Efficacy of Intravenous Midazolam for Status Epilepticus in Childhood Kitami Hayashi, MD, PhD1, Makiko Osawa, MD, PhD1, Masao Aihara, MD, PhD2, and others*; and Research Committee on Clinical Evidence of Medical Treatment for Status Epilepticus in Childhood A retrospective multicenter study was conducted, designed to evaluate the efficacy and safety of midazolam for the treatment of status epilepticus. The subjects were 358 inpatients who received intravenous midazolam therapy for status epilepticus. The mean age was 48.6 ⴞ 46.5 months. The underlying disorder was epilepsy in 195 cases, and acute symptomatic diseases in 163 (encephalitis or encephalopathy in 88 cases). Midazolam was administered as a bolus dose (0.25 ⴞ 0.21 mg/kg), followed if necessary by continuous infusion (0.26 ⴞ 0.25 mg/kg/hr). The bolus injection was effective in 162 (56.6%) of the 286 cases. In the end, seizure suppression was obtained in 231 cases (64.5% of the total). The effectiveness of midazolam was lower in patients in whom midazolam was initiated more than 3 hours after seizure onset, and this tendency was particularly marked in the epilepsy group. During the treatment period, 10 patients died, but none of these deaths were associated with midazolam therapy. The incidence and types of adverse events were consistent with previously reported data. The present results indicate that midazolam is highly effective for the management of status epilepticus, if used sufficiently early after seizure onset. © 2007 by Elsevier Inc. All rights reserved.
early stage treatment is essential, and intravenous anticonvulsant therapy plays a central role in the management of this condition. Diazepam, phenytoin, and pentobarbiturate have been approved and widely used in the intravenous treatment of status epilepticus in Japan. Midazolam has recently been used as a first- or second-line drug in treating status epilepticus because of its efficacy, safety, and ease of administration. Midazolam has not, however, been officially approved as a treatment for status epilepticus in Japan, so such treatment constitutes off-label use. Sufficient data concerning midazolam therapy for status epilepticus have not yet been accumulated, and information essential for the safe clinical use of midazolam is lacking. To rectify this situation, we recently conducted a nationwide retrospective multicenter study of the efficacy and safety of midazolam in treating status epilepticus (a condition characterized by prolonged and repeated seizures).
Subjects and Methods
Status epilepticus is a commonly encountered emergency in the field of pediatric neurology. Appropriate
A retrospective multicenter study was conducted in Japan with the participation of 16 institutions nationwide, institutions in which pediatric neurologists have considerable experience in treating status epilepticus. A survey form, including case background, the etiology of status epilepticus, midazolam dose, and results and adverse events associated with treatment, as well as a leaflet explaining how to fill out the form, was delivered to all participants, assuring uniform evaluation of drug efficacy among the 16 institutions and their affiliates. The survey included all children with status epilepticus and frequent repetitive seizures, aged from 1 month to less than 16 years, who had received intravenous bolus or continuous infusion of midazolam during the period from January 1991 to October 2002. The method of case search differed among hospitals or departments, mainly because of database differences: some hospitals have computer-based databases and some have paper-based databases.
From the 1Department of Pediatrics, Tokyo Women’s Medical University, School of Medicine, Tokyo, Japan; 2Department of Pediatrics, Faculty of Medicine, University of Yamanashi, Chuo Yamanashi, Japan; ⴱ *Additional authors and author affiliations can be found on page 371.
Communications should be addressed to: Dr. Hayashi; 477-96 Owada-Shinden; Yachiyo; Chiba 276-0046, Japan. E-mail:
[email protected] Received April 19, 2006; accepted February 26, 2007.
Hayashi K, Osawa M, Aihara M, and others; and Research Committee on Clinical Evidence of Medical Treatment for Status Epilepticus in Childhood. Efficacy of intravenous midazolam for status epilepticus in childhood. Pediatr Neurol 2007;36:366-372.
Introduction
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PEDIATRIC NEUROLOGY
Vol. 36 No. 6
© 2007 by Elsevier Inc. All rights reserved. doi:10.1016/j.pediatrneurol.2007.02.012 ● 0887-8994/07/$—see front matter
Case cards were collected for 479 cases (some patients receiving treatment for multiple episodes were counted the corresponding number of times) from databases of the participating facilities. From these, 358 status epilepticus cases were included in the analysis, categorized as either (1) cases with prolonged seizures or (2) cases with repeated seizures who showed loss of consciousness between each seizure. Prolonged seizures that persisted more than 10 minutes and were treated with midazolam were included in the present study. Nonconvulsive status epilepticus was excluded from the present study, because the treatment strategy might be somewhat different from that of convulsive status epilepticus. In this retrospective study, the following factors or variables differed among participating facilities: midazolam dosage, the method for increasing the midazolam dosage, duration of treatment, timing of efficacy assessment, and the method for midazolam discontinuation. The findings of ictal or postictal electroencephalography were not requested, because not all cases were evaluated by electroencephalography during treatment of status epilepticus. Exclusion of nonconvulsive status epilepticus was based, with caution, on descriptions from the medical records (e.g., physical signs and symptoms, including the patient’s posture, muscle tone, eye position, face color, respiration, and so on). Those cases in the prolonged seizures group in which seizures persisted even with midazolam and those cases in the repeated seizures group in which seizure frequency did not decrease to less than 50% of pretreatment level were considered nonresponders to midazolam. The cases in the repeated seizures group in which seizures frequency decreased to less than 50% of pretreatment level were considered partial responders. Only in cases showing complete seizure disappearance (for at least 24 hours after discontinuation of midazolam) was the treatment rated effective. Adverse events (i.e., physical abnormalities other than seizures) were identified by reviewing the medical records of individual cases. Causal relationships with midazolam were assessed as “absent,” “difficult to judge,” or “present.” The 2 test, unpaired t test, and a logistic regression model were used for statistical analyses. A value of P ⬍ 0.05 was regarded as significant.
Table 1.
Etiology, age of onset, and efficacy of midazolam
Etiology Epilepsy C/SGE SLRE UDFG Others Acute Symptomatic Factors Enceph FC Others Total
Cases, no.
Age of onset, mo ⴞ SD
Effectively treated, no. (%)
195 35 95 57 8 163
55.4 ⫾ 44.4* 62.7 ⫾ 44.9 62.2 ⫾ 45.3 38.5 ⫾ 38.0 62.3 ⫾ 50.6 34.6 ⫾ 36.1*
128 (65.6) 25 (71.4) 58 (61.1) 39 (68.4) 6 (75) 103 (63.2)
88 48 27 358
35.9 ⫾ 39.8 35.5 ⫾ 29.7 29.1 ⫾ 34.2 48.6 ⫾ 46.5
50 (56.8)** 40 (83.3)** 13 (48.1)** 231 (64.5)
Abbreviations: C/SGE ⫽ Cryptogenic/symptomatic generalized epilepsy Encephal ⫽ Encephalitis and encephalopathy FC ⫽ Febrile convulsions SD ⫽ Standard deviation SLRE ⫽ Symptomatic localization-related epilepsy UDFG ⫽ Epilepsies and syndromes undetermined, focal or generalized * The Epilepsy group was significantly different from the Acute Symptomatic Factors group at P ⬍ 0.01. ** The Acute Symptomatic Factors subgroups differed from each other at P ⬍ 0.002.
litis or encephalopathy (54.0%), followed by febrile seizures (29.4%). Cases related to head trauma, cerebrovascular disorders, or metabolic disorders were included under Others (Table 1).
Results
Midazolam Therapy
Age of Subjects
The interval between seizure onset and initiation of midazolam therapy was less than 30 minutes in 38 cases (10.6%), within 1 hour in 132 (36.9%), within 2 hours in 60 (16.8%), within 3 hours in 41 (11.5%), within 24 hours in 51 (14.2%), and later than 24 hours in 36 (10.1%); 31 of the latter 36 cases were in the repeated seizures group (Table 2). Including all treatments administered before admission to one of the participating institutions, midazolam was the first-line treatment in 70 cases; it was the second choice in 115 cases, and the third choice in 94. Including only treatment at the participating institutions, midazolam was the therapy of first choice in 120 cases. In 286 cases, bolus midazolam (or the total dose, in cases given multiple doses) ranged from 0.03 to 1.15 mg/kg (mean ⫾ standard deviation ⫽ 0.25 ⫾ 0.21 mg/kg) and was less than 0.3 mg/kg in 74.1% of all cases. For the 306 cases given continuous midazolam infusion, the starting dose was 0.17 ⫾ 0.20 mg/kg/hr and the maximum dose ranged from 0.04 to 1.2 mg/kg/hr (mean ⫾ standard deviation ⫽ 0.26 ⫾ 0.25 mg/kg/hr), the one exception being a patient in whom the maximum dose was 3 mg/kg/hr. The dose administered by continuous infusion was less than 0.4 mg/kg/hr in 81% of all cases. The
The mean age at status epilepticus onset was 48.6 ⫾ 46.5 months (mean ⫾ standard deviation). Children less than 1 year of age accounted for the highest percentage of cases (19.3%, 69 cases). The seizures had developed before 3 years of age in 192 cases (53.6%) and before age 6 in 286 cases (79.9%). The overall median age at seizure onset was 31 months. It was 55.4 ⫾ 44.4 months in the epilepsy group and 34.6 ⫾ 36.1 months in the acute symptomatic group (P ⬍ 0.001) (Table 1). Etiology of Status Epilepticus In the epilepsy group (195 cases), symptomatic localization-related epilepsy accounted for the highest percentage of cases (48.7%, 95 cases). The second largest subgroup (29.2%, 57 cases) consisted of children who were classified as having epilepsies and syndromes undetermined as focal or generalized (e.g., severe myoclonic epilepsy in infancy). There were no cases of idiopathic epilepsy. In the acute symptomatic group (163 cases), status epilepticus was most frequently associated with encepha-
Hayashi et al: Midazolam for Status Epilepticus 367
Table 2.
Interval till treatment and midazolam efficacy
Etiology
