e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y x x x ( 2 0 1 4 ) 1 e6

Official Journal of the European Paediatric Neurology Society

Original article

Efficacy and safety of intramuscular midazolam versus rectal diazepam in controlling status epilepticus in children Ali Akbar Momen a, Reza Azizi Malamiri a,*, Ali Nikkhah a, Maryam Jafari b, Abbas Fayezi b, Kourosh Riahi b, Elham Maraghi c a

Department of Paediatric Neurology, Golestan Medical, Educational, and Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran b Department of Paediatrics, Golestan Medical, Educational, and Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran c Department of Epidemiology and Biostatistics, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran

article info

abstract

Article history:

Objective: The aim of this study was to evaluate the efficacy and safety of intramuscular

Received 14 July 2014

midazolam in controlling convulsive status epilepticus in children, by comparing it with

Received in revised form

rectal diazepam.

27 October 2014

Methods: In this randomized trial, 100 children (50 in each group) with convulsive status

Accepted 16 November 2014

epilepticus aged 1 month to 16 years were enrolled and randomly assigned into two groups to receive either 0.3 mg/kg intramuscular midazolam or 0.5 mg/kg rectal diazepam. Main

Keywords:

outcome measure was stopping of all motor activity after drug administration. Another

Convulsive status epilepticus

measures were times between patient's arrival to emergency department till drug

Rectal diazepam

administration, between drug administration to seizure cessation, and between patient's

Intramuscular midazolam

arrival to seizure cessation.

Children

Results: Both medication were effective for seizure control and no significant difference was found between successful treatments after administering the medication (P ¼ 0.061). In the midazolam group, in 96% (48/50) of cases treatment was successful and in the diazepam group, in 94% (47/50) of cases treatment was successful. Time from arrival to administering the medication was significantly shorter in midazolam group (P ¼ 0.017). The majority of seizures in midazolam group were stopped in less than 66 s (median) compared to 130 s (median) for diazepam group, (P < 0.001). No serious adverse effects were seen in both groups.

* Corresponding author. Department of Paediatric Neurology, Golestan Medical, Educational, and Research Center, Ahvaz Jundishapur University of Medical Sciences, #90, Golestan Blvd., P.O. Box 6135733118, Ahvaz, IRAN. Tel./fax: þ98 613 3743063. E-mail address: [email protected] (R. Azizi Malamiri). http://dx.doi.org/10.1016/j.ejpn.2014.11.007 1090-3798/© 2014 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

Please cite this article in press as: Momen AA, et al., Efficacy and safety of intramuscular midazolam versus rectal diazepam in controlling status epilepticus in children, European Journal of Paediatric Neurology (2014), http://dx.doi.org/10.1016/ j.ejpn.2014.11.007

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e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y x x x ( 2 0 1 4 ) 1 e6

Conclusion: IM midazolam is not superior but may be at least as effective as rectal diazepam for controlling of status epilepticus in children. Midazolam via IM route could be one of the choices in children with convulsive status seizures who have difficult IV access. © 2014 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

1.

Introduction

Convulsive status epilepticus is one of the most common neurological emergencies that occurs in children. Such seizures usually are associated with high morbidity and mortality, therefore, urgent treatment is warranted. Based on the etiology, co-morbidities, and duration of seizures, long term outcomes would be different and all the previous studies claimed that early treatment by an effective agent usually leads to better outcome. To cease convulsive seizure rapidly, the medication should reach the brain quickly while lacks serious adverse effects. For this purpose, IV administration of anticonvulsants could be the best route but in a child with active convulsions IV access could be very difficult, therefore, other routes for drug administration should be considered.1e4 Standard protocols recommend IV diazepam and lorazepam as the standard acute treatment for status epilepticus but as previously mentioned when getting IV access is difficult other routes for drug administration should be considered. Rectal, buccal, and nasal routes are well-studied for drug administration in convulsive status epilepticus. Many studies recommend rectal diazepam for home treatment of status seizure and in many emergency departments in our country the rectal diazepam is the main initial treatment for status seizures. One of the limits of rectal diazepam is that many parents in developed and developing countries are not satisfied to administer drug via the rectum.1,3 A number of studies demonstrated that buccal and nasal midazolam could be an effective and safe choice for controlling convulsive status seizures but these routes could be unreliable in a number of patients because it may be very difficult to open the mouth of the patient during the seizure when the jaw is locked and nasal congestion and copious discharges during active seizures could lead to insufficient absorption of drug via nasal mucosa.1,5e15 IM drug administration during active seizures could be very easy and safe and a number of studies demonstrated that IM midazolam could be an initial agent for controlling status seizures in home, office, and pre-hospital settings. Previous studies indicated that anticonvulsant activity of IM midazolam is equal to or better than diazepam, moreover, after IM administration, midazolam would be completely absorbed and reached the brain rapidly.3,4,15e19 Many children with status epilepticus who referred to our emergency departments have difficult IV access and rectal diazepam administration in our country is mostly unacceptable by parents. In addition, rectal gel diazepam is very expensive and inaccessible in our country and almost always injectable formulation of diazepam instead of rectal gel is administered via rectum after dilution with normal saline.

Opening the vials of diazepam and drawing the content into a syringe and diluting the content by normal saline and attachment of a tube to syringe before insertion into the rectum would lead to significant delay in drug administration. Because of these limitations, we carried out a trial to show the efficacy of IM midazolam as the initial agent in controlling convulsive status seizures in children who had no IV access comparing it with rectally administered diazepam.

2.

Materials and methods

2.1.

Study design and location

We conducted a not blinded, controlled, randomized trial to evaluate the efficacy and safety of IM midazolam to control status epilepticus in children comparing it with rectal diazepam as control group. The study was conducted at the emergency departments of Golestan and Abuzar Hospitals, two University affiliated tertiary referral children's hospitals in Ahvaz, Iran. Golestan Hospital is an urban university affiliated general Hospital with pediatric subspecialty wards and Abuzar Hospital is an urban university affiliated pediatric referral Hospital. The study was conducted between November 2012 and September 2013. The study design was approved by the ethical board committees of the medical centers and Ahvaz Jundishapur University of Medical Sciences. Because of the study design and situation, taking written informed consents from the parents or care givers had many complexities but staffs at the emergency departments who performed the study, were fully trained to rapidly describe the situation to the parents and to give a verbal consent from them to participate in the study. After this brief description, either during seizure control or after seizure control written informed consents were taken from all the parents.

2.2.

Patients

We enrolled children aged one month and older presenting with convulsive status epilepticus. We used a practical definition for convulsive status epilepticus to define eligible patients that is proposed by Lowenstein et al.,20 who defined status epilepticus as a continuous, generalized, convulsive seizure lasting longer than 5 min. Based on this definition, we enrolled all children who were convulsing while arriving to emergency departments. We enrolled all children whose parents brought them to the emergency departments and those children who were brought by paramedics were enrolled only when they had no IV access. None of the children was enrolled more than once for different episodes of status epilepticus.

Please cite this article in press as: Momen AA, et al., Efficacy and safety of intramuscular midazolam versus rectal diazepam in controlling status epilepticus in children, European Journal of Paediatric Neurology (2014), http://dx.doi.org/10.1016/ j.ejpn.2014.11.007

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e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y x x x ( 2 0 1 4 ) 1 e6

2.3.

Inclusion and exclusion criteria

We enrolled all those children aged one month and older who were convulsing while attending our emergency departments. We excluded all those children who had one of the following criteria; those children with convulsive status seizures who had an established IV access on arrival to our emergency departments, those children who were previously administered rectal or nasal benzodiazepines by parents or paramedics, all those children whose parents were reluctant to give a verbal consent to participate in the study, and all those children having serial seizures without recovery of consciousness between seizures. We also excluded those children who had a history of serious adverse reactions to IM midazolam or rectal diazepam.

2.4.

Randomization and intervention

Consecutive patients were enrolled and randomized to receive either IM midazolam or rectal diazepam. We used a random number table for randomization. Because of our emergency departments' protocol for status seizures control, in all children who enrolled into the study an IV access was established to administer an anticonvulsant with long lasting effect after seizure control by either IM midazolam or rectal diazepam. To reduce bias in time measurements after administering the medication, in each center one set of staff conducted the intervention and measured the times and another staff were getting IV access and attempts were made to secure IV access after the medications were given. IM midazolam was used with a dose of 0.3 mg/kg and rectal diazepam was used with a dose of 0.5 mg/kg. Midazolam was injected into the left quadriceps muscle if the child was younger than two and if the child was older than two the left deltoid muscle was considered for injection. In the diazepam group, the drug was drawn into a syringe, a tube was inserted into the rectum and the syringe was attached to the tube, following which the diazepam was expelled into the tube. To ensure that the drug was administered correctly, the buttocks were held together for 5 min to prevent expulsion and then the tube and the syringe were removed. All children who enrolled were admitted for at least 48 h depending on the cause of seizures and the required investigations were conducted including; blood chemistry, EEG, CT, or MRI.

2.5.

2.6.

Time measurement

In each center a fully trained staff measured the following times using a digital chronometer; time from arrival to administer medication, time to cessation after medication, time to cessation after arrival, and time of any seizure recurrence after stopping of the seizures. These staff were not blinded to treatment groups but for reducing bias they were asked to measure precise times and to register them. To reduce inter observer variations in time measurements the staffs who registered the times had a full mobile access to one of the research team members to clear ambiguities in time measurements.

2.7.

Adverse effects

In all children respiratory rate and blood pressure were assessed and registered to monitor adverse effects.

2.8.

Statistics and data analysis

Based on the previous studies, the sample size was calculated with the Type I error a ¼ 0.05 and Type II error b ¼ 0.2. Based on previously published findings, the necessary sample size was calculated to be at least 50 patients in each treatment group in order to detect a difference in efficacy with the power of 80%.1,3 For each patient randomized to receive either midazolam or diazepam, the median and the mean (±SD) time after arrival to administer medication, time to cessation after medication, time to cessation after medication were measured and showed. All data were analyzed for normality before choosing parametric and non parametric tests. Quantitative variables were analyzed using student t test or Mann Whitney U when appropriate. For categorical data, we used either Fisher exact or c2-test when appropriate. In all statistical evaluations, P < 0.05 was considered significant. To reduce the bias in data analysis, all data were analyzed by a biostatistician who was blinded to the study purpose and groups.

3.

Results

3.1.

Baseline characteristics

A total of 100 children (50 in each group) with generalized convulsive status seizures were enrolled. The baseline

Outcome measures

The main outcome measure was stopping of all motor activity after drug administration without recurrence within 60 min after stopping of seizures, otherwise, the treatment was considered to be a failure and the patient was treated with IV diazepam then IV phenytoin which are the standard therapy in our emergency departments. However, these patients with treatment failure were considered in data analysis. Treatment was defined successful if the seizures were stopped in less than 10 min after administration without recurrence after 60 min of cessation of all motor activities. None of the children had EEGs to assess seizure control.

Table 1 e Baseline characteristics of the children in both groups. Characteristics Boys, n (%) Girls, n (%) Age (years), mean (SD) [range] Seizure etiology, n (%) Febrile status Remote symptomatic Idiopathic

Midazolam n ¼ 50

Diazepam n ¼ 50

31 (62) 19 (38) 2 (1.1) [4 mone15 yr]

27 (54) 23 (46) 2.5 (1.4) [5 mone13 yr]

23 15 12

26 10 14

Please cite this article in press as: Momen AA, et al., Efficacy and safety of intramuscular midazolam versus rectal diazepam in controlling status epilepticus in children, European Journal of Paediatric Neurology (2014), http://dx.doi.org/10.1016/ j.ejpn.2014.11.007

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e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y x x x ( 2 0 1 4 ) 1 e6

characteristics of the children in both groups are summarized in Table 1. Participants in the treatment groups were not significantly different in terms of age, gender, and seizure etiology.

3.2.

Response assessment

3.2.1.

Seizure control and seizure recurrence

Our results showed that both medication were effective for seizure control and no significant difference was found between successful treatments after administering the medication (P ¼ 0.061, c2 test). In the midazolam group, in 96% (48/ 50) of cases treatment was successful and in 4% (2/50) treatment was failed. In the diazepam group, in 94% (47/50) of cases treatment was successful and in 6% (3/50) the treatment was failed. Interestingly, none of the patients in both groups showed recurrence with 60 min after stopping of all motor activities.

3.2.2.

Time measurements

We compared both groups of patients for time from arrival to emergency departments to administering the medication, time from administering to stopping of seizures, and finally we calculated time from arrival to stopping of seizures. Our results showed that time from arrival to administering the medication had significant difference between both groups (P ¼ 0.017, by ManneWhitney Rank Sum Test, T ¼ 2575.500 n(small) ¼ 47 n(big) ¼ 48). Interestingly, our results showed that after administering the medication, the majority of seizures in midazolam group were stopped in less than 66 s and a significant difference was found between times from administering the medication to stopping of seizures between both groups (midazolam, median 66 s, diazepam, median 130 s, P < 0.001, ManneWhitney U Statistic ¼ 385.500, T ¼ 2998.500 n(small) ¼ 47 n(big) ¼ 48). These times are summarized in Table 2.

3.2.3.

Adverse effects

Interestingly, none of the children in our study showed respiratory depression in both groups but one patient in the midazolam group who mistakenly received double dose of midazolam (0.6 mg/kg) and developed signs of respiratory depression. Fortunately, this patient was a child with febrile status seizure who was recovered fully after a simple respiratory aid of oxygen and Ambu bag and mask ventilation.

Table 2 e Times from arrival, to administering the medication, and to stopping the seizures in both groups. Time, seconds (medians) [range]

Midazolam

Diazepam

P

From arrival to administering 65 [54e95] 65 [55e190] 0.017 From administering to 66 [24e245] 130 [45e600]

Efficacy and safety of intramuscular midazolam versus rectal diazepam in controlling status epilepticus in children.

The aim of this study was to evaluate the efficacy and safety of intramuscular midazolam in controlling convulsive status epilepticus in children, by ...
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