The new england
`journal of medicine
`
`established in 1812
`
`february 16, 2012
`
`vol. 366 no. 7
`
`Intramuscular versus Intravenous Therapy for Prehospital
`Status Epilepticus
`Robert Silbergleit, M.D., Valerie Durkalski, Ph.D., Daniel Lowenstein, M.D., Robin Conwit, M.D.,
`Arthur Pancioli, M.D., Yuko Palesch, Ph.D., and William Barsan, M.D., for the NETT Investigators*
`
`Abs tr act
`
`Background
`Early termination of prolonged seizures with intravenous administration of benzodi-
`azepines improves outcomes. For faster and more reliable administration, paramed-
`ics increasingly use an intramuscular route.
`
`Methods
`This double-blind, randomized, noninferiority trial compared the efficacy of intra-
`muscular 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 infu-
`sion. The primary outcome was absence of seizures at the time of arrival in the emer-
`gency department without the need for rescue therapy. Secondary outcomes included
`endotracheal intubation, recurrent seizures, and timing of treatment relative to the ces-
`sation of convulsive seizures. This trial tested the hypothesis that intramuscular mid-
`azolam was noninferior to intravenous lorazepam by a margin of 10 percentage points.
`
`Results
`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 noninfe-
`riority 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%, re-
`spectively). Among subjects whose seizures ceased before arrival in the emergency de-
`partment, 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.
`
`From the Department of Emergency
`Medicine, University of Michigan, Ann
`Arbor (R.S., W.B.); the Department of
`Medicine, Division of Biostatistics and
`Epidemiology, Medical University of
`South Carolina, Charleston (V.D., Y.P.);
`the Department of Neurology, University
`of California, San Francisco, San Francis-
`co (D.L.); the National Institute of Neuro-
`logical Disorders and Stroke, National
`Institutes of Health, Bethesda, MD
`(R.C.); and the Department of Emergen-
`cy Medicine, University of Cincinnati,
`Cincinnati (A.P.). Address reprint re-
`quests to Dr. Silbergleit at the Depart-
`ment of Emergency Medicine, Suite 3100,
`24 Frank Lloyd Wright Dr., Ann Arbor, MI
`48105, or at robert.silbergleit@umich
`.edu.
`
`*The Neurological Emergencies Treatment
`Trials (NETT) investigators are listed in
`the Supplementary Appendix, available at
`NEJM.org.
`
`This article (10.1056/NEJMoa1107494) was
`updated on February 16, 2012.
`
`N Engl J Med 2012;366:591-600.
`Copyright © 2012 Massachusetts Medical Society.
`
`Conclusions
`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; ClinicalTrials.gov
`number, NCT00809146.)
`
`ARGENTUM Exhibit 1131
` Argentum Pharmaceuticals LLC v. Research Corporation Technologies, Inc.
`IPR2016-00204
`
`n engl j med 366;7 nejm.org february 16, 2012
`
`591
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`The New England Journal of Medicine
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`Downloaded from nejm.org on November 13, 2016. For personal use only. No other uses without permission.
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` Copyright © 2012 Massachusetts Medical Society. All rights reserved.
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`

`
`T h e ne w e ngl a nd jou r na l o f m e dicine
`
`Early termination of prolonged epi-
`
`leptic seizures in response to intravenous
`administration of benzodiazepines by para-
`medics in the prehospital setting is associated
`with better patient outcomes. The randomized,
`controlled Prehospital Treatment of Status Epilep-
`ticus (PHTSE) trial (ClinicalTrials.gov number,
`NCT00004297) compared diazepam, lorazepam,
`and placebo given intravenously by paramedics to
`treat subjects with prolonged convulsive seizures.1
`The trial showed that both these benzodiazepines
`were an effective prehospital treatment for seizures,
`as compared with placebo. The proportion of sub-
`jects whose seizures were terminated at the time
`of arrival in the emergency department was 59.1%
`in the group receiving intravenous lorazepam,
`42.6% in the group receiving intravenous diaze-
`pam, and 21.1% in the group receiving intrave-
`nous placebo.
`Many emergency medical services (EMS) sys-
`tems, however, have begun to use intramuscular
`midazolam rather than an intravenous agent,
`largely because intramuscular administration is
`faster and is consistently achievable.2 This prac-
`tice has become increasingly common despite the
`lack of clinical-trial data regarding the efficacy and
`safety of intramuscular midazolam. Although in-
`travenous lorazepam is the preferred treatment for
`patients with seizures in the emergency depart-
`ment (and was the most effective treatment in the
`PHTSE trial), it is rarely used by paramedics in the
`prehospital setting because of the potential diffi-
`culty with intravenous administration, as well as
`the short shelf-life of lorazepam when it is not re-
`frigerated.3 EMS medical directors need a practical
`alternative that is at least as safe and effective as
`intravenous lorazepam. We therefore performed a
`noninferiority study to determine whether intra-
`muscular midazolam is as effective as intravenous
`lorazepam, with a similar degree of safety, for
`terminating status epilepticus seizures before ar-
`rival at the hospital.
`
`Methods
`
`Study Design
`The Rapid Anticonvulsant Medication Prior to Ar-
`rival Trial (RAMPART) was a randomized, double-
`blind, phase 3, noninferiority clinical trial. It was
`designed and conducted by the Neurological Emer-
`gencies Treatment Trials (NETT) network, a multi-
`disciplinary clinical trials infrastructure funded by
`
`the National Institute of Neurological Disorders
`and Stroke (NINDS). The investigators were re-
`sponsible for all elements of the trial, including
`design, data collection, and analysis. The authors
`wrote the manuscript and vouch for the data and
`analysis. The trial was performed under an Inves-
`tigational New Drug application with the Food
`and Drug Administration (FDA). Autoinjectors
`with active medication and placebo were pur-
`chased by the Department of Defense and pro-
`vided to the NINDS through a cooperative agree-
`ment. The Department of Defense had no role in
`the design of the study, accrual or analysis of
`data, or preparation of the manuscript. The study
`was conducted in accordance with the protocol,
`which is available with the full text of this article
`at NEJM.org.
`RAMPART involved 4314 paramedics, 33 EMS
`agencies, and 79 receiving hospitals across the
`United States. Paramedics received continuing
`medical education in the management of seizures
`and other neurologic emergencies, as well as sup-
`plemental training in human subjects research and
`protections and in the study protocol, with re-
`fresher protocol training provided throughout the
`trial.
`The trial met the exception from informed-
`consent requirements for emergency research un-
`der the FDA code of regulations 21 CFR 50.24.4
`Institutional review boards for all entities engaged
`in this research reviewed local community consul-
`tation activity, according to the regulations regard-
`ing the exception from informed consent, and
`provided approval. Subjects or their legally autho-
`rized representatives were notified about enroll-
`ment in the trial by the study team as soon as
`possible, usually while the subject was still in the
`emergency department, and provided written in-
`formed consent to allow continued data collection
`until follow-up was completed.
`
`Study Subjects
`The intended study population included children
`with an estimated body weight of 13 kg or more
`and adults requiring treatment with benzodiaze-
`pines for status epilepticus in the prehospital set-
`ting. Subjects were enrolled if they were having
`convulsive seizures at the time of treatment by
`paramedics and were reported by reliable witness-
`es to have been continuously convulsing for longer
`than 5 minutes or if they were having convulsive
`seizures at the time of treatment after having in-
`
`592
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`
` Copyright © 2012 Massachusetts Medical Society. All rights reserved.
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`

`
`Prehospital Control of Status Epilepticus
`
`termittent seizures without regaining conscious-
`ness for longer than 5 minutes.
`Subjects were excluded for the following rea-
`sons: the acute precipitant of the seizures was
`major trauma, hypoglycemia, cardiac arrest, or a
`heart rate of less than 40 beats per minute (since
`these conditions require alternative treatments);
`they had a known allergy to midazolam or lo-
`razepam; they were known to be pregnant or a
`prisoner; they were being treated as part of an-
`other study; or, preemptively, they opted out of
`this study by wearing a medical-alert tag marked
`“RAMPART declined.”
`
`Study Intervention
`When they arrived at the scene, the study paramed-
`ics rapidly performed an initial assessment and
`stabilized subjects who were in status epilepticus,
`according to their local EMS protocols. For subjects
`who met the eligibility criteria, the paramedics
`began the study procedure by opening an instru-
`mented box containing a study drug kit. Each kit
`contained two color-coded, shrink-wrapped study-
`drug bundles, one for each dose tier; each bundle
`consisted of one intramuscular autoinjector (In-
`vestigational Midazolam Autoinjector [Meridian
`Medical Technologies]) and one prefilled intrave-
`nous syringe (Carpuject System [Hospira]). All
`adults and those children with an estimated body
`weight of more than 40 kg received either 10 mg of
`intramuscular midazolam followed by intravenous
`placebo or intramuscular placebo followed by 4 mg
`of intravenous lorazepam. In children with an es-
`timated weight of 13 to 40 kg, the active treatment
`was 5 mg of intramuscular midazolam or 2 mg of
`intravenous lorazepam. Blinding and simple ran-
`domization with equal numbers of subjects as-
`signed to the two study groups were achieved with
`the use of a double-dummy strategy, in which each
`kit was randomly assigned at the central pharma-
`cy to contain either the active intramuscular drug
`with intravenous placebo or intramuscular placebo
`with the active intravenous drug. All subjects were
`treated with the intramuscular autoinjector, after
`which venous access was immediately achieved
`and treatment was administered by means of in-
`travenous syringe. Subjects were considered to be
`enrolled in the trial when the intramuscular auto-
`injector was applied, regardless of whether the in-
`tramuscular dose was successfully delivered.
`A voice recorder was activated by opening the
`study box. Paramedics were instructed to record
`
`oral statements when intramuscular treatment was
`administered, when intravenous access was ob-
`tained, when the intravenous study drug was ad-
`ministered, when any rescue treatments were giv-
`en, and when convulsions were observed to stop.
`Each statement was time-stamped by the study
`box’s internal clock. Paramedics also stated wheth-
`er the subject was convulsing on arrival at the
`emergency department.
`When it was difficult to obtain intravenous ac-
`cess, paramedics were instructed to continue at-
`tempts for at least 10 minutes, but they were per-
`mitted to use intraosseous access at any time in
`lieu of intravenous access. For the purposes of this
`trial, intraosseous access to the vascular space was
`considered equivalent to intravenous access. Res-
`cue therapy, as dictated by local EMS protocol,
`was recommended for use in subjects who were
`still convulsing 10 minutes after the last study
`medication was administered. If there was a delay
`in obtaining intravenous access and the subject
`stopped having seizures before the intravenous
`study drug could be given, the intravenous study
`medication was not used. If convulsions resumed
`later during EMS transport, rescue therapy (accord-
`ing to the local protocol) was to be given.
`
`Study Outcomes
`The primary outcome was termination of seizures
`before arrival in the emergency department with-
`out the need for the paramedics to provide rescue
`therapy. Subjects did not reach the primary out-
`come if they were having seizures on arrival in the
`emergency department or if they received rescue
`medication before arrival. Termination of seizures
`on arrival was determined according to the clinical
`judgment of the attending emergency physician and
`was based on examination of the subjects, their
`clinical course, and results of any routine diagnos-
`tic testing (Section 6.1 of the protocol). This out-
`come measure was previously used in the PHTSE
`trial.1,5
`Key secondary outcome measures included the
`time from study-box opening to termination of
`convulsions and the time from initiation of active-
`drug administration to termination of convulsions
`(among subjects in whom convulsions ceased be-
`fore arrival in the emergency department), the
`frequency and duration of hospitalization and of
`admissions to the intensive care unit, and the fre-
`quencies of acute endotracheal intubation and
`acute seizure recurrence. Acute endotracheal in-
`
`n engl j med 366;7 nejm.org february 16, 2012
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`593
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`T h e ne w e ngl a nd jou r na l o f m e dicine
`
`2145 Patients were assessed for eligibility
`and treated with benzodiazepine by EMS
`
`1122 Were excluded
`760 Were ineligible
`274 Had unspecified reasons
`47 Did not have study kit available
`29 Were omitted because para-
`medics forgot about the study
`6 Had autoinjector misfire before
`administration
`5 Had been enrolled previously
`1 Was directed not to enroll by
`doctor on scene
`
`1023 Were enrolled and underwent randomization
`
`130 Were excluded from intention-to-
`treat population owing to repeat
`enrollment
`66 Received IM midazolam
`64 Received IV lorazepam
`
`893 Were assigned to a treatment group
`
`448 Were assigned to IM midazolam
`443 Received intervention
`5 Did not receive intervention owing
`to autoinjector malfunction
`
`445 Were assigned to IV lorazepam
`297 Received intervention
`148 Did not receive intervention
`95 Had convulsions stop before
`intervention
`42 Had paramedics who could not
`start IV
`11 Had other reasons
`
`86 Were excluded from per-
`protocol analysis
`29 Had eligibility violations
`16 Received incorrect dose
`23 Received incorrect admini-
`stration of study medicine
`18 Had more than one of the
`above reasons
`
`75 Were excluded from per-
`protocol analysis
`17 Had eligibility violations
`10 Received incorrect dose
`30 Received incorrect admini-
`stration of study medicine
`18 Had more than one of the
` above reasons
`
`448 Were included in the intention-to-
`treat analysis
`362 Were included in the per-protocol
`analysis
`
`445 Were included in the intention-to-
`treat analysis
`370 Were included in the per-protocol
`analysis
`
`Figure 1. Screening, Enrollment, Randomization, and Inclusion in Intention-to-Treat and Per-Protocol Analyses.
`The number of patients who were assessed and enrolled includes any repeat assessments and enrollments for those
`who presented to emergency medical services (EMS) with status epilepticus more than once. The number assigned to
`treatment in the intention-to-treat analysis includes every patient who was enrolled in the study but only the initial en-
`rollment for those enrolled more than once. Randomization was defined as occurring when an autoinjector was ap-
`plied to the subject. “Misfire” refers to instances when the autoinjector was inadvertently triggered before it could be
`applied to the subject. “Malfunction” refers to instances when the autoinjector was applied but the drug was not ad-
`ministered because of operator error or mechanical failure. IM denotes intramuscular, and IV intravenous.
`
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` Copyright © 2012 Massachusetts Medical Society. All rights reserved.
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`
`Prehospital Control of Status Epilepticus
`
`tubation was defined as intubation performed or
`attempted by EMS personnel or performed within
`30 minutes after arrival in the emergency depart-
`ment. Acute seizure recurrence was defined as any
`further convulsive or electrographic seizures that
`required additional antiepileptic medications dur-
`ing the first 12 hours of hospitalization in sub-
`jects who did not have seizures on arrival in the
`emergency department. Serious adverse events
`were recorded through the end of the study for
`every subject (see Table A2 in the Supplementary
`Appendix, available at NEJM.org).
`
`Statistical Analysis
`The primary objective of the study was to show that
`the proportion of subjects whose seizures were
`terminated before arrival in the emergency de-
`partment (without the use of rescue medications)
`in the intramuscular midazolam group was not
`inferior to that in the intravenous lorazepam group
`by more than a prespecified amount (the noninfe-
`riority margin). The null hypothesis of inferiority
`was tested with the use of a one-sided z statistic.6
`The primary analysis was followed by a one-sided
`test (conditional on the finding of noninferiority)
`for superiority at a significance level of 0.025, al-
`though this was not prespecified in the protocol.
`On the basis of published studies of similar patient
`populations, and accounting for differences in the
`dose of lorazepam and in the definition of effica-
`cy, we estimated that after an initial dose of intra-
`venous lorazepam had been administered, seizures
`would be terminated in 70% of subjects before ar-
`rival in the emergency department. Sample size
`was estimated on the basis of the comparison of
`independent proportions, with two planned inter-
`im analyses for futility with respect to the pri-
`mary outcome; 90% power to show the noninferi-
`ority of intramuscular midazolam; a noninferiority
`margin of 10 percentage points; and a one-sided
`test with the probability of a type I error of 0.025.
`The maximum sample size required for random-
`ization was 890 subjects (445 per treatment
`group). Because some patients have recurring
`episodes of status epilepticus, the total sample
`size was inflated by 15% (1024 subjects) to ac-
`count for inadvertent repeated enrollment of the
`same subjects. (Repeated enrollments of the
`same subject were not analyzed.) Secondary out-
`comes were compared in a superiority frame-
`work with the use of a two-sided test with the
`
`Table 1. Characteristics of the Subjects at Baseline.*
`
`Characteristic
`Age
`Mean (range) — yr
`Age group — no. (%)
`0–5 yr
`6–10 yr
`11–20 yr
`
`21–40 yr
`41–60 yr
`≥61 yr
`Male sex — no. (%)
`Race — no. (%)†
`Black
`White
`Other, mixed, or unknown
`Ethnic group — no. (%)†
`Non-Hispanic
`Hispanic
`Unknown
`Dose tier — no. (%)‡
`Low
`High
`History of epilepsy — no. (%)
`Yes
`No
`Not documented
`Final diagnosis — no. (%)
`Status epilepticus
`Nonepileptic spell
`Undetermined
`Precipitating cause of status epilepticus —
`no. (%)
`Noncompliance with or discontinuation
`of anticonvulsant therapy
`Idiopathic or breakthrough status
`epilepticus
`Coexisting condition that lowered seizure
`threshold
`
`IM Midazolam
`(N = 448)
`
`IV Lorazepam
`(N = 445)
`
`43±22 (0–102)
`
`44±22 (1–94)
`
`32 (7)
`15 (3)
`28 (6)
`
`114 (25)
`169 (38)
`90 (20)
`250 (56)
`
`229 (51)
`165 (37)
`54 (12)
`
`310 (69)
`49 (11)
`89 (20)
`
`62 (14)
`386 (86)
`
`293 (65)
`111 (25)
`44 (10)
`
`404 (90)
`31 (7)
`13 (3)
`
`29 (7)
`20 (4)
`21 (5)
`
`112 (25)
`169 (38)
`94 (21)
`238 (53)
`
`224 (50)
`183 (41)
`38 (9)
`
`290 (65)
`57 (13)
`98 (22)
`
`59 (13)
`386 (87)
`
`295 (66)
`103 (23)
`47 (11)
`
`399 (90)
`32 (7)
`14 (3)
`
`137 (31)
`
`141 (32)
`
`121 (27)
`
`121 (27)
`
`33 (7)
`
`29 (7)
`
`* Plus–minus values are means ±SD. There were no significant differences be-
`tween the two groups with respect to baseline characteristics.
`† Race and ethnic group were reported by the investigators. More detailed data
`for race are provided in Table A3 in the Supplementary Appendix.
`‡ The high-dose tier included children whose estimated body weight was above
`40 kg and all adults, and active treatment consisted of either 10 mg of intra-
`muscular (IM) midazolam or 4 mg of intravenous (IV) lorazepam. The low-dose
`tier included children whose estimated body weight was 13 to 40 kg, and active
`treatment consisted of either 5 mg of IM midazolam or 2 mg of IV lorazepam.
`
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`probability of a type I error of less than 0.05. All
`analyses were conducted with the intention-to-
`treat population defined as all subjects randomly
`assigned to a study medication. A sensitivity anal-
`ysis was conducted with the per-protocol popu-
`lation, which excluded subjects with any of the
`following three predefined protocol deviations:
`eligibility violation, incorrect dose of study medi-
`cation, or incorrect administration.
`
`R esults
`
`Subjects and Enrollment
`Between June 15, 2009, and January 14, 2011, a to-
`tal of 893 subjects were enrolled (with a total of
`1023 enrollments and a reenrollment rate of 13%)
`(Fig. 1). The two treatment groups were well bal-
`anced with respect to demographic and clinical
`
`Noninferiority
`margin, −0.1
`
`PointEstimates
`(95%CI)
`PIM=0.73 (0.69–0.78)
`PIV=0.63 (0.59–0.68)
`
`0.04
`
`0.16
`
`−0.2
`
`−0.1
`
`0.0
`
`0.1
`
`0.2
`
`IM inferior
`
`IM noninferior
`PIM−PIV
`
`Figure 2. Primary Outcome According to Treatment
`Group.
`PIM−PIV represents the absolute difference in the prima-
`ry outcome between the proportion of subjects treated
`with IM midazolam and the proportion treated with IV
`lorazepam (i.e., the proportion of subjects who did not
`have seizures on arrival in the emergency department
`and who did not receive rescue medication). CI denotes
`confidence interval.
`
`Table 2. Primary and Secondary Outcomes.*
`
`Outcome
`
`Intention-to-Treat Analysis† (N = 893)
`
`Per-Protocol Analysis‡ (N = 732)
`
`IM Midazolam
`(N = 448)
`
`IV Lorazepam
`(N = 445)
`
`IM Midazolam
`(N = 362)
`
`IV Lorazepam
`(N = 370)
`
`Primary outcome
`Seizures terminated, no rescue therapy given
`No. of subjects
`% of subjects (95% CI)§
`Treatment failed — no. of subjects (%)
`Seizures not terminated, no rescue therapy given
`Seizures not terminated, rescue therapy given
`Seizures terminated, rescue therapy given
`Secondary outcomes
`Endotracheal intubation within 30 min after ED arrival
`No. of subjects — %
`Relative risk (95% CI)
`Hospitalization
`No. of subjects — %
`Relative risk (95% CI)
`ICU admission
`No. of subjects — %
`Relative risk (95% CI)
`Recurrent seizure within 12 hr after ED arrival
`No. of subjects — %
`Relative risk (95% CI)
`Hypotension
`No. of subjects — %
`Relative risk (95% CI)
`
`329
`73.4 (69.3–77.5)
`119 (26.6)
`50 (11.2)
`22 (4.9)
`47 (10.5)
`
`282
`63.4 (58.9–67.9)
`163 (36.6)
`64 (14.4)
`42 (9.4)
`57 (12.8)
`
`271
`74.9 (70.4–79.3)
`91 (25.1)
`42 (11.6)
`14 (3.9)
`35 (9.7)
`
`238
`64.3 (59.4–69.2)
`132 (35.7)
`51 (13.8)
`38 (10.3)
`43 (11.6)
`
`63 (14.1)
`0.98 (0.70–1.34)
`
`64 (14.4)
`
`258 (57.6)
`0.88 (0.79–0.98)
`
`292 (65.6)
`
`128 (28.6)
`0.79 (0.65–0.95)
`
`51 (11.4)
`1.08 (0.74–1.56)
`
`12 (2.7)
`0.92 (0.42–1.98)
`
`161 (36.2)
`
`47 (10.6)
`
`13 (2.9)
`
`53 (14.6)
`1.02 (0.71–1.45)
`
`210 (58.0)
`0.86 (0.77–0.96)
`
`102 (28.2)
`0.76 (0.61–0.93)
`
`37 (10.2)
`0.97 (0.63–1.48)
`
`5 (1.4)
`0.57 (0.19–1.67)
`
`53 (14.3)
`
`250 (67.6)
`
`138 (37.3)
`
`39 (10.5)
`
`9 (2.4)
`
`596
`
`n engl j med 366;7 nejm.org february 16, 2012
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`The New England Journal of Medicine
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`Downloaded from nejm.org on November 13, 2016. For personal use only. No other uses without permission.
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` Copyright © 2012 Massachusetts Medical Society. All rights reserved.
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`
`Prehospital Control of Status Epilepticus
`
`Intention-to-Treat Analysis† (N = 893)
`
`Per-Protocol Analysis‡ (N = 732)
`
`IM Midazolam
`(N = 448)
`
`IV Lorazepam
`(N = 445)
`
`IM Midazolam
`(N = 362)
`
`IV Lorazepam
`(N = 370)
`
`Table 2. (Continued.)*
`
`Outcome
`
`IM injection-site complications
`
`No. of subjects (%)
`
`Relative risk (95% CI)
`
`4 (0.9)
`
`1.99 (0.30–10.70)
`
`IV injection-site complications — no. of subjects (%)
`
`0
`
`Length of ICU stay — days
`
`No. of subjects with length-of-stay data
`
`Mean
`
`Median (minimum, maximum)
`
`P value¶
`
`Length of hospital stay — days
`
`No. of subjects with length-of-stay data
`
`Mean
`
`Median (minimum, maximum)
`
`P value¶
`
`123
`
`5.7±9.5
`
`3 (1, 75)
`
`0.09
`
`251
`
`6.7±10.0
`
`4 (1, 90)
`
`0.11
`
`2 (0.5)
`
`3 (0.7)
`
`155
`
`4.1±4.7
`
`3 (1, 31)
`
`285
`
`5.5±6.4
`
`3 (1, 58)
`
`4 (1.1)
`
`1 (0.3)
`
`4.09 (0.45–36.40)
`
`0
`
`98
`
`4.8±7.2
`
`3 (1, 65)
`
`0.33
`
`204
`
`5.8±7.0
`
`3 (1, 65)
`
`0.71
`
`3 (0.8)
`
`132
`
`4.0±4.7
`
`2 (1, 31)
`
`243
`
`5.5±6.4
`
`4 (1, 58)
`
`* Plus–minus values are means ±SD. The relative risk is for the subjects given IM midazolam, as compared with those given IV lorazepam.
`† The intention-to-treat analysis included only the initial enrollment of all subjects; repeated enrollments of the same subject were not included.
`CI denotes confidence interval, ED emergency department, and ICU intensive care unit.
`‡ The per-protocol analysis excluded subjects with any of the following three predefined types of protocol deviations: eligibility violations, in-
`correct dose of study medication, or incorrect administration.
`§ P<0.001 for noninferiority and for superiority in both the intention-to-treat and per-protocol analyses. P values for noninferiority reflect one-
`sided tests for differences not exceeding 10 percentage points. The primary analysis was followed by a one-sided test for superiority,7 although
`this was not prespecified in the protocol.
`¶ P values were calculated with the use of t-tests for the means.
`
`characteristics, dose tier, presence or absence of a
`history of epilepsy, accuracy of the diagnosis of sta-
`tus epilepticus (vs. a discharge diagnosis of a non-
`epileptic spell), and the diagnosis of the underlying
`cause of status epilepticus (Table 1). The overall
`number of subjects who were black reflected the
`proportion of blacks in the subject population
`from which the sample was drawn.
`
`Primary Outcome
`Seizures were absent without rescue therapy on
`arrival in the emergency department in 329 of
`448 subjects assigned to active treatment with
`intramuscular midazolam (73.4%) and in 282 of
`445 assigned to active treatment with intravenous
`lorazepam (63.4%) (difference, 10 percentage
`points; 95% confidence interval [CI], 4.0 to 16.1;
`P<0.001 for noninferiority and P<0.001 for supe-
`riority) (Fig. 2). The primary results were similar
`in the per-protocol analysis. Table 2 shows the
`number of subjects who were having seizures at
`the time of arrival in the emergency department
`
`and the number who needed rescue medication.
`Subjects randomly assigned to the intramuscular
`group were less likely to be having seizures on
`arrival in the emergency department (regardless
`of the use or nonuse of rescue therapy) than were
`those randomly assigned to the intravenous group
`(proportion of subjects without seizures, 83.9% vs.
`76.2%; difference, 7.7 percentage points; 95% CI,
`2.5 to 12.9). Inability to start an intravenous infu-
`sion was anticipated to be a common reason for
`failure of intravenous therapy. Among subjects in
`the intravenous group who did not reach the pri-
`mary outcome, 31 never received the intravenous
`study medication because of failure to obtain vas-
`cular access, whereas only 5 in the entire intra-
`muscular group did not receive the intramuscular
`study medication owing to malfunction or mis-
`application of the autoinjector.
`
`Secondary and Safety Outcomes
`The secondary and safety outcomes were consis-
`tent with the primary outcome and reinforced the
`
`n engl j med 366;7 nejm.org february 16, 2012
`
`597
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`The New England Journal of Medicine
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`Downloaded from nejm.org on November 13, 2016. For personal use only. No other uses without permission.
`
` Copyright © 2012 Massachusetts Medical Society. All rights reserved.
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`

`
`T h e ne w e ngl a nd jou r na l o f m e dicine
`
`Time from active treatment to cessation of convulsions
`
`IV lorazepam
`
`IM midazolam
`
`Time from box opening to cessation of convulsions
`
`IV lorazepam
`
`IM midazolam
`
`Time from box opening to active treatment
`
`*
`
`*
`
`*
`
`*
`
`IV lorazepam
`
`IM midazolam
`
`*
`
`0
`
`*
`
`5
`
`10
`
`15
`Minutes
`
`20
`
`25
`
`30
`
`Figure 3. Intervals between Active Treatment and Cessation of Convulsions, Box Opening and Cessation of Convulsions,
`and Box Opening and Active Treatment.
`The shorter time to IM drug administration was offset by the faster onset of action after IV drug administration, re-
`sulting in similar latency periods until convulsions were terminated. Time to IV administration includes the nominal
`time (about 20 seconds) needed to administer the drug by means of IM autoinjector. Asterisks indicate means, boxes
`interquartile ranges, bold vertical lines within boxes medians, I bars 1.5 times the interquartile range, and circles
`outliers.
`
`finding that intramuscular midazolam was non-
`inferior to intravenous lorazepam. The frequencies
`of endotracheal intubation, recurrent seizures, and
`other predefined safety outcomes were similar in
`the two study groups (Table 2). Among subjects
`admitted to the hospital, the lengths of stay in the
`intensive care unit and in the hospital did not
`differ significantly between the groups, but the
`proportion of subjects admitted was significantly
`lower (and the proportion discharged from the
`emergency department was significantly higher) in
`the intramuscular group than in the intravenous
`group (P = 0.01).
`Figure 3 shows the temporal data (the times
`from administration of active treatment to cessa-
`tion of convulsions, from box opening to cessation
`of convulsions, and from box opening to admin-
`istration of active treatment) for the 317 subjects in
`the intention-to-treat analysis who met the primary
`outcome and for whom times of active treatment
`and of cessation of convulsions were recorded. The
`median time to administration of active treat-
`ment was significantly shorter by the intramus-
`cular route than by the intravenous route (1.2 vs.
`4.8 minutes), but the onset of action (i.e., termina-
`tion of convulsions) occurred sooner after intra-
`venous administration than after intramuscular
`administration (1.6 vs. 3.3 minutes). The overall
`interval until termination of convulsions was simi-
`lar in the two treatment groups.
`
`Discussion
`
`This double-blind, randomized trial showed that
`prehospital treatment with intramuscular mid-
`azolam was at least as effective as intravenous loraz-
`epam in subjects in status epilepticus (P<0.001 for
`noninferiority and for superiority). Establishing
`intravenous access in patients who are having sei-
`zures in the prehospital environment can be chal-
`lenging and time-consuming. Since intramuscular
`treatments can be given more quickly and reliably
`than intravenous treatments and have noninferior
`efficacy, our data support the use of the former
`route of administration by EMS personnel.
`The use by EMS systems of intramuscular mid-
`azolam for status epilepticus has been increasing
`because small studies have indicated its efficacy
`and because this drug is rapidly absorbed intra-
`muscularly. According to a meta-analysis of small
`trials, the use of nonintravenous midazolam in the
`hospital setting compared favorably with intrave-
`nous diazepam in the emergency treatment of
`status epilepticus.8 Furthermore, unlike loraze-
`pam, midazolam does not have the problem of
`poor stability whe