Epilepsy & Behavior 5 (2004) 253–255
`
`Brief Communication
`
`Epilepsy
`&
`Behavior
`
`www.elsevier.com/locate/yebeh
`
`Comparison of intranasal midazolam with intravenous diazepam
`for treating acute seizures in children
`
`T. Mahmoudian* and M. Mohammadi Zadeh
`
`Department of Child Neurology, Medical University of Isfahan, Isfahan, Iran
`
`Received 10 September 2003; revised 16 November 2003; accepted 5 January 2004
`
`Abstract
`
`Midazolam, a water-soluble benzodiazepine, is usually given intravenously in status epilepticus. The aim of this study was to
`determine whether intranasal midazolam is as safe and effective as intravenous diazepam in the treatment of acute childhood sei-
`zures. Seventy children aged 2 months to 15 years with acute seizures (febrile or afebrile) admitted to the pediatric emergency
`department of a general hospital during a 14-month period were eligible for inclusion. Intranasal midazolam 0.2 mg/kg and in-
`travenous diazepam 0.2 mg/kg were administered after intravenous lines were established. Intranasal midazolam and intravenous
`diazepam were equally effective. The mean time to control of seizures was 3.58 (SD 1.68) minutes in the midazolam group and 2.94
`(SD 2.62) in the diazepam group, not counting the time required to insert the intravenous line. No significant side effects were
`observed in either group. Although intranasal midazolam was as safe and effective as diazepam, seizures were controlled more
`quickly with intravenous diazepam than with intranasal midazolam. Intranasal midazolam can possibly be used not only in medical
`centers, but also in general practice and at home after appropriate instructions are given to families of children with recurrent
`seizures.
`Ó 2004 Elsevier Inc. All rights reserved.
`
`Keywords: Midazolam; Diazepam; Seizure disorder
`
`1. Introduction
`
`In the acute treatment of seizures, diazepam is un-
`doubtedly the benzodiazepine most widely used, but its
`tendency to accumulate with repeated doses and very
`short duration of action are significant. Midazolam can
`be given intravenously, intramuscularly, and rectally, as
`well as via the nasal mucosa.
`Midazolam acts rapidly and is less likely than diaze-
`pam to accumulate [1]. The plasma concentration of
`midazolam after intranasal administration of 0.2 mg/kg
`is 100 ng/ml at about 6 minutes [2]. OÕ Regan and col-
`leagues examined the effectiveness of intranasal midaz-
`olam on seizure discharges recorded concurrently by
`electroencephalography (EEG). Their findings demon-
`strate unequivocally that midazolam 0.2 mg/kg is ab-
`sorbed rapidly through the nasal mucosa and can
`eliminate spike activity on the electroencephalogram [1].
`
`* Corresponding author. Fax: +98-311-6240027.
`E-mail address: t_mahmoudian@med.mui.ac.ir (T. Mahmoudian).
`
`In this study we compare intranasal midazolam with
`intravenous diazepam for the treatment of acute child-
`hood seizures.
`
`2. Methods
`
`The study was conducted in the pediatric emergency
`department of the Medical University of Isfahan, be-
`tween September 1998 and October 1999. We randomly
`assigned 70 patients between 2 months and 15 years of
`age admitted to the emergency department of Alzahra
`Hospital in Isfahan with acute seizures.
`Randomization was performed in advance with an
`odd and even number table by a pediatric assistant not
`involved in the study, and treatment allocations were
`sealed in opaque envelopes. Investigators were blind to
`these allocations. Intravenous diazepam 0.2 mg/kg was
`administered to patients with odd numbers after an in-
`travenous line was introduced; midazolam solution
`(5 mg/ml) was dropped by syringe into both nostrils in
`
`1525-5050/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved.
`doi:10.1016/j.yebeh.2004.01.003
`
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`254
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`Brief Communication / Epilepsy & Behavior 5 (2004) 253–255
`
`equal doses to those with even numbers and an intra-
`venous line was immediately introduced. Children who
`had received anticonvulsants before admission were
`excluded. The time from treatment with intranasal
`midazolam or intravenous diazepam to cessation of
`seizures was recorded. Treatment was considered suc-
`cessful if seizures ceased within 10 minutes. Seizures that
`did not stop within 10 minutes of treatment were defined
`as treatment failures, and intravenous diazepam was
`given to the midazolam group and phenobarbital to the
`diazepam group. During seizure activity, high-flow ox-
`ygen by mask and routine life support were provided.
`All children were admitted to the pediatric ward for
`evaluation of the etiology of seizures. The effectiveness
`of the drugs was tested with the v2 method, and the
`mean time required to achieve control was tested with
`the Mann–Whitney method.
`
`3. Results
`
`During 14 months, 70 patients were included in this
`study. In all patients, in both groups, seizure control was
`achieved within 10 minutes, and there was no significant
`difference in effectiveness between intranasal midazolam
`and intravenous diazepam (P > 0:05). The mean inter-
`val between drug administration and seizure control was
`3.58 (SD 1.68) minutes for midazolam and 2.94 (SD
`2.62) minutes for diazepam. The time required to insert
`the intravenous line was not included. There was a sig-
`nificant difference in the mean time required to achieve
`control between the midazolam and diazepam groups
`(P ¼ 0:007). Time from seizure start to treatment was
`faster in the midazolam group but seizures were con-
`trolled faster in the diazepam group. None of the chil-
`dren had clinical
`signs of
`respiratory distress,
`bradycardia, or other side effects.
`The overall times required for seizure control in the
`two groups are presented in Fig. 1. The etiology of
`
`Fig. 1. Duration interval between administration of drug and response
`to treatment.
`
`Table 1
`Etiology of seizures
`
`Etiology of Seizures
`
`Midazolam
`
`Diazepam
`
`Hypocalcemia
`Hypoglycemia
`Febrile convulsions
`Epilepsy
`Head trauma
`CNS infection
`Hyponatremia
`
`Total
`
`2
`—
`14
`14
`—
`4
`1
`
`35
`
`8
`2
`1
`13
`1
`10
`—
`
`35
`
`Table 2
`Various types of seizures
`
`Type of seizure
`
`Midazolam
`
`Diazepam
`
`GTCa
`SPS
`CPS
`Myoclonic
`
`25
`3
`4
`3
`
`25
`3
`8
`2
`
`Total
`35
`35
`a GTC, generalized tonic–clonic seizures; SPS, simple partial
`seizures; CPS, complex partial seizures.
`
`seizures in both groups is given in Table 1. The various
`types of seizures are listed in Table 2.
`
`4. Discussion
`
`is an
`Midazolam, a water-soluble benzodiazepine,
`effective anticonvulsant given intravenously and intra-
`muscularly. Intranasal midazolam is a safe and effective
`anesthetic in children and can suppress epileptic activity
`[3,4]. Midazolam can be effective in the treatment of
`status epilepticus [5,6].
`Absorption of drugs is modified by, among other
`things, the circulation to the site of absorption, the area
`of the absorbing surface to which the drug is exposed,
`and the concentration of the drug. It is well recognized
`that for many children, especially those who have febrile
`seizures, upper respiratory tract infections are present at
`the times at which acute medication to terminate seizure
`is required. Although the infection might help absorp-
`tion by increasing blood flow to the nasal mucous
`membrane, the presence of nasal secretions could dilute
`the midazolam solution and make it more difficult for
`this agent to contact the absorbing surface.
`The elimination half-life of midazolam is usually be-
`tween 1.5 and 3.5 hours [7]. One study found that in-
`tranasal midazolam is absorbed in epileptic children; the
`mean time to seizure control was 3.5 (range 2.5–5)
`minutes and there were no recurrences of seizures within
`60 minutes of treatment [3].
`Lathat et al. reported that intranasal midazolam and
`intravenous diazepam are equally effective in children
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`Brief Communication / Epilepsy & Behavior 5 (2004) 253–255
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`255
`
`with prolonged febrile seizures [3]. The mean time to
`cessation of seizures was 3.1 (SD 2.2) minutes in the
`midazolam group and 2.5 (SD 1.9) minutes in the di-
`azepam group.
`We showed that intranasal midazolam is effective in
`the management of acute seizures in children. In 21 of 35
`(60%) children, seizure control was achieved in less than
`5 minutes, and the other 14 within 10 minutes; in the
`diazepam group, however, in 28 of 35 (80%), seizures
`ceased in less 5 minutes, and in the other 7, within
`10 minutes. The mean time to seizure control was sig-
`nificantly shorter in the diazepam group (2.94 (SD 2.62)
`minutes) than in the midazolam group (3.58 (SD 1.68)
`minutes). No patient had to be intubated or mechani-
`cally ventilated.
`The introduction of an intravenous line may be dif-
`ficult and if the time required for this procedure is added
`to the time to cessation of seizures, treatment with in-
`tranasal midazolam may work faster than treatment
`with intravenous diazepam [3].
`Although acute seizures have been treated with rectal
`diazepam [8], the rectal route is not always reliable.
`Further studies are needed to determine whether intra-
`nasal midazolam can be used not only in medical cen-
`
`ters, but also at home after appropriate instructions are
`given to parents of children with acute seizures.
`
`References
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`[3] Lahthat E, Goldman M, Barr J, et al. Intranasal midazolam for
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`[4] OÕ Regan ME, Brown JK, Clarke M. Nasal rather than rectal
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