YEBEH-04248; No of Pages 12 Epilepsy & Behavior xxx (2015) xxx–xxx

Contents lists available at ScienceDirect

Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh

Review

Nonintravenous midazolam versus intravenous or rectal diazepam for the treatment of early status epilepticus: A systematic review with meta-analysis Francesco Brigo a,b,⁎, Raffaele Nardone b,c, Frediano Tezzon b, Eugen Trinka c,d,e a

Department of Neurological and Movement Sciences, University of Verona, Italy Department of Neurology, Franz Tappeiner Hospital, Merano, Italy c Department of Neurology, Christian Doppler Klinik, Paracelsus Medical University, Salzburg, Austria d Centre for Cognitive Neuroscience, Salzburg, Austria e Department of Public Health Technology Assessment, UMIT — University for Health Sciences, Medical Informatics and Technology, Hall.i.T., Austria b

a r t i c l e

i n f o

Article history: Revised 23 February 2015 Accepted 24 February 2015 Available online xxxx Keywords: Diazepam Meta-analysis Midazolam Seizures Status epilepticus

a b s t r a c t Background: Prompt treatment of status epilepticus (SE) is associated with better outcomes. Rectal diazepam (DZP) and nonintravenous (non-IV) midazolam (MDZ) are often used in the treatment of early SE instead of intravenous applications. The aim of this review was to determine if nonintravenous MDZ is as effective and safe as intravenous or rectal DZP in terminating early SE seizures in children and adults. Methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), ClinicalTrials.gov, and MEDLINE for randomized controlled trials comparing non-IV MDZ with DZP (by any route) in patients (all ages) with early SE defined either as seizures lasting N5 min or as seizures at arrival in the emergency department. The following outcomes were assessed: clinical seizure cessation within 15 min of drug administration, serious adverse effects, time interval to drug administration, and time from arrival in the emergency department to seizure cessation. Outcomes were assessed using a random-effects Mantel–Haenszel meta-analysis to calculate risk ratio (RR), odds ratio (OR) and mean difference with 95% confidence intervals (95% CIs). Results: Nineteen studies with 1933 seizures in 1602 patients (some trials included patients with more than one seizure) were included. One thousand five hundred seventy-three patients were younger than 16 years. For seizure cessation, non-IV MDZ was as effective as DZP (any route) (1933 seizures; RR: 1.03; 95% CIs: 0.98 to 1.08). No difference in adverse effects was found between non-IM MDZ and DZP by any route (1933 seizures; RR: 0.87; 95% CIs: 0.50 to 1.50). Time interval between arrival and seizure cessation was significantly shorter with non-IV MDZ by any route than with DZP by any route (338 seizures; mean difference: −3.67 min; 95% CIs: −5.98 to −1.36); a similar result was found for time from arrival to drug administration (348 seizures; mean difference: −3.56 min; 95% CIs: −5.00 to −2.11). A minimal difference was found for time interval from drug administration to clinical seizure cessation, which was shorter for DZP by any route than for non-IV MDZ by any route (812 seizures; mean difference: 0.56 min; 95% CIs: 0.15 to 0.98 min). Not all studies reported information on time intervals. Comparison by each way of administration failed to find a significant difference in terms of clinical seizure cessation and occurrence of adverse effects. The only exception was the comparison between buccal MDZ and rectal DZP, where MDZ was more effective than rectal DZP in terminating SE but only when results were expressed as OR (769 seizures; OR: 1.78; 95% CIs: 1.11 to 2.85; RR: 1.15; 95% CIs: 0.85 to 1.54). Only one study was entirely conducted in an adult population (21 patients, aged 31 to 69 years), showing no difference in efficacy or time to seizure cessation after drug administration between intranasal MDZ and rectal DZP. Conclusions: Non-IV MDZ is as effective and safe as intravenous or rectal DZP in terminating early SE in children and probably also in adults. Times from arrival in the emergency department to drug administration and to seizure cessation are shorter with non-IV MDZ than with intravenous or rectal DZP, but this does not necessarily result in higher seizure control. An exception may be the buccal MDZ, which, besides being socially more acceptable and easier to administer, might also have a higher efficacy than rectal DZP in seizure control. This article is part of a Special Issue entitled Status Epilepticus. © 2015 Elsevier Inc. All rights reserved.

⁎ Corresponding author at: Department of Neurological and Movement Sciences, University of Verona, Piazzale L.A. Scuro, 10, 37134 Verona, Italy. Tel.: +39 0458124174; fax: +39 0458124873. E-mail address: [email protected] (F. Brigo).

http://dx.doi.org/10.1016/j.yebeh.2015.02.030 1525-5050/© 2015 Elsevier Inc. All rights reserved.

Please cite this article as: Brigo F, et al, Nonintravenous midazolam versus intravenous or rectal diazepam for the treatment of early status epilepticus: A systematic review with meta-analysis, Epilepsy Behav (2015), http://dx.doi.org/10.1016/j.yebeh.2015.02.030

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F. Brigo et al. / Epilepsy & Behavior xxx (2015) xxx–xxx

1. Introduction Status epilepticus (SE) can be regarded as the most extreme and severe form of seizure activity, being associated with high morbidity and mortality [1]. In clinical practice, SE has been traditionally defined as epileptic activity persisting for more than 30 min or as two or more sequential seizures without full interictal recovery [2]. However, over the years, this timeframe has been progressively shortened to the pragmatic definition of 5 min because of the seriousness of the condition and the urge to treat it as early as possible [3]. Its prompt treatment can prevent death or irreversible brain damage. In fact, early treatment is associated with lower morbidity and mortality, fewer drugs required in hospitals, and shorter overall seizure duration [4,5]. There are, however, several factors, including education regarding seizure emergencies and transferring of patients to the hospital, that may hinder prompt treatment, resulting in a significant treatment delay. Hence, prehospital management of SE might be beneficial provided that administered drugs are effective in terminating seizures, safe, and easy to use. Diazepam (DZP) and midazolam (MDZ) are commonly used in the treatment of early (stage I) SE. Midazolam is a water-soluble benzodiazepine, which may be administered by different routes: intravenous, intramuscular, buccal, and intranasal. Conversely, DZP can be administered either intravenously or per rectum. Rectal DZP is the most common drug used in the prehospital management of early SE in Spain [6] and possibly also in other countries. However, its administration is most of the time socially unacceptable. Furthermore, its administration requires the removal of clothes and positioning the patient appropriately, which may result in relevant treatment delay. The same limitation holds true for intravenous administration of DZP or other drugs such as lorazepam, which requires the placement of an intravenous access. Hence, MDZ, which can be administered by different and more practical routes (buccal, intranasal, intramuscular), has emerged as an alternative to drugs administered by intravenous or rectal route, such as lorazepam or DZP [7,8]. The aim of this systematic review was to determine if nonintravenous (non-IV) MDZ is as effective and safe as intravenous or rectal DZP in terminating early SE in children and adults. Furthermore, we aimed to evaluate whether non-IV MDZ administration is faster than intravenous or rectal DZP administration and, if so, whether this “time gain” results in higher seizure control. 2. Methods This review was guided by a written prespecified protocol describing research questions, review methods, and a plan for data extraction and synthesis. The protocol is available at: http://www.crd.york.ac. uk/PROSPERO/DisplayPDF.php?ID=CRD42015016179. 2.1. Criteria for considering studies for this review We included randomized controlled trials (RCTs), blinded or unblinded. Uncontrolled and nonrandomized trials were excluded. We included patients of any age diagnosed with early (stage I) SE defined either as seizures lasting N 5 min [3] or as seizures at arrival to the emergency department. We considered all trials in which non-IV MDZ used as a first-line agent in monotherapy was compared with DZP (first-line drug given singly) by any route. The following outcomes were considered: Efficacy ▪ The number of status epilepticus episodes which were terminated within 15 min after drug (MDZ or DZP) administration or before emergency medical service support arrived (only for studies conducted in prehospital settings);

▪ Time from arrival at the emergency department to drug administration (or time from seizure initiation to drug administration for studies conducted in prehospital settings); ▪ Time from drug administration to clinical seizure cessation; and ▪ Time from arrival at the emergency department to clinical seizure cessation (or time from seizure initiation to clinical seizure cessation for studies conducted in prehospital settings). Tolerability and safety ▪ The number of patients experiencing serious adverse effects (respiratory depression or hypotension). 2.4. Search methods for identification of studies A comprehensive review of the literature of computerized databases as well as searches to find unpublished trials were performed to minimize publication bias. The following electronic databases and data sources were searched: 1. MEDLINE (January 1966–20th of January 2015), accessed through PubMed; 2. Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 12, The Cochrane Library, December 2014) (accessed 20th of January 2015); the following search strategy was adopted: ((“Status Epilepticus”[Mesh] OR “status epilepticus” OR seizur*) AND midazolam). All resulting titles and abstracts were evaluated, and any relevant article was considered. There were no language restrictions; 3. ClinicalTrials.gov (available at: https://clinicaltrials.gov/; accessed 20th of January 2015); the following search strategy for this database was adopted: ((“Status Epilepticus” OR seizure OR seizures) AND midazolam). There were no language restrictions; 4. Handsearching of the references quoted in the identified trials; 5. Contact with pharmaceutical companies (Viropharma and Accord Healthcare) to identify unpublished trials or data missing from articles (January 2015); and 6. Contact with authors and known experts to identify any additional data. 3. Data collection and analysis 3.1. Study selection Retrieved articles were independently assessed for inclusion by two review authors; any disagreement was resolved through discussion. 3.2. Quality assessment Trials were scrutinized, and the methodological quality of all included studies was evaluated. Quality assessment included the following aspects of methodology: study design, definition and clinical relevance of outcomes, type of control, method of allocation concealment, total study duration, completeness of follow-up, intention-totreat analysis, data concerning adverse effects, risk of bias, and conflict of interests. The randomized trials were judged on the reported method of allocation concealment and on the risk of bias as outlined in the Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011] [9]. We also evaluated whether authors disclosed their conflict of interest and whether pharmaceutical companies sponsored the studies. 3.3. Data extraction The following trial data were extracted: main study author and age of publication; country; definition of SE applied in the study; type of participants (children and/or adults); total number, age, and sex of

Please cite this article as: Brigo F, et al, Nonintravenous midazolam versus intravenous or rectal diazepam for the treatment of early status epilepticus: A systematic review with meta-analysis, Epilepsy Behav (2015), http://dx.doi.org/10.1016/j.yebeh.2015.02.030

F. Brigo et al. / Epilepsy & Behavior xxx (2015) xxx–xxx

participants for each treatment group; seizure type; intervention details (dose, route of administration); definition of successful treatment adopted in each trial; proportion of seizures controlled after drug administration in each treatment group; time from arrival at the ED to drug administration; time from drug administration to clinical seizure cessation; time from arrival at the ED to clinical seizure cessation; and proportion of serious adverse effects (respiratory depression and/or hypotension) in each group. 3.4. Data analysis We sought data on the number of participants in the treatment groups and with each outcome in the articles. Provided that we thought that it was clinically appropriate and no important clinical and methodological heterogeneity was found, we planned to summarize results in a meta-analysis. The trials comparing the same drugs were combined. Pooled risk ratios were determined using Mantel–Haenszel random-effects models. Data were stratified into subgroups comparing the following: 1. 2. 3. 4. 5. 6. 7. 8. 9. 10.

Non-IV MDZ by any route versus DZP by any route; Intranasal MDZ versus DZP by any route; Buccal MDZ versus DZP by any route; Intramuscular MDZ versus DZP by any route; Intranasal MDZ versus intravenous DZP; Intranasal MDZ versus rectal DZP; Buccal MDZ versus intravenous DZP; Buccal MDZ versus rectal DZP; Intramuscular MDZ versus intravenous DZP; and Intramuscular DZP versus rectal DZP.

Where study data were available, we assessed the mean differences in times between arrival at the ED and drug administration (non-IV MDZ by any route versus DZP by any route) or clinical seizure cessation and between drug administration and cessation of seizure activity. Dichotomous outcomes (clinical seizure cessation and occurrence of serious adverse effects) were analyzed by calculating risk ratio (RR) for each trial, with the uncertainty in each trial being expressed using 95% confidence intervals (CIs). For each outcome, a weighted treatment effect across trials was calculated. Odds ratio (OR) were also calculated. To evaluate consistency across study results, results expressed as OR were compared with results expressed as RR. Continuous data (time intervals from arrival to the emergency department to drug administration or clinical seizure cessation) were analyzed by calculating the mean difference for each trial, with the uncertainty in each study being expressed using 95% CIs. Homogeneity among study results was evaluated using a standard chi-squared test, combined with the I2 statistics, and the hypothesis of homogeneity was rejected if the p-value was less than 0.10. The interpretation of I2 for heterogeneity was made as follows: 0–25% represents low heterogeneity, 25–50% moderate heterogeneity, 50–75% substantial heterogeneity, and 75–100% high heterogeneity [10]. Trial outcomes were combined to obtain a summary estimate of effect (and the corresponding CI) using a random-effects model. A random-effects model is considered more conservative than a fixed-effect model since it takes into account the variability between studies, thus leading to wider CIs. Statistical analyses were undertaken with the Review Manager software developed by the Cochrane Collaboration (5.3). 4. Results

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2015), but no additional unpublished trials were found. After excluding duplicate publications (38), case reports and case series, letters, reviews, and uncontrolled and nonrandomized trials, 30 studies potentially includible were provisionally selected. No additional unpublished study was identified. We excluded 11 studies after reading the full published papers (a list of these articles and reasons for exclusion are reported in Supplementary material 1). Thus, nineteen trials [11–29] contributed to this review: the earliest was published in 1997 and the most recent in 2014 (Fig. 1). All studies were conducted in children except one which included both children and young adults [12] and one which included only adults [23]. All studies were conducted in hospital settings (emergency departments) except for one RCT where caregivers administered MDZ or DZP at home if seizures lasted more than 5 min [24]. All studies had two arms and used DZP (intravenous or rectal) as the active comparator. One study adopted a cross-over design [23]. Six different comparisons were available (intranasal MDZ versus IV DZP, intranasal MDZ versus rectal DZP, buccal MDZ versus intravenous DZP, buccal MDZ versus rectal DZP, intramuscular MDZ versus intravenous DZP, and intramuscular MDZ versus rectal DZP). 4.2. Risk of bias in included studies (Table 3) All studies were described as RCTs. Two studies, however, involved a systematic, nonrandom approach (sequence generation was generated by a rule based on day of admission, which was not further explained) [14,16]. Four studies used blockrandomization [20,24,26,29]. Other studies used a random number table [13,15,17,21,22,25,27,28] or generated the sequence of randomization by shuffling envelopes [12,19]. Authors of three trials did not specify how random sequence was generated [11,18,23]. Allocation concealment was adequate in five RCTs [13,15,20,24,27] and probably adequate in three studies [12,19,29] where it was not reported whether an opaque envelope containing the name of the drug to be administered was used. One study explicitly specified that allocation was not concealed from attending staff [17]. The other studies did not describe in sufficient detail the concealment of allocations prior to assignment. In five studies, investigators masked to therapeutic assignment assessed the outcomes [13,15,20,24,27]. In one study [20], the study team was not aware of which treatment a patient received, but they were aware of the treatment code to which a patient was assigned, potentially introducing bias. In one RCT, attending physicians, research assistants, and patients/caregivers were blinded to the drug to be prescribed until written consent was obtained [24]. In all other studies, except six which were specified to be not blinded [22,24–26,28,29] and one which was defined as single-masked without further specifications [19], blinding of participants and personnel was not explicitly reported. No trial, except one [20], specified whether similar-looking comparison drugs were used. However, the ‘hard’ outcomes chosen in all studies are not probably to be influenced by lack of blinding. As a consequence, all studies have a low risk of performance and detection bias. In ten studies, authors failed to disclose conflict of interests [11,12, 14–16,18,19,21,22,26], so it was not possible to evaluate a possible sponsorship/funding by pharmaceutical companies. The other studies explicitly reported the conflict of interest of authors involved, and none of them was funded/sponsored by pharmaceutical companies. 4.3. Effects of interventions and meta-analysis outcomes: quantitative data synthesis

4.1. Description of studies (Tables 1 and 2) The search strategy described earlier yielded 771 results (671 MEDLINE, 84 CENTRAL, and 16 ClinicalTrials.gov). The pharmaceutical companies Viropharma and Accord Healthcare were contacted (January

Nineteen studies with 1933 seizures in 1602 patients (some trials included patients with more than one episode) were included in the quantitative data synthesis. Eighteen out of the 19 studies included in this systematic review were conducted in children (one of these 18

Please cite this article as: Brigo F, et al, Nonintravenous midazolam versus intravenous or rectal diazepam for the treatment of early status epilepticus: A systematic review with meta-analysis, Epilepsy Behav (2015), http://dx.doi.org/10.1016/j.yebeh.2015.02.030

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Table 1 Characteristics of included studies. Study

Country

Definition of status epilepticus

Participants

Intranasal midazolam versus intravenous diazepam Lahat et al. [13] Israel Febrile seizures N 10 min Children

Midazolam group M/F ratio Age

Diazepam group M/F ratio Age

23 patients 21 patients M/F: 12/11 M/F: 13/8 18 (6–40) 16 (6–38) (median (range), mo) (median (range), mo) 70 patients (both groups) M/F: NR 2 mo–15 ys (both groups, range) 30 patients 30 patients M/F: 17/13 M/F: 16/14 2.5[1.2] 2.3[1.5] (median [IQR], ys) (median [IQR], ys)

Mahmoudian Iran and Zadeh [15]

Seizures at arrival to the emergency department

Children

Javadzadeh et al. [26]

Iran

Seizures at arrival to the emergency department

Children

Thakker and Shanbag [27]

India

Seizures N 10 min

Children

27 patients M/F: 15/12 3.84 ± 2.93 (mean ± SD, ys)

23 patients M/F: 12/11 3.97 ± 3.33 (mean ± SD, ys)

Children

23 patients M/F: 8/15 3.80 (mean, ys)

22 patients M/F: 11/11 2.02 (mean, ys)

23 patients 23 patients M/F: 16/7 M/F: 13/10 74.53 ± 38.29 60.47 ± 45.35 (mean ± SD, mo) (mean ± SD, mo) 21 patients (both groups) M/F: 8/13 (both groups) 40.3 ± 10.5 (31–69) (both groups) (mean ± SD (range), ys) 42 patients 50 patients M/F: 22/30 M/F: 24/26 6.9 [3.8–10.8] 5.6 [2.5–0.7] (median [IQR], ys) (median [IQR], ys)

Intranasal midazolam versus rectal diazepam Fişgin et al., Turkey Seizures at arrival to the 2002 [14] emergency department

Bhattacharyya et al. [19]

India

Seizures at arrival to the emergency department

Children

de Haan et al. [23]

The Netherlands

Seizures N 5 min

Adults

Holsti et al. [24]

USA

Seizures N 5 min

Children

Buccal midazolam versus intravenous diazepam India Seizures at arrival to the Talukdar and emergency department Chakrabarty [21] Tonekaboni et al. [25]

Iran

Seizures at arrival to the emergency department

Buccal midazolam versus rectal diazepam Scott et al. [12] UK Seizures at arrival of paramedics

Baysun et al. [16] Turkey

Febrile seizures at arrival to the emergency department

McIntyre et al. [17]

United Kingdom

Seizures at arrival to the emergency department

Mpimbaza et al. [20]

Uganda

Seizures at arrival to the emergency department or N5 min

Ashrafi et al. [22] Iran

Seizures at arrival to the emergency department or N5 min

Intramuscular midazolam versus intravenous diazepam Chamberlain USA Seizures N 10 min et al. [11]

Children

Children

60 patients M/F: 42/18 30.4 ± 38.1 (mean ± SD, mo) 32 patients M/F: 14/18 18.4 ± 10.3 (mean ± SD, mo)

60 patients M/F: 40/20 45.3 ± 45.4 (mean ± SD, mo) 60 patients M/F: 37/23 17.1 ± 10.1 (mean ± SD, mo)

Children/adults 14 patientsa 14 patientsa M/F: N/R (both groups) 14.5 ± 4.13 (5–19) (both groups) (mean ± SD (range), ys) 20 patients Children 23 patients M/F: 11/9 M/F: 11/12 2.85 ± 3.13 (4 mo–9 ys) 3.87 ± 3.39 (2 mo–12 ys) (mean ± SD (range), ys) (mean ± SD (range), ys) 110 patients Children 92 patients M/F: 59/50 (no. of episodes) M/F: 64/46 (no. of episodes) 2[1–5] (median [IQR], ys) 3 [1–6] (median [IQR], ys) 165 patients Children 165 patients M/F: 82/83 M/F: 84/81 18.0[11.5–36.0] 17.0[10.5–30.0] (median [IQR], mo) (median [IQR], mo) 49 patients Children 49 patients M/F: 32/17 M/F: 26/23 48 (median, mo) 24 (median, mo)

Children

13 patients M/F: 8/5 42 (9–165) (median (range), mo)

11 patients M/F: 9/2 39 (3–112) (median (range), mo)

Seizure type

Febrile convulsive (tonic, clonic, tonic–clonic) seizures

Generalized tonic–clonic seizures, simple partial seizures, complex partial seizures, and myoclonic seizures Simple febrile seizures, complex febrile seizures, generalized tonic–clonic seizures, partial seizures with 2nd generalization, Lennox–Gastaut syndrome, infantile spasms, and undetermined Generalized tonic–clonic seizures, simple partial seizures, complex partial seizures, and subtle convulsions

Febrile and nonfebrile convulsions (simple focal, after focal secondarily generalized, generalized tonic–clonic, generalized tonic, myoclonic) Simple partial seizures, generalized tonic–clonic seizures, myoclonic seizures, others (e.g., absence, atonic seizures) Tonic seizures, tonic–clonic seizures, and complex partial seizures

Seizures (any type)

Partial and generalized tonic, clonic, and tonic–clonic seizures

Tonic, tonic–clonic, and atonic seizures

Tonic–clonic seizures, complex partial seizures, absences, myoclonic seizures, atonic seizures, and tonic seizures Generalized tonic–clonic, generalized tonic, simple partial, and complex partial seizures Convulsive seizures

Generalized, focal, and febrile convulsions

Generalized tonic–clonic seizures, myoclonic seizures, focal tonic seizures, and focal clonic seizures

Generalized tonic–clonic seizures and focal motor seizures

Please cite this article as: Brigo F, et al, Nonintravenous midazolam versus intravenous or rectal diazepam for the treatment of early status epilepticus: A systematic review with meta-analysis, Epilepsy Behav (2015), http://dx.doi.org/10.1016/j.yebeh.2015.02.030

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Table 1 (continued) Study

Country

Definition of status epilepticus

Intramuscular midazolam versus intravenous diazepam India Seizures at arrival to the Shah and emergency department Deshmukh [18] Portela et al. Brazil Seizures at arrival to the [29] emergency department

Intramuscular midazolam versus rectal diazepam Momen et al. Iran Convulsive generalized [28] seizures at arrival to the emergency department (N5 min)

Participants

Midazolam group M/F ratio Age

Children

115 patients (both groups) M/F: NR 1 mo to 12 ys (both groups) 16 patients M/F: 12/4 46.4 ± 53.1 (mean ± SD, mo) 13.9 (10.7–70.0) (median (range), mo)

Children

Children

50 patients M/F: 31/19 2 ± 1.1 (4 mo–15 ys) (mean ± SD (range), ys)

Diazepam group M/F ratio Age

16 patients M/F: 8/8 45.0 ± 49.2 (mean ± SD, mo) 14.3 (4.4–90.8) (median (range), mo)

Seizure type

Generalized tonic–clonic seizures, focal convulsions, tonic convulsions, and clonic convulsions Febrile and nonfebrile convulsive seizures

Generalized convulsive seizures 50 patients M/F: 27/23 2.5 ± 1.4 (5 mo–13 ys) (mean ± SD (range), ys)

F: female, IQR: interquartile range, M: male, mo: months, NR: not explicitly reported, SD: standard deviation, and ys: years. a This study included 18 patients; some patients had more than one seizure and were assigned to both treatments (they are, therefore, represented in both groups).

studies included also young adults [12]) resulting in a total of 1573 patients younger than 16 years. Details of each meta-analytic comparison are reported in Supplementary material 2. 4.4. Non-IV MDZ versus DZP (all routes of administration) For seizure cessation, non-IV MDZ was as effective as DZP (any route) (RR: 1.03; 95% CIs: 0.98 to 1.08) (Fig. 2a). No difference in adverse effects was found between non-IM MDZ and DZP by any route (RR: 0.87; 95% CIs: 0.50 to 1.50) (Fig. 2b). After excluding the two studies which included also adults [12,23] (sensitivity analysis), no differences were found between non-IV MDZ and DZP by any route both for seizure cessation (RR: 1.03; 95% CIs: 0.98 to 1.09) and for occurrence of adverse effects (RR: 0.87; 95% CIs: 0.50 to 1.50). Time interval between arrival and seizure cessation was significantly shorter with non-IV MDZ by any route than with DZP by any route (mean difference: − 3.67 min; 95% CIs: − 5.98 to − 1.36 min) (Fig. 3c); a similar result was found for time from arrival to drug administration (mean difference: −3.56 min; 95% CIs: −5.00 to −2.11 min) (Fig. 3a). A minimal difference was found for time interval from drug administration to clinical seizure cessation, which was shorter for DZP by any route than for non-IV MDZ by any route (mean difference: 0.56 min; 95% CIs: 0.15 to 0.98 min) (Fig. 3b); this statistically significant difference has, most likely, too low a magnitude to be clinically relevant. Because of lack of data and differences in reporting time values (mean, median, SD, range, interquartile range), meta-analytic comparisons evaluating time intervals between arrival and drug administration or seizure cessation were not performed for each route of administration. However, we reported in Table 2 the time intervals and the degree of statistical significance between the different groups from each study reporting this information. 4.5. Intranasal, buccal, and muscular MDZ versus intravenous and rectal DZP Comparison by each route of administration (intranasal MDZ versus DZP by any route, buccal MDZ versus DZP by any route, intramuscular MDZ versus DZP by any route, intranasal MDZ versus intravenous DZP, intranasal MDZ versus rectal DZP, buccal MDZ versus intravenous DZP, buccal MDZ versus rectal DZP, intramuscular MDZ versus intravenous DZP, and intramuscular MDZ versus rectal DZP) failed to find a significant difference in terms of clinical seizure cessation and occurrence

of adverse effects. The only exception was the comparison between buccal MDZ and rectal DZP, where MDZ was more effective than rectal DZP in terminating SE but only when results were expressed as OR (OR: 1.78; 95% CIs: 1.11 to 2.85; RR 1.15; 95% CIs 0.85 to 1.54) (Fig. 4). The superiority of buccal MDZ over rectal DZP in terms of seizure control was observed even after performing a sensitivity analysis by excluding one study that also included adult patients [12] (OR: 1.67; 95% CIs: 0.89 to 3.14). However, this superiority was not evident with results expressed as RR (RR 1.12; 95% CIs 0.81 to 1.56). Details of each metaanalytic comparison are reported in Supplementary material 2. 5. Discussion In this systematic review, we used systematic and explicit methods to identify, select, and critically appraise studies and to extract and analyze data with a meta-analysis. A meta-analysis is the statistical combination of results from two or more separate studies (pairwise comparisons of interventions), allowing an increase in statistical power and an improvement in precision and sometimes permitting questions to be answered that were not posed by individual studies and to settle controversies arising from conflicting claims. In the present meta-analysis, we found that non-IV MDZ is as effective and safe as intravenous or rectal DZP in terminating early SE. With the exception of buccal MDZ, which was more effective than rectal DZP, no other route of administration of MDZ was found to be more effective than intravenous or rectal DZP but only when results are expressed as OR. However, this absence of evidence of a difference in efficacy and safety is not evidence that there is no difference [30] as it is probable that for some comparisons, sample size is smaller than what would be required to detect a clinically important benefit. Hence, it is likely that some subanalyses lacked sufficient statistical power to detect a difference given the relatively small number of studies included in metaanalytic comparisons. The only differences in results expressed as OR and as RR were found for the comparison between buccal MDZ and rectal DZP. Rectal MDZ was found to be more effective than rectal DZP but only when results were expressed as OR. This finding suggests that the difference in efficacy between the two drugs, although significant, might be small. The possible higher efficacy of buccal MDZ compared to rectal DZP may be explained by the facts that transmucosal MDZ is rapidly effective [31, 32] and the sublingual absorption might be more complete and rapid than after rectal administration [33], although no pharmacokinetics study directly comparing the two drugs has been published so far. However, the mouth and the rectum have similar pH and surface areas rich

Please cite this article as: Brigo F, et al, Nonintravenous midazolam versus intravenous or rectal diazepam for the treatment of early status epilepticus: A systematic review with meta-analysis, Epilepsy Behav (2015), http://dx.doi.org/10.1016/j.yebeh.2015.02.030

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Study

Interventions

Intranasal midazolam versus intravenous diazepam Lahat et al. [13] IN MDZ 0.2 mg/kg (max dose: 10 mg) vs. IV DZP 0.3 mg/kg (max dose: 10 mg) Mahmoudian and IN MDZ 0.2 mg/kg vs. Zadeh [15] IV DZP 0.2 mg/kg

Definition of successful treatment

Clinical seizure cessation

Time from arrival in the emergency department to drug administration

Time from drug administration to clinical seizure cessation

Time from arrival in the emergency department to clinical seizure cessation

Serious adverse effects (hypotension or respiratory depression)

Seizure cessation within 10 min of drug administration

MDZ: 23/26a DZP: 24/26a

MDZ: 3.5 ± 1.8 DZP: 5.5 ± 2.0 (mean ± SD, min) p b 0.001

MDZ: 6.1 ± 3.6 DZP: 8.0 ± 4.1 (mean ± SD, min) p b 0.001

MDZ: 0/26b DZP: 0/26b

Seizure cessation within 10 min of drug administration

MDZ: 35/35 DZP: 35/35

MDZ: 3.1 ± 2.2 DZP: 2.5 ± 1.9 (mean ± SD, min) p b 0.001 MDZ: 3.58 ± 1.68c DZP: 2.94 ± 2.62 (mean ± SD, min) p = 0.007 MDZ: 3.16 ± 1.24 DZP: 2.16 ± 1.02 (mean ± SD, min) p = 0.001 MDZ: 3.01 ± 2.79 DZP: 2.67 ± 2.31 (mean ± SD, min) p = 0.05

Javadzadeh et al. [26]

IN MDZ 0.2 mg/kg vs. IV DZP 0.3 mg/kg

Seizure cessation within 10 min of drug administration

MDZ: 30/30 DZP: 30/30

Thakker and Shanbag [27]

IN MDZ 0.2 mg/kg vs. IV DZP 0.3 mg/kg

Seizure cessation within 10 min of drug administration

MDZ: 18/27 DZP: 15/23

Intranasal midazolam versus rectal diazepam Fişgin et al. 2002 IN MDZ 0.2 mg/kg vs. [14] rectal DZP 0.3 mg/kg Bhattacharyya et al. [19] IN MDZ 0.2 mg/kg vs. rectal DZP 0.3 mg/kg

Seizure cessation within 10 min of drug administration Seizure cessation within 10 min of drug administration

MDZ: 20/23 DZP: 13/22 MDZ: 89/92a DZP: 85/96a

Seizure cessation within 15 min of drug administration

MDZ: 50/61 DZP: 56/63

de Haan et al. [23]

Holsti et al. [24]

IN MDZ 10 mg vs. rectal DZP 10 mg

IN MDZ 0.2 mg/kg (max dose: 10 mg) vs. rectal DZP0.3 to 0.5 mg (max dose: 20 mg)

Buccal midazolam versus intravenous diazepam Talukdar and Buccal MDZ 0.2 mg/kg Chakrabarty [21] vs. IV DZP 0.3 mg/kg

Tonekaboni et al. [25]

Buccal MDZ 2.5 mg (age 6–12 months), 5 mg (1–4 years), 7.5 mg (5–9 years), and 10 mg (≥10 years) vs. IV DZP 0.3 mg/kg

MDZ: 3.37 ± 2.46 DZP: 14.13 ± 3.39 (mean ± SD, min) p = 0.001

MDZ: 50.6 ± 14.1 DZP: 68.3 ± 55.1 (mean ± SD, s) p = 0.002

Seizure cessation (time not reported)

Seizure cessation before emergency medical ervices arrived MDZ: 42/50 DZP: 34/42

MDZ: 5.0 [4.0–7.0] DZP: 5.0 [4.0–8.0] (median [IQR], min) p = 0.57

Seizure cessation within 5 min of drug administration

MDZ: 51/60 DZP: 56/60

MDZ: 0.97 ± 0.23 DZP: 2.07 ± 0.84 (mean ± SD, min) p b 0.001

Seizure cessation within 10 min of drug administration

MDZ: 22/32 DZP: 42/60

MDZ: 116.7 ± 126.9 DZP: 178.6 ± 179.4 (mean ± SD, s) p = 0.005 MDZ: 4.6 ± 3.4 DZP: 4.3 ± 3.4 (mean ± SD, min) p = 0.6 MDZ: 3.0 [1.0–10.0] DZP: 4.3 [2.0–14.5] (median [IQR], min) P = 0.09

MDZ: 1.69 ± 0.93 DZP: 1.13 ± 0.5 (mean ± SD, min) p b 0.001 MDZ: 5.68 ± 2.39 DZP: 4.52 ± 2.68 (mean ± SD, min) p = 0.09

MDZ: 0/35 DZP: 0/35

MDZ: 3.16 ± 1.24 DZP: 6.42 ± 2.59 (mean ± SD, min) p b 0.001 MDZ: 6.67 ± 3.12 DZP: 17.18 ± 5.09 (mean ± SD, min) p = 0.001

MDZ: 0/30 DZP: 0/30

MDZ: 0/27 DZP: 1/23

MDZ: 0/23 DZP: 0/22 MDZ: 0/92b DZP: 1/96b

MDZ: 0/61 DZP: 0/63 MDZ: 10.5[7.0–18.0] DZP: 12.5[7.0–30.0] (median [IQR], min) p = 0.25

MDZ: 4/50 DZP: 1/42

MDZ: 2.39 ± 1.04 DZP: 2.98 ± 1.01 (mean ± SD, min) p = 0.004

MDZ: 0/60 DZP: 0/60

MDZ: 7/32b DZP: 13/60b

F. Brigo et al. / Epilepsy & Behavior xxx (2015) xxx–xxx

Please cite this article as: Brigo F, et al, Nonintravenous midazolam versus intravenous or rectal diazepam for the treatment of early status epilepticus: A systematic review with meta-analysis, Epilepsy Behav (2015), http://dx.doi.org/10.1016/j.yebeh.2015.02.030

Table 2 Efficacy and safety outcomes in included studies.

Seizure cessation within 10 min of drug administration

MDZ: 30/40a DZP: 23/39a

Buccal MDZ 0.25 mg/kg vs. rectal DZP 0.5 mg/kg (children ≤ 5 years) or 0.3 mg/kg (children ≥ 6 years) Buccal MDZ 0.5 mg/kg vs. rectal DZP 0.5 mg/kg

Seizure cessation within 10 min of drug administration

MDZ: 18/23 DZP: 17/20

Seizure cessation within 10 min of drug administration, no recurrence within 1 h

Mpimbaza et al. [20]

Buccal MDZ 0.5 mg/kg vs. rectal DZP 0.5 mg/kg

Seizure cessation within 10 min of drug administration, no recurrence within 1 h

Ashrafi et al. [22]

Buccal MDZ 0.3–0.5 mg/kg versus rectal DZP 0.5 mg/kg

Seizure cessation within 5 min of drug administration, no recurrence within 1 h

MDZ: 61/109a DZP: 30/110a Initial seizure control: MDZ: 71/109a DZP: 45/110a MDZ: 115/165 DZP: 94/165 Initial seizure control: MDZ: 125/165 DZP: 114/165 MDZ: 49/49 DZP: 40/49 Seizure control within 8 min: MDZ: 49/49 DZP: 49/49

Baysun et al. [16]

McIntyre et al. [17]

Intramuscular midazolam versus intravenous diazepam Chamberlain et al. [11] IM MDZ 0.2 mg/kg (max dose: 7 mg) vs. IV DZP 0.3 mg/kg (max dose: 10 mg) Shah and Deshmukh [18] IM MDZ 0.2 mg/kg vs. IV DZP 0.2 mg/kg

Portela et al. [29]

IM MDZ 0.5 mg/kg (max dose: 10 mg) versus IV DZP 0.5 mg/kg (max dose: 15 mg)

Intramuscular midazolam versus rectal diazepam Momen et al. [28] IM MDZ 0.3 mg/kg vs. rectal DZP 0.5 mg/kg

MDZ: 2[1–4] DZP: 2[1–3] (median [IQR], min) p = 0.81

MDZ: 0/40b DZP: 0/39b

MDZ: 4–5 DZP: 4–5 (median, min) p=1

MDZ: 0/23 DZP: 1/20

MDZ: 8 [5–20] DZP: 15 [5–31] (median [IQR], min) p b 0.001

MDZ: 5/109b DZP: 7/110b

MDZ: 4.75[3.02–6.52] DZP: 4.35 [2.72–6.58] (median [IQR], min) p = 0.518

MDZ: 2/165 DZP: 2/165

MDZ: 2 DZP: 3 (median, min) p b 0.001

MDZ: 4 DZP: 5 (median, min) p b 0.001

MDZ: 0/49 DZP: 0/49

MDZ: 3.3 ± 2.0 DZP: 7.8 ± 3.2 (mean ± SD, min) p = 0.001

MDZ: 7.3 ± 1.4 DZP: 10.6 ± 3.9 (mean ± SD, min) p = 0.006

MDZ: 1/16 DZP: 2/16

MDZ: 127 (83–320) DZP: 243 (115–725) (median (range),s) p b 0.001

MDZ: 0/50 DZP: 0/50

Seizure cessation within 10 min of drug administration

MDZ: 12/13 DZP: 10/11

Seizure cessation within 5 min of drug administration

MDZ: 45/50 DZP: 29/31 (without IV access) DZP: 25/34 (with IV access)

Seizure cessation within 5 min of drug administration

MDZ: 14/16 DZP: 14/16

MDZ: 2.8 ± 1.5 DZP: 7.4 ± 4.1 (mean ± SD, min) p = 0.001

MDZ: 4.5 ± 3.0 DZP: 3.4 ± 2.0 (mean ± SD, min) p = 0.32 MDZ: 97.22 (15–240) DZP: 250.35 (90–300) (without IV access) p b 0.005 DZP: 119.44 (1–270) (with IV access) p = 0.17 (mean (range), s) MDZ: 4.4 ± 0.5 DZP: 3.3 ± 0.8 (mean ± SD, min) p b 0.001

Seizure cessation within 10 min of drug administration, no recurrence within 1 h

Initial seizure control: MDZ: 48/50 DZP: 47/50 None of the patients showed recurrence within 1 h

MDZ: 65(54–95) DZP: 65(55–190) (median (range), s) p b 0.017

MDZ: 66(24–245) DZP: 130 (45–600) (median (range), s) p b 0.001

MDZ: 7.8 ± 4.1 DZP: 11.2 ± 3.6 (mean ± SD, min) p = 0.047

MDZ: 0/13 DZP: 0/11

MDZ: 0/50 DZP: 0/31 DZP: 0/34

F. Brigo et al. / Epilepsy & Behavior xxx (2015) xxx–xxx

Please cite this article as: Brigo F, et al, Nonintravenous midazolam versus intravenous or rectal diazepam for the treatment of early status epilepticus: A systematic review with meta-analysis, Epilepsy Behav (2015), http://dx.doi.org/10.1016/j.yebeh.2015.02.030

Buccal midazolam versus rectal diazepam Scott et al. [12] Buccal MDZ 10 mg vs. rectal DZP 10 mg

DZP: diazepam, h: hour, IM: intramuscular, IN: intranasal, IQR: interquartile range, IV: intravenous, MDZ: midazolam, and SD: standard deviation. a Expressed as the number of episodes; some patients experienced more than one seizure. b Expressed as the number of episodes; some patients experienced more than one adverse effect. c Time required inserting the intravenous line not included.

7

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Fig. 1. Study flow diagram.

in blood supply which are responsible for drug absorption into the systemic circulation and avoidance of first-pass metabolism. The same advantage occurs after intranasal administration, which prevents passing

through the portal circulation with consequent biotransformation of MDZ through hydroxylation by hepatic microsomal oxidative mechanisms. Furthermore, buccal MDZ as well as intranasal MDZ may be administered more rapidly than rectal DZP without the need to remove clothing and position the patient appropriately. The same limitation holds true for intravenous administration of DZP, which requires the placement of an intravenous access, leading to a delay before drug administration [18]. In addition, gaining access to an intravenous route requires some expertise and may be difficult in patients with convulsive seizures or in infants. The faster administration of non-IV MDZ (administered by buccal, intranasal, or intramuscular route) may explain why, in this systematic review, times from arrival in the emergency department to drug administration and to seizure cessation were shorter with non-IV MDZ than with intravenous or rectal DZP. The motto “time is brain” applies not only for stroke but also for SE as the overall duration of seizure activity represents a primary determinant of outcome [34]. Transferring a patient with SE from home to hospital by ambulance may result in delayed treatment with reduced chances of successful response to a single drug [4]. Hence, the availability of effective drugs, which can be administered easily by nonmedical staff in prehospital settings, is welcome. However, to be clinically relevant, shorter time to drug administration should result also in higher seizure control. The present meta-analysis shows that the faster administration of non-IV MDZ does not necessarily result in higher seizure control. However, the absence of evidence that a difference exists does not mean that a difference would not be realized if the sample size had been larger [35]. Our review, however, suggests that the magnitude of difference between non-IV MDZ and intravenous or rectal DZP may be not so high. Diazepam is more widely available throughout the world than either lorazepam or MDZ. Rectal DZP administration is a valuable option to treat emergency seizure situations when the intravenous route is not feasible, for example, in a number of prehospital settings particularly in the absence of skilled health-care personnel. However, there is a trend for rectal DZP to be substituted by buccal or intranasal MDZ, which is socially more accepted. The present review suggests that buccal MDZ, besides being more acceptable and easy to use, is also more effective than rectal DZP for seizure control. Hence, whenever possible, the administration of buccal MDZ should be preferred over rectal DZP. This conclusion is further supported by the fact that in four RCTs specifically assessing this aspect, buccal MDZ [20,22] and intranasal MDZ [23,24] were found to be significantly preferable (overall satisfaction, easiness of use) than rectal DZP. Eighteen out of the 19 studies included in this systematic review were conducted in children (1573 patients younger than 16 years).

Table 3 Risk of bias in included studies. Study

Random sequence generation (selection bias)

Allocation concealment (selection bias)

Blinding of participants and personnel (performance bias)

Blinding of outcome assessment (detection bias)

Incomplete outcome data (attrition bias)

Sponsored by pharmaceutical company

Chamberlainet al. [11] Scott et al. [32] Lahat et al. [13] Fişgin et al. 2002 [14] Mahmoudian and Zadeh [15] Baysun et al. [16] McIntyre et al. [17] Shah and Deshmukh [18] Bhattacharyya, 2006 Mpimbaza et al. [20] Talukdar and Chakrabarty [21] Ashrafi et al. [22] de Haan et al. [23] Holsti et al. [24] Javadzadeh et al. [26] Tonekaboni et al. [25] Thakker and Shanbag [27] Momen et al. [28] Portela et al. [29]

Unclear Low Low High Low High Low Unclear Low Unclear Low Low Unclear Unclear Unclear Low Low Low Unclear

Unclear Low Low Unclear Low Unclear High Unclear Low Low Unclear Unclear Unclear Low Unclear Unclear Low Unclear Low

Unclear Low Low Low Low Low Low Low Low Low Low Low Low Low Low Low Low Low Low

Low Low Low Low Low Low Low Low Low Low Low Low Low Low Low Low Low Low Low

Low Low Low Low Low Low Low Low Low Low Low Low Low Low Low Low Low Low Low

Unclear Unclear No Unclear Unclear Unclear No Unclear Unclear No Unclear Unclear No No Unclear No No No No

Please cite this article as: Brigo F, et al, Nonintravenous midazolam versus intravenous or rectal diazepam for the treatment of early status epilepticus: A systematic review with meta-analysis, Epilepsy Behav (2015), http://dx.doi.org/10.1016/j.yebeh.2015.02.030

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Fig. 2. Non-IV MDZ versus DZP (all routes of administration). (a) Clinical seizure cessation after drug administration and (b) serious adverse effects.

Consequently, the generalizability of results of this systematic review is restricted to children. Only one study was entirely conducted in an adult population (21 patients, aged 31 to 69 years), showing no difference in efficacy or time to seizure cessation after drug administration between intranasal MDZ and rectal DZP [23]. 5.1. Comparison with a previous systematic review with meta-analysis A systematic review previously compared non-IV MDZ with DZP by any route in early SE seizures in children and adults, pooling data from several RCTs into a meta-analysis [36]. Six studies with 774 subjects were included. Midazolam by any route was superior to DZP by any route for seizure cessation (RR: 1.52; 95% CIs: 1.27 to 1.82). Non-IV MDZ was found to be as effective as intravenous DZP (RR: 0.79; 95% CIs: 0.19 to 3.36) and buccal MDZ more effective than rectal DZP in achieving seizure control (RR: 1.54; 95% CIs: 1.29 to 1.85). Time for drug administration was faster for MDZ than for DZP (mean difference:

2.46 min; 95% CIs: 1.52 to 3.39 min), whereas times between drug administration and seizure cessation were similar between the two drugs. Our systematic review confirms these results, especially with regard to superiority of buccal MDZ over rectal DZP in seizure control and in shorter interval between arrival at the emergency department and drug administration for non-IV MDZ. Conversely, our review did not show any difference in terms of seizure cessation between non-IV MDZ by any route and DZP by any route. This difference may be due to the fact that our review differs from that conducted by McMullan et al. [36] in several aspects: (1) obviously, our review includes studies which were not considered in the previous review as they were not yet published [22–29]; (2) the choice of the efficacy outcomes is slightly different as we chose to consider clinical seizure cessation within 15 min of drug administration instead of failure to achieve seizure cessation as made by McMullan et al.; (3) our meta-analytic comparisons were conducted using a random-effects model, and not a fixed-effect model, as

Please cite this article as: Brigo F, et al, Nonintravenous midazolam versus intravenous or rectal diazepam for the treatment of early status epilepticus: A systematic review with meta-analysis, Epilepsy Behav (2015), http://dx.doi.org/10.1016/j.yebeh.2015.02.030

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Fig. 3. Non-IV MDZ versus DZP (all routes of administration). (a) Time from arrival to drug administration, (b) time from drug administration to clinical seizure cessation, and (c) time from arrival to clinical seizure cessation.

we preferred a more conservative statistical model to take into account the variability between studies; and (4) we analyzed the quality assessment of potentially eligible studies focusing more on the methodological quality of the trial conduction than on the accuracy and quality of reporting study results. 5.2. Exploration of heterogeneity The results of the present meta-analysis should be read with caution mainly because of the considerable statistical heterogeneity found in most meta-analytic comparisons that is indicative of inconsistency in the results of included studies. The term “statistical heterogeneity” describes the degree of variation in the effect estimates from a set of studies and indicates the presence of variability among studies beyond the amount expected due solely to the play of chance. Such a statistical heterogeneity may be explained both by differences in clinical characteristics of study participants (clinical heterogeneity) and by different drug regimens (methodological heterogeneity) adopted. Regarding clinical heterogeneity, potentially relevant aspects to be taken into account are differences in age of patients, seizure duration, seizure type, and seizure etiology. Repeating pooled analyses on clinical seizure cessation and occurrence of adverse effects by excluding the RCTs with adult patients [12,

23], we did not find a relevant reduction in statistical inconsistency among studies, suggesting that age alone does not explain the variability in study results. It is unlikely that minimal time differences in seizure duration (5 min versus 10 min) may represent a relevant source of heterogeneity. Conversely, the lack of individual patient data on seizure type and etiology (both relevant prognostic factors) prevented us from performing a more detailed sensitivity analysis taking into account these aspects. Regarding seizure type, most studies included patients with different types of convulsive seizures, and in some cases, studies did not specify in further detail the clinical semiology of seizures. One RCT reported data on seizure control according to seizure types and found no difference between buccal MDZ and intravenous DZP for generalized tonic–clonic seizures (88.9% versus 90.2%, respectively; p = 0.559) and tonic seizures (100% versus 100%, respectively; p = 0.999). In another study from India, buccal MDZ was less effective than intravenous DZP in controlling “clonic partial seizures” (63.6% versus 100%, respectively; p = 0.01) [21]. These findings suggest that MDZ or DZP might be more effective in some subtypes of convulsive seizures. However, this hypothesis needs to be tested in further studies with larger sample size. Regarding methodological heterogeneity, potentially relevant aspects to be considered are differences in randomization/allocation concealment and blinding; sponsorship by pharmaceutical

Please cite this article as: Brigo F, et al, Nonintravenous midazolam versus intravenous or rectal diazepam for the treatment of early status epilepticus: A systematic review with meta-analysis, Epilepsy Behav (2015), http://dx.doi.org/10.1016/j.yebeh.2015.02.030

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Fig. 4. Buccal MDZ versus rectal DZP. Clinical seizure cessation after drug administration. Results are expressed as Odds Ratio.

companies; definition of SE (seizures lasting N 5 min, seizures lasting N10 min, seizures at arrival to the emergency department); drug dosage; and intervention settings (hospital or prehospital). Randomization was adequate in the great majority of studies, and overall, the methodological quality of studies was good. Even if some studies were not blinded and in others, blinding was not explicitly reported, the ‘hard’ outcomes chosen in all studies (clinical seizure cessation, serious adverse effects) were not probably influenced by lack of blinding. As a consequence, all studies have a low risk of performance and detection bias. However, because of the limited information available, we were not able to assess to what extent these factors may impact on inconsistency among trial results.

6. Conclusions Non-IV MDZ is as effective and safe as intravenous or rectal DZP in terminating early SE in children. Times from arrival in the emergency department to drug administration and to seizure cessation are shorter with non-IV MDZ than with intravenous or rectal DZP, but this does not necessarily translate into higher seizure control. An exception may be the buccal MDZ, which, besides being socially more acceptable and easier to administer, might also have higher efficacy than rectal DZP in seizure control. The generalizability of these results is restricted to children as no sufficient data are available for adults. Several areas require attention in future research in the treatment of SE: investigators should use acceptable and uniform definitions of SE (including different stages of SE) and clear and uniform methods of data presentation to facilitate meta-analysis [37]. Datasets with individual patient data (raw data) should be made publicly available by trial authors to facilitate subgroup metaanalyses for relevant prognostic aspects such as etiology and seizure type.

Acknowledgments We thank Piero Bonzano and Vincenzo De Simone (Accord Healthcare) and Alberto Liuti (ViroPharma) for seeking information on unpublished randomized controlled trials on buccal midazolam or studies in progress. Conflict of interest FB received speakers' honoraria from UCB Pharma. ET has acted as a paid consultant to Bial, Biogen Idec, Eisai, Ever Neuropharma, Medtronics, Takeda, Upsher-Smith, and UCB; has received speakers' honoraria from Bial, Boehringer, Eisai, GL Lannacher, and UCB Pharma; and has received research funding from Biogen Idec, Merck, Novartis, Red Bull, UCB Pharma, the European Union, FWF (Österreichischer Fond zur Wissenschaftsförderung), and Bundesministerium für Wissenschaft und Forschung. RN and FT declare no conflicts of interest.

Appendix A. Supplementary data Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.yebeh.2015.02.030.

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Please cite this article as: Brigo F, et al, Nonintravenous midazolam versus intravenous or rectal diazepam for the treatment of early status epilepticus: A systematic review with meta-analysis, Epilepsy Behav (2015), http://dx.doi.org/10.1016/j.yebeh.2015.02.030

Nonintravenous midazolam versus intravenous or rectal diazepam for the treatment of early status epilepticus: A systematic review with meta-analysis.

Prompt treatment of status epilepticus (SE) is associated with better outcomes. Rectal diazepam (DZP) and nonintravenous (non-IV) midazolam (MDZ) are ...
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