pearce, L. K. (1990) Potassium bromide as an adjunct to phenobarbital for the management of uncontrolled seizures in dogs. Progress in Veterinary Neurology 1, 95-101 Podell, M. & Fenner, W. R. (1993) Bromide therapy in refractory canine idiopathic epilepsy. Journal of Veterinary Internal Medicine 7, 318-327
Journal of Small Animal Practice
•
Vol 55
•
February 2014
•
Rauws, A. G., (1983) Pharmacokinetics of bromide ion - an overview. Food and Chemical Toxicology 4, 379-382 Rauws, A. G. & Van Logten, M. J. (1975) The influence of dietary chloride on bromide excretion in the rat. Toxicology 3, 29-32 Rosenblum, I. (1958) Bromide intoxication. I. Production of experimental intoxication in dogs. Journal of Pharmacology and Experimental Therapeutics 122, 379-385 Schwartz-Porsche, D., Jurgens, N., May, T., et al. (1990) Pharmacokinetics of bromide and bromide therapy in canine epilepsy. Proceedings of the 4th Annual Symposium of the European Society of Veterinary Neurology. Bern, Switzerland, October 19 to 20. pp 32-34 Sisson, A. (1997) Current experiences with anticonvulsants in dogs and cats. Proceedings of the fifteenth annual veterinary medical forum. Lakewood, CO, USA. American College of Veterinary Internal Medicine, pp 596-598 Soremark, R. (1960) Distribution and kinetics of bromide ions in the mammalian body. Acta Radiologica. Supplementum 190, 114 Trepanier, L. A. (1995) Use of bromide as an anticonvulsant for dogs with epilepsy. Journal of American Veterinary Medical Association 207, 163-166 Trepanier, L. A. & Babish, J. G. (1995) Effect of dietary chloride content on the elimination of bromide by dogs. Research in Veterinary Science 58, 252-255 Trepanier, L. A. & Babish, J. G., (1995) Pharmacokinetic properties of bromide in dogs after the intravenous and oral administration of single doses. Research in Veterinary Science 58, 248-251 Trepanier, L. A., Van Schoick, A., Schwark, W. S., et al. (1998) Therapeutic serum drug concentrations in epileptic dogs treated with potassium bromide alone or in combination with other anticonvulsants: 122 cases. Journal of American Veterinary Medical Association 213, 1449-1453
© 2014 British Small Animal Veterinary Association
111
