Intramuscular Versus Intravenous Therapy for Prehospital Status Epilepticus

Department of Emergency Medicine, University of Michigan, Ann Arbor, MI 48105, USA.
New England Journal of Medicine (Impact Factor: 55.87). 02/2012; 366(7):591-600. DOI: 10.1056/NEJMoa1107494
Source: PubMed


Early termination of prolonged seizures with intravenous administration of benzodiazepines improves outcomes. For faster and more reliable administration, paramedics increasingly use an intramuscular route.
This double-blind, randomized, noninferiority trial compared the efficacy of intramuscular midazolam with that of intravenous lorazepam for children and adults in status epilepticus treated by paramedics. Subjects whose convulsions had persisted for more than 5 minutes and who were still convulsing after paramedics arrived were given the study medication by either intramuscular autoinjector or intravenous infusion. The primary outcome was absence of seizures at the time of arrival in the emergency department without the need for rescue therapy. Secondary outcomes included endotracheal intubation, recurrent seizures, and timing of treatment relative to the cessation of convulsive seizures. This trial tested the hypothesis that intramuscular midazolam was noninferior to intravenous lorazepam by a margin of 10 percentage points.
At the time of arrival in the emergency department, seizures were absent without rescue therapy in 329 of 448 subjects (73.4%) in the intramuscular-midazolam group and in 282 of 445 (63.4%) in the intravenous-lorazepam group (absolute difference, 10 percentage points; 95% confidence interval, 4.0 to 16.1; P<0.001 for both noninferiority and superiority). The two treatment groups were similar with respect to need for endotracheal intubation (14.1% of subjects with intramuscular midazolam and 14.4% with intravenous lorazepam) and recurrence of seizures (11.4% and 10.6%, respectively). Among subjects whose seizures ceased before arrival in the emergency department, the median times to active treatment were 1.2 minutes in the intramuscular-midazolam group and 4.8 minutes in the intravenous-lorazepam group, with corresponding median times from active treatment to cessation of convulsions of 3.3 minutes and 1.6 minutes. Adverse-event rates were similar in the two groups.
For subjects in status epilepticus, intramuscular midazolam is at least as safe and effective as intravenous lorazepam for prehospital seizure cessation. (Funded by the National Institute of Neurological Disorders and Stroke and others; number, NCT00809146.).

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    • "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]. "
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    ABSTRACT: 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. We searched the Cochrane Central Register of Controlled Trials (CENTRAL),, 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 >5min or as seizures at arrival in the emergency department. The following outcomes were assessed: clinical seizure cessation within 15min 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). 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 16years. 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: -3.67min; 95% CIs: -5.98 to -1.36); a similar result was found for time from arrival to drug administration (348 seizures; mean difference: -3.56min; 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: 0.56min; 95% CIs: 0.15 to 0.98min). 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 69years), showing no difference in efficacy or time to seizure cessation after drug administration between intranasal MDZ and rectal DZP. 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. Copyright © 2015 Elsevier Inc. All rights reserved.
    Epilepsy & Behavior 03/2015; 49. DOI:10.1016/j.yebeh.2015.02.030 · 2.26 Impact Factor
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    • "This study describes the use of an ARS during EFIC community consultations for a single site of the RAMPART study.10 We retrospectively compared ARS and non-ARS CC sites for potential differences in baseline demographic characteristics and average rank scores of the final paper survey. "
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    ABSTRACT: Introduction The Department of Health and Human Services and Food and Drug Administration described guidelines for exception from informed consent (EFIC) research. These guidelines require community consultation (CC) events, which allow members of the community to understand the study, provide feedback and give advice. A real-time gauge of audience understanding would allow the speaker to modify the discussion. The objective of the study is to describe the use of audience response survey (ARS) technology in EFIC CCs. Methods As part of the Rapid Anticonvulsant Medication Prior to Arrival Trial (RAMPART), 13 CC events were conducted. We prepared a PowerPoint™ presentation with 4 embedded ARS questions,according to specific IRB guidelines to ensure that the pertinent information would reach our targeted audience. During 6 CCs, an ARS was used to gauge audience comprehension. Participants completed paper surveys regarding their opinion of the study following each CC. Results The ARS was used with minimal explanation and only one ARS was lost. Greater than 80% of the participants correctly answered 3 of the 4 ARS questions with 61% correctly answering the question regarding EFIC. A total of 105 participants answered the paper survey; 80–90% of the responses to the paper survey were either strongly agree or agree. The average scores on the paper survey in the ARS sites compared to the non-ARS sites were significantly more positive. Conclusion The use of an audience response system during the community consultation aspects of EFIC is feasible and provides a real-time assessment of audience comprehension of the study and EFIC process. It may improve the community’s opinion and support of the study.
    The western journal of emergency medicine 07/2014; 15(4):414-8. DOI:10.5811/westjem.2014.3.19426
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    • "There is general agreement that treatment of SE should follow a staged treatment protocol [10]. Randomized controlled trials show that intravenous lorazepam [11–13] or intramuscular midazolam [14, 15] are the most efficient treatment in early status. Approximately 30–40 % of all patients fail to respond to initial treatment with benzodiazepines and need further treatment with intravenous antiepileptic drugs (AEDs). "
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    ABSTRACT: The effectiveness of valproate (VPA) in the treatment of focal and generalized epilepsies is well established. The drug has a wide spectrum of action, good tolerability, and has been available as an injectable formulation since 1993. Despite the lack of class A evidence, it has been used extensively in various forms of status epilepticus (SE). Our aim was to present a systematic review of data from randomized and non-randomized controlled trials to evaluate the efficacy and safety of intravenous VPA for the treatment of SE. Data sources included MEDLINE, back tracing of references in pertinent studies, and contact with the manufacturer of VPA (Sanofi-Aventis). Overall, the search strategy yielded 433 results (425 MEDLINE, seven congress abstracts, one unpublished study); after excluding duplicate publications and case reports, 30 studies were identified (the earliest was published in 1993, the most recent in 2012); ten were controlled (six randomized controlled trials, four non-randomized controlled studies), and 20 uncontrolled trials (eight prospective observational studies, 12 retrospective case series). The cumulative literature describes the experiences of 860 patients with various forms of SE treated with intravenous VPA. The overall response rate to abrogate SE was 70.9 % (601/848; 95 % confidence interval [CI] 67.8-73.9). Response rates to intravenous VPA were better in children than in adults and did not differ between the SE types. The most commonly reported effective doses were between 15 and 45 mg/kg in bolus (6 mg/kg/min) followed by 1-3 mg/kg/h infusion. Safety studies of intravenous VPA administration in patients with SE showed a low incidence of adverse events overall (<10 %), mainly dizziness, thrombocytopenia, and mild hypotension, which was independent of infusion rates. Of note, good cardiovascular and respiratory tolerability was observed in these studies, even at high doses and fast infusion rates (up to 30 mg/kg at 10 mg/kg/min), despite multiple morbidities or other antiepileptic drugs. The most serious concern relates to the possibility of acute encephalopathy, sometimes related to hepatic abnormalities or hyperammonemia. The published experience is consistent with VPA being a safe and effective therapeutic option for patients with established SE who have previously failed conventional first-line treatment with benzodiazepines, but high-quality randomized controlled trials are needed to inform clinicians on its comparative effectiveness in SE.
    CNS Drugs 05/2014; 28(7). DOI:10.1007/s40263-014-0167-1 · 5.11 Impact Factor
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