Original Articles

Home Use of Rectal Diazepam for Cllister and Prolonged Seizures: Efficacy, Adverse

Reactions, Quality of Life, and Cost Analysis Robert L. Kriel, MD*:% ,lames C. Cloyd, PharmD ~, Ronald S. Hadsall, PhD*,

Angeline M. Carlson, BS :, Kelly L. Floren, BS% and Carolyn M. Jones-Saete, RN: ~

From 1982 through 1987, 128 families, who were in- structed in the use of rectally administered diazepam (R-DZP) fi~r the treatment of severe epileptic seizures, were surveyed. Sixty-seven families returned question- naires and met inclusion/exclusion criteria; the results were used to analyze the medical, psychosocial, and economic impact of this p rogram during the first year following instruction. Twenty-six families did not use R-DZP, pr imari ly because of patient improvement . Among families using R-DZP, a total ot' 428 doses were administered to 41 children. R-DZP was effective in controlling seizures in 85% of patients. Adverse reac- tions usually were mild, consisting of drowsiness and/or bebavioral changes. Compared to the year prior to instruction, emergency room visits decreased in both R-DZP- t rea ted and -nont rea ted children; however, co s t - s av ings were g r e a t e r fo r the R - D Z P g r o u p ($1,039.00 vs $420.00 per patient per year). Improve- ments in quality of life associated with the availability of R-DZP were observed by 58% of users and 27% of nonusers which included improved management of their chi ldren 's seizures, increased flexibility in family activities, and greater peace of mind. R-DZP appears to be a practical method in the effective treatment of severe seizures at home.

Kriel RL, Cloyd JC, Hadsall RS, Carlson AM, Floren KL, Jones-Saete CM. Home use of rectal diazepam for cluster and prolonged seizures: Efficacy, adverse reactions, qual- ity of life, and cost analysis. Pediatr Neurol 1991:7: 13-7.

Introduction

Approximately 40% of children with epilepsy will have recurrent seizures despite serum antiepileptic drag (AED) concentrations within the therapeutic range [ 1 ]. Among the

consequences of incomplete seizure control are the devel- opment of cluster and prolonged seizures and status epi- lepticus 12-51. Cluster seizures may be associated with a temporary in3pairment in neurologic function and occa- sionally precede prolonged seizures or status epilepticus [6,71. Status epilepticus is the most serious complication of childhood epilepsy: as many as 20-50% of patients suffer long-term neurologic sequelae (estimated naortality rate: 6-1 I%)14,7,81. As the duration of status epilepticus increases, so does the risk of morbidity and mortality [4]. Cluster and prolonged seizures and status epilepticus often arc preceded by recognizable events, such as stress, lever, infection, or missed medications [6,71.

There is no generally accepted treatment for cluster seizures, although some clinicians recommend the use of intemfittent benzodiazepines administered orally or rectal- ly 19,101. The conventional rnanagement of prolonged seizures and status epilepticus involves parenteral admin- istration of a short-acting benzodiazepine, such as diaze- pam, followed by phenytoin or phenobarbital [ I 1 ]. Intra- venous adrninistration of these drugs is associated with adverse reactions, including hypotension, cardiac dys- rhythmias, or central nervous system depression [ I 1 ]. Con- ventional therapy requires the presence of skilled person- nel in an acute care facility: this requirement inevitably increases the time between seizure onset and medical in- tervention. Following treatment in the emergency room (ER), patients often are hospitalized for diagnostic evalua- tion and medication adjustment, thereby greatly increasing medical costs and family stress.

Rectally-administered diazepam (R-DZP) solution is a practical alternative to conventional therapy. It is rapidly absorbed, has a short onset of action, and is effective in preventing febrile seizures and terminating status epi- lepticus [9,10,12-17]. Parents or other care givers can be trained easily to administer drugs rectally at home, thus reducing ER visits and hospitalizations [15].

From tile +:Dept. of Neurology: Hennepin County Medical Center: tDept, of Phammcy Practice; Univ. of Minnesota: Mpls, MN: ~:Dept. of Pediatric Neurology: Gillette Children's Hospital: St. Paul. MN. This stud), was presented in part at the Child Neurology Society Meeting, Halifax, Nova Scotia, 1988 and the American Epilepsy Society Meeting, San Francisco, CA, 1988.

Communications should be addressed to: Dr. Cloyd: Department of Pharmacy Practice: College of Pharmacy; University of Minnesota; IVlinneapolis, MN 55455. Received September 12, 1990: accepted November 15, 1990.

Kriel et al: Rectal Diazepam 13

In 1981, we initiated a protocol in which R-DZP was made available for home use for children with epilepsy. This report presents a retrospective analysis of the medi- cal, psychosocial, and economic impact of this program.

Methods

From 1982 through 1987, families included in this study were in- slructed in the preparation and administration of R-DZP from 1982 through 1987. The children lived at home and had histories of cluster seizures, prolonged seizures, or status epilepticus. All children were under the care of I of 3 child neurologists who were practicing in the same medical center. Patients had undergone a thorough diagnostic evaluation and their physicians made extensive efforts to optimize oral maintenance AED therapy. Cluster seizures were defined as an unusual. generally sudden, increase in seizure frequency which required inter- vention. Prolonged seizures were defined as those lasting longer than 5 rain, but shorter than 30 rain. Status epilepticus was defined as a seizure so prolonged or frequently repeated as to result in an impair- ment o f consciousness lasting 30 rain or longer [ l l l . Patients with febrile convulsions, with concomitant oral benzodiazepine therapy, or residing in a supervised care facility were excluded from the study. The study was approved by an institutional review board and informed con- sent was obtained from all parents or guardians.

In all cases commercially available diazepam injectable solution in a dose ranging from 0.3-0.5 mg/kg was used for rectal administration. It was administered with a needleless, lubricated 3 ml plastic syringe in- serted 2-4 cm into the rectal cavity. Parents were advised to administer R-DZP at the time a cluster or prolonged seizure was recognized. Ver- bal and written instructions followed by a demonstration were provided to at least one care giver for every patient.

Questionnaires were mailed to families 1-5 years following R-DZP instruction. The questionnaire, which was designed to obtain informa- tion for 1 year prior to and following the date of R-DZP instruction, was mailed to each family identified through the chart review. It in- eluded items regarding frequency of seizures, the number of ER visits for cluster or prolonged seizures or status epilepticus, the use of R-DZP, the parents' assessment of R-DZP efficacy and adverse reac- tions, psychosoeial impact of R-DZP, and relevant demographic data. Questionnaires were not used when respondents failed to provide com- plete information regarding R-DZP usage and ER visits before and after instruction or indicated that they failed to comprehend the questions,

A randomized sample stratified by year of instruction was identified to assess changes in the severity of epilepsy before and after R-DZP instruction. The medical charts of 10 patients who used R-DZP and 10 who did not were reviewed in a blind fashion by a child neurologist (RLK) using a previously developed severity of epilepsy scale [18]. The' possible effects of changes in maintenance AED therapy on seizure Control before and after instruction were investigated by ex- amining medical records from 9 randomly selected patients who re- ceived R-DZP.

The estimated cost of a single dose of R-DZP was determined using the 1988 average Wholesale price of diazepam injectable solution (5 m g / ~ , 2 ml vial), plus the cost of suppfies required for administration. The acquisition cost of a diazepam kit was calculated based on a gross margin of 40%. The average annual drug cost per patient was deter- mined by multiplying the mean number of doses by the acquisition ¢~Sts of a S'.mgi~ kit. The cost of ER care associated with uncontrolled s e i z ~ Was ba~ed on actual charges incurred by patients treated in local ERs. .

Comparisons between nonrespnndents and the study group were made using a 2-tailed, unpaired t test, or ehi square analysis. Differ- enees in pre- and post-instruction ER visits were assessed by a 2-tailed p ~ t test and severity o f epilepsy between users and nonusers by ANOVA,~Statistical. significance was established at the 0.05 level. The relatiouship~ between the number of ER visits and frequency of R-DZP usage was assessed by a simple correlation analysis (Pearson's r test).

Table 1. Factors associated with nonuse of R-DZP

Number of Responses Reason

17 No need

I R-DZP not available when needed

I R-DZP previously ineffective

I School personnel reluctant to use R-DZP

6 No reason given

Results

Questionnaires were mailed to 128 families who had received R-DZP instruction from 1982 through 1987. Forty-three families failed to return their questionnaires; they were designated as nonrespondents. Eighty-five families returned questionnaires, of which 18 did not meet inclusion/exclusion criteria. The remaining 67 families were designated as the study group. Forty-one families gave their children R-DZP (users) 1 or more times during the year following instruction; the indication for R-DZP was prolonged seizures/status epilepticus in 26 and cluster seizures in 15. Twenty-six families reported that they had not given R-DZP (nonusers) to their children during the year following instruction. Among nonusers, the original indication for R-DZP was prolonged seizures in 25 pa- tients and cluster seizures in 1. As listed in Table 1, a majority of nonusers (17/26) had no need to administer R-DZP because their children did not have the type of seizure for which R-DZP was prescribed.

The study group and nonrespondents were similar in several aspects: indication for use of R-DZP, date of R-DZP instruction, and location of families (percentage living in Minneapolis-St. Paul metropolitan area: 48% of the study group vs 51% of the nonrespondent group). There were 2 minor differences: the study group was youn- ger (11.9 vs 13.98 years; P = 0.04) and had fewer males (46 vs 67%; P = 0.03). We conclude that there were no clinically important differences between the study group and nonrespondents. There were no significant differences between users and nonusers with regard to patient sex (23 females and 18 males vs 13 females and 13 males, respec- tively) or age (7.5 + 4.0 vs 6.9 + 3.5 years) or in the respondents' sex, age and educational level.

A total of 428 R-DZP doses (median: 5; range: 1-50) was given during the year following instruction. Thirty- five users (85%) reported that R-DZP was effective in controlling most or all seizures for which it was pre- scribed. Six users (15%) believed that R-DZP was ineffec- tive after the first or subsequent doses. Nineteen children (45%) had undesirable reactions on one or more occasions following drug administration; 14 experienced drowsiness and/or behavioral changes, while 5 had some respiratory difficulty, including 1 patient believed to have had a

z~4~: ~m,.~uc ~fi~UROLOOY VoL 7 No. ]

T a b l e 2. C o m p a r i s o n of e m e r g e n c y room visits for uncon- t ro l led se izures be tween users a n d n o n u s e r s of R - D Z P

N u m b e r of E m e r g e n c y Room Visits Before Af ter

Ins l ruc t i (m Ins t ruc t ion*

Users (N = 4 1 ) 156 52 (3.8 _+ 5.6); ( 1.3 +_ 3.9)

Nonusers (N = 26) 28 6 11.1 +_ 1.4) 10.2 _+ 0.6)

* P < 0.001 for users iuld nonusers. Mean + S.D.

"'respiratory arrest." The respondent reported that the child was not taken to an ER and recovered uneventfully. In most cases it was impossible to ascertain whether R-DZP or seizures caused the undesirable reactions.

Table 2 presents the total and mean number of ER visits for management of uncontrolled seizures. ER usage decreased significantly during the year following R-DZP instruction for both the users and nonusers. As dernon- strated in Figure 1, those patients who frequently required R-DZP (> 12/yr) had approximately the same number of ER visits as other patients. Overall, post-instruction ER visits among users ranged from 0-24, but were not con'e- lated with frequency of R-DZP use (r = 0.33; P > 0.05). One patient, whose seizures appeared to be refractory to R-DZP, received 35 doses followed by 24 ER visits for uncontrolled seizures.

Figure 2 presents severity and frequency of seizure scores for users and nonusers prior to and following R-DZP instruction. Nonusers improved clinically while users remained unchanged. Maintenance AED therapy in patients receiving R-DZP did not change significantly be- tween the pre- and post-instruction periods (2.2 vs 1.8 AEDs per patient).

Families reported psychologic and social benefits as- sociated with R-DZP. Twenty-four of 41 families (58%)

5.0 o =,

4.0-

E o o'6 o = 3.0-

w

~ ~.o-

1 . 0 -

'~ o.o Low High

R-DZP Use

Figure 1. The relationship bem'een fi'equen O' of R-DZP use and mtmher of ER visits. Horizontal lines r~Twesent the mean (± S,D.) num- ber" of ER visits in the )'eat" following R-DZP instruction Jot" low- (< 12) attd high-use (> 12) groups. ER visits for 25 low- and 13 high-use patients were 0.68 ± 1.31 vs 0.82 + 1.77. respectively (P > 0.05). A patient who received 35R-DZP doses followed by 24 ER visits was classified as an outlier astd was excluded from analysis.

believed that the availability of R-DZP made them more capable of managing the seizure disorder, enabled them to leave their children with other caretakers, resulted in in- creased flexibility of schedules, and offered them peace of mind. Four users (9.8%) had negative responses, all of which dealt with undesirable reactions associated with R-DZP. Seven of the 26 nonusers (27%) believed that the availability of R-DZP gave them peace of mind even though they did not need to use it. The remainder of the nonusers had no comments.

The cost of an emergency room visit associated with the treatment of severe seizures was $467.00 (1987 dollars). The cost savings associated with the home administration of R-DZP averaged $1,039.37 per patient per year based on a reduction in ER-related expenditures (Table 3). Among nonusers cost savings due to reduction in ER visits amounted to $420.30 during the year following R-DZP instruction. Users had a larger cost savings due to their proportionately greater reduction in ER visits. Actual sav- ings were greater since our calculations did not include the costs of emergency transportation, lost wages, or hospital- ization for those patients admitted from the ER.

Discussion

Intravenously administered diazepam is commonly used for terminating prolonged seizures, such as status epilep- ticus [11]. The risk of serious adverse reactions and the difficulties related to intravenous administration necessi- tate the presence of medical personnel. R-DZP has been proposed as an alternative [14]. The parenteral solution, when administered rectally, is rapidly and well absorbed, usually reaching effective serum concentrations (> 200 p.g/L) within 10 min [9,12, 16]. The time to reach effective concentrations is comparable to the solution given orally and earlier than with intramuscular administration [9,12]. European investigators have emphasized the safety and efficacy of home use of R-DZP in the treatment of epilep- tic seizures, particularly when treatment is initiated within 15 min of seizure onset [15,17].

Other studies have demonstrated that R-DZP is effective for prophylaxis of febrile seizures [ 14,19-21 ]. Use of inter-

15 8

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> ,

10 ( / )

g == ¢r 5 ¢D

~ Users

Nonusers

Before After

R-DZP Instruction

Figure 2. Epileptic condition of users and nonusers during the veal" prior to attd following R-DZP instruction as measured by seizure severity and frequency score. Pre- and post-instruction scores for users and nonusers were 9.3 ± 2.9 vs 9.0 + 3.3 and 8.1 + 4.6 vs 6.3 + 5.0. respectively [F(1.18) = 3.16; P = 0.09].

Kriel et al: Rectal Diazepam 15

Table 3. Cost analysis of emergency room care related to R-DZP instruction

R-DZP Uses Average Savings Per Year Cost of

Group R E R V in ERV* (R-DZPU) R-DZW

Nonusers 0.9 visits/year $420.30 0 0 Users 2.5 visits/year $1,167.50 10.7 $127.63

* Cost savings in ERV = RERV x (average ER costs: $467.00). t Cost of R-DZP = R-DZPU × $11.90 (estimated cost for one administration of R-DZP). * Cost savings = (cost savings of ERV) - (cost of R-DZP).

Abbreviations:

ERV = Emergency room visits

R-DZP = Rectal diazepam

R-DZPU = Rectal diazepam uses per year RERV = Reduction in emergency room visits

Cost Savings '~

$420.30 $1.039.37

mittent R-DZP for this indication may increase in light of the recent report by Farwell et al. which revealed that children with recurrent febrile seizures treated with daily phenobarbital had the same rate of recurrence as the placebo group and experienced a significant reduction in cognitive function [22].

Recently, home use of R-DZP has been initiated in North America. Camfield et al. evaluated R-DZP in 17 children with either prolonged, epileptic, or febrile sei- zures [23]. There were no complications associated with R-DZP and seizures were promptly terminated in 15 pa- tients. Lombroso compared intermittent rectal with oral DZP for status epilepticus and cluster seizures [9]. Regard- less of the route of administration, seizures were termin- ated in less than 15 min in 83% of the episodes. There were no reports of respiratory depression; however, some de- gree of lethargy was observed in 25% of patients. In a retrospective study involving 7 children, Garofalo et al. reported that R-DZP or rectal lorazepam was effective in interrupting cluster seizures, resulting in a 50% reduction in ER visits. Side effects were limited to drowsiness or transient irritability; tolerance was observed in 1 pa- tient [10].

Our results extend the findings of earlier studies. Most parents or other care givers can be trained easily to identify seizures treatable with R-DZP, prepare the proper dose, and safely administer the drug. Treatment is highly effec- tive in most patients resulting in termination of severe seizures in 85% of our patients. Patients whose seizures were refractory to R-DZP often responded to rectal paral- dehyde. R-DZP remained efficacious despite frequent use (i.e., 12-50 doses per year) as evidenced by the low num- ber of ER visits by the high-use group (Fig 1); however, 1 family reported that R-DZP was effective initially, but failed to control seizures with repeated use. The develop- ment of tolerance to AED activity during chronic diaze- pam administration has been demonstrated in animals and observed in patients, suggesting that daily use of R-DZP should be avoided [24,25]. Likewise, the addition of main- tenance benzodiazepine therapy in patients benefitting from periodic R-DZP may promote the development of

cross-tolerance diminishing the effectiveness of both agents [26,27].

Several explanations could account for the decrease in ER use observed in users and nonusers, including im- provement in seizure control due to changes in mainte- nance AED therapy, an age-related decrease in severity of epilepsy, more appropriate use of ER facilities, effective- ness of R-DZP in terminating seizures, and parental con- fidence in managing severe seizures with R-DZP. Among nonusers, 65% of the parents stated there was no need to give R-DZP. There was also a trend toward improvement among nonusers in their seizure severity/frequency scores. These results suggest that nonusers experienced improve- ment in their epileptic conditions, which would partially account for the decrease in ER visits observed in this group. In evaluating users, we found that neither the severity of epilepsy nor maintenance AED therapy changed significantly during the study period. Based on survey results, we conclude that efficacy of R-DZP and increased parental confidence in managing severe seizures are the primary reasons for the decrease in ER visits ob- served in the user group.

Childhood epilepsy places the family under consider- able psychologic, sociologic, and financial stress [28-30]. The improvements in quality of life and economic benefits of home R-DZP use are as important as its medical effec- tiveness. The availability of a safe and effective home treatment appeared to provide families with some measure of control over an inherently stressful situation. Over one- half of the user families reported that the availability of R-DZP made possible a more normal life style. Knowl- edge that parents could effectively manage severe seizures gave them the confidence to occasionally leave their chil- dren with others, enabled children to return quickly to school, permitted families to participate in leisure activ- ities (e.g., vacations), and allowed family members to con- tinue or resume employment. Interestingly, even nonuser families reported that the availability of R-DZP afforded them greater peace of mind. The reassurance associated with the availability of R-DZP in nonuser families may have contributed to their post-instruction decrease in ER

16 PEDIATRIC NEUROLOGY Vol. 7 No. I

usage, al though the extent of this effect could not be determined.

The $1,039 in annual savings attributable to R-DZP is a

conservat ive estimate; it does not include factors, such as

medical transportation, hospitalization, and loss of wages.

Furthermore, some ER visits among the users may have

been medical ly unnecessary, As an example, 1 mother

reported that she took her child to the ER 6 t imes during

the pos t - ins t ruc t ion per iod , even though R - D Z P had

promptly terminated the seizure in each case.

We acknowledge several l imitations of this study. First,

the retrospect ive nature of the investigation limited our

ability to control variables. For example, some families

were asked to recall events up to 5 years previously. Sec-

ond, the response rate warrants cautious interpretation of

the results. Finally, the small sample sizes, which were

used in assessing the severity of epi lepsy and in est imating

ER costs, l imit the ability to extrapolate these data to larger populations.

Wheneve r R-DZP is prescribed, parents or other care

givers need to be instructed on the correct identification of

c i rcumstances required for drug administrat ion and also on

how to prepare and safely administer the dose. Periodic

fo l low-up is necessary to ensure that parents remain com-

petent in providing treatment. Because there is no com-

mercial product available, kits containing diazepam injec-

table solution, needles, syringes, and lubricant must be

assembled. Consequently, communica t ion be tween nurses,

pharmacists , and physicians is essential in order to assure

that f ami l i es can obtain R - D Z P with min ima l incon-

venience and delay.

H o m e use of R -DZP is effect ive and safe and decreases

medical expenses related to severe seizures. Availabili ty

of R - D Z P reduces family stress and permits family m e m -

bers to enjoy a more normal life style.

This study was funded by grants from the Ramsey Foundation, American Society of Hospital Pharmacists Foundation, and the Upjohn Company.

We thank Frank Ritter, MD and Judy Wulf, MSN for their assistance in the design of this study.

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Kriel et al: Rectal Diazepam 17