A single antiepileptic drug (AED), (phenobarbital

Transcription

1 The Use of Diazepam Per Rectum at Home for the Acute Management of Cluster Seizures in Dogs Michael Podell The use of diazepam per rectum (RDZ) in the home to control generalized cluster seizures in dogs diagnosed with idiopathic epilepsy was evaluated over a 6-month period. All dogs had a prior history of clusters of generalized seizures and were treated with multiple antiepileptic drugs. Owners were instructed to administer diazepam injectable solution (5 mg/ml) per rectum to their dogs at a dose of.5 mg/kg when an initial generalized seizure occurred and when a second or third generalized seizure occurred within 4 hours of the first seizure. Seizure activity was recorded by owners in a daily log before the onset of RDZ use and for the duration of RDZ use, which ranged from 57 to 464 days (median = 57 days). The median age at which the first seizure occurred and the median age at the time of enrollment in the study were 9 and 4 months, respectively. All dogs were treated with phenobarbital, with dogs receiving concomitant bromide therapy. No significant correlation between the duration of the first, second, or third antiepileptic drug therapy and the change in the number of cluster seizure events before or after use of RDZ was found. Comparisons of seizure activity were done for the same time interval before and after the onset of RDZ availability. A significant decrease in the total number of seizure events and the total number of cluster seizures events was found after RDZ availability. Similarly, a significant difference in the average number of seizures per cluster seizure event and the total number of isolated seizure events occurred before and after RDZ therapy. Eight of the dogs (73%) that received RDZ for or more times after the first or second seizure had a % success rate in prevention of further seizure activity after the first dose. In 3 dogs, success and compliance rates were both equal at OO%, thus suggesting % efficacy of RDZ in blocking further seizure activity over the next 4 hours in these dogs. Owners had a large cost-savings because of the decrease in emergency clinic visits after initiating treatment with RDZ. Before RDZ use, the average number of emergency clinic visits was 3, with an average cost of $38 per dog. After RDZ use, the average number of emergency clinic visits was, with an average cost of $8 per dog. The results of this study suggest that RDZ may be an effective method of home treatment of generalized cluster seizures in dogs with idiopathic epilepsy, regardless of prior antiepileptic drug history. J Vet Intern Med 995;8: Copyright 995 by the American College of Veterinary Internal Medicine. pproximately % to 5%'** of dogs treated with a A single antiepileptic drug (AED), (phenobarbital [PB]) develop functional tolerance to the drug and are thereby labeled refractory epileptics with recurrent breakthrough seizures. Many of these dogs have clusters of generalized seizures or status epilepticus that requires emergency therapy at a veterinary h~spital.~ The financial and emotional constraints of repeated emergency therapy are often the limiting factors in an owner's decision to continue treating their pet. Prolonged and recurrent seizures also have a high potential for morbidity and possible death.4 Thus, an im- From Lhe Ohio Slate Universilj~, Department of Veterinary Clinicut Sciences, College of Veterinary Medicine. Colwnhus, OH 43 I Acceplcd Nov~~mher 5, 994. Reprint reqimls: Michuel Podell, D VM, Departrncmt of Veterinury Clinical Sciences. 6 Tharp Sf, Collrige of Veterinarv Medicincz, Crdtimbus, OH 43. The author woiild ihunk Karen Lee.& her help in data collection and Dr. William R. Fennerfi,r his comments in the preparufion of the munuscript. Copyright 995 by the American College qf Veterinary Internal Medicine S9-664/95/U-$3./ portant need exists to investigate potential at-home emergency therapy for animals with cluster seizures. Diazepam (DZ) is the accepted first choice drug for emergency treatment of prolonged seizures, including status epilepticus and cluster seizures in people and animal^.^,^ The preferred route of administration in a hospital environment is IV injection. Comparative pharmacokinetic data in people for single IV, IM, PO, and per rectum (PR) administration of DZ showed that rectal absorption was significantly faster than IM or PO absorption.6 Clinical trials in children and adults showed that cluster seizures can be treated successfully with intermittent home therapy using rectal administration of the parenteral formulation of DZ (RDZ).7-9 As a home treatment in humans, RDZ is effective in reducing emergency care and costs along with alleviating the overall stress associated with having an epileptic child or adult in the house.g Preliminary data in the dog indicates that, after RDZ, there is rapid absorption within minutes, with the bioavailability of the active metabolites of DZ remaining above 65%. No clinical reports were found on the use of RDZ administration to treat cluster seizures in the home environment in the dog. The purpose of this paper is to present information on the use of RDZ at-home for the emergency man- 68 Journal of Veterinaw Internal Medicine. Vol9, No (March-April) pp 68-74

2 DZ PER RECTUM FOR SEIZURE THERAPY 69 agement of cluster seizures in dogs. The effectiveness of RDZ to decrease the number of seizures per cluster seizure event ( event representing all seizures that occurred in a 4-hour period), to prevent seizures after the first dose in a 4-hour period, and to reduce the number Of emergency and costs was evaluated over a 6-month period in a population of dogs with idiopathic epilepsy. Methods and Materials Dogs From March, 99, to July, 993, owners of dogs evaluated at the Ohio State University Veterinary Teaching Hospital (OSUVTH) were instructed in the preparation and administration of RDZ. All dogs had histories of clusters of generalized seizures for at least 6 months before inclusion, and were classified as having idiopathic epilepsy based on normal intenctal behavior according to the owner, early age of seizure onset, normal interictal neurologic examination, and a normal complete blood count (Coulter counter Model Senior; Coulter Electronic, Hialeah, FL), serum chemistry profile (Technicon 8/6; Technicon Industrial Systems, lnc, Tarrytown, NY), urinalysis (Chemstrip 7 urine test strips; Boehringer Mannheim, Indianapolis, IN), and cerebrospinal fluid analysis (Cytospin, Shandon Elliott, Surrey, England; Microprotein Rapid Stat Kit, Rockford, IL). The latter included cell count (normal = <5 white blood cells/ pl), cytological evaluation after cytocentrifugation (normal = predominance of small mononuclear cells), and quantitative protein analysis (normal = <5 mg/dl). All dogs were treated with multiple AEDs in the course of their disease. Phenobarbital was used in all dogs, with a documented trough PB serum concentration within the therapeutic range of to 4 pg/ml at the time of onset of instruction of RDZ use as a requirement for inclusion. Potassium bromide (BR) was used in of the dogs for varying durations as a supplemental AED with PB. The serum concentration of BR was within the range of to mg/dl. R D Z A dm inistration Technique In all cases, commercially available DZ injectable solution (Diazepam injection, 5 mg/ml, Elkins-Simm, Inc, Cherry Hill, NJ) at a dose of.5 mg/kg was used for rectal administration. Owners were instructed to administer the RDZ with a plastic -inch teat cannula (J- teat infusion cannula [ f in]; Jorgensen Labs, Loveland, CO) attached to a plastic syringe and inserted approximately cm into the rectum when an initial generalized seizure with paddling or abnormal muscle movements occurred or when a second or third generalized seizure occurred within 4 hours of the previous seizure. RDZ was not administered if () a 4th seizure occurred within a 4-hour period; () the dog was having difficulty breathing Or appeared excessively depressed; or (3) any blood was seen around the rectal region from a previous dose. If these conditions occurred, owners were instructed to bring their pet into a veterinary emergency haspital or the OSUVTH. Data Analysis All seizure activity was recorded by owners in a daily log before the onset of and for the duration of RDZ use. Owners maintained a careful record of their dog's seizure activity by including the date, time, and description of any observed seizure; the amount of DZ dosed per rectum each time; any problems associated with the injection (eg, rectal bleeding); any behavior changes occumng after the dose (eg, excessive depression); and the description and time of any subsequent seizures within 4 hours after the RDZ dose. Owners responded to written questionnaires concerning the ease of technique, the perceived benefit of RDZ to eliminate cluster seizure events, the increase or decrease in anxiety associated with RDZ use for the owner, and the influence of RDZ to continue treatment of their pet. The data was analyzed for comparison between the total number of seizure events (a seizure event was defined as all seizures that occurred within a 4-hour period), the number of cluster seizure events ( or more seizures in a 4-hour period), the average number of seizures per cluster seizure event, the number of isolated seizure events ( seizure within a 4-hour period), and the number of emergency clinic visits and their costs before and after RDZ using the Wilcoxon signed-rank test." The time period of seizure activity analyzed was equal before and after RDZ use for each dog. Therefore, all comparisons were made for an identical time period. Correlations were performed using the Spearman rank correlation coefficient test" between the delta seizure value (number of cluster seizures events of or more seizures in a 4-hour period before RDZ use minus the number of cluster seizure events after RDZ use) and other dependent variables to include the duration of time without AED treatment; the duration oftreatment with the first, second, or third AED; and the duration of treatment with BR. Significance was set at the.5 level (Statview SE and Graphics, Macintosh, Abascus Concepts, Berkeley, CA). Success rate to stop recurrent seizures after the first RDZ injection at the time of the first or second observed seizure was calculated according to the formula: Number of times RDZ was associated with no further seizures when dosed at the first or second seizure X, divided by the total number of times RDZ was dosed at the first or second seizure. Compliance rate of owners to follow instructions to administer RDZ at the first observed seizure was determined to compare to the success rate. Compliance rate was calcu-

3 7 MICHAEL PODELL Dog No Median Mean Table. Patient Characteristics Age at Owner Ageof Instruction First Weight for RDZ Seizure Breed Sex (kg) (moi (mo) Shetland Sheepdog F/S 8.5 Dalmatian F/S Mixed Breed F/S German SheDherd doa M Keeshond German Shepherd dog German Shepherd dog Curly-Coated retriever Collie Mixed Breed Mixed Breed F/S M 47 M/C 36 M 36 M/C 64 F/S M Abbreviations RDZ, diazepam per rectum, M, male, M/C, male castrated; F, female, F/S, female spayed within 4 months of their first seizure. The median time without treatment after the first seizure was 69 days (range, to 95 days). The median duration of treatment before RDZ use was 63 days (range, 4 to 87 days). Ten dogs had PB as the first AED, with dog treated with primidone as the first AED. Other AEDs included BR, primidone, oral DZ, and phenytoin; dogs were treated with concomitant PB and BR therapy. The median duration of the first AED was 99 days; the second AED was 4 days; and the third AED was 5 days. There was no significant correlation between the duration of the first, second, or third AED, or BR therapy and the change in the number of cluster seizure events before and after use of the RDZ (P =.53,.8,.8,.73, respectively). Furthermore, no significant correlation between the duration of time untreated (from the first seizure until the start of the first AED) and the decrease in cluster seizure events after RDZ use was found (P =.4). lated according to the following formula: Total number of times RDZ was injected at the first seizure X, divided by the total number of seizure events. Complete compliance (%) was defined as an owner who gave RDZ at the time of the first seizure for all seizure events. Results Signalment Eight of the dogs were purebred, with German Shepherd dogs being the most common breed in the study group (n = 3) (Table ). There were 4 male, male castrated, and 5 female spayed dogs. The enrollment ages ranged from 8 to 89 months, with a median of 4 months. The median weight for all dogs at enrollment was 36 kg (range, to 64 kg). Of the dogs, were euthanized because of refractory epilepsy (dogs, 6) and died after being hit by a car (dog 8). The remaining dogs are still alive and receiving therapy for their epilepsy. Prior Seizure History and Therapy Eight dogs (73%) experienced their st seizure between and 5 years of age, with a median age of 9 months (Table ; range, 3 to 47). Concerning prior AED therapy, 5 dogs had 3 AEDs (dogs,, 3,4, 7), and the other 6 (dogs 5, 6, 8, 9,, ) had AEDs before the use of RDZ. Seven dogs (64%) were treated Response to the Use of Diazepam PR Diazepam per rectum was to OwnerS to treat cluster seizure events in their dogs for a median time of 57 days (range, 57 to 464 days). During that time, a significant decrease in the total number of seizure events after the onset of RDZ therapy was found, when compared with the identical time period before RDZ use. (P =.) (Fig ). The number of cluster - cn.5 T.5 I - TOTAL EVENTS TOTAL EVENTS TOTAL CLUSTER TOTAL CLUSTER PRE-RDZ POST-RDZ EVENTS EVENTS PRE-RDZ POST-RDZ Fig. Box-and-whisker plots for the total number of seizure events and cluster seizure events before (a) and after () the onset of RDZ doses for the dogs in this study. The "waist" of each vertical plot represents the median number. The vertical line belowthe box represents the first quartile of the data and the vertical line above the box represents the last quartile of the data. Circles represent outlying data points.

4 PER RECTUM FOR SEIZURE THERAPY 7 v) lo W z 8 W a W v) Y O 4, W E - Fig. Box-and-whisker plots for the average number of seizures (SZ) per cluster seizure event and the total number of isolated seizure events before (illll) and after () the onset of RDZ injections for the dogs in this study. The "waist" of each vertical plot represents the median number. The vertical line below the box represents the first quartile of the data and the vertical line above the box represents the last quartile of the data. Circles represent outlying data points. seizure events after the onset of RDZ therapy was also significantly different from a median of 9 (range, 3 to 5) before RDZ therapy to a median of (range, to 8) after RDZ therapy (P =.) (Fig ). For all dogs, 58% of all RDZ doses were given at the time of the first seizure. The number of seizures per cluster seizure event for all dogs was significantly decreased from a median of 4 to a median of after the initiation of RDZ therapy (P =.) (Fig ). A concomitant significant increase from a median of to median of 3 in the total number of reported isolated seizure events for all dogs occurred after RDZ therapy (P =.3) (Fig ). The number of times recurrent seizure activity was present after the first observed seizure, whether or not RDZ was used as instructed, is summarized in Table. Recurrent seizure activity was not detected after the first dose of RDZ at the first or second observed seizure at least time in 9 of I dogs (8%). In contrast, when RDZ was available but owners elected not to use it, recurrent seizure activity was not detected in only 3 dogs (7%). The average success rate of this first RDZ dose was 73%. Eight of the dogs (73%) had a success rate of %. Two dogs did not show any benefit from this first dose to stop further seizures (dogs 4 and 6). The median compliance rate for the group was 88% (Table ). For 7 dogs, the success rate was greater than or equal to the compliance rate (64%). Three of these dogs (8%) had equal compliance and success rates of %. The remaining 4 dogs had compliance rates greater than their success rates. Owners had a cost savings because of the reduction in emergency clinic visits after the onset of RDZ use. Owners took their dog to an emergency clinic an average of 3 times before RDZ use, ranging from to visits. The costs for these visits, averaged $38, with a minimum of $ and a maximum of $,936 spent per dog for the comparable period before RDZ use. In contrast, after using RDZ, the number of emergency clinic visits decreased to an average of visit and ranged from to 5. The emergency clinic costs were also decreased, averaging $8, with a minimum of $ and maximum of $574 spent per dog. Although there was not a significant difference in the number of EC visits pre-rdz versus post-rdz use (P =.659), a significant difference in total costs per dog for the same time period of evaluation was found (P =.38). All owners responded to letter questionnaires concerning their perceptions of the benefit of RDZ. All owners strongly agreed that the technique of dosing was easy to perform. No observable adverse effects were reported. Furthermore, all owners strongly agreed that RDZ allowed them to feel in better control of their dog's seizure problem and, therefore, less anxious during a seizure event. Three owners indicated that they did not think RDZ considerably helped their dog stop seizuring (owners of dogs 4, 6, and 7), although l of these owners acknowledged that RDZ played a role in continuing to treat their dog as an epileptic (dog 4). Discussion This study shows that home therapy of dogs with idiopathic epilepsy and generalized cluster seizures using RDZ is associated with a significant decrease in the number of cluster seizure events in a 4-hour period, and a decrease in the total number of seizure events when compared with an identical time period without such therapy. As a consequence of this change, there was a significant decrease in the total cost in emergency care per dog compared with a similar time period before the onset of RDZ use. These financial savings were associated with a reduced number of emergency clinic visits and a reduced level of owner anxiety. The response to RDZ was not correlated with prior duration of treatment with other AEDs. Furthermore, the response was not influenced by the duration of time without treatment between

5 7 MICHAEL PODELL the first seizure and the administration of the first AED. These findings suggest that prior AED therapy type or duration does not influence the potential response to RDZ treatment. Thus, all dogs with idiopathic epilepsy and cluster seizures may benefit from this treatment regimen. The pharmacokinetics DZ administered PO or IV in the dog have been reported. Dogs differ from people in that DZ is rapidly metabolized to the major active metabolites desmethyldiazepam and oxazepam, with little measurable parent drug after the first hour. * The maximal achievable serum concentrations of these metabolites are obtained in to hours, therefore making oral emergency therapy less desirable. Administration PR in dogs, however, potentially avoids some of the first pass effect observed after DZ is given PO because a portion of the venous blood return from the rectum via the caudal rectal veins bypasses the portal cir~uation.l~ Comparative pharmacokinetic data in people for single IV, PR, IM, and PO administration of DZ showed that rectal absorption was significantly faster than IM or PO absorption.6 Comparison between IV and rectal administration in the dog showed that both low dose (.5 mg/kg) and high dose (. mg/kg) DZ rectal dosing resulted in relatively high bioavailability, with the higher dose providing a rapid ( minutes) and prolonged duration of the total benzodiazepine serum concentration. lo The risk of adverse reactions and the difficulties related to IV administration necessitate the presence of medical personnel. Diazepam PR, however, has been used as an alternative home treatment in people because it is easy to administer and is well-absorbed from the rectal mucosa.6 In children, RDZ has been shown to be effective as a home therapy to treat cluster seizures, resulting in significant monetary savings and alleviation of parental an~iety.~?~ Success rates for seizure termination in children ranged from 53% to 85%.8,9 Similar findings have been reported for adults with recurrent generalized and partial seizures.4 Diazepam administration PR has been shown to be effective in treating a variety of seizure types in people. Studies in children involve primarily populations with generalized seizures of idiopathic or febrile etiol- Both partial and absence recurrent seizures have been controlled by RDZ in adults, as documented by cessation of electroencephalographic (EEG) epileptiform change^.'^.'^ In children, seizure events unresponsive to both IV and RDZ were associated with hypsarrhythmic EEG changes (children less than months of age) and an unorganized paroxysmal EEG pattern (children over months of age). Only % of human patients unresponsive to RDZ were controlled with IV DZ injection. In this study, all dogs had generalized seizures and had a significant reduction in the total number of cluster seizure events after RDZ therapy. Electroencephalographic data was not available for all dogs to evaluate as predictors of response. Earlier treatment in the course of the seizure (<5 minutes) was associated with a significantly greater success rate in stopping further seizure activity in hu- Table. Analysis of the Use of RDZ Success in Preventing Recurrent Seizure Activity No Times No Recurrent No of Times No Recurrent Do9 Seizures After First RDZ Seizures Without RDZ Success Rate to Stop Recurrent Compliance No Injection Injection Seizures After First Injection (%) Rate (%) Median Mean Abbreviation RDZ, diazepam per rectum Number of times RDZ was associated with no further seizures when injected at the first or second seizure Success Rate = Total number of times RDZ was injected at the first or second seizure Total number of times RDZ was injected at the first seizure Compliance Rate = Total number of seizure events

6 DZ PER RECTUM FOR SEIZURE THERAPY 73 man patients. Comparison of compliance rate to success rate is a way of determining if owner compliance could have influenced the benefit of RDZ injection to stop further seizures if given at the first seizure. Cases with success rates greater than or equal to compliance rates suggest that cluster seizure events are responsive to RDZ therapy and that better control may be possible with improved compliance. The association of RDZ with cessation of further seizure activity in this study was complicated by the lack of total compliance of owners to administer RDZ at the first seizure as instructed. That 73% of the dogs that received RDZ for or more times after the first or second seizure had a % success rate to prevent any further seizure activity after the first dose attests to the general benefit of RDZ in suppressing recurrent seizure activity over a short time frame. In 3 dogs, success and compliance rates were both equal at loo%, thus suggesting % efficacy of RDZ in blocking further seizure activity over the next 4 hours in these dogs. The median compliance rate of 88% correlates closely to the cooperation rate of 8% reported for a population of families instructed to use RDZ in children with febrile seizures. The failure of RDZ to be associated with complete suppression of all further seizures in the next 4 hours could be related to complications in administration, poor absorption, insufficient cerebrospinal ff uid concentration of the active metabolites of DZ, or functional tolerance to the drug. A dose of.5 mg/kg was determined in children and adult human epileptic~ ~ to be most effective in suppressing epileptiform activity. A more prolonged duration of drug effect or higher cerebrospinal fluid concentrations obtained from higher doses than that provided by.5 mg/kg may be needed in some dogs with epilepsy. Other benzodiazepines with longer duration, such as lorazepam, may represent another alternative. Diazepam per rectum at.5 mg/kg was well tolerated by all dogs in this study, as shown by owners and lack of any need for emergency care directly related to RDZ administration. Local irritation of the rectal mucosa associated with burning sensation was seen more commonly in adult humans with DZ solution concentrations above.5 mg/kg. Other potential complications found in people are sedation, ataxia, cardiovascular depression, respiratory depression/arrest, muscular hypotonia, and rebound seizure activity. In the dog, IV DZ at this dose does not alter heart rate, mean arterial blood pressure, or cardiac output. Stabilization of these factors is important to avoid potentiation of any deleterious cerebrovascular dynamic changes during seizure events. Recurrent seizure activity can lead to functional and pathological changes in the brain that can potentiate AED refract~riness.~~ The ability to reduce the total number of seizures and, in particular, cluster seizure events, as shown in this study may be quite beneficial in the overall success in treating dogs with idiopathic epilepsy. The finding of a significant difference in total costs per dog for emergency care suggests that less treatment was also needed per dog for the necessary emergency clinic visits after the onset of RDZ. Coupled with a reduction in owner anxiety and financial commitment in maintaining a dog with epilepsy, a more comprehensive plan of treatment may be formulated. The influence of maintenance AED therapy cannot be ignored as a variable in contributing to the reduction in seizure number and cluster seizure events. There was no significant correlation between the duration of the first, second, or third AED, or BR therapy and the change in the number of cluster seizure events after use of the RDZ. Therefore, the duration of any of the prior treatments was not solely responsible for the improvement of cluster seizure control. Furthermore, no significant correlation between the duration of time untreated (from the first seizure until the start of the first AED) and the reduction in cluster seizure events after RDZ use was found. Therefore, the duration of time the patient was not treated before using RDZ did not influence the response to RDZ. Concomitant BR and PB therapy, however, may have influenced the response through a synergistic effect, as this AED combination has been shown to reduce the total number of seizure events and change the type of seizure to a less severe form.4 Other variables that might have influenced the benefit of RDZ are the possibility that owners missed the first seizure and/or that a particular dog was poorly observed, tended to seizure only when owners were away, or had cluster seizures only twice without RDZ therapy. These factors are difficult to control in a study that relies on owner input. The fact that these dogs with refractory idiopathic epilepsy were cared for as epileptics for a median time of 63 days attests to the dedication of the owners to try to control their seizures as much as possible. Overall, the results of this study suggest that RDZ maybe an effective method of treatment of generalized cluster seizures in idiopathic epilepsy regardless of prior AED history and duration. The documented ability to reduce the number of cluster seizure events is also beneficial in the overall successful therapeutic control of idiopathic epilepsy. Although additional

7 74 MICHAEL PODELL prospective evaluation with a larger sample size is needed, this study suggests that RDZ contributes to fostering a better home environment for the epileptic dog and its owner through the reduction of total seizure activity, yearly emergency clinic costs, and owner anxiety. References. Farnbach GC. Serum concentrations and efficacy of phenytoin, phenobarbital, and primidone in canine epilepsy. J Am Vet Med Assoc 984: 84: I 7-.. Schwartze-Porche D, Loscher W, Frey HH. Therapeutic efficacy of phenobarbital and primidone in canine epilepsy: A comparison. J Vet PharmacolTher 985:8: Farnbach GC. Seizures in the dog. Part. Control. Comp Cont Ed 985;7: Delgado-Escueta AV, Wasterlain CG, Treiman DM, et al. Status epilepticus: mechanisms of brain damage and treatment. New York, NY: Raven Press: 983:l lndrieri R. Status epilepticus. In: Indrieri R, ed. Problems in Veterinary Medicine. Baltimore, MD: Lippincott; 989: Moolenaar F, Bakker S, Visser J, et al. Biopharmaceutics of rectal administration of drugs in man. IX. Comparative biopharmaceutics of diazepam after single rectal, oral, intramuscular and intravenous administration in man. Int J Pharmaceutics I98;5: Knudsen FU. Rectal administration of diazepam in solution in the acute treatment of convulsions in infants and children. Arch Dis Childhood 979;54: Lombroso CT. Intermittent home treatment of status and clusters of seizures. Epilepsia 989: 3:s I Kriel RL, Cloyd JC, Hadsall RS, et al. Home use of rectal diazepam for cluster and prolonged seizures: efficacy, adverse reactions, quality of life, and cost analysis. Pediatr Neurol 99 I ;7: Alcorn J, Papich M. Absorption ofdiazepam following rectal administration in dogs. Proceedings of the th Annual Veterinary Medical Forum, ACVlM 993:934. I. Daniel WW. Biostufisticx A Fotindutionjiir Anulysis in the Hculrh Scienc<>.s, 5th ed. New York. NY: John Wiley and Sons; 99: Loscher W, Frey HH. Pharmacokinetics of diazepam in the dog. Arch Int Pharmcodyn 98:54: Evans HE, Christensen GC. Miller s Anatomy of the Dog. Philadelphia, PA: W. B. Saunders: 979: Remy C, Jourdil N, Villemain D, et al. Intrarectal diazepam in epileptic adults. Epilepsia 99:33: Milligan N, Dhillon S, Richens A, et al. Rectal diazepam in the treatment of status: A pharmacodynamic study. J Neurol Neurosurg Psychiatry 98:44: De Negri M, Gagger R, Veneselli E, et al. Rapid diazepam introduction (venous or rectal) in childhood epilepsy: Taxonomic and therapeutic considerations. Brain Dev 99 I: 3: Rossi LN, Rossi G, Bossi A, et al. Behaviour and confidence of parents instructed in home management of febrile seizures by rectal diazepam. Helv Paediatr Acta 989:43: Frey HH, Philippin HP, Scherkl R. Development of tolerance to the anticonvulsant effect of benzodiazepines in dogs. In: Koella WP, et al., ed. Tolerance to Beneficial and Adverse Effectsof Antiepileptic Drugs. New York, NY: Raven Press: 986: Dulac, Alcari J. Rey E, et al. Blood levels of diazepam after single rectal administration in infants and children. J Pediatr 978;93: 39-4 I.. Deshmukh A, Wittert W, Schnitzler E, et al. Lorazepam in the treatment of refractory neonatal seizures. Am J Dis Child 986; 4: Seigler RS. The administration of rectal diazepam for acute management of seizures. J Emerg Med 99;8: Jones DJ, Stehling LC, Zauder HL. Cardiovascular responses to diazepam and midazolam maleate in the dog. Anesthesiology 979; 5 : Koestner A. Neuropathology of canine epilepsy. In: lndrieri R, ed. Problems in Veterinary Medicine. Baltimore, MD: Lippin- Cotti Podell M, Fenner WR. Bromide therapy in refractory canine idiopathic epilepsy. J Vet Int Med 993; 7:38-37.