Original Article
`
`Prehospital Intranasal Midazolam for the Treatment
`of Pediatric Seizures
`Maija Holsti, MD, MPH,* Benjamin L. Sill, BS,y Sean D. Firth, PhD, MPH,z Francis M. Filloux, MD,x
`Steven M. Joyce, MD,k and Ronald A. Furnival, MD*
`
`Background: The local emergency medical services (EMS) council
`implemented a new pediatric treatment protocol using a Mucosal
`Atomization Device (MAD) to deliver intranasal (IN) midazolam
`for seizure activity.
`Methods: We sought to compare outcomes in seizing pediatric
`patients treated with IN midazolam using a MAD (IN-MAD
`midazolam) to those treated with rectal (PR) diazepam, 18 months
`before and after the implementation of the protocol.
`Results: Of 857 seizure patients brought by EMS to our emergency
`department (ED), 124 patients (14%) had seizure activity in the
`presence of EMS and were eligible for inclusion in this study. Of
`the 124 patients eligible for this study, 67 patients (54%) received
`no medications in the prehospital setting, 39 patients (32%) were
`treated with IN-MAD midazolam, and 18 patients (15%) were
`treated with PR diazepam. Median seizure time noted by EMS was
`19 minutes longer for PR diazepam (30 minutes) when compared
`with IN-MAD midazolam (11 minutes, P = 0.003). Patients treated
`with PR diazepam in the prehospital setting were significantly more
`likely to have a seizure in the ED (odds ratio [OR], 8.4; confidence
`interval [CI], 1.6 – 43.7), ED intubation (OR, 12.2; CI, 2.0 – 75.4),
`seizure medications in the ED to treat ongoing seizure activity (OR,
`12.1; CI, 2.2 – 67.8), admission to the hospital (OR, 29.3; CI, 3.0 –
`288.6), and admission to the pediatric intensive care unit (OR, 53.5;
`CI, 2.7 – 1046.8).
`Conclusions: The IN-MAD midazolam controlled seizures better
`than PR diazepam in the prehospital setting and resulted in fewer
`respiratory complications and fewer admissions.
`
`Key Words: seizures, prehospital, emergency medical services
`(EMS), intranasal
`
`Seizures are the most common medical problem for
`
`emergency medical services (EMS) transport in pediatric
`
`*Division of Pediatric Emergency Medicine, Department of Pediatrics,
`Primary Children’s Medical Center/University of Utah; yUniversity of
`Utah School of Medicine; zDepartment of Pediatrics, Primary Children’s
`Medical Center/University of Utah; xDivision of Pediatric Neurology,
`Department of Pediatrics, Primary Children’s Medical Center/University
`of Utah and kDepartment of Emergency Medicine, University of Utah,
`Salt Lake City, UT.
`Presented at the Oral Presentation at the American Academy of Pediatrics
`National Conference and Exhibition, October 2004, San Francisco, CA.
`Address correspondence and reprint requests to Maija Holsti, MD, MPH,
`Division of Pediatric Emergency Medicine, Department of Pediatrics,
`Primary Children’s Medical Center/University of Utah, PO BOX
`581289, Salt Lake City, UT 84158. E-mail: maija.holsti@hsc.utah.edu.
`Copyright n 2007 by Lippincott Williams & Wilkins
`ISSN: 0749-5161/07/2303-0148
`
`patients, accounting for roughly 15% of all pediatric EMS
`calls in the United States.1 Prolonged or recurrent seizure
`activity persisting for 30 minutes or more can cause
`significant morbidity and mortality that is directly correlated
`with seizure duration.1 – 3 The sooner that a seizure is treated,
`the more likely the seizure will be controlled.1 It
`is
`recommended that seizures lasting longer than 5 minutes
`should be treated with an anticonvulsant.1 The administra-
`tion of anticonvulsant therapy in the prehospital setting may
`shorten the duration of a seizure.4
`Benzodiazepines are currently the first-line therapy for
`seizures. Diazepam is typically the sole anticonvulsant
`medication available on most ambulances for the acute
`management of all
`types of seizures in the prehospital
`setting.1 Diazepam may be administered intravenously (IV),
`rectally (PR), or
`through an endotracheal
`tube;
`it
`is
`ineffective for seizure control when given intramuscularly
`(IM) and is not suitable for intranasal (IN) administration.5,6
`Rectal diazepam has been available for seizure control
`in the prehospital setting for more than 20 years.7 – 9 Its
`popularity is due partly to the potential difficulty of IV
`placement, especially in a child with seizures. However,
`disadvantages of PR diazepam include the social awkward-
`ness for patients and providers, potential for rejection, variable
`and unpredictable drug absorption, hepatic first-pass metabo-
`lism, and higher doses may be required for a clinical
`response.8,9 Diazepam accumulation can cause respiratory
`depression, which may require endotracheal
`intubation,
`especially if used in conjunction with other anticonvulsants.10
`The cost of PR diazepam (Diastat) is roughly $100/dose.
`In the prehospital setting, midazolam may provide an
`alternative to PR diazepam.7,8,10 – 22 Midazolam can be
`administered via different routes: IV, IM, endotracheal tube,
`PR, buccal, and IN.23 Its cost ranges from $10 to $13/dose.
`Midazolam is water soluble but becomes fat soluble at
`physiological pH allowing it to cross the nasal mucosa into
`the cerebral spinal fluid with a rapid onset of action and rapid
`metabolism.23 Because IN midazolam is directly absorbed
`into the cerebral spinal fluid, it is not subject to hepatic first-
`pass metabolism and less likely to accumulate.23 Because PR
`diazepam is absorbed through the gastrointestinal tract, it is
`subject to ‘‘first pass metabolism’’ and is more likely to
`accumulate with successive doses than diazepam.23 In
`addition to the pharmacological advantages, the convenience
`of IN administration and the social acceptability may make
`IN midazolam the preferred treatment of seizures in the
`prehospital setting.7
`
`148
`
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`

`Pediatric Emergency Care  Volume 23, Number 3, March 2007 Prehospital IN Midazolam for the Treatment of Pediatric Seizures
`
`Implementation of this new protocol provided the
`opportunity to compare IN-MAD midazolam with PR
`diazepam. Patients treated with IN-MAD midazolam for
`seizures after July 1, 2003, were compared with historical
`controls treated with PR diazepam. Historical controls were
`patients younger than 18 years treated with PR diazepam by
`EMS for seizure activity that came directly to our hospital.
`Patients were identified using an ED computerized patient
`tracking system (Logicare, Eau Claire, Wis). All patients
`who were transported to the ED via ambulance or helicopter
`from January 1, 2002, to December 31, 2004, with a chief
`complaint or discharge diagnosis of seizure (of any type)
`were eligible for inclusion in the study.
`Patients were included in the study if they were
`younger than 18 years, had a seizure in the presence of an
`EMS provider, received PR diazepam or IN midazolam for
`their seizure in the prehospital setting, and arrived at the
`study ED via EMS.
`Patients were excluded from the study if they were
`transferred from another facility,
`they received a rescue
`medication at home for seizure activity before EMS arrival,
`they received more than 1 prehospital medication, or the
`seizure was not witnessed by EMS providers.
`Emergency medical services, ED, and hospital medical
`records were reviewed. Data collected included demographic
`information, medications, medical history, seizure activity
`noted in the ED, respiratory complications, and disposition.
`Information regarding the prehospital and ED treatment of
`the seizure and vital signs was recorded. Emergency medical
`services-witnessed seizure times was defined as prolonged or
`recurrent seizure activity persisting for 30 minutes or more.
`Emergency medical services – witnessed seizure time were
`defined as the time from EMS arrival to time seizure stopped
`or patient arrival to the hospital. Total seizure time was the
`estimation of the total length of 1 seizure or the sum time of
`multiple seizures from parental history, EMS records, and
`hospital records. When available, EMS-witnessed seizure
`time, total seizure time, and total hospital charges were
`calculated.
`Our primary outcome measure was the presence of a
`seizure in the ED. Our secondary outcome measures were
`total
`seizure time, EMS seizure duration,
`respiratory
`
`TABLE 1. Comparison of Midazolam and Diazepam Protocols
`
`Instructions
`
`Preparation
`
`Indication
`Dose
`Route
`
`Maximum dose
`Repeat dose
`
`Midazolam
`
`Diazepam
`
`Apply oxygen
`Suction nose if
`there are secretions
`Seizure >5 min
`0.2 mg/kg
`Intranasal: divided into each
`nares using the MAD
`10 mg
`0.2 mg/kg 5 min
`after first dose
`
`Apply oxygen
`
`Seizure >5 min
`0.3 – 0.5 mg/kg
`Rectal
`
`20 mg
`0.25 mg/kg if
`seizure persists
`
`FIGURE 1. Mucosal Atomization Device.
`
`The local EMS council enacted a new protocol using
`IN midazolam for
`first-line treatment of seizures, and
`emergency medical technician (EMT) paramedics received
`training for the administration of IN midazolam.24 Adults
`and children with active seizure activity (of any type)
`received IN midazolam using a Mucosal Atomization Device
`(MAD)
`instead of
`the traditional
`treatment with PR
`diazepam.24 The MAD is an applicator placed on top of a
`syringe that distributes midazolam in a 30-m particle size,
`coating the nasal mucosa (Fig. 1), and its cost is $2.45.25
`Intranasal midazolam administered with the MAD (IN-MAD
`midazolam) should enhance rapid nasal absorption, achiev-
`ing effective plasma and cerebral spinal fluid concentra-
`tions.25 This study uniquely uses the MAD for administration
`of midazolam.
`We sought to compare the effectiveness and compli-
`cations of IN-MAD midazolam with that of PR diazepam for
`treatment of childhood seizures in the prehospital setting.
`
`METHODS
`The setting for this study was a freestanding children’s
`hospital that serves as an American College of Surgeons
`level I trauma and referral center for 5 states. The EMS
`council oversees prehospital care for the most populous
`region in the state. The EMS council has representatives
`from roughly 70 organizations, including 13 hospitals, law
`enforcement, and other nonresponder agencies. The county
`surrounding this children’s hospital has approximately 50
`EMS agencies.
`The local EMS council’s new protocol directed EMT
`paramedics to treat seizure activity in children and adults
`using IN-MAD midazolam. Paramedics received training to
`use IN-MAD midazolam as a first-line therapy for the
`treatment of seizures lasting longer than 5 minutes. This
`new protocol replaced diazepam as the first-line treatment
`of seizure activity; other protocol changes are outlined in
`Table 1. All patients who received IN-MAD midazolam
`were transported to an ED by EMT paramedics. The State
`Department of Health Bureau approved the protocol changes.
`
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`
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`

`Holsti et al
`
`Pediatric Emergency Care  Volume 23, Number 3, March 2007
`
`TABLE 2. Demographic Data and Seizure Time for Patients
`Treated With IN-MAD Midazolam and PR Diazepam
`
`Characteristics
`
`IN Midazolam PR Diazepam P
`
`Seven hundred thirty-three patients were excluded
`from the study for the following reasons: 431 patients (59%)
`had no seizure activity in the presence of EMS, 265 patients
`(36%) were transferred from an outside facility to our
`institution, 27 patients (4%) did not have a seizure, 8 patients
`(1%) were 18 years or older, and 2 patients (<1%) left without
`being seen.
`Of the 124 patients eligible for inclusion in the study
`with seizure activity witnessed by EMS, 67 patients (54%)
`received no medications in the prehospital setting, 39
`patients (32%) were treated with IN-MAD midazolam, and
`18 patients (15%) were treated with PR diazepam. During
`the course of the study, it is noteworthy that the proportion of
`patients treated with an anticonvulsant in the prehospital
`setting did not vary (14/41 or 34% before July 1, 2003, and
`41/83 or 49% after July 1, 2003; OR, 1.78; CI, 0.77 – 4.14).
`Fifty-seven patients (39 patients treated with IN-MAD and
`18 patients treated with PR diazepam) make up the study
`group.
`Table 2 presents the demographic data and seizure
`time for the 57 study patients. There were no significant
`differences between the IN-MAD midazolam and PR
`diazepam groups with regard to age, sex, history of seizures,
`and history of seizure medications. As noted in Table 1, the
`medication dose in the protocol is 0.2 mg/kg up to 10 mg for
`IN-MAD midazolam and 0.3 to 0.5 mg/kg up to 20 mg for
`PR diazepam. The median dose and range are noted in
`Table 2. We compared the difference of the protocol median
`dose of IN-MAD midazolam (0.2 mg/kg) and PR diazepam
`(0.4 mg/kg) with that of the actual dose that the patient
`received. There was no difference noted between the 2
`groups ( P = 0.12, Mann-Whitney U test).
`the seizure was
`Distribution of
`the etiology of
`compared between the 2 groups (Table 3). The seizure was
`categorized in one of the following groups: seizure not
`otherwise specified, febrile, generalized, absence, complex
`partial, simple partial, traumatic, metabolic, ingestion, or
`status epilepticus. There was no statistical difference in
`
`TABLE 3. Etiology of Seizure: IN Midazolam Versus PR
`Diazepam
`
`IN Midazolam,
`n (%)
`
`PR Diazepam,
`n (%)
`
`7 (18)
`
`0 (0)
`
`4 (10)
`13 (33)
`4 (10)
`1 (3)
`10 (25)
`39
`—
`
`1 (6)
`6 (33)
`2 (11)
`0 (0)
`9 (50)
`18
`
`—
`
`P
`
`—
`
`—
`—
`—
`—
`—
`—
`0.29*
`
`Type of Seizure
`
`Seizure not otherwise
`specified
`Febrile seizure
`Generalized seizure
`Complex partial seizure
`Metabolic
`Status epilepticus
`Total
`Distributional differences
`in type of seizures
`between the 2 groups
`
`*Pearson x2 test.
`
`39
`4.5 yrs
`8 mo – 16 yrs
`18 (46)
`32 (82)
`
`24 (62)
`
`0.2
`
`Demographic data
`No. patients (n = 57)
`Median age
`Age range
`Male, n (%)
`History of seizures,
`n (%)
`History of anticonvulsants,
`n (%)
`Median dose of medication
`given (mg/kg)
`Range of dose given
`(mg/kg)
`EMS-witnessed seizure time (min)
`Median (n)
`11 (25)
`Range
`1 – 50
`Total seizure time (min)
`Median (n)
`Range
`Median total hospital
`charges ($)
`
`0.1 – 0.4
`
`25 (36)
`4 – 105
`1459
`
`18
`2.9 yrs
`1 – 17 yrs
`10 (56)
`12 (67)
`
`12 (67)
`
`—
`0.27*
`
`y
`0.51
`y
`0.20
`
`y
`0.71
`
`0.3
`
`—
`
`0.1 – 0.7 —
`
`30 (13)
`5 – 80
`
`0.003*
`—
`
`45 (17) <0.001*
`25 – 480 —
`6980 <0.0001*
`
`*Mann-Whitney U test.
`yx2 test.
`
`complications, status epilepticus (defined as seizure greater
`than 30 minutes), anticonvulsants given in the ED,
`disposition, and total hospital charges. We distinguished
`those patients who received any anticonvulsants in the ED
`from those who received an anticonvulsant for the acute
`treatment of ongoing seizure activity.
`Data distributions for each variable were assessed and
`the appropriate parametric or nonparametric test was
`selected. T test, Mann-Whitney U test, x2 test (Pearson and
`Fisher exact), and crude odds ratios (ORs) were used for
`bivariate analyses. Multivariate analyses were conducted
`by calculating adjusted ORs controlling for age, sex, history
`of seizures, and history of seizure medications using
`unconditional logistic regression. Significance was defined
`as a less than 0.05. Approval for research of human sub-
`jects was obtained from the University of Utah Institu-
`tional Review Board,
`the State Department of Health,
`and the Bureau of EMS. This research was not sponsored
`by any companies. This has no relationship between the
`authors and the development, evaluation, and promotion of
`the MAD.
`
`RESULTS
`During the study period, we identified 857 patients
`who were brought into the ED by EMS with the chief
`complaint or discharge diagnosis of seizure.
`
`150
`
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`

`Pediatric Emergency Care  Volume 23, Number 3, March 2007 Prehospital IN Midazolam for the Treatment of Pediatric Seizures
`
`TABLE 4. The Outcome Measures of Patients Treated With IN-MAD Midazolam Versus PR Diazepam for Seizure Activity
`Noted by EMS
`
`Outcome Measures
`
`Oxygen given by EMS
`EMS bag-mask ventilation
`EMS intubation
`Seizure in ED
`Oxygen required at ED disposition
`ED intubation
`Anticonvulsants given in ED
`Anticonvulsants given in ED
`to treat seizure activity
`Status epilepticus (>30 min)
`Hospital admission
`PICU admission
`
`IN Midazolam,
`n (%) (n = 39)
`
`PR Diazepam,
`n (%) (n = 18)
`
`OR
`
`95% CI
`
`Adjusted OR*
`
`95% CI
`
`33 (92)
`2 (6)
`1 (6)
`15 (38)
`9 (23)
`2 (5)
`22 (56)
`13 (33)
`
`10 (26)
`19 (49)
`3 (16)
`
`15 (94)
`5 (31)
`1 (3)
`13 (72)
`14 (78)
`7 (39)
`16 (89)
`13 (72)
`
`9 (50)
`17 (94)
`10 (59)
`
`1.36
`7.73
`2.24
`4.16
`11.67
`11.77
`6.18
`5.2
`
`2.8
`17.89
`7.62
`
`0.10 – 76.29
`1.03 – 87.70
`0.03 – 179.99
`1.08 – 17.64
`2.64 – 58.37
`1.79 – 125.09
`1.16 – 61.00
`1.33 – 22.23
`
`0.74 – 10.56
`2.26 – 784.27
`1.31 – 53.32
`
`0.95
`6.65
`2.79
`8.43
`26.97
`12.21
`9.23
`12.14
`
`4.35
`29.32
`53.54
`
`0.08 – 11.70
`0.90 – 49.29
`0.12 – 65.72
`1.63 – 43.71
`4.47 – 162.79
`1.98 – 75.37
`1.49 – 57.19
`2.17 – 67.79
`
`1.04 – 18.18
`2.98 – 288.63
`2.74 – 1046.84
`
`*Adjusted for age, sex, history of seizures, and history of seizure medications.
`Data in boldface are statistically significant.
`
`the distribution of seizure etiology between the IN-MAD
`midazolam and the PR diazepam group (P = 0.29).
`Emergency medical services– witnessed seizure time
`data were available for 25 (64%) of the 39 patients who
`received IN-MAD midazolam and 13 (72%) of the 18 patients
`who received PR diazepam. There was no statistical difference
`noted between the proportion of the 2 groups which had data
`available (P = 0.546). For total seizure time, data were available
`for 36 of the 39 patients who received IN-MAD midazolam
`and 17 of the 18 patients who received PR diazepam. Median
`seizure time noted by EMS was 19 minutes longer (30 minutes
`vs. 11 minutes, P = 0.003), and total seizure time was 20
`minutes longer (45 minutes vs. 25 minutes, P < 0.001) for PR
`diazepam when compared with IN-MAD midazolam (Table 2).
`Median total hospital charges were significantly lower ($1459
`vs. $6980, P < 0.0001) for the patients who received IN-MAD
`midazolam as compared with PR diazepam.
`Univariate and logistic regression analyses were per-
`formed to compare outcome variables in both treatment groups
`(Table 4). Patients treated with PR diazepam were significantly
`more likely to require EMS bag-mask ventilation, have a
`seizure in the ED, require ED intubation, require oxygen at ED
`disposition, require anticonvulsants in the ED, require anti-
`convulsants in the ED to treat seizure activity, need hospital
`admission, and need pediatric intensive care unit (PICU)
`admission. There were no differences between the groups for
`oxygen given by EMS (standard EMS procedure for both
`seizure protocols), EMS intubation, or status epilepticus.
`Logistic regression analysis was then performed to
`control for potential effect measure modification or con-
`founding by age, sex, history of seizures, and use of seizure
`medications (Table 4). Adjusted ORs demonstrated that
`the need for EMS bag-mask ventilation was no longer
`significantly different between the 2 groups, but status
`epilepticus was now more likely for the PR diazepam group
`
`when controlling for age, sex, history of seizures, and history
`of seizure medications. Patients who were treated with PR
`diazepam were still significantly more likely to have a seizure
`in the ED, require ED intubation, require oxygen at ED dis-
`position, require anticonvulsants in the ED, require anticon-
`vulsants in the ED to treat seizure activity, need hospital
`admission, and need PICU admission when compared with the
`IN-MAD midazolam group.
`
`DISCUSSION
`We compared IN midazolam using the MAD with PR
`diazepam for the prehospital treatment of pediatric seizures.
`Our data demonstrate that IN-MAD midazolam is superior
`and has fewer side effects. This is the first study that looks at
`the use of MAD to administer IN midazolam for the
`treatment of pediatric seizures.
`In our study, the 2 treatment groups were similar with
`regard to age, sex, history of seizures, and previous seizure
`medications. Yet,
`the patients
`treated with IN-MAD
`midazolam had significantly shorter
`total seizure time,
`shorter EMS-witnessed seizure time, and lower total hospital
`charges. Patients who received IN-MAD midazolam were
`also less likely to have recurrent seizures,
`respiratory
`complications, hospital admissions, or PICU admissions
`when compared with those receiving PR diazepam. Although
`not statistically significant, more patients were treated for
`their seizures after July 1, 2003, with the new IN-MAD
`midazolam protocol. We believe that this is secondary to the
`ease in administration.
`Studies in other settings found IV diazepam and IN or
`IV midazolam to be equally effective in controlling seizures
`with no difference in side effects.7,8,10 – 18,20 – 23,26,27 In 70
`pediatric inpatients, Mahmoudian and Zadeh27 showed that
`IN midazolam and IV diazepam had equal efficacy without
`
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`Holsti et al
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`Pediatric Emergency Care  Volume 23, Number 3, March 2007
`
`significant side effects. The mean time to seizure control
`(time from start of seizure to treatment) was significantly
`faster ( P = 0.007) in the midazolam group compared with
`the diazepam group.27 One study limitation is that placement
`of an IV may have delayed treatment in the diazepam group.
`Another study compared IN midazolam to that of
`IV
`diazepam in the ED setting.16
`Intranasal midazolam
`controlled seizures in 23 of 26 patients, and IV diazepam
`controlled seizures in 24 of 26 patients.16 They demonstrated
`no difference in side effects but showed that
`the mean
`time from arrival to the hospital to starting treatment and the
`mean time to control seizures was reduced by 2 minutes in
`the midazolam group.16 Sample size may have limited the
`investigator’s ability to show a difference in side effects
`between the 2 groups. Although our study also had a small
`sample size, we were able to show a difference in side effects
`(respiratory depression). Rainbow et al19 demonstrated that
`IM or IV midazolam controls seizures as effectively as IV or
`PR diazepam in the prehospital setting. Here, patients
`treated with midazolam had less respiratory depression and
`decreased time to treatment.19 This investigation did not
`distinguish the route of medication administration. All of
`these studies used IV diazepam for the treatment of seizures.
`Although these 3 studies demonstrate no difference in safety
`between midazolam and diazepam, placing an IV line in a
`patient with seizure activity can be difficult for even an
`experienced person and may delay treatment.
`Intranasal midazolam has been shown to be as
`effective as PR diazepam in various community settings.10,13
`Fisgin et al13 compared IN midazolam with PR diazepam for
`the treatment of pediatric seizures in the ED. Intranasal
`midazolam was more likely to treat seizure activity within
`the first 10 minutes (87%, 20/23 vs. 60%, 13/22; P < 0.05).13
`In addition, more patients required a second anticonvulsant
`to stop seizures in the diazepam group (P < 0.05).13
`Although the results of this study are encouraging, it was
`not conducted in the prehospital setting. Scheepers et al10
`describe using IN midazolam in adolescents and adults
`with severe epilepsy at an Inpatient Epilepsy Treatment
`Center. Of the 84 seizures in 22 patients, 79 of these were
`successfully treated.10 Of the 5 treatment failures, 3 were
`thought to be secondary to poor technique delivering the
`medication.10 Two treatment failures received the drug
`buccally; 1 patient was thought
`to have a psychogenic
`nonepileptic seizure, and the other patient
`responded
`initially but
`then had another seizure within an hour
`rescue treatment.10
`In these studies,
`requiring further
`midazolam was dripped into the nares with a syringe
`whereby it is more likely ingested. Our study used the MAD
`to effectively coat the nasal mucosa, which theoretically
`would achieve cerebral spinal fluid concentrations rapidly.
`In community settings, several studies have described
`IN midazolam for the treatment of seizures, noting very few
`side effects.7,8,13 Jeannet et al8 used IN midazolam to control
`seizure activity in 26 patients (11 treated at home and 17
`treated in the hospital). These 26 children had a total of 125
`seizures; 122 seizures (98%) stopped within 10 minutes
`(average of 3.6 minutes) without serious side effects noted.8
`
`Two of the hospitalized patients did not respond, and 3
`patients had a seizure reoccur within 3 hours.8 Fisgin et al12
`administered IN midazolam to 22 children for a total of 54
`seizures that were stopped on 48 occasions (89%) without
`any respiratory compromise. Questionnaires were given to
`all
`those who used IN midazolam (30 parents, school
`assistants, and teachers).12 Ninety percent had no difficulty
`giving the medication and of the 15 people who had also
`administered PR diazepam in the past, 14 preferred IN
`midazolam.12 These 2 descriptive studies demonstrate that
`IN midazolam may be effective and safe for community use.
`However, community studies comparing IN midazolam to
`other anticonvulsants have not been performed.
`The chief limitation of our study was the incomplete
`documentation, especially with regard to EMS data sheets.
`Seizure duration data were not uniformly available. Detailed
`dictated and written ED notes on all patients provided
`complete information on seizure in the ED, respiratory
`depression, medications needed to treat the seizure, and ED
`disposition. In addition, seizure time noted by EMS did not
`control for duration of transport to the hospital. Although
`there was no difference in etiology of seizure (Table 3), we
`did not compare the comorbidities of our patients. This
`might have confounded our results of seizure duration,
`complications, disposition, and total hospital charges. The
`protocol was gradually implemented across 50 agencies,
`whereas EMS personnel received training. Training may
`have varied. Lastly,
`the 2 treatments groups were not
`randomized, and the providers were not blinded to the
`medication used.
`In summary, previous studies demonstrate IN mid-
`azolam to be equally or more effective than IV diazepam.
`However, IV placement may be difficult in a child with
`seizures and delay treatment. Rectal diazepam is an effective
`and popular anticonvulsant in the prehospital setting but is
`socially awkward to administer. In hospital settings, IN
`midazolam is as effective or more effective and associated
`with fewer complications than PR diazepam. Furthermore,
`descriptive studies demonstrated IN midazolam to be an
`effective and safe anticonvulsant
`for
`the community.
`Uniquely, our study used the MAD for administration of
`midazolam and compared IN-MAD midazolam to PR
`diazepam in the prehospital environment. Our study results
`demonstrate that IN-MAD midazolam is more effective and
`safe and had lower total hospital charges when compared
`with PR diazepam for the prehospital treatment of pediatric
`seizures.
`Early treatment of seizures reduces reoccurrence of
`seizures and the morbidity and mortality associated with
`seizure activity.1 – 3,11 We have shown IN-MAD midazolam
`controlled seizures better than PR diazepam in the prehospital
`setting with fewer respiratory complications, fewer hospital
`and PICU admissions, and lower total hospital charges. Given
`the ease of administration of IN-MAD midazolam and the
`results of our study, we recommend the use of IN-MAD
`midazolam for
`the prehospital
`treatment of pediatric
`seizures. Future studies should compare IN-MAD mid-
`azolam with PR diazepam for community and home use.
`
`152
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`n 2007 Lippincott Williams & Wilkins
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`AQUESTIVE EXHIBIT 1121 Page 0005
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`

`

`Pediatric Emergency Care  Volume 23, Number 3, March 2007 Prehospital IN Midazolam for the Treatment of Pediatric Seizures
`
`ACKNOWLEDGMENT
`The authors thank Jeff Schunk for helping to review
`the manuscript.
`
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